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Hyperpolarized (HP) 13 C MRI has shown promise as a valuable modality for in vivo measurements of metabolism and is currently in human trials at 15 research sites worldwide. With this growth, it is important to adopt standardized data storage practices as it will allow sites to meaningfully compare data. In this paper, we (1) describe data that we believe should be stored and (2) demonstrate pipelines and methods that utilize the Digital Imaging and Communications in Medicine (DICOM) standard. This includes proposing a set of minimum set of information that is specific to HP 13 C MRI studies. We then show where the majority of these can be fit into existing DICOM attributes, primarily via the "Contrast/Bolus" module. We also demonstrate pipelines for utilizing DICOM for HP 13 C MRI. DICOM is the most common standard for clinical medical image storage and provides the flexibility to accommodate the unique aspects of HP 13 C MRI, including the HP agent information but also spectroscopic and metabolite dimensions. The pipelines shown include creating DICOM objects for studies on human and animal imaging systems with various pulse sequences. We also show a python-based method to efficiently modify DICOM objects to incorporate the unique HP 13 C MRI information that is not captured by existing pipelines. Moreover, we propose best practices for HP 13 C MRI data storage that will support future multi-site trials, research studies, and technical developments of this imaging technique., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Background: Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related death in the United States. However, early response assessment using the current approach of measuring changes in tumor size on computed tomography (CT) or MRI is challenging., Purpose: To investigate the feasibility of hyperpolarized (HP) [1- 13 C]pyruvate MRI to quantify metabolism in the normal appearing pancreas and PDA, and to assess changes in PDA metabolism following systemic chemotherapy., Study Type: Prospective., Subjects: Six patients (65.0 ± 7.6 years, 2 females) with locally advanced or metastatic PDA enrolled prior to starting a new line of systemic chemotherapy., Field Strength/sequence: 3-T, T1-weighted gradient echo, metabolite-selective 13 C echoplanar imaging., Assessment: Time-resolved HP [1- 13 C]pyruvate data were acquired before (N = 6) and 4-weeks after (N = 3) treatment initiation. Pyruvate metabolism, as quantified by pharmacokinetic modeling and metabolite area-under-the-curve ratios, was assessed in manually segmented PDA and normal appearing pancreas ROIs (N = 5). The change in tumor metabolism before and 4-weeks after treatment initiation was assessed in primary PDA (N = 2) and liver metastases (N = 1), and was compared to objective tumor response defined by response evaluation criteria in solid tumors (RECIST) on subsequent CTs., Statistical Tests: Descriptive tests (mean ± standard deviation), model fit error for pharmacokinetic rate constants., Results: Primary PDA showed reduced alanine-to-lactate ratios when compared to normal pancreas, due to increased lactate-to-pyruvate or reduced alanine-to-pyruvate ratios. Of the three patients who received HP [1- 13 C]pyruvate MRI before and 4-weeks after treatment initiation, one patient had a primary tumor with early metabolic response (increase in alanine-to-lactate) and subsequent partial response according to RECIST, one patient had a primary tumor with relatively stable metabolism and subsequent stable disease by RECIST, and one patient had metastatic PDA with increase in lactate-to-pyruvate of the liver metastases and corresponding progressive disease according to RECIST., Data Conclusion: Altered pyruvate metabolism with increased lactate or reduced alanine was observed in the primary tumor. Early metabolic response assessed at 4-weeks after treatment initiation correlated with subsequent objective tumor response assessed using RECIST., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 2., (© 2023 International Society for Magnetic Resonance in Medicine.)

Purpose: Improving the quality and maintaining the fidelity of large coverage abdominal hyperpolarized (HP) 13 C MRI studies with a patch based global-local higher-order singular value decomposition (GL-HOVSD) spatiotemporal denoising approach., Methods: Denoising performance was first evaluated using the simulated [1- 13 C]pyruvate dynamics at different noise levels to determine optimal k global and k local parameters. The GL-HOSVD spatiotemporal denoising method with the optimized parameters was then applied to two HP [1- 13 C]pyruvate EPI abdominal human cohorts (n = 7 healthy volunteers and n = 8 pancreatic cancer patients)., Results: The parameterization of k global  = 0.2 and k local  = 0.9 denoises abdominal HP data while retaining image fidelity when evaluated by RMSE. The k PX (conversion rate of pyruvate-to-metabolite, X = lactate or alanine) difference was shown to be <20% with respect to ground-truth metabolic conversion rates when there is adequate SNR (SNR AUC  > 5) for downstream metabolites. In both human cohorts, there was a greater than nine-fold gain in peak [1- 13 C]pyruvate, [1- 13 C]lactate, and [1- 13 C]alanine apparent SNR AUC . The improvement in metabolite SNR enabled a more robust quantification of k PL and k PA . After denoising, we observed a 2.1 ± 0.4 and 4.8 ± 2.5-fold increase in the number of voxels reliably fit across abdominal FOVs for k PL and k PA quantification maps., Conclusion: Spatiotemporal denoising greatly improves visualization of low SNR metabolites particularly [1- 13 C]alanine and quantification of [1- 13 C]pyruvate metabolism in large FOV HP 13 C MRI studies of the human abdomen., (© 2024 International Society for Magnetic Resonance in Medicine.)

