Bilateral asymmetry of quantitative parenchymal kinetics at ultrafast DCE-MRI predict response to neoadjuvant chemotherapy in patients with HER2+ breast cancer.

PURPOSE: To assess whether measurement of the bilateral asymmetry of semiquantitative and quantitative perfusion parameters from ultrafast dynamic contrast-enhanced MRI (DCE-MRI), allows early prediction of pathologic response after neoadjuvant chemotherapy (NAC) in patients with HER2+ breast cancer. MATERIALS AND METHODS: Twenty-eight female patients with HER2+ breast cancer treated with NAC who underwent pre-NAC ultrafast DCE-MRI (3-9 s/phase) were enrolled for this study. Four semiquantitative and two quantitative parenchymal parameters were calculated for each patient. Ipsilateral/contralateral (I/C) ratio (for four parameters) and the difference between (for two parameters) ipsi- and contra-lateral parenchymal kinetic parameters (kBPE) were compared for patients with pathologic complete response (pCR) and those having residual disease. Lasso regression with leave-one-out cross validation was used to determine the optimal combination of parameters for a regression model and multivariable logistic regression was used to identify independent predictors for pCR. Chi-squared test, two-sided t-test and Kruskal-Wallis test were used. RESULTS: The Ktrans I/C ratio cutoff value of 1.11 had a sensitivity of 83.3% and specificity of 75% for pCR. The ve I/C ratio cutoff value of 1.1 had a sensitivity of 75% and specificity of 81.3% for pCR. The area under the receiver operating characteristic curve of the three-kBPE parameter model, including initial area under the enhancement curve (AUC30) I/C ratio, KtransI/C ratio and ve I/C ratio, was 0.89 with sensitivity of 91.7% at specificity of 81.3%. CONCLUSION: Quantitative assessment of bilateral asymmetry kBPE from pre-NAC ultrafast DCE-MRI can predict pCR in patients with HER2+ breast cancer.

Pharmacokinetic Analysis of Enhancement-Constrained Acceleration (ECA) reconstruction-based high temporal resolution breast DCE-MRI.

The high spatial and temporal resolution of dynamic contrast-enhanced MRI (DCE-MRI) can improve the diagnostic accuracy of breast cancer screening in patients who have dense breasts or are at high risk of breast cancer. However, the spatiotemporal resolution of DCE-MRI is limited by technical issues in clinical practice. Our earlier work demonstrated the use of image reconstruction with enhancement-constrained acceleration (ECA) to increase temporal resolution. ECA exploits the correlation in k-space between successive image acquisitions. Because of this correlation, and due to the very sparse enhancement at early times after contrast media injection, we can reconstruct images from highly under-sampled k-space data. Our previous results showed that ECA reconstruction at 0.25 seconds per image (4 Hz) can estimate bolus arrival time (BAT) and initial enhancement slope (iSlope) more accurately than a standard inverse fast Fourier transform (IFFT) when k-space data is sampled following a Cartesian based sampling trajectory with adequate signal-to-noise ratio (SNR). In this follow-up study, we investigated the effect of different Cartesian based sampling trajectories, SNRs and acceleration rates on the performance of ECA reconstruction in estimating contrast media kinetics in lesions (BAT, iSlope and Ktrans) and in arteries (Peak signal intensity of first pass, time to peak, and BAT). We further validated ECA reconstruction with a flow phantom experiment. Our results show that ECA reconstruction of k-space data acquired with 'Under-sampling with Repeated Advancing Phase' (UnWRAP) trajectories with an acceleration factor of 14, and temporal resolution of 0.5 s/image and high SNR (SNR ≥ 30 dB, noise standard deviation (std) < 3%) ensures minor errors (5% or 1 s error) in lesion kinetics. Medium SNR (SNR ≥ 20 dB, noise std ≤ 10%) was needed to accurately measure arterial enhancement kinetics. Our results also suggest that accelerated temporal resolution with ECA with 0.5 s/image is practical.

Differences Between Ipsilateral and Contralateral Early Parenchymal Enhancement Kinetics Predict Response of Breast Cancer to Neoadjuvant Therapy.

