Federico D. Pineda

Kinetic Analysis of Benign and Malignant Breast Lesions With Ultrafast Dynamic Contrast-Enhanced MRI: Comparison With Standard Kinetic Assessment

OBJECTIVE The purposes of this study were to evaluate diagnostic parameters measured with ultrafast MRI acquisition and with standard acquisition and to compare diagnostic utility for differentiating benign from malignant lesions. MATERIALS AND METHODS Ultrafast acquisition is a high-temporal-resolution (7 seconds) imaging technique for obtaining 3D whole-breast images. The dynamic contrast-enhanced 3-T MRI protocol consists of an unenhanced standard and an ultrafast acquisition that includes eight contrast-enhanced ultrafast images and four standard images. Retrospective assessment was performed for 60 patients with 33 malignant and 29 benign lesions. A computer-aided detection system was used to obtain initial enhancement rate and signal enhancement ratio (SER) by means of identification of a voxel showing the highest signal intensity in the first phase of standard imaging. From the same voxel, the enhancement rate at each time point of the ultrafast acquisition and the AUC of the kinetic curve from zero to each time point of ultrafast imaging were obtained. RESULTS There was a statistically significant difference between benign and malignant lesions in enhancement rate and kinetic AUC for ultrafast imaging and also in initial enhancement rate and SER for standard imaging. ROC analysis showed no significant differences between enhancement rate in ultrafast imaging and SER or initial enhancement rate in standard imaging. CONCLUSION Ultrafast imaging is useful for discriminating benign from malignant lesions. The differential utility of ultrafast imaging is comparable to that of standard kinetic assessment in a shorter study time.

Gadolinium-Functionalized Peptide Amphiphile Micelles for Multimodal Imaging of Atherosclerotic Lesions

The leading causes of morbidity and mortality globally are cardiovascular diseases, and nanomedicine can provide many improvements including disease-specific targeting, early detection, and local delivery of diagnostic agents. To this end, we designed fibrin-binding, peptide amphiphile micelles (PAMs), achieved by incorporating the targeting peptide cysteine-arginine-glutamic acid-lysine-alanine (CREKA), with two types of amphiphilic molecules containing the gadoliniuim (Gd) chelator diethylenetriaminepentaacetic acid (DTPA), DTPA-bis(stearylamide)(Gd), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[(poly(ethylene glycol) (PEG))-2000]-DTPA(Gd) (DSPE-PEG2000-DTPA(Gd)). The material characteristics of the resulting nanoparticle diagnostic probes, clot-binding properties in vitro, and contrast enhancement and safety for dual, optical imaging–magnetic resonance imaging (MRI) were evaluated in the atherosclerotic mouse model. Transmission electron micrographs showed a homogenous population of spherical micelles for formulations containing DSPE-PEG2000-DTPA(Gd), whereas both spherical and cylindrical micelles were formed upon mixing DTPA-BSA(Gd) and CREKA amphiphiles. Clot-binding assays confirmed DSPE-PEG2000-DTPA(Gd)-based CREKA micelles targeted clots over 8-fold higher than nontargeting (NT) counterpart micelles, whereas no difference was found between CREKA and NT, DTPA-BSA(Gd) micelles. However, in vivo MRI and optical imaging studies of the aortas and hearts showed fibrin specificity was conferred by the peptide ligand without much difference between the nanoparticle formulations or shapes. Biodistribution studies confirmed that all micelles were cleared through both the reticuloendothelial system and renal clearance, and histology showed no signs of necrosis. In summary, these studies demonstrate the successful synthesis, and the molecular imaging capabilities of two types of CREKA-Gd PAMs for atherosclerosis. Moreover, we demonstrate the differences in micelle formulations and shapes and their outcomes in vitro versus in vivo for site-specific, diagnostic strategies, and provide the groundwork for the detection of thrombosis via contrast-enhancing agents and concurrent therapeutic delivery for theranostic applications.

B1 and T1 mapping of the breast with a reference tissue method.

To develop a method for mapping the B1 field using a reference signal from a tissue with known T1.

Comparison of dynamic contrast-enhanced MRI parameters of breast lesions at 1.5 and 3.0 T: a pilot study