Hyperpolarized (HP) 13 C Magnetic Resonance Imaging (MRI) was applied for the first time to image and quantify the uptake and metabolism of [2- 13 C]pyruvate in the human brain to provide new metabolic information on cerebral energy metabolism. HP [2- 13 C]pyruvate was injected intravenously and imaged in 5 healthy human volunteer exams with whole brain coverage in a 1-minute acquisition using a specialized spectral-spatial multi-slice echoplanar imaging (EPI) pulse sequence to acquire 13 C-labeled volumetric and dynamic images of [2- 13 C]pyruvate and downstream metabolites [5- 13 C]glutamate and [2- 13 C]lactate. Metabolic ratios and apparent conversion rates of pyruvate-to-lactate (k PL ) and pyruvate-to-glutamate (k PG ) were quantified to investigate simultaneously glycolytic and oxidative metabolism in a single injection., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yaewon Kim reports financial support was provided by NIH., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: To improve hyperpolarized 13 C (HP- 13 C) MRI by image denoising with a new approach, patch-based higher-order singular value decomposition (HOSVD)., Methods: The benefit of using a patch-based HOSVD method to denoise dynamic HP- 13 C MR imaging data was investigated. Image quality and the accuracy of quantitative analyses following denoising were evaluated first using simulated data of [1- 13 C]pyruvate and its metabolic product, [1- 13 C]lactate, and compared the results to a global HOSVD method. The patch-based HOSVD method was then applied to healthy volunteer HP [1- 13 C]pyruvate EPI studies. Voxel-wise kinetic modeling was performed on both non-denoised and denoised data to compare the number of voxels quantifiable based on SNR criteria and fitting error., Results: Simulation results demonstrated an 8-fold increase in the calculated SNR of [1- 13 C]pyruvate and [1- 13 C]lactate with the patch-based HOSVD denoising. The voxel-wise quantification of k PL (pyruvate-to-lactate conversion rate) showed a 9-fold decrease in standard errors for the fitted k PL after denoising. The patch-based denoising performed superior to the global denoising in recovering k PL information. In volunteer data sets, [1- 13 C]lactate and [ 13 C]bicarbonate signals became distinguishable from noise across captured time points with over a 5-fold apparent SNR gain. This resulted in >3-fold increase in the number of voxels quantifiable for mapping k PB (pyruvate-to-bicarbonate conversion rate) and whole brain coverage for mapping k PL ., Conclusions: Sensitivity enhancement provided by this denoising significantly improved quantification of metabolite dynamics and could benefit future studies by improving image quality, enabling higher spatial resolution, and facilitating the extraction of metabolic information for clinical research., (© 2021 International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a novel post-processing pipeline for hyperpolarized (HP) 13 C MRSI that integrates tensor denoising and B 1 + correction to measure pyruvate-to-lactate conversion rates (k PL ) in patients with liver tumors., Methods: Seven HP 13 C MR scans of progressing liver tumors were acquired using a custom 13 C surface transmit/receive coil and the echo-planar spectroscopic imaging (EPSI) data analysis included B 0 correction, tensor rank truncation, and zero- and first-order phase corrections to recover metabolite signals that would otherwise be obscured by spectral noise as well as a correction for inhomogeneous transmit ( B 1 + ) using a B 1 + map aligned to the coil position for each patient scan. Processed HP data and corrected flip angles were analyzed with an inputless two-site exchange model to calculate k PL ., Results: Denoising averages SNR increases of pyruvate, lactate, and alanine were 37.4-, 34.0-, and 20.1-fold, respectively, with lactate and alanine dynamics most noticeably recovered and better defined. In agreement with Monte Carlo simulations, over-flipped regions underestimated k PL and under-flipped regions overestimated k PL . B 1 + correction addressed this issue., Conclusion: The new HP 13 C EPSI post-processing pipeline integrated tensor denoising and B 1 + correction to measure k PL in patients with liver tumors. These technical developments not only recovered metabolite signals in voxels that did not receive the prescribed flip angle, but also increased the extent and accuracy of k PL estimations throughout the tumor and adjacent regions including normal-appearing tissue and additional lesions., (© 2021 International Society for Magnetic Resonance in Medicine.)

Based on the expanding set of applications for hyperpolarized carbon-13 (HP- 13 C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state-of-the-art HP- 13 C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging-based methods, this guide provides an extensible framework for handling a variety of HP- 13 C applications, which derives from two examples with dynamic acquisitions: 3D echo-planar spectroscopic imaging of the human prostate and frequency-specific 2D multislice echo-planar imaging of the human brain. Details of sequence-specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual-use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open-source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information., (© 2020 John Wiley & Sons, Ltd.)

MRI with hyperpolarized carbon-13 agents has created a new type of noninvasive, in vivo metabolic imaging that can be applied in cell, animal, and human studies. The use of 13 C-labeled agents, primarily [1- 13 C]pyruvate, enables monitoring of key metabolic pathways with the ability to image substrate and products based on their chemical shift. Over 10 sites worldwide are now performing human studies with this new approach for studies of cancer, heart disease, liver disease, and kidney disease. Hyperpolarized metabolic imaging studies must be performed within several minutes following creation of the hyperpolarized agent due to irreversible decay of the net magnetization back to equilibrium, so fast imaging methods are critical. The imaging methods must include multiple metabolites, separated based on their chemical shift, which are also undergoing rapid metabolic conversion (via label exchange), further exacerbating the challenges of fast imaging. This review describes the state-of-the-art in fast imaging methods for hyperpolarized metabolic imaging. This includes the approach and tradeoffs between three major categories of fast imaging methods-fast spectroscopic imaging, model-based strategies, and metabolite specific imaging-as well additional options of parallel imaging, compressed sensing, tailored RF flip angles, refocused imaging methods, and calibration methods that can improve the scan coverage, speed, signal-to-noise ratio (SNR), resolution, and/or robustness of these studies. To date, these approaches have produced extremely promising initial human imaging results. Improvements to fast hyperpolarized metabolic imaging methods will provide better coverage, SNR, resolution, and reproducibility for future human imaging studies. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY STAGE: 1., (© 2020 International Society for Magnetic Resonance in Medicine.)

Purpose: With the initiation of human hyperpolarized 13 C (HP- 13 C) trials at multiple sites and the development of improved acquisition methods, there is an imminent need to maximally extract diagnostic information to facilitate clinical interpretation. This study aims to improve human HP- 13 C MR spectroscopic imaging through means of Tensor Rank truncation-Image enhancement (TRI) and optimal receiver combination (ORC)., Methods: A data-driven processing framework for dynamic HP 13 C MR spectroscopic imaging (MRSI) was developed. Using patient data sets acquired with both multichannel arrays and single-element receivers from the brain, abdomen, and pelvis, we examined the theory and application of TRI, as well as 2 ORC techniques: whitened singular value decomposition (WSVD) and first-point phasing. Optimal conditions for TRI were derived based on bias-variance trade-off., Results: TRI and ORC techniques together provided a 63-fold mean apparent signal-to-noise ratio (aSNR) gain for receiver arrays and a 31-fold gain for single-element configurations, which particularly improved quantification of the lower-SNR-[ 13 C]bicarbonate and [1- 13 C]alanine signals that were otherwise not detectable in many cases. Substantial SNR enhancements were observed for data sets that were acquired even with suboptimal experimental conditions, including delayed (114 s) injection (8× aSNR gain solely by TRI), or from challenging anatomy or geometry, as in the case of a pediatric patient with brainstem tumor (597× using combined TRI and WSVD). Improved correlation between elevated pyruvate-to-lactate conversion, biopsy-confirmed cancer, and mp-MRI lesions demonstrated that TRI recovered quantitative diagnostic information., Conclusion: Overall, this combined approach was effective across imaging targets and receiver configurations and could greatly benefit ongoing and future HP 13 C MRI research through major aSNR improvements., (© 2020 International Society for Magnetic Resonance in Medicine.)

