Correlation of dynamic contrast enhancement MRI parameters with microvessel density and VEGF for assessment of angiogenesis in breast cancer

PURPOSE: To investigate the association between parameters obtained from dynamic contrast enhanced MRI (DCE-MRI) of breast cancer using different analysis approaches, as well as their correlation with angiogenesis biomarkers (vascular endothelial growth factor and vessel density). MATERIALS AND METHODS: DCE-MRI results were obtained from 105 patients with breast cancer (108 lesions). Three analysis methods were applied: 1) whole tumor analysis, 2) regional hot-spot analysis, and 3) intratumor pixel-by-pixel analysis. Early enhancement intensities and fitted pharmacokinetic parameters were studied. Paraffin blocks of 71 surgically resected specimens were analyzed by immunohistochemical staining to measure microvessel counts (with CD31) and vascular endothelial growth factor (VEGF) expression levels. RESULTS: MRI parameters obtained from the three analysis methods showed significant correlations (P < 0.0001), but a substantial dispersion from the linear regression line was noted (r = 0.72-0.97). The entire region of interest (ROI) vs. pixel population analyses had a significantly higher association compared to the entire ROI vs. hot-spot analyses. Cancer specimens with high VEGF expression had significantly higher CD31 microvessel densities than did specimens with low VEGF levels (P < 0.005). No significant association was found between MRI parameters obtained from the three analysis strategies and IHC based measurements of angiogenesis. CONCLUSION: A consistent analysis strategy was important in the DCE-MRI study. In this series, none of these strategies yielded results for MRI based quantitation of tumor vascularity that were associated with IHC based measurements. Therefore, different analyses could not account for the lack of association.     

Pharmacokinetic mapping for lesion classification in dynamic breast MRI

Purpose:

To prospectively investigate whether a rapid dynamic MRI protocol, in conjunction with pharmacokinetic modeling, could provide diagnostically useful information for discriminating biopsy‐proven benign lesions from malignancies.

Materials and Methods:

Patients referred to breast biopsy based on suspicious screening findings were eligible. After anatomic imaging, patients were scanned using a dynamic protocol with complete bilateral breast coverage. Maps of pharmacokinetic parameters representing transfer constant (K^trans), efflux rate constant (k_ep), blood plasma volume fraction (v_p), and extracellular extravascular volume fraction (v_e) were averaged over lesions and used, with biopsy results, to generate receiver operating characteristic curves for linear classifiers using one, two, or three parameters.

Results:

Biopsy and imaging results were obtained from 93 lesions in 74 of 78 study patients. Classification based on K^trans and k_ep gave the greatest accuracy, with an area under the receiver operating characteristic curve of 0.915, sensitivity of 91%, and specificity of 85%, compared with values of 88% and 68%, respectively, obtained in a recent study of clinical breast MRI in a similar patient population.

Conclusion:

Pharmacokinetic classification of breast lesions is practical on modern MRI hardware and provides significant accuracy for identification of malignancies. Sensitivity of a two‐parameter linear classifier is comparable to that reported in a recent multicenter study of clinical breast MRI, while specificity is significantly higher. J. Magn. Reson. Imaging 2010;31:1371–1378. © 2010 Wiley‐Liss, Inc.     

Combined diffusion-weighted and dynamic contrast-enhanced MRI for prostate cancer diagnosis--correlation with biopsy and histopathology

PURPOSE: To determine whether the combination of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI provides higher diagnostic sensitivity for prostate cancer than each technique alone. MATERIALS AND METHODS: Fourteen patients with a clinical suspicion of prostate cancer underwent endorectal MRI on a 1.5T scanner prior to transrectal ultrasound (TRUS)-guided biopsies. The average values of the apparent diffusion coefficient (ADC, calculated from b-values of 0 and 600), K(trans), v(e), maximum gadolinium (Gd) concentration, onset time, mean gradient, and maximum enhancement were determined. Correlation with histology was based on biopsy (six patients) and prostatectomy specimen (eight patients) results. The Tukey-Kramer test was used for statistical analysis. RESULTS: The average values of all MRI parameters, except v(e) and maximum Gd concentration, showed significant differences between tumor and normal prostate. The sensitivity and specificity values were respectively 54% (35-72%) and 100% (95-100%) for the ADC data, and 59% (39-77%) and 74% (63-83%) for the DCE data. When both ADC and DCE results were combined, the sensitivity increased to 87% (68-95%) and specificity decreased to 74% (62-83%). CONCLUSION: All but two DW- and DCE-MRI parameters showed significant differences between tumor and normal prostate. Combining both techniques provides better sensitivity, with a small decrease in specificity.     