OBJECTIVE To compare dynamic contrast-enhanced (DCE) MRI parameters from scans of breast lesions at 1.5 and 3.0 T. METHODS 11 patients underwent paired MRI examinations in both Philips 1.5 and 3.0 T systems (Best, Netherlands) using a standard clinical fat-suppressed, T1 weighted DCE-MRI protocol, with 70-76 s temporal resolution. Signal intensity vs time curves were fit with an empirical mathematical model to obtain semi-quantitative measures of uptake and washout rates as well as time-to-peak enhancement (TTP). Maximum percent enhancement and signal enhancement ratio (SER) were also measured for each lesion. Percent differences between parameters measured at the two field strengths were compared. RESULTS TTP and SER parameters measured at 1.5 and 3.0 T were similar; with mean absolute differences of 19% and 22%, respectively. Maximum percent signal enhancement was significantly higher at 3 T than at 1.5 T (p = 0.006). Qualitative assessment showed that image quality was significantly higher at 3 T (p = 0.005). CONCLUSION Our results suggest that TTP and SER are more robust to field strength change than other measured kinetic parameters, and therefore measurements of these parameters can be more easily standardized than measurements of other parameters derived from DCE-MRI. Semi-quantitative measures of overall kinetic curve shape showed higher reproducibility than do discrete classification of kinetic curve early and delayed phases in a majority of the cases studied. ADVANCES IN KNOWLEDGE Qualitative measures of curve shape are not consistent across field strength even when acquisition parameters are standardized. Quantitative measures of overall kinetic curve shape, by contrast, have higher reproducibility.

Arterial input functions (AIFs) measured directly from arteries with low and standard doses of contrast agent, and AIFs derived from reference tissues.

Measurements of arterial input function (AIF) can have large systematic errors at standard contrast agent doses in dynamic contrast enhanced MRI (DCE-MRI). We compared measured AIFs from low dose (AIFLD) and standard dose (AIFSD) contrast agent injections, as well as the AIF derived from a muscle reference tissue and artery (AIFref). Twenty-two prostate cancer patients underwent DCE-MRI. Data were acquired on a 3T scanner using an mDixon sequence. Gadobenate dimeglumine was injected twice, at doses of 0.015 and 0.085 mmol/kg. Directly measured AIFs were fitted with empirical mathematical models (EMMs) and compared to the AIF derived from a muscle reference tissue (AIFref). EMMs accurately fitted the AIFs. The 1st and 2nd pass peaks were visualized in AIFLD, but not in AIFSD, thus the peak and shape of AIFSD could not be accurately measured directly. The average scaling factor between AIFSD and AIFLD in the washout phase was only 56% of the contrast dose ratio (~6:1). The shape and magnitude of AIFref closely approximated that of AIFLD after empirically determined dose-dependent normalization. This suggests that AIFref may be a good approximation of the local AIF.

Evaluation of Kinetic Entropy of Breast Masses Initially Found on MRI using Whole-lesion Curve Distribution Data: Comparison with the Standard Kinetic Analysis

ObjectivesTo quantify kinetic heterogeneity of breast masses that were initially detected with dynamic contrast-enhanced MRI, using whole-lesion kinetic distribution data obtained from computer-aided evaluation (CAE), and to compare that with standard kinetic curve analysis.MethodsClinical MR images from 2006 to 2011 with breast masses initially detected with MRI were evaluated with CAE. The relative frequencies of six kinetic patterns (medium-persistent, medium-plateau, medium-washout, rapid-persistent, rapid-plateau, rapid-washout) within the entire lesion were used to calculate kinetic entropy (KE), a quantitative measure of enhancement pattern heterogeneity. Initial uptake (IU) and signal enhancement ratio (SER) were obtained from the most-suspicious kinetic curve. Mann-Whitney U test and ROC analysis were conducted for differentiation of malignant and benign masses.ResultsForty benign and 37 malignant masses comprised the case set. IU and SER were not significantly different between malignant and benign masses, whereas KE was significantly greater for malignant than benign masses (p = 0.748, p = 0.083, and p < 0.0001, respectively). Areas under ROC curve for IU, SER, and KE were 0.479, 0.615, and 0.662, respectively.ConclusionQuantification of kinetic heterogeneity of whole-lesion time-curve data with KE has the potential to improve differentiation of malignant from benign breast masses on breast MRI.Key points• Kinetic heterogeneity can be quantified by computer-aided evaluation of breast MRI• Kinetic entropy was greater in malignant masses than benign masses• Kinetic entropy has the potential to improve differentiation of breast masses

Fibrin-Targeting, Peptide Amphiphile Micelles as Contrast Agents for Molecular MRI

Magnetic resonance imaging (MRI) provides a nonionizing and safe imaging modality for cancer diagnostics. Here, we took advantage of the fibrin deposition that is characteristic of tumors and the ability to incorporate multiple functionalities within peptide amphiphile micelles (PAMs) to design a new class of contrast agents for molecular MRI. We report on synthesis, formulation, and preliminary tests for MRI of spherical PAMs that were self-assembled by combining 18:0 PE-DTPA (Gd) and peptide amphiphiles containing the fibrin-binding pentapeptide, cysteinearginine- glutamic acid-lysine-alanine, or CREKA. Conjugation of the CREKA peptide to micelles increased the average particle size and zeta potential, and T1 relaxivities of CREKA-Gd PAMs (per mmol of Gd) were found to be comparable to contrast agents which are used routinely in clinical settings at 1.5T and 3T. Moreover, when murine fibroblasts were cultured with CREKA-Gd PAMs, no cytotoxicity was demonstrated and cell viability was comparable to that of PBS-treated controls for up to 3 days.Our study provides proof-of-concept of CREKA-Gd PAMs as contrast agents for molecular MRI, and a facile strategy for incorporating contrast agents and bioactive molecules into nano carriers to develop safe, targeted diagnostic carriers for clinical application.