Background: Hyperpolarized (HP) 13 C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP 13 C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera., Methods: Six patients who had metastatic castration-resistant prostate cancer were recruited. Carbon-13 MR examination were conducted on a clinical 3T MRI following injection of 250 mM hyperpolarized 13 C-pyruvate, where pyruvate-to-lactate conversion rate (k PL ) was calculated. Paired metastatic tumor biopsy was performed with histopathological and RNA-seq analyses., Results: We observed a high rate of glycolytic metabolism in prostate cancer metastases, with a mean k PL value of 0.020 ± 0.006 (s -1 ) and 0.026 ± 0.000 (s -1 ) in bone (N = 4) and liver (N = 2) metastases, respectively. Overall, high k PL showed concordance with biopsy-confirmed high-grade prostate cancer including neuroendocrine differentiation in one case. Interval decrease of k PL from 0.026 at baseline to 0.015 (s -1 ) was observed in a liver metastasis 2 months after the initiation of taxane plus platinum chemotherapy. RNA-seq found higher levels of the lactate dehydrogenase isoform A (Ldha,15.7 ± 0.7) expression relative to the dominant isoform of pyruvate dehydrogenase (Pdha1, 12.8 ± 0.9)., Conclusions: HP 13 C-pyruvate MRI can detect real-time glycolytic metabolism within prostate cancer metastases, and can measure changes in quantitative k PL values following treatment response at early time points. This first feasibility study supports future clinical studies of HP 13 C-pyruvate MRI in the setting of advanced prostate cancer.

Purpose: To compare the performance of an 8-channel surface coil/clamshell transmitter and 32-channel head array coil/birdcage transmitter for hyperpolarized 13 C brain metabolic imaging., Methods: To determine the field homogeneity of the radiofrequency transmitters, B 1 + mapping was performed on an ethylene glycol head phantom and evaluated by means of the double angle method. Using a 3D echo-planar imaging sequence, coil sensitivity and noise-only phantom data were acquired with the 8- and 32-channel receiver arrays, and compared against data from the birdcage in transceiver mode. Multislice frequency-specific 13 C dynamic echo-planar imaging was performed on a patient with a brain tumor for each hardware configuration following injection of hyperpolarized [1- 13 C]pyruvate. Signal-to-noise ratio (SNR) was evaluated from pre-whitened phantom and temporally summed patient data after coil combination based on optimal weights., Results: The birdcage transmitter produced more uniform B 1 + compared with the clamshell: 0.07 versus 0.12 (fractional error). Phantom experiments conducted with matched lateral housing separation demonstrated 8- versus 32-channel mean transceiver-normalized SNR performance: 0.91 versus 0.97 at the head center; 6.67 versus 2.08 on the sides; 0.66 versus 2.73 at the anterior; and 0.67 versus 3.17 on the posterior aspect. While the 8-channel receiver array showed SNR benefits along lateral aspects, the 32-channel array exhibited greater coverage and a more uniform coil-combined profile. Temporally summed, parameter-normalized patient data showed SNR mean,slice ratios (8-channel/32-channel) ranging 0.5-2.00 from apical to central brain. White matter lactate-to-pyruvate ratios were conserved across hardware: 0.45 ± 0.12 (8-channel) versus 0.43 ± 0.14 (32-channel)., Conclusion: The 8- and 32-channel hardware configurations each have advantages in particular brain anatomy., (© 2019 International Society for Magnetic Resonance in Medicine.)

Hyperpolarized 13 C MRI takes advantage of the unprecedented 50 000-fold signal-to-noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate-to-lactate conversion rate, k PL , a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate k PL reliably. In this study, three sequence components and parameters that modulate k PL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient-induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF-induced magnetization spoiling can be substantially improved using an inputless k PL fitting. In vivo studies found a significantly higher apparent k PL with an additional gradient that leads to flow suppression (k PL,FID-Delay,Crush /k PL,FID-Delay  = 1.37 ± 0.33, P < 0.01, N = 6), which agrees with simulation outcomes (12.5% k PL error with Δv = 40 cm/s), indicating that the gradients predominantly suppressed flowing pyruvate spins. Significantly lower k PL was found using a delayed free induction decay (FID) acquisition versus a minimum-T E version (k PL,FID-Delay /k PL,FID  = 0.67 ± 0.09, P < 0.01, N = 5), and the lactate peak had broader linewidth than pyruvate (Δω lactate /Δω pyruvate  = 1.32 ± 0.07, P < 0.000 01, N = 13). This illustrated that lactate's T 2 *, shorter than that of pyruvate, can affect calculated k PL values. We also found that an FID sequence yielded significantly lower k PL versus a double spin-echo sequence that includes spin-echo spoiling, flow suppression from crusher gradients, and more T 2 weighting (k PL,DSE /k PL,FID  = 2.40 ± 0.98, P < 0.0001, N = 7). In summary, the pulse sequence, as well as its interaction with pharmacokinetics and the tissue microenvironment, can impact and be optimized for the measurement of k PL . The data acquisition and analysis pipelines can work synergistically to provide more robust and reproducible k PL measures for future preclinical and clinical studies., (© 2019 John Wiley & Sons, Ltd.)

We present a method of generating spatial maps of kinetic parameters from dynamic sequences of images collected in hyperpolarized carbon-13 magnetic resonance imaging (MRI) experiments. The technique exploits spatial correlations in the dynamic traces via regularization in the space of parameter maps. Similar techniques have proven successful in other dynamic imaging problems, such as dynamic contrast enhanced MRI. In this paper, we apply these techniques for the first time to hyperpolarized MRI problems, which are particularly challenging due to limited signal-to-noise ratio (SNR). We formulate the reconstruction as an optimization problem and present an efficient iterative algorithm for solving it based on the alternation direction method of multipliers. We demonstrate that this technique improves the qualitative appearance of parameter maps estimated from low SNR dynamic image sequences, first in simulation then on a number of data sets collected in vivo. The improvement this method provides is particularly pronounced at low SNR levels.

MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1- 13 C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate-to-lactate conversion rate, k PL , as well as the lactate-to-pyruvate area-under-curve (AUC) ratio. The kinetic modeling included an "inputless" method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in k PL , signal-to-noise ratio (SNR), bolus characteristics, relaxation rates, and B 1 variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate k PL maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless k PL fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1- 13 C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1- 13 C]pyruvate parameters (SNR, k PL , bolus characteristics) in the human prostate., (© 2018 John Wiley & Sons, Ltd.)

New magnetic resonance (MR) molecular imaging techniques offer the potential for noninvasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a three-dimensional dynamic dual-agent hyperpolarized 13 C magnetic resonance spectroscopic imaging approach with 13 C-pyruvate and 13 C-urea to investigate differences in perfusion and metabolism between low- and high-grade tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux ( k PL ) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. k PL values were relatively higher for high-grade TRAMP tumors. The increase in k PL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1, and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased k trans , attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased k PL This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials. Cancer Res; 77(12); 3207-16. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: Hyperpolarized 13 C MRI is a powerful tool for studying metabolism, but can lack tissue specificity. Gadoxetate is a gadolinium-based MRI contrast agent that is selectively taken into hepatocytes. The goal of this project was to investigate whether gadoxetate can be used to selectively suppress the hyperpolarized signal arising from hepatocytes, which could in future studies be applied to generate specificity for signal from abnormal cell types., Methods: Baseline gadoxetate uptake kinetics were measured using T 1 -weighted contrast enhanced imaging. Relaxivity of gadoxetate was measured for [1- 13 C]pyruvate, [1- 13 C]lactate, and [1- 13 C]alanine. Four healthy rats were imaged with hyperpolarized [1- 13 C]pyruvate using a three-dimensional (3D) MRSI sequence prior to and 15 min following administration of gadoxetate. The lactate:pyruvate ratio and alanine:pyruvate ratios were measured in liver and kidney., Results: Overall, the hyperpolarized signal decreased approximately 60% as a result of pre-injection of gadoxetate. In liver, the lactate:pyruvate and alanine:pyruvate ratios decreased 42% and 78%, respectively (P < 0.05) following gadoxetate administration. In kidneys, these ratios did not change significantly. Relaxivity of gadoxetate for [1- 13 C]alanine was 12.6 times higher than relaxivity of gadoxetate for [1- 13 C]pyruvate, explaining the greater selective relaxation effect on alanine., Conclusions: The liver-specific gadolinium contrast-agent gadoxetate can selectively suppress normal hepatocyte contributions to hyperpolarized 13 C MRI signals. Magn Reson Med 77:2356-2363, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

The goal of this project was to develop and apply techniques for T 2 mapping and 3D high resolution (1.5mm isotropic; 0.003cm 3 ) 13 C imaging of hyperpolarized (HP) probes [1- 13 C]lactate, [1- 13 C]pyruvate, [2- 13 C]pyruvate, and [ 13 C, 15 N 2 ]urea in vivo. A specialized 2D bSSFP sequence was implemented on a clinical 3T scanner and used to obtain the first high resolution T 2 maps of these different hyperpolarized compounds in both rats and tumor-bearing mice. These maps were first used to optimize timings for highest SNR for single time-point 3D bSSFP acquisitions with a 1.5mm isotropic spatial resolution of normal rats. This 3D acquisition approach was extended to serial dynamic imaging with 2-fold compressed sensing acceleration without changing spatial resolution. The T 2 mapping experiments yielded measurements of T 2 values of >1s for all compounds within rat kidneys/vasculature and TRAMP tumors, except for [2- 13 C]pyruvate which was ~730ms and ~320ms, respectively. The high resolution 3D imaging enabled visualization the biodistribution of [1- 13 C]lactate, [1- 13 C]pyruvate, and [2- 13 C]pyruvate within different kidney compartments as well as in the vasculature. While the mouse anatomy is smaller, the resolution was also sufficient to image the distribution of all compounds within kidney, vasculature, and tumor. The development of the specialized 3D sequence with compressed sensing provided improved structural and functional assessments at a high (0.003cm 3 ) spatial and 2s temporal resolution in vivo utilizing HP 13 C substrates by exploiting their long T 2 values. This 1.5mm isotropic resolution is comparable to 1 H imaging and application of this approach could be extended to future studies of uptake, metabolism, and perfusion in cancer and other disease models and may ultimately be of value for clinical imaging., (Copyright © 2017 Elsevier Inc. All rights reserved.)

N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), one of Good's buffers, was applied to pH imaging using hyperpolarized (13)C magnetic resonance spectroscopy. Rapid NMR- and MRI-based pH measurements were obtained by exploiting the sensitive pH-dependence of its (13)C chemical shift within the physiologic range.

Purpose: A novel application of two-dimensional (2D) spatially selective radiofrequency (2DRF) excitation pulses in hyperpolarized 13C imaging is proposed for monitoring the bolus injection with highly efficient sampling of the initially polarized substrate, thus leaving more polarization available for detection of the subsequently generated metabolic products., Methods: A 2DRF pulse was designed with a spiral trajectory and conventional clinical gradient performance. To demonstrate the ability of our 2DRF bolus tracking pulse sequence, hyperpolarized [1-(13)ruvate in vivo imaging experiments were performed in normal rats, with a comparison to 1DRF excitation pulses., Results: Our designed 2DRF pulse was able to rapidly and efficiently monitor the injected bolus dynamics in vivo, with an 8-fold enhanced time resolution in comparison with 1DRF in our experimental settings. When applied at the pyruvate frequency for bolus tracking, our 2DRF pulse demonstrated reduced saturation of the hyperpolarization for the substrate and metabolic products compared to a 1DRF pulse, while being immune to ±0.5 ppm magnetic field inhomogeneity at 3T., Conclusion: 2DRF pulses in hyperpolarized 13C imaging can be used to efficiently monitor the bolus injection with reduced hyperpolarization saturation compared to 1DRF pulses. The parameters of our design are based on clinical scanner limits, which allows for rapid translation to human studies., (© 2014 Wiley Periodicals, Inc.)