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.     

Independent component analysis of dynamic contrast-enhanced magnetic resonance images of breast carcinoma: a feasibility study

PURPOSE: To study the possibility of using independent component analysis (ICA) to identify breast lesions as separate hemodynamic sources on dynamic contrast-enhanced (DCE) MR images, as depicted by the passage of contrast medium. MATERIALS AND METHODS: Six patients who were histopathologically confirmed with breast carcinoma underwent DCE MRI with 5 precontrast and 60 postcontrast scans at a time-resolution of 8 s. A spatial ICA algorithm was applied on the DCE MRI data set to extract spatial component maps corresponding to source locations with different signal time-intensity patterns. To verify the present hypothesis of the ability of ICA to reveal tumor voxels as a separate hemodynamic phase, tumor margins were outlined by an experienced radiologist who was blinded from the ICA results, and the manual outlines were compared with the ICA maps. RESULTS: Consistently for each of the six patient study cases, it was found that ICA yields a tumor component map associated with typical tumor enhancement patterns of rapid enhancement with washout or plateau. Tumor outlines manually drawn by the radiologist were in good agreement with the tumor locations depicted in the tumor component maps. CONCLUSION: ICA may provide an objective method for identifying the outlines of enhancing breast tumors on DCE MR images and to automatically extract the tumor signal intensity-time curve for subsequent tracer kinetics analysis.     

Enhanced mass on contrast-enhanced breast MR imaging: Lesion characterization using combination of dynamic contrast-enhanced and diffusion-weighted MR images

Purpose

To evaluate the diagnostic accuracy of a combination of dynamic contrast‐enhanced MR imaging (DCE‐MRI) and diffusion‐weighted MR imaging (DWI) in characterization of enhanced mass on breast MR imaging and to find the strongest discriminators between carcinoma and benignancy.

Materials and Methods

We analyzed consecutive breast MR images in 270 patients; however, 13 lesions in 93 patients were excluded based on our criteria. We analyzed tumor size, shape, margin, internal mass enhancement, kinetic curve pattern, and apparent diffusion coefficient (ADC) values. We applied univariate and multivariate analyses to find the strongest indicators of malignancy and calculate a predictive probability for malignancy. We added the corresponding categories to these prediction probabilities for malignancy and calculated diagnostic accuracy when we consider category 4b, 4c, and 5 lesions as malignant and category 4a, 3, and 2 lesions as benign. In a validation study, 75 enhancing lesions in 71 patients were examined consecutively.

Results

Irregular margin, heterogeneous internal enhancement, rim enhancement, plateau time–intensity curve (TIC) pattern, and washout TIC pattern were the strongest indicators of malignancy as well as past studies, and ADC values less than 1.1 × 10^?3 mm²/s were also the strongest indicators of malignancy. In a validation study, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 92% (56/61), 86% (12/14), 97% (56/58), 71% (12/17), and 91% (68/75), respectively.

Conclusion

The combination of DWI and DCE‐MRI could produce high diagnostic accuracy in the characterization of enhanced mass on breast MR imaging. J. Magn. Reson. Imaging 2008;28:1157–1165. © 2008 Wiley‐Liss, Inc.

     

Assessment of tumor microcirculation with dynamic contrast-enhanced MRI in patients with esophageal cancer: initial experience

PURPOSE: To investigate the feasibility and impact of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on tumor characterization and response to radiochemotherapy (RCT) in patients with esophageal cancer. MATERIALS AND METHODS: A total of 48 patients underwent DCE-MRI to assess tumor microcirculation based on a two-compartment model function. Effects of RCT on kinetic parameters were studied in 12 patients with squamous cell carcinoma. RESULTS: Tumor microcirculation differs with respect to histological subtype: squamous cell carcinomas showed lower values of amplitude A (leakage space, P = 0.015) and higher contrast agent exchange rates (k(21), P = 0.225) compared with adenocarcinomas. RCT led to a significant decrease of the contrast agent exchange rate (P = 0.005), while amplitude A increased moderately after therapy (P = 0.136). CONCLUSION: DCE-MRI is feasible in patients with esophageal cancer, reveals therapeutic effects, and may thus be useful in therapy management and monitoring.     

