A Novel Tissue-Free Method to Estimate Tumor-Derived Cell-Free DNA Quantity Using Tumor Methylation Patterns.

Estimating the abundance of cell-free DNA (cfDNA) fragments shed from a tumor (i.e., circulating tumor DNA (ctDNA)) can approximate tumor burden, which has numerous clinical applications. We derived a novel, broadly applicable statistical method to quantify cancer-indicative methylation patterns within cfDNA to estimate ctDNA abundance, even at low levels. Our algorithm identified differentially methylated regions (DMRs) between a reference database of cancer tissue biopsy samples and cfDNA from individuals without cancer. Then, without utilizing matched tissue biopsy, counts of fragments matching the cancer-indicative hyper/hypo-methylated patterns within DMRs were used to determine a tumor methylated fraction (TMeF; a methylation-based quantification of the circulating tumor allele fraction and estimate of ctDNA abundance) for plasma samples. TMeF and small variant allele fraction (SVAF) estimates of the same cancer plasma samples were correlated (Spearman's correlation coefficient: 0.73), and synthetic dilutions to expected TMeF of 10-3 and 10-4 had estimated TMeF within two-fold for 95% and 77% of samples, respectively. TMeF increased with cancer stage and tumor size and inversely correlated with survival probability. Therefore, tumor-derived fragments in the cfDNA of patients with cancer can be leveraged to estimate ctDNA abundance without the need for a tumor biopsy, which may provide non-invasive clinical approximations of tumor burden.

Fat-based registration of breast dynamic contrast enhanced water images.

PURPOSE: In this study, a 3D fat-based deformable registration algorithm was developed for registering dynamic contrast-enhanced breast images. METHODS: The mutual information similarity measure with free-form deformation motion correction in rapidly enhancing lesions can introduce motion. However, in Dixon-based fat-water separated acquisitions, the nonenhancing fat signal can directly be used to estimate deformable motion, which can be later used to deform the water images. Qualitative comparison of the fat-based registration method to a water-based registration method, and to the unregistered images, was performed by two experienced readers. Quantitative analysis of the registration was evaluated by estimating the mean-squared signal difference on the fat images. RESULTS: Using a scale of 0 (no motion) to 2 ( > 4 voxels of motion), the average image quality score of the fat-based registered images was 0.5 ± 0.6, water-based registration was 0.8 ± 0.8, and the unregistered dataset was 1.6 ± 0.6. The mean-squared-signal-difference metric on the fat images was significantly lower for fat-based registered images compared with both water-based registered and unregistered images. CONCLUSIONS: Fat-based registration of breast dynamic contrast-enhanced images is a promising technique for performing deformable motion correction of breast without introducing new motion. Magn Reson Med 79:2408-2414, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Free-breathing variable flip angle balanced SSFP cardiac cine imaging with reduced SAR at 3T.

PURPOSE: To develop a free-breathing variable flip angle (VFA) balanced steady-state free precession (bSSFP) cardiac cine imaging technique with reduced specific absorption rate (SAR) at 3 Tesla. METHODS: Free-breathing VFA (FB-VFA) images in the short-axis and four-chamber views were acquired using an optimal VFA scheme, then compared with conventional breath-hold constant flip angle (BH-CFA) acquisitions. Two cardiac MRI experts used a 5-point scale to score images from healthy subjects (N = 10). The left ventricular ejection fraction, end diastolic volume (LVEDV), end systolic volume, stroke volume (LVSV), and end diastolic myocardial mass (LVEDM) were determined by manual contour analysis for BH-CFA and FB-VFA. A pilot evaluation of FB-VFA was performed in one patient with Duchenne muscular dystrophy. RESULTS: FB-VFA SAR was 25% lower than BH-CFA with similar blood-myocardium contrast. The qualitative FB-VFA score was lower than the BH-CFA for the short-axis (3.1 ± 0.5 versus 4.3 ± 0.8; P < 0.05) and the four-chamber view (3.4 ± 0.4 versus 4.6 ± 0.6; P < 0.05). The LVEDV and the LVSV were 5% and 12% larger (P < 0.05) for FB-VFA compared with BH-CFA. There was no difference in LVEDM. CONCLUSION: FB-VFA bSSFP cardiac cine imaging decreased the SAR at 3T with image quality sufficient to perform cardiac functional analysis. Magn Reson Med 76:1210-1216, 2016. © 2015 Wiley Periodicals, Inc.