RATIONALE AND OBJECTIVES: To determine whether kinetics measured with ultrafast dynamic contrast-enhanced magnetic resonance imaging in tumor and normal parenchyma pre- and post-neoadjuvant therapy (NAT) can predict the response of breast cancer to NAT. MATERIALS AND METHODS: Twenty-four patients with histologically confirmed invasive breast cancer were enrolled. They were scanned with ultrafast dynamic contrast-enhanced magnetic resonance imaging (3-7 seconds/frame) pre- and post-NAT. Four kinetic parameters were calculated in the segmented tumors, and ipsi- and contra-lateral normal parenchyma: (1) tumor (tSE30) or background parenchymal relative enhancement at 30 seconds (BPE30), (2) maximum relative enhancement slope (MaxSlope), (3) bolus arrival time (BAT), and (4) area under relative signal enhancement curve for the initial 30 seconds (AUC30). The tumor kinetics and the differences between ipsi- and contra-lateral parenchymal kinetics were compared for patients achieving pathologic complete response (pCR) vs those who had residual disease after NAT. The chi-squared test and two-sided t-test were used for baseline demographics. The Wilcoxon rank sum test and one-way analysis of variance were used for differential responses to therapy. RESULTS: Patients with similar pre-NAT mean BPE30, median BAT and mean AUC30 in the ipsi- and contralateral normal parenchyma were more likely to achieve pCR following NAT (p < 0.02). Patients classified as having residual cancer burden (RCB) II after NAT showed higher post-NAT tSE30 and tumor AUC30 and higher post-NAT MaxSlope in ipsilateral normal parenchyma compared to those classified as RCB I or pCR (p < 0.05). CONCLUSION: Bilateral asymmetry in normal parenchyma could predict treatment outcome prior to NAT. Post-NAT tumor kinetics could evaluate the aggressiveness of residual tumor.

Enhancement-constrained acceleration: A robust reconstruction framework in breast DCE-MRI.

In patients with dense breasts or at high risk of breast cancer, dynamic contrast enhanced MRI (DCE-MRI) is a highly sensitive diagnostic tool. However, its specificity is highly variable and sometimes low; quantitative measurements of contrast uptake parameters may improve specificity and mitigate this issue. To improve diagnostic accuracy, data need to be captured at high spatial and temporal resolution. While many methods exist to accelerate MRI temporal resolution, not all are optimized to capture breast DCE-MRI dynamics. We propose a novel, flexible, and powerful framework for the reconstruction of highly-undersampled DCE-MRI data: enhancement-constrained acceleration (ECA). Enhancement-constrained acceleration uses an assumption of smooth enhancement at small time-scale to estimate points of smooth enhancement curves in small time intervals at each voxel. This method is tested in silico with physiologically realistic virtual phantoms, simulating state-of-the-art ultrafast acquisitions at 3.5s temporal resolution reconstructed at 0.25s temporal resolution (demo code available here). Virtual phantoms were developed from real patient data and parametrized in continuous time with arterial input function (AIF) models and lesion enhancement functions. Enhancement-constrained acceleration was compared to standard ultrafast reconstruction in estimating the bolus arrival time and initial slope of enhancement from reconstructed images. We found that the ECA method reconstructed images at 0.25s temporal resolution with no significant loss in image fidelity, a 4x reduction in the error of bolus arrival time estimation in lesions (p < 0.01) and 11x error reduction in blood vessels (p < 0.01). Our results suggest that ECA is a powerful and versatile tool for breast DCE-MRI.

A compact solution for estimation of physiological parameters from ultrafast prostate dynamic contrast enhanced MRI.

The Tofts pharmacokinetic model requires multiple calculations for analysis of dynamic contrast enhanced (DCE) MRI. In addition, the Tofts model may not be appropriate for the prostate. This can result in error propagation that reduces the accuracy of pharmacokinetic measurements. In this study, we present a compact solution allowing estimation of physiological parameters K trans and v e from ultrafast DCE acquisitions, without fitting DCE-MRI data to the standard Tofts pharmacokinetic model. Since the standard Tofts model can be simplified to the Patlak model at early times when contrast efflux from the extravascular extracellular space back to plasma is negligible, K trans can be solved explicitly for a specific time. Further, v e can be estimated directly from the late steady-state signal using the derivative form of Tofts model. Ultrafast DCE-MRI data were acquired from 18 prostate cancer patients on a Philips Achieva 3T-TX scanner. Regions-of-interest (ROIs) for prostate cancer, normal tissue, gluteal muscle, and iliac artery were manually traced. The contrast media concentration as function of time was calculated over each ROI using gradient echo signal equation with pre-contrast tissue T1 values, and using the 'reference tissue' model with a linear approximation. There was strong correlation (r = 0.88-0.91, p  < 0.0001) between K trans extracted from the Tofts model and K trans estimated from the compact solution for prostate cancer and normal tissue. Additionally, there was moderate correlation (r = 0.65-0.73, p  < 0.0001) between extracted versus estimated v e. Bland-Altman analysis showed moderate to good agreement between physiological parameters extracted from the Tofts model and those estimated from the compact solution with absolute bias less than 0.20 min-1 and 0.10 for K trans and v e, respectively. The compact solution may decrease systematic errors and error propagation, and could increase the efficiency of clinical workflow. The compact solution requires high temporal resolution DCE-MRI due to the need to adequately sample the early phase of contrast media uptake.