13C-bicarbonate is a crucial measure of pyruvate oxidation and TCA cycle flux, but is challenging to measure due to its relatively low concentration and thus will greatly benefit from improved signal-to-noise ratio (SNR). To address this, we developed and investigated the feasibility of a 3D stack-of-spirals metabolite-specific balanced steady-state free precession (MS-bSSFP) sequence for improving the SNR and spatial resolution of dynamic 13C-bicarbonate imaging in hyperpolarized [1-13C]pyruvate studies. The bicarbonate MS-bSSFP sequence was evaluated by simulations, phantoms studies, preclinical studies on five rats, brain studies on two healthy volunteers and renal study on one renal cell carcinoma patient. The simulations and phantom results showed that the bicarbonate-specific pulse had minimal perturbation of other metabolites (

PurposeModel-constrained reconstruction with Fourier-based undersampling (MoReFUn) is introduced to accelerate the acquisition of dynamic MRI using hyperpolarized [1-13 C]-pyruvate.MethodsThe MoReFUn method resolves spatial aliasing using constraints introduced by a pharmacokinetic model that describes the signal evolution of both pyruvate and lactate. Acceleration was evaluated on three single-channel data sets: a numerical digital phantom that is used to validate the accuracy of reconstruction and model parameter restoration under various SNR and undersampling ratios, prospectively and retrospectively sampled data of an in vitro dynamic multispectral phantom, and retrospectively undersampled imaging data from a prostate cancer patient to test the fidelity of reconstructed metabolite time series.ResultsAll three data sets showed successful reconstruction using MoReFUn. In simulation and retrospective phantom data, the restored time series of pyruvate and lactate maintained the image details, and the mean square residual error of the accelerated reconstruction increased only slightly (

BackgroundHyperpolarized 13 C MRI quantitatively measures enzyme-catalyzed metabolism in cancer and metabolic diseases. Whole-abdomen imaging will permit dynamic metabolic imaging of several abdominal organs simultaneously in healthy and diseased subjects.PurposeImage hyperpolarized [1-13 C]pyruvate and products in the abdomens of healthy volunteers, overcoming challenges of motion, magnetic field variations, and spatial coverage. Compare hyperpolarized [1-13 C]pyruvate metabolism across abdominal organs of healthy volunteers.Study typeProspective technical development.SubjectsA total of 13 healthy volunteers (8 male), 21-64 years (median 36).Field strength/sequenceA 3 T. Proton: T1 -weighted spoiled gradient echo, T2 -weighted single-shot fast spin echo, multiecho fat/water imaging. Carbon-13: echo-planar spectroscopic imaging, metabolite-specific echo-planar imaging.AssessmentTransmit magnetic field was measured. Variations in main magnetic field (ΔB0 ) determined using multiecho proton acquisitions were compared to carbon-13 acquisitions. Changes in ΔB0 were measured after localized shimming. Improvements in metabolite signal-to-noise ratio were calculated. Whole-organ regions of interests were drawn over the liver, spleen, pancreas, and kidneys by a single investigator. Metabolite signals, time-to-peak, decay times, and mean first-order rate constants for pyruvate-to-lactate (kPL ) and alanine (kPA ) conversion were measured in each organ.Statistical testsLinear regression, one-sample Kolmogorov-Smirnov tests, paired t-tests, one-way ANOVA, Tukey's multiple comparisons tests. P ≤ 0.05 considered statistically significant.ResultsProton ΔB0 maps correlated with carbon-13 ΔB0 maps (slope = 0.93, y-intercept = -2.88, R2  = 0.73). Localized shimming resulted in mean frequency offset within ±25 Hz for all organs. Metabolite SNR significantly increased after denoising. Mean kPL and kPA were highest in liver, followed by pancreas, spleen, and kidneys (all comparisons with liver were significant).Data conclusionWhole-abdomen coverage with hyperpolarized carbon-13 MRI was feasible despite technical challenges. Multiecho gradient echo 1 H acquisitions accurately predicted chemical shifts observed using carbon-13 spectroscopy. Carbon-13 acquisitions benefited from local shimming. Metabolite energetics in the abdomen compiled for healthy volunteers can be used to design larger clinical trials in patients with metabolic diseases.Evidence level2 TECHNICAL EFFICACY: Stage 1.

PurposeTo develop techniques and establish a workflow using hyperpolarized carbon-13 (13 C) MRI and the pyruvate-to-lactate conversion rate (kPL ) biomarker to guide MR-transrectal ultrasound fusion prostate biopsies.MethodsThe integrated multiparametric MRI (mpMRI) exam consisted of a 1-min hyperpolarized 13 C-pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of kPL values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T2 -weighted anatomic images. Abdominal radiologists identified 13 C research biopsy targets based on the general recommendation of focal lesions with kPL  >0.02(s-1 ), and created a targeting report for each study. Urologists conducted transrectal ultrasound-guided MR fusion biopsies, including the standard 1 H-mpMRI targets as well as 12-14 core systematic biopsies informed by the research 13 C-kPL targets. All biopsy results were included in the final pathology report and calculated toward clinical risk.ResultsThis study demonstrated the safety and technical feasibility of integrating hyperpolarized 13 C metabolic targeting into routine 1 H-mpMRI and transrectal ultrasound fusion biopsy workflows, evaluated via 5 men (median age 71 years, prostate-specific antigen 8.4 ng/mL, Cancer of the Prostate Risk Assessment score 2) on active surveillance undergoing integrated scan and subsequent biopsies. No adverse event was reported. Median turnaround time was less than 3 days from scan to 13 C-kPL targeting, and scan-to-biopsy time was 2 weeks. Median number of 13 C targets was 1 (range: 1-2) per patient, measuring 1.0 cm (range: 0.6-1.9) in diameter, with a median kPL of 0.0319 s-1 (range: 0.0198-0.0410).ConclusionsThis proof-of-concept work demonstrated the safety and feasibility of integrating hyperpolarized 13 C MR biomarkers to the standard mpMRI workflow to guide MR-transrectal ultrasound fusion biopsies.