Wash-in rate on the basis of dynamic contrast-enhanced MRI: usefulness for prostate cancer detection and localization

PURPOSE: To evaluate the usefulness of the wash-in rate based on dynamic contrast-enhanced (DCE) MRI for the detection and localization of prostate cancer. MATERIALS AND METHODS: In 53 patients, the wash-in rate was measured in the cancer area and in three normal areas (the peripheral zone, inner portion of the transitional zone, and outer portion of the transitional zone). On the basis of these data, parametric imaging was generated and then its accuracy for cancer detection and location was evaluated compared to that of T2-weighted imaging without the use of an endorectal coil. For that purpose the entire prostate was divided into 18 segments. RESULTS: The wash-in rate value was greater in cancer tissue (9.2/second) than in three normal tissues (3.3/second, 6.7/second, and 3.2/second, respectively; P<0.001). The sensitivity and specificity were greater on parametric imaging of the wash-in rate compared to T2-weighted imaging in the entire prostate (96% and 82% vs. 65% and 60%, respectively) and the peripheral zone (96% and 97% vs. 75% and 53%; P<0.05). In the transitional zone, the sensitivity was greater on parametric imaging (96%) than on T2-weighted imaging (45%; P=0.016), but the specificity was similar (51% vs. 73%; P=0.102). CONCLUSION: The wash-in rate based on DCE-MRI is a useful parameter for prostate cancer detection and localization.     

Tumor response assessments with diffusion and perfusion MRI

There is an increasing awareness that the evaluation of tumor response to oncologic treatments based solely on anatomic imaging assessments face many limitations, particularly in this era of novel biologic targeted therapies. Functional imaging techniques such as diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) have the ability to depict important tumor biologic features and are able to predict therapy response based on assessments of cellularity and tumor vascularity, which often precede morphologic alterations. In this article we focus on DW-MRI and DCE-MRI as response parameters addressing the technologies involved, quantification methods, and validation for each technique and their current role in imaging response to conventional and novel therapies. We also discuss the challenges that lie ahead in the deployment of these imaging methods into the clinical environment.     

Comparison of tumor blood perfusion assessed by dynamic contrast-enhanced MRI with tumor blood supply assessed by invasive imaging

PURPOSE: To evaluate the potential of Gd-DTPA-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for providing high-resolution tumor blood perfusion images. MATERIALS AND METHODS: Xenografted tumors from two amelanotic human melanoma lines (A-07 and R-18) were used as preclinical models of human cancer. DCE-MRI was performed at a voxel size of 0.5 x 0.2 x 2.0 mm(3) with the use of spoiled gradient recalled sequences. We produced tumor images of E . F (where E is the initial extraction fraction, and F is perfusion) by subjecting the DCE-MRI data to Kety analysis, and then compared those images with images of tumor blood supply. We obtained high-resolution tumor blood supply images using the Bioscope silicon strip detector system to measure the uptake of Na(99m)TcO(4) in histological preparations. We assessed the global blood supply by measuring the tumor uptake of three freely diffusible blood flow tracers: (86)RbCl, [(14)C]IAP, and Na(99m)TcO(4). RESULTS: E . F was found to mirror the blood supply well in A-07 and R-18 tumors. The mean E . F differed between the A-07 and R-18 tumors by a factor of approximately 1.6, and this difference was similar to the difference in the global blood supply. The intratumor heterogeneity in E . F was significant for tumors of both lines, and this heterogeneity was similar to the intratumor heterogeneity in the blood supply. The intratumor heterogeneity in the blood supply differed slightly between the A-07 and R-18 tumors, and even this difference was mirrored by the E . F images. CONCLUSION: E . F images of xenografted tumors reflect blood perfusion. This implies that E . F may be a useful parameter for improving cancer diagnostics and individualizing cancer treatment. This possibility deserves to be investigated thoroughly in clinical studies.     