Ultrafast Dynamic Contrast-Enhanced Breast MRI: Kinetic Curve Assessment Using Empirical Mathematical Model Validated with Histological Microvessel Density.

RATIONALE AND OBJECTIVES: To evaluate whether parameters from empirical mathematical model (EMM) for ultrafast dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) correlate with histological microvessel density (MVD) in invasive breast cancer. MATERIALS AND METHODS: Ninety-eight consecutive patients with invasive breast cancer underwent an institutional review board-approved ultrafast DCE-MRI including a pre- and 18 postcontrast whole breast ultrafast scans (3 seconds) followed by four standard scans (60 seconds) using a 3T system. Region of interest was placed within each lesion where the highest signal increase was observed on ultrafast DCE-MRI, and the increase rate of enhancement was calculated as follows: ΔS = (SIpost - SIpre)/SIpre. The kinetic curve obtained from ultrafast DCE-MRI was analyzed using a truncated EMM: ΔS(t) = A(1 - e-αt), where A is the upper limit of the signal intensity, α (min-1) is the rate of signal increase. The initial slope of the kinetic curve is given by Aα. Initial area under curve (AUC30) and time of initial enhancement was calculated. From the standard DCE-MRI, the initial enhancement rate (IER) and the signal enhancement ratio (SER) were calculated as follows: IER = (SIearly - SIpre)/SIpre, SER = (SIearly - SIpre)/(SIdelayed - SIpre). The parameters were compared to MVD obtained from surgical specimens. RESULTS: A, α, Aα, AUC30, and time of initial enhancement significantly correlated with MVD (r = 0.29, 0.40, 0.51, 0.43, and -0.32 with p = 0.0027, p < 0.0001, p < 0.0001, p < 0.0001, and p = 0.0012, respectively), whereas IER and SER from standard DCE-MRI did not. CONCLUSION: The parameters of the EMM, especially the initial slope or Aα, for ultrafast DCE-MRI correlated with MVD in invasive breast cancer.

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.

Dynamic field-of-view imaging to increase temporal resolution in the early phase of contrast media uptake in breast DCE-MRI: A feasibility study.

PURPOSE: To increase diagnostic accuracy of breast MRI by increasing temporal resolution and more accurately sampling the early kinetics of contrast media uptake. We tested the feasibility of accelerating bilateral breast DCE-MRI by reducing the FOV, allowing aliasing, and unfolding the resulting images. METHODS: Previous experience with an "ultrafast" protocol for bilateral breast DCE-MRI (6-10 s temporal resolution) showed that the number of significantly enhancing voxels is very low in the first 30-45 s after contrast media injection. This suggests that overlap of enhancing voxels in aliased images will be very infrequent. Therefore, aliased images can be acquired during the first 30-45 s after contrast media injection and unfolded to produce full-FOV images with few errors. In a proof-of-principle test, aliased images were simulated from the first 30 s of full-FOV acquisitions. Cases with relatively dense early enhancement were selected to test this method in a worst-case scenario. In an initial test, an FOV of 60% the size of the full FOV was simulated. To reduce the probability of errors due to overlapping voxels in aliased images, we then tested a dynamic FOV approach. The FOV was progressively increased so that enhancing voxels could not overlap at multiple time-points, and areas where enhancing voxels overlapped at a given time-point could be unfolded by interpolating between the preceding and subsequent time-points (acquired with different FOVs). The simulated FOV sizes for each of the time-points were 31%, 44%, and 77% of the full FOV. Subtraction images (post- minus precontrast) were generated for aliased images and filtered to select significantly enhancing voxels. Comparison of early, highly aliased images, with later, less aliased images then helped to identify the true locations of enhancing voxels. RESULTS: In the initial aliasing simulations, an average of 2.9% of the enhancing voxels above the chest wall overlapped in the aliased images (range 0.1%-6.7%). The similarity between simulated unfolded images and the correct full-FOV images, evaluated using CW-SSIM (complex wavelet similarity index), was 0.50 ± 0.26, 0.76 ± 0.09, and 0.80 ± 0.10 for the first, second, and third time-point, respectively (numbers closer to 1 indicate more similar images). For the dynamic FOV tests, an average of 11% of the enhancing voxels above the chest wall overlapped (range 0%-40%) due to greater aliasing at early time-points. Despite more voxels overlapping, the CW-SSIM values for the data acquired with dynamic FOVs were 0.64 ± 0.25, 0.93 ± 0.04, and 0.97 ± 0.02 for the first, second, and third time-points, respectively. CONCLUSIONS: Dynamic FOV imaging allows accelerated bilateral breast DCE-MRI during the early contrast media uptake phase. This method relies on the sparsity of enhancement at the early phases of DCE-MRI of the breast. The results of simulations suggest that dynamic FOV imaging and unfolding produces images that are very close to fully sampled images, and allows temporal resolution as high as 2 s per image.