PurposeThis study aimed to develop and demonstrate the in vivo feasibility of a 3D stack-of-spiral balanced steady-state free precession(3D-bSSFP) urea sequence, interleaved with a metabolite-specific gradient echo (GRE) sequence for pyruvate and metabolic products, for improving the SNR and spatial resolution of the first hyperpolarized 13 C-MRI human study with injection of co-hyperpolarized [1-13 C]pyruvate and [13 C,15 N2 ]urea.MethodsA metabolite-specific bSSFP urea imaging sequence was designed using a urea-specific excitation pulse, optimized TR, and 3D stack-of-spiral readouts. Simulations and phantom studies were performed to validate the spectral response of the sequence. The image quality of urea data acquired by the 3D-bSSFP sequence and the 2D-GRE sequence was evaluated with 2 identical injections of co-hyperpolarized [1-13 C]pyruvate and [13 C,15 N2 ]urea formula in a rat. Subsequently, the feasibility of the acquisition strategy was validated in a prostate cancer patient.ResultsSimulations and phantom studies demonstrated that 3D-bSSFP sequence achieved urea-only excitation, while minimally perturbing other metabolites (

BackgroundReal-time metabolic conversion of intravenously-injected hyperpolarized [1-13C]pyruvate to [1-13C]lactate and [13C]bicarbonate in the brain can be measured using dynamic hyperpolarized carbon-13 (HP-13C) MRI. However, voxel-wise evaluation of metabolism in patients with glioma is challenged by the limited signal-to-noise ratio (SNR) of downstream 13C metabolites, especially within lesions. The purpose of this study was to evaluate the ability of higher-order singular value decomposition (HOSVD) denoising methods to enhance dynamic HP [1-13C]pyruvate MRI data acquired from patients with glioma.MethodsDynamic HP-13C MRI were acquired from 14 patients with glioma. The effects of two HOSVD denoising techniques, tensor rank truncation-image enhancement (TRI) and global-local HOSVD (GL-HOSVD), on the SNR and kinetic modeling were analyzed in [1-13C]lactate data with simulated noise that matched the levels of [13C]bicarbonate signals. Both methods were then evaluated in patient data based on their ability to improve [1-13C]pyruvate, [1-13C]lactate and [13C]bicarbonate SNR. The effects of denoising on voxel-wise kinetic modeling of kPL and kPB was also evaluated. The number of voxels with reliable kinetic modeling of pyruvate-to-lactate (kPL) and pyruvate-to-bicarbonate (kPB) conversion rates within regions of interest (ROIs) before and after denoising was then compared.ResultsBoth denoising methods improved metabolite SNR and regional signal coverage. In patient data, the average increase in peak dynamic metabolite SNR was 2-fold using TRI and 4-5 folds using GL-HOSVD denoising compared to acquired data. Denoising reduced kPL modeling errors from a native average of 23% to 16% (TRI) and 15% (GL-HOSVD); and kPB error from 42% to 34% (TRI) and 37% (GL-HOSVD) (values were averaged voxelwise over all datasets). In contrast-enhancing lesions, the average number of voxels demonstrating within-tolerance kPL modeling error relative to the total voxels increased from 48% in the original data to 84% (TRI) and 90% (GL-HOSVD), while the number of voxels showing within-tolerance kPB modeling error increased from 0% to 15% (TRI) and 8% (GL-HOSVD).ConclusionPost-processing denoising methods significantly improved the SNR of dynamic HP-13C imaging data, resulting in a greater number of voxels satisfying minimum SNR criteria and maximum kinetic modeling errors in tumor lesions. This enhancement can aid in the voxel-wise analysis of HP-13C data and thereby improve monitoring of metabolic changes in patients with glioma following treatment.

PurposeTo improve hyperpolarized 13 C (HP-13 C) MRI by image denoising with a new approach, patch-based higher-order singular value decomposition (HOSVD).MethodsThe benefit of using a patch-based HOSVD method to denoise dynamic HP-13 C MR imaging data was investigated. Image quality and the accuracy of quantitative analyses following denoising were evaluated first using simulated data of [1-13 C]pyruvate and its metabolic product, [1-13 C]lactate, and compared the results to a global HOSVD method. The patch-based HOSVD method was then applied to healthy volunteer HP [1-13 C]pyruvate EPI studies. Voxel-wise kinetic modeling was performed on both non-denoised and denoised data to compare the number of voxels quantifiable based on SNR criteria and fitting error.ResultsSimulation results demonstrated an 8-fold increase in the calculated SNR of [1-13 C]pyruvate and [1-13 C]lactate with the patch-based HOSVD denoising. The voxel-wise quantification of kPL (pyruvate-to-lactate conversion rate) showed a 9-fold decrease in standard errors for the fitted kPL after denoising. The patch-based denoising performed superior to the global denoising in recovering kPL information. In volunteer data sets, [1-13 C]lactate and [13 C]bicarbonate signals became distinguishable from noise across captured time points with over a 5-fold apparent SNR gain. This resulted in >3-fold increase in the number of voxels quantifiable for mapping kPB (pyruvate-to-bicarbonate conversion rate) and whole brain coverage for mapping kPL .ConclusionsSensitivity enhancement provided by this denoising significantly improved quantification of metabolite dynamics and could benefit future studies by improving image quality, enabling higher spatial resolution, and facilitating the extraction of metabolic information for clinical research.

PurposeTo develop a novel post-processing pipeline for hyperpolarized (HP) 13 C MRSI that integrates tensor denoising and B1+ correction to measure pyruvate-to-lactate conversion rates (kPL ) in patients with liver tumors.MethodsSeven HP 13 C MR scans of progressing liver tumors were acquired using a custom 13 C surface transmit/receive coil and the echo-planar spectroscopic imaging (EPSI) data analysis included B0 correction, tensor rank truncation, and zero- and first-order phase corrections to recover metabolite signals that would otherwise be obscured by spectral noise as well as a correction for inhomogeneous transmit ( B1+ ) using a B1+ map aligned to the coil position for each patient scan. Processed HP data and corrected flip angles were analyzed with an inputless two-site exchange model to calculate kPL .ResultsDenoising averages SNR increases of pyruvate, lactate, and alanine were 37.4-, 34.0-, and 20.1-fold, respectively, with lactate and alanine dynamics most noticeably recovered and better defined. In agreement with Monte Carlo simulations, over-flipped regions underestimated kPL and under-flipped regions overestimated kPL . B1+ correction addressed this issue.ConclusionThe new HP 13 C EPSI post-processing pipeline integrated tensor denoising and B1+ correction to measure kPL in patients with liver tumors. These technical developments not only recovered metabolite signals in voxels that did not receive the prescribed flip angle, but also increased the extent and accuracy of kPL estimations throughout the tumor and adjacent regions including normal-appearing tissue and additional lesions.