Improved diagnostic accuracy of breast MRI through combined apparent diffusion coefficients and dynamic contrast‐enhanced kinetics

This study investigated the relationship between apparent diffusion coefficient (ADC) measures and dynamic contrast‐enhanced magnetic resonance imaging (MRI) kinetics in breast lesions and evaluated the relative diagnostic value of each quantitative parameter. Seventy‐seven women with 100 breast lesions (27 malignant and 73 benign) underwent both dynamic contrast‐enhanced MRI and diffusion weighted MRI. Dynamic contrast‐enhanced MRI kinetic parameters included peak initial enhancement, predominant delayed kinetic curve type (persistent, plateau, or washout), and worst delayed kinetic curve type (washout > plateau > persistent). Associations between ADC and dynamic contrast‐enhanced MRI kinetic parameters and predictions of malignancy were evaluated. Results showed that ADC was significantly associated with predominant curve type (ADC was higher for lesions exhibiting predominantly persistent enhancement compared with those exhibiting predominantly washout or plateau, P = 0.006), but was not significantly associated with peak initial enhancement or worst curve type (P > 0.05). Univariate analysis showed significant differences between benign and malignant lesions in both ADC (P < 0.001) and worst curve (P = 0.003). In multivariate analysis, worst curve type and ADC were significant independent predictors of benign versus malignant outcome and in combination produced the highest area under the receiver operating characteristic curve (0.85 and 0.78 with 5‐fold cross validation). Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Fundamentals of tracer kinetics for dynamic contrast-enhanced MRI

Tracer kinetic methods employed for quantitative analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) share common roots with earlier tracer studies involving arterial-venous sampling and other dynamic imaging modalities. This article reviews the essential foundation concepts and principles in tracer kinetics that are relevant to DCE MRI, including the notions of impulse response and convolution, which are central to the analysis of DCE MRI data. We further examine the formulation and solutions of various compartmental models frequently used in the literature. Topics of recent interest in the processing of DCE MRI data, such as the account of water exchange and the use of reference tissue methods to obviate the measurement of an arterial input, are also discussed. Although the primary focus of this review is on the tracer models and methods for T(1) -weighted DCE MRI, some of these concepts and methods are also applicable for analysis of dynamic susceptibility contrast-enhanced MRI data.     

Dynamic contrast-enhanced MRI using Gd-DTPA: interindividual variability of the arterial input function and consequences for the assessment of kinetics in tumors.

Gd-DTPA kinetics in arterial blood was investigated by dynamic MRI in 47 patients with malignant and benign mammary tumors. Signal enhancement was monitored for 10 min after the beginning of a 1-min infusion of 0.1 mmol/kg Gd-DTPA. Kinetics in blood was biexponential with median half-lives of 21 sec and 11.1 min, respectively. Peak signal enhancement and the area under the signal enhancement-time curve varied 2.5- and 3.7-fold between patients. The shortest mean residence time in one of up to three tumor compartments, MRT*, was estimated using either the individual (reference) or a mean population (surrogate) arterial input function (AIF). MRT* (reference estimate) was 1.0 (0-1.5), 1.9 (1.5-2.3), and 2.5 (2.3-2.8) min in carcinomas, fibroadenomas, and mastopathies, respectively (median and interquartile distance). Surrogate estimates were unbiased but differed from the reference estimates 1.5-fold or more in 23% of cases. AIFs should be monitored individually if accurate estimates of individual MRT* are desired.     

Diffusion-weighted and dynamic contrast-enhanced MRI in evaluation of early treatment effects during neoadjuvant chemotherapy in breast cancer patients

Purpose:

To use dynamic contrast‐enhanced (DCE) and diffusion‐weighted (DW) MRI at 3 Tesla (T) for early evaluation of treatment effects in breast cancer patients undergoing neoadjuvant chemotherapy (NAC), and assess the reliability of DW‐MRI.

Materials and Methods:

DW‐ and DCE‐MRI acquisitions of 15 breast cancer patients were performed before and after one cycle of NAC. MRI tumor diameter and volume, apparent diffusion coefficient (ADC) and kinetic parameters (K^trans, v_e) were derived. The reliability of ADC before NAC was assessed. Changes in MRI parameters after NAC were analyzed, and logistic regression analysis was used to find the best predictors for pathologic response.

Results:

The reliability for ADC values was high, with intraclass correlation coefficient of 0.84 (P = 0.001). After one cycle of NAC, MRI tumor diameter (8%, P = 0.005) and tumor volume (30%, P = 0.008) was reduced for all patients, while ADC mean values increased (0.12 mm²/s, P = 0.008). The best predictor for treatment response was a change in MRI tumor diameter with mean error rate of 0.167 (13% for responders, 5% for nonresponders, P = 0.291).

Conclusion:

Changes in MRI derived tumor diameter and ADC after only one cycle of NAC could provide a valuable tool for early evaluation of treatment effects in breast cancer patients. J. Magn. Reson. Imaging 2011;. © 2011 Wiley Periodicals, Inc.     