Performance of Ultrafast DCE-MRI for Diagnosis of Prostate Cancer

RATIONALE AND OBJECTIVES This study aimed to test high temporal resolution dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for different zones of the prostate and evaluate its performance in the diagnosis of prostate cancer (PCa). Determine whether the addition of ultrafast DCE-MRI improves the performance of multiparametric MRI. MATERIALS AND METHODS Patients (n = 20) with pathologically confirmed PCa underwent preoperative 3T MRI with T2-weighted, diffusion-weighted, and high temporal resolution (~2.2 seconds) DCE-MRI using gadoterate meglumine (Guerbet, Bloomington, IN) without an endorectal coil. DCE-MRI data were analyzed by fitting signal intensity with an empirical mathematical model to obtain parameters: percent signal enhancement, enhancement rate (α), washout rate (β), initial enhancement slope, and enhancement start time along with apparent diffusion coefficient (ADC) and T2 values. Regions of interests were placed on sites of prostatectomy verified malignancy (n = 46) and normal tissue (n = 71) from different zones. RESULTS Cancer (α = 6.45 ± 4.71 s-1, β = 0.067 ± 0.042 s-1, slope = 3.78 ± 1.90 s-1) showed significantly (P <.05) faster signal enhancement and washout rates than normal tissue (α = 3.0 ± 2.1 s-1, β = 0.034 ± 0.050 s-1, slope = 1.9 ± 1.4 s-1), but showed similar percentage signal enhancement and enhancement start time. Receiver operating characteristic analysis showed area under the curve for DCE parameters was comparable to ADC and T2 in the peripheral (DCE 0.67-0.82, ADC 0.80, T2 0.89) and transition zones (DCE 0.61-0.72, ADC 0.69, T2 0.75), but higher in the central zone (DCE 0.79-0.88, ADC 0.45, T2 0.45) and anterior fibromuscular stroma (DCE 0.86-0.89, ADC 0.35, T2 0.12). Importantly, combining DCE with ADC and T2 increased area under the curve by ~30%, further improving the diagnostic accuracy of PCa detection. CONCLUSION Quantitative parameters from empirical mathematical model fits to ultrafast DCE-MRI improve diagnosis of PCa. DCE-MRI with higher temporal resolution may capture clinically useful information for PCa diagnosis that would be missed by low temporal resolution DCE-MRI. This new information could improve the performance of multiparametric MRI in PCa detection.

Quantitative analysis of vascular properties derived from ultrafast DCE-MRI to discriminate malignant and benign breast tumors

We propose a novel methodology to integrate morphological and functional information of tumor‐associated vessels to assist in the diagnosis of suspicious breast lesions.

Fast Temporal Resolution Dynamic Contrast-Enhanced MRI: Histogram Analysis Versus Visual Analysis for Differentiating Benign and Malignant Breast Lesions

OBJECTIVE The purpose of this study was to validate a kinetic assessment based on visually identified peak enhancement, which is routinely used in clinical practice, for differentiating benign from malignant lesions during fast dynamic contrast-enhanced MRI. MATERIALS AND METHODS Between January 2015 and December 2016, 90 consecutively registered patients with 105 breast lesions (40 benign, 65 malignant) underwent dynamic contrast-enhanced 1.5-T MRI that included one unenhanced and eight contrast-enhanced fast temporal resolution (10 seconds) whole-breast acquisitions. Histogram analysis was performed to measure the voxel-based enhancement of the entire lesion to obtain 90th, 75th, and 50th percentile values at each time point and to generate kinetic curves. Two observers selected visually identified peak enhancement within the lesions to generate the kinetic curves. The kinetic curves from histogram and visually identified peak enhancement analyses were fitted by means of an empiric mathematic model (EMM): ΔS(t) = A × (1 - e-αt), where A is the upper limit of signal intensity, e indicates the exponential function, and α (min-1) is the rate of increase in signal intensity. The initial slope of the kinetic curve (A × α) and the initial AUC (AUC30) were calculated. These parameters were compared between benign and malignant lesions, and results from visually identified peak enhancement analysis were compared with those from histogram analysis. RESULTS Benign lesions were successfully differentiated from malignant lesions in both visually identified peak enhancement and histogram analyses (90th and 75th percentile values) on the basis of α, A × α, and AUC30 from the EMM. There was no significant difference in ROC AUC in these EMM parameters between visually identified peak enhancement and histogram analyses (p = 0.21). CONCLUSION Kinetic assessment with visually identified peak enhancement was acceptable for differentiating benign from malignant lesions.