Based on the expanding set of applications for hyperpolarized carbon-13 (HP-13 C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state-of-the-art HP-13 C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging-based methods, this guide provides an extensible framework for handling a variety of HP-13 C applications, which derives from two examples with dynamic acquisitions: 3D echo-planar spectroscopic imaging of the human prostate and frequency-specific 2D multislice echo-planar imaging of the human brain. Details of sequence-specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual-use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open-source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information.

PurposeWith the initiation of human hyperpolarized 13 C (HP-13 C) trials at multiple sites and the development of improved acquisition methods, there is an imminent need to maximally extract diagnostic information to facilitate clinical interpretation. This study aims to improve human HP-13 C MR spectroscopic imaging through means of Tensor Rank truncation-Image enhancement (TRI) and optimal receiver combination (ORC).MethodsA data-driven processing framework for dynamic HP 13 C MR spectroscopic imaging (MRSI) was developed. Using patient data sets acquired with both multichannel arrays and single-element receivers from the brain, abdomen, and pelvis, we examined the theory and application of TRI, as well as 2 ORC techniques: whitened singular value decomposition (WSVD) and first-point phasing. Optimal conditions for TRI were derived based on bias-variance trade-off.ResultsTRI and ORC techniques together provided a 63-fold mean apparent signal-to-noise ratio (aSNR) gain for receiver arrays and a 31-fold gain for single-element configurations, which particularly improved quantification of the lower-SNR-[13 C]bicarbonate and [1-13 C]alanine signals that were otherwise not detectable in many cases. Substantial SNR enhancements were observed for data sets that were acquired even with suboptimal experimental conditions, including delayed (114 s) injection (8× aSNR gain solely by TRI), or from challenging anatomy or geometry, as in the case of a pediatric patient with brainstem tumor (597× using combined TRI and WSVD). Improved correlation between elevated pyruvate-to-lactate conversion, biopsy-confirmed cancer, and mp-MRI lesions demonstrated that TRI recovered quantitative diagnostic information.ConclusionOverall, this combined approach was effective across imaging targets and receiver configurations and could greatly benefit ongoing and future HP 13 C MRI research through major aSNR improvements.

BackgroundHyperpolarized (HP) 13C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP 13C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera.MethodsSix patients who had metastatic castration-resistant prostate cancer were recruited. Carbon-13 MR examination were conducted on a clinical 3T MRI following injection of 250 mM hyperpolarized 13C-pyruvate, where pyruvate-to-lactate conversion rate (kPL) was calculated. Paired metastatic tumor biopsy was performed with histopathological and RNA-seq analyses.ResultsWe observed a high rate of glycolytic metabolism in prostate cancer metastases, with a mean kPL value of 0.020 ± 0.006 (s-1) and 0.026 ± 0.000 (s-1) in bone (N = 4) and liver (N = 2) metastases, respectively. Overall, high kPL showed concordance with biopsy-confirmed high-grade prostate cancer including neuroendocrine differentiation in one case. Interval decrease of kPL from 0.026 at baseline to 0.015 (s-1) was observed in a liver metastasis 2 months after the initiation of taxane plus platinum chemotherapy. RNA-seq found higher levels of the lactate dehydrogenase isoform A (Ldha,15.7 ± 0.7) expression relative to the dominant isoform of pyruvate dehydrogenase (Pdha1, 12.8 ± 0.9).ConclusionsHP 13C-pyruvate MRI can detect real-time glycolytic metabolism within prostate cancer metastases, and can measure changes in quantitative kPL values following treatment response at early time points. This first feasibility study supports future clinical studies of HP 13C-pyruvate MRI in the setting of advanced prostate cancer.

BackgroundHyperpolarized carbon-13 (HP-13C) MRI is a non-invasive imaging technique for probing brain metabolism, which may improve clinical cancer surveillance. This work aimed to characterize the consistency of serial HP-13C imaging in patients undergoing treatment for brain tumors and determine whether there is evidence of aberrant metabolism in the tumor lesion compared to normal-appearing tissue.MethodsSerial dynamic HP [1-13C]pyruvate MRI was performed on 3 healthy volunteers (6 total examinations) and 5 patients (21 total examinations) with diffuse infiltrating glioma during their course of treatment, using a frequency-selective echo-planar imaging (EPI) sequence. HP-13C imaging at routine clinical timepoints overlapped treatment, including radiotherapy (RT), temozolomide (TMZ) chemotherapy, and anti-angiogenic/investigational agents. Apparent rate constants for [1-13C]pyruvate conversion to [1-13C]lactate (kPL) and [13C]bicarbonate (kPB) were simultaneously quantified based on an inputless kinetic model within normal-appearing white matter (NAWM) and anatomic lesions defined from 1H MRI. The inter/intra-subject consistency of kPL-NAWM and kPB-NAWM was measured in terms of the coefficient of variation (CV).ResultsWhen excluding scans following anti-angiogenic therapy, patient values of kPL-NAWM and kPB-NAWM were 0.020 s-1 ± 23.8% and 0.0058 s-1 ± 27.7% (mean ± CV) across 17 HP-13C MRIs, with intra-patient serial kPL-NAWM/kPB-NAWM CVs ranging 6.8-16.6%/10.6-40.7%. In 4/5 patients, these values (0.018 s-1 ± 13.4% and 0.0058 s-1 ± 24.4%; n = 13) were more similar to those from healthy volunteers (0.018 s-1 ± 5.0% and 0.0043 s-1 ± 12.6%; n = 6) (mean ± CV). The anti-angiogenic agent bevacizumab was associated with global elevations in apparent rate constants, with maximum kPL-NAWM in 2 patients reaching 0.047 ± 0.001 and 0.047 ± 0.003 s-1 (±model error). In 3 patients with progressive disease, anatomic lesions showed elevated kPL relative to kPL-NAWM of 0.024 ± 0.001 s-1 (±model error) in the absence of gadolinium enhancement, and 0.032 ± 0.008, 0.040 ± 0.003 and 0.041 ± 0.009 s-1 with gadolinium enhancement. The lesion kPB in patients was reduced to unquantifiable values compared to kPB-NAWM.ConclusionSerial measures of HP [1-13C]pyruvate metabolism displayed consistency in the NAWM of healthy volunteers and patients. Both kPL and kPB were globally elevated following bevacizumab treatment, while progressive disease demonstrated elevated kPL in gadolinium-enhancing and non-enhancing lesions. Larger prospective studies with homogeneous patient populations are planned to evaluate metabolic changes following treatment.