Fast 3D T2 -weighted imaging using variable flip angle transition into driven equilibrium (3D T2 -TIDE) balanced SSFP for prostate imaging at 3T.

PURPOSE: Three-dimensional (3D) T2 -weighted fast spin echo (FSE) imaging of the prostate currently requires long acquisition times. Our objective was to develop a fast 3D T2 -weighted sequence for prostate imaging at 3T using a variable flip angle transition into driven equilibrium (T2 -TIDE) scheme. METHODS: 3D T2 -TIDE uses interleaved spiral-out phase encode ordering to efficiently sample the ky -kz phase encodes and also uses the transient balanced steady-state free precession signal to acquire the center of k-space for T2 -weighted imaging. Bloch simulations and images from 10 healthy subjects were acquired to evaluate the performance of 3D T2 -TIDE compared to 3D FSE. RESULTS: 3D T2 -TIDE images were acquired in 2:54 minutes compared to 7:02 minutes for 3D FSE with identical imaging parameters. The signal-to-noise ratio (SNR) efficiency was significantly higher for 3D T2 -TIDE compared to 3D FSE in nearly all tissues, including periprostatic fat (45 ± 12 vs. 31 ± 7, P < 0.01), gluteal fat (48 ± 8 vs. 41 ± 10, P = 0.12), right peripheral zone (20 ± 4 vs. 16 ± 8, P = 0.12), left peripheral zone (17 ± 2 vs. 12 ± 3, P < 0.01), and anterior fibromuscular stroma (12 ± 4 vs. 4 ± 2, P < 0.01). CONCLUSION: 3D T2 -TIDE images of the prostate can be acquired quickly with SNR efficiency that exceeds that of 3D FSE.

Optimal flip angle for high contrast balanced SSFP cardiac cine imaging.

PURPOSE: To determine the optimal flip angle (FA) for cardiac cine imaging that maximizes myocardial signal and blood-myocardium contrast. METHODS: Bloch equation simulations of stationary myocardium and flowing blood with an imperfect slice profile were compared to in vivo measurements of blood and myocardium signal-to-noise ratio (SNR) and blood-myocardium contrast-to-noise ratio (CNR) in healthy subjects (N = 10) in the short-axis and four-chamber views and in patients (N = 7) in the three-chamber imaging plane. RESULTS: Left ventricular (LV) and right ventricular (RV) blood SNR and blood-myocardium CNR increases with increasing FA up to ≈105° in the short-axis view. A similar trend is seen in the RV four-chamber view, but a marked SNR difference between the LV and RV blood appears for FA>75°, especially during systole. Notable RV and LV SNR and CNR differences are also evident in the three-chamber view due to the predominant LV in-plane flow versus RV through-plane flow. CONCLUSION: Very high blood-myocardium CNR can be obtained with a FA of ≈105° in the short-axis plane and ≈75° in the three-chamber and four-chamber imaging planes. However, if through-plane flow is limited, as may occur for patients with low ejection fraction or low heart rates, then the FA may be limited to ≈ 75°.

Complementary radial tagging for improved myocardial tagging contrast.