Challenges in dynamic contrast-enhanced MRI imaging of cervical lymph nodes to detect metastatic disease

PURPOSE: To identify and overcome challenges in using dynamic contrast-enhanced magnetic resonance imaging (MRI) to distinguish tumor from nontumor in the cervical lymph nodes of patients with squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: Signal-to-noise ratio (S/N), motion, node heterogeneity, and tissue normalizations were examined. Twenty-one patients with squamous cell carcinoma of the head and neck were scanned before a neck dissection (two-dimensional fast spoiled gradient-echo: 10 locations/13 seconds). Peak time, peak enhancement, maximum upslope, and washout slope were measured in pathologically confirmed tumor and nontumor nodes and in the submandibular gland and the sternocleidomastoid muscle. RESULTS: Surface coil arrays provided high coverage and high S/N. Motion averaged 1.1 pixels and was corrected. Large tumor nodes were heterogeneous in their contrast enhancement, while the nontumor nodes were homogeneous. The contrast enhancement parameters were significantly different for all regions except for the submandibular gland compared to the nontumor nodes. CONCLUSION: Challenges of dynamic imaging of cervical lymph nodes were overcome and significant differences were found between the tumor and nontumor nodes, indicating that dynamic imaging is feasible and may aid this patient population.     

Quantifying angiogenesis in VEGF-enhanced tissue-engineered bladder constructs by dynamic contrast-enhanced MRI using contrast agents of different molecular weights

PURPOSE: To compare Gadomer, a macromolecular magnetic resonance (MR) contrast agent, and gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) for quantifying angiogenesis in tissue-engineered bladder constructs. MATERIALS AND METHODS: Constructs enhanced with vascular endothelial growth factor (VEGF) were grafted onto the bladder of 12 rabbits (N= 3/VEGF, VEGF = 0,10,15,20 ng/g tissue). After eight days dynamic contrast-enhanced MRI (DCE-MRI) was performed in each animal using Gadomer and Gd-DTPA, separated by a one-hour interval. DCE-MRI parameters were calculated from two-compartment pharmacokinetics (plasma volume fraction, v(p); transfer constant, K(trans)) and model-free analysis, area under the concentration-time curve (AUC). Histology assessment of microvessel density (MVD) and Evans blue permeability were compared to DCE-MRI. RESULTS: MVD was elevated (P < 0.05) at the highest VEGF but not among lower levels; permeability differences were absent. Contrast enhancement increased with VEGF and was better resolved with Gadomer than Gd-DTPA. Gadomer was the better assay for estimating plasma volume: v(p) provided the best distinction (P < 0.005), but both v(p) and AUC were correlated to MVD. With Gd-DTPA, only AUC distinguished MVD differences (P< 0.05). Changes in K(trans) were insignificant. CONCLUSION: Macromolecular contrast agents are valuable for monitoring angiogenesis in tissue-engineered bladder grafts. Compared to Gd-DTPA, Gadomer provides more accurate and precise quantification of microvessel function, and is better suited to pharmacokinetic analysis for accurate physiological quantification.     

Quantification of renal perfusion: comparison of arterial spin labeling and dynamic contrast-enhanced MRI

Purpose:

To provide the first comparison of absolute renal perfusion obtained by arterial spin labeling (ASL) and separable compartment modeling of dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI). Moreover, we provide the first application of the dual bolus approach to quantitative DCE‐MRI perfusion measurements in the kidney.

Materials and Methods:

Consecutive ASL and DCE‐MRI acquisitions were performed on six rabbits on a 1.5 T MRI system. Gadolinium (Gd)‐DTPA was administered in two separate injections to decouple measurement of the arterial input function and tissue uptake curves. For DCE perfusion, pixel‐wise and mean cortex region‐of‐interest tissue curves were fit to a separable compartment model.

Results:

Absolute renal cortex perfusion estimates obtained by DCE and ASL were in close agreement: 3.28 ± 0.59 mL/g/min (ASL), 2.98 ± 0.60 mL/g/min (DCE), and 3.57 ± 0.96 mL/g/min (pixel‐wise DCE). Renal medulla perfusion was 1.53 ± 0.35 mL/g/min (ASL) but was not adequately described by the separable compartment model.

Conclusion:

ASL and DCE‐MRI provided similar measures of absolute perfusion in the renal cortex, offering both noncontrast and contrast‐based alternatives to improve current renal MRI assessment of kidney function. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.