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.

Ultrafast Bilateral DCE-MRI of the Breast with Conventional Fourier Sampling: Preliminary Evaluation of Semi-quantitative Analysis.

RATIONALE AND OBJECTIVES: The study aimed to evaluate the feasibility and advantages of a combined high temporal and high spatial resolution protocol for dynamic contrast-enhanced magnetic resonance imaging of the breast. MATERIALS AND METHODS: Twenty-three patients with enhancing lesions were imaged at 3T. The acquisition protocol consisted of a series of bilateral, fat-suppressed "ultrafast" acquisitions, with 6.9- to 9.9-second temporal resolution for the first minute following contrast injection, followed by four high spatial resolution acquisitions with 60- to 79.5-second temporal resolution. All images were acquired with standard uniform Fourier sampling. A filtering method was developed to reduce noise and detect significant enhancement in the high temporal resolution images. Time of arrival (TOA) was defined as the time at which each voxel first satisfied all the filter conditions, relative to the time of initial arterial enhancement. RESULTS: Ultrafast images improved visualization of the vasculature feeding and draining lesions. A small percentage of the entire field of view (<6%) enhanced significantly in the 30 seconds following contrast injection. Lesion conspicuity was highest in early ultrafast images, especially in cases with marked parenchymal enhancement. Although the sample size was relatively small, the average TOA for malignant lesions was significantly shorter than the TOA for benign lesions. Significant differences were also measured in other parameters descriptive of early contrast media uptake kinetics (P < 0.05). CONCLUSIONS: Ultrafast imaging in the first minute of dynamic contrast-enhanced magnetic resonance imaging of the breast has the potential to add valuable information on early contrast dynamics. Ultrafast imaging could allow radiologists to confidently identify lesions in the presence of marked background parenchymal enhancement.

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.

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

PURPOSE: To develop a method for mapping the B1 field using a reference signal from a tissue with known T1. METHODS: Flip angle correction factors were calculated in a region with a known "gold standard" T1; by comparing T1 values from a variable flip angle (VFA) sequence to the "gold standard" and correcting the value of the Ernst angle. The resulting partial B1 map was interpolated for all other regions. In the breast, fat is an ideal reference tissue because its T1 is spatially homogeneous and interpatient variability is low. This method was tested with scans of phantoms and patients (n = 4) on a 3T magnet. The performance of the method was evaluated by comparing the results of VFA T1 mapping with and without B1 correction to inversion recovery (IR) T1 maps. RESULTS: Phantom data determined that a linear inverse distance weighted interpolation accurately recovered the full B1 map. Use of interpolated maps to correct the VFA data in vivo, reduced the average difference in the T1 of parenchyma between VFA and IR results from 58% to 8%. CONCLUSION: This proof-of-principle study showed that it is possible to recover a full and accurate map of the B1 field in the breast by using a reference tissue (fat) with an accurately measured T1.

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

OBJECTIVES: To 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. METHODS: Clinical 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. RESULTS: Forty 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. CONCLUSION: Quantification 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.