PURPOSE: To develop and evaluate complementary radial tagging (CRT) for improved myocardial tagging contrast. METHODS: We sought to develop and evaluate CRT, which aims to preserve the radial tag contrast throughout the cardiac cycle. Similar to complementary spatial modulation of magnetization, CRT acquires two sets of images with a phase shift in the tag pattern. The combination of a ramped imaging flip angle and image subtraction enhances tag contrast throughout the cardiac cycle. The proposed CRT technique uses a small table shift away from the isocenter to improve the uniformity of the radial tag pattern. We provide a mathematical solution for the optimal table shift and validate the solution in using a retrospective analysis of images from 500 patients in the Cardiac Atlas Project database. RESULTS: CRT simulations, phantom experiments, and in vivo images all demonstrate the improved tag contrast of CRT compared to RT. The retrospective evaluation demonstrated that acceptable CRT images could be acquired in over 98% of the clinical exams. CONCLUSION: The CRT technique improves radial tag contrast throughout the cardiac cycle and should produce high quality tag patterns in nearly all patients.

Modeling and incorporating cardiac-induced lung tissue motion in a breathing motion model.

PURPOSE: The purpose of this work is to develop a cardiac-induced lung motion model to be integrated into an existing breathing motion model. METHODS: The authors' proposed cardiac-induced lung motion model represents the lung tissue's specific response to the subject's cardiac cycle. The model is mathematically defined as a product of a converging polynomial function h of the cardiac phase (c) and the maximum displacement y(X0) of each voxel (X0) among all the cardiac phases. The function h(c) was estimated from cardiac-gated MR imaging of ten healthy volunteers using an Akaike Information Criteria optimization algorithm. For each volunteer, a total of 24 short-axis and 18 radial planar views were acquired on a 1.5 T MR scanner during a series of 12-15 s breath-hold maneuvers. Each view contained 30 temporal frames of equal time-duration beginning with the end-diastolic cardiac phase. The frames in each of the planar views were resampled to create a set of three-dimensional (3D) anatomical volumes representing thoracic anatomy at different cardiac phases. A 3D multiresolution optical flow deformable image registration algorithm was used to quantify the difference in tissue position between the end-diastolic cardiac phase and the remaining cardiac phases. To account for image noise, voxel displacements whose maximum values were less than 0.3 mm, were excluded. In addition, the blood vessels were segmented and excluded in order to eliminate registration artifacts caused by blood-flow. RESULTS: The average cardiac-induced lung motions for displacements greater than 0.3 mm were found to be 0.86 ± 0.74 and 0.97 ± 0.93 mm in the left and right lungs, respectively. The average model residual error for the ten healthy volunteers was found to be 0.29 ± 0.08 mm in the left lung and 0.38 ± 0.14 mm in the right lung for tissue displacements greater than 0.3 mm. The relative error decreased with increasing cardiac-induced lung tissue motion. While the relative error was > 60% for submillimeter cardiac-induced lung tissue motion, the relative error decreased to < 5% for cardiac-induced lung tissue motion that exceeded 10 mm in displacement. CONCLUSIONS: The authors' studies implied that modeling and including cardiac-induced lung motion would improve breathing motion model accuracy for tissues with cardiac-induced motion greater than 0.3 mm.

Noncontrast enhanced four-dimensional dynamic MRA with golden angle radial acquisition and K-space weighted image contrast (KWIC) reconstruction.

PURPOSE: To explore the feasibility of 2D and 3D golden-angle radial acquisition strategies in conjunction with k-space weighted image contrast (KWIC) temporal filtering to achieve noncontrast enhanced dynamic MRA (dMRA) with high spatial resolution, low streaking artifacts and high temporal fidelity. METHODS: Simulations and in vivo examinations in eight normal volunteers and an arteriovenous malformation patient were carried out. Both 2D and 3D golden angle radial sequences, preceded by spin tagging, were used for dMRA of the brain. The radial dMRA data were temporally filtered using the KWIC strategy and compared with matched standard Cartesian techniques. RESULTS: The 2D and 3D dynamic MRA image series acquired with the proposed radial techniques demonstrated excellent image quality without discernible temporal blurring compared with standard Cartesian based approaches. The image quality of radial dMRA was equivalent to or higher than that of Cartesian dMRA by visual inspection. A reduction factor of up to 10 and 3 in scan time was achieved for 2D and 3D radial dMRA compared with the Cartesian-based counterparts. CONCLUSION: The proposed 2D and 3D radial dMRA techniques demonstrated image quality comparable or even superior to those obtained with standard Cartesian methods, but within a fraction of the scan time.

Variable flip angle balanced steady-state free precession for lower SAR or higher contrast cardiac cine imaging.

PURPOSE: Cardiac cine balanced steady-state free precession (bSSFP) imaging uses a high flip angle (FA) to obtain high blood-myocardium signal-to-noise and contrast-to-noise ratios (CNR). Use of high FAs, however, results in substantially increased SAR. Our objective was to develop a variable FA bSSFP cardiac cine imaging technique with: (1) low SAR and blood-myocardium CNR similar to conventional constant FA bSSFP (CFA-bSSFP) or (2) increased blood-myocardium CNR compared to CFA-bSSFP with similar SAR. METHODS: Variable FA bSSFP cardiac cine imaging was achieved using an asynchronous k-space acquisition, which is asynchronous to the cardiac cycle (aVFA-bSSFP). Bloch simulations and phantom experiments were performed to compare the signal, resolution, and frequency response of the variable FA bSSFP and CFA-bSSFP schemes. Ten volunteers were imaged with different aVFA-bSSFP and asynchronous CFA-bSSFP schemes and compared to conventional segmented CFA-bSSFP. RESULTS: The SAR of aVFA-bSSFP is significantly decreased by 36% compared to asynchronous CFA-bSSFP (1.9 ± 0.2 vs. 3.0 ± 0.2 W/kg, P < 10(-10)) for similar blood-myocardium CNR (34 ± 6 vs. 35 ± 9, P = 0.5). Alternately, the CNR of the aVFA-bSSFP is improved by 28% compared to asynchronous CFA-bSSFP (49 ± 9 vs. 38 ± 8, P < 10(-4)) with similar SAR (3.2 ± 0.5 vs. 3.3 ± 0.5 W/kg, P = 0.6). CONCLUSION: aVFA-bSSFP can be used for lower SAR or higher contrast cardiac cine imaging compared to the conventional segmented CFA-bSSFP imaging.

Free-breathing 3D whole-heart black-blood imaging with motion sensitized driven equilibrium.

PURPOSE: To assess the efficacy and robustness of motion sensitized driven equilibrium (MSDE) for blood suppression in volumetric 3D whole-heart cardiac MR. MATERIALS AND METHODS: To investigate the efficacy of MSDE on blood suppression and myocardial signal-to-noise ratio (SNR) loss on different imaging sequences, seven healthy adult subjects were imaged using 3D electrocardiogram (ECG)-triggered MSDE-prep T(1) -weighted turbo spin echo (TSE), and spoiled gradient echo (GRE), after optimization of MSDE parameters in a pilot study of five subjects. Imaging artifacts, myocardial and blood SNR were assessed. Subsequently, the feasibility of isotropic spatial resolution MSDE-prep black-blood was assessed in six subjects. Finally, 15 patients with known or suspected cardiovascular disease were recruited to be imaged using a conventional multislice 2D double inversion recovery (DIR) TSE imaging sequence and a 3D MSDE-prep spoiled GRE. RESULTS: The MSDE-prep yielded significant blood suppression (75%-92%), enabling a volumetric 3D black-blood assessment of the whole heart with significantly improved visualization of the chamber walls. The MSDE-prep also allowed successful acquisition of black-blood images with isotropic spatial resolution. In the patient study, 3D black-blood MSDE-prep and DIR resulted in similar blood suppression in left ventricle and right ventricle walls but the MSDE-prep had superior myocardial signal and wall sharpness. CONCLUSION: MSDE-prep allows volumetric black-blood imaging of the heart.