We developed methods for the preparation of hyperpolarized (HP) sterile [2-13C]pyruvate to test its feasibility in first-ever human NMR studies following FDA-IND & IRB approval. Spectral results using this MR stable-isotope imaging approach demonstrated the feasibility of investigating human cerebral energy metabolism by measuring the dynamic conversion of HP [2-13C]pyruvate to [2-13C]lactate and [5-13C]glutamate in the brain of four healthy volunteers. Metabolite kinetics, signal-to-noise (SNR) and area-under-curve (AUC) ratios, and calculated [2-13C]pyruvate to [2-13C]lactate conversion rates (kPL) were measured and showed similar but not identical inter-subject values. The kPL measurements were equivalent with prior human HP [1-13C]pyruvate measurements.

PurposeTo compare the performance of an 8-channel surface coil/clamshell transmitter and 32-channel head array coil/birdcage transmitter for hyperpolarized 13 C brain metabolic imaging.MethodsTo determine the field homogeneity of the radiofrequency transmitters, B1 + mapping was performed on an ethylene glycol head phantom and evaluated by means of the double angle method. Using a 3D echo-planar imaging sequence, coil sensitivity and noise-only phantom data were acquired with the 8- and 32-channel receiver arrays, and compared against data from the birdcage in transceiver mode. Multislice frequency-specific 13 C dynamic echo-planar imaging was performed on a patient with a brain tumor for each hardware configuration following injection of hyperpolarized [1-13 C]pyruvate. Signal-to-noise ratio (SNR) was evaluated from pre-whitened phantom and temporally summed patient data after coil combination based on optimal weights.ResultsThe birdcage transmitter produced more uniform B1 + compared with the clamshell: 0.07 versus 0.12 (fractional error). Phantom experiments conducted with matched lateral housing separation demonstrated 8- versus 32-channel mean transceiver-normalized SNR performance: 0.91 versus 0.97 at the head center; 6.67 versus 2.08 on the sides; 0.66 versus 2.73 at the anterior; and 0.67 versus 3.17 on the posterior aspect. While the 8-channel receiver array showed SNR benefits along lateral aspects, the 32-channel array exhibited greater coverage and a more uniform coil-combined profile. Temporally summed, parameter-normalized patient data showed SNRmean,slice ratios (8-channel/32-channel) ranging 0.5-2.00 from apical to central brain. White matter lactate-to-pyruvate ratios were conserved across hardware: 0.45 ± 0.12 (8-channel) versus 0.43 ± 0.14 (32-channel).ConclusionThe 8- and 32-channel hardware configurations each have advantages in particular brain anatomy.

Hyperpolarized 13 C MRI takes advantage of the unprecedented 50 000-fold signal-to-noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate-to-lactate conversion rate, kPL , a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate kPL reliably. In this study, three sequence components and parameters that modulate kPL estimation were identified and investigated in model simulations and through in vivo animal studies using several specifically designed pulse sequences. These factors included a magnetization spoiling effect due to RF pulses, a crusher gradient-induced flow suppression, and intrinsic image weightings due to relaxation. Simulation showed that the RF-induced magnetization spoiling can be substantially improved using an inputless kPL fitting. In vivo studies found a significantly higher apparent kPL with an additional gradient that leads to flow suppression (kPL,FID-Delay,Crush /kPL,FID-Delay  = 1.37 ± 0.33, P

PurposeHyperpolarized 13 C MRI is a powerful tool for studying metabolism, but can lack tissue specificity. Gadoxetate is a gadolinium-based MRI contrast agent that is selectively taken into hepatocytes. The goal of this project was to investigate whether gadoxetate can be used to selectively suppress the hyperpolarized signal arising from hepatocytes, which could in future studies be applied to generate specificity for signal from abnormal cell types.MethodsBaseline gadoxetate uptake kinetics were measured using T1 -weighted contrast enhanced imaging. Relaxivity of gadoxetate was measured for [1-13 C]pyruvate, [1-13 C]lactate, and [1-13 C]alanine. Four healthy rats were imaged with hyperpolarized [1-13 C]pyruvate using a three-dimensional (3D) MRSI sequence prior to and 15 min following administration of gadoxetate. The lactate:pyruvate ratio and alanine:pyruvate ratios were measured in liver and kidney.ResultsOverall, the hyperpolarized signal decreased approximately 60% as a result of pre-injection of gadoxetate. In liver, the lactate:pyruvate and alanine:pyruvate ratios decreased 42% and 78%, respectively (P

The goal of this project was to develop and apply techniques for T2 mapping and 3D high resolution (1.5mm isotropic; 0.003cm3) 13C imaging of hyperpolarized (HP) probes [1-13C]lactate, [1-13C]pyruvate, [2-13C]pyruvate, and [13C,15N2]urea in vivo. A specialized 2D bSSFP sequence was implemented on a clinical 3T scanner and used to obtain the first high resolution T2 maps of these different hyperpolarized compounds in both rats and tumor-bearing mice. These maps were first used to optimize timings for highest SNR for single time-point 3D bSSFP acquisitions with a 1.5mm isotropic spatial resolution of normal rats. This 3D acquisition approach was extended to serial dynamic imaging with 2-fold compressed sensing acceleration without changing spatial resolution. The T2 mapping experiments yielded measurements of T2 values of >1s for all compounds within rat kidneys/vasculature and TRAMP tumors, except for [2-13C]pyruvate which was ~730ms and ~320ms, respectively. The high resolution 3D imaging enabled visualization the biodistribution of [1-13C]lactate, [1-13C]pyruvate, and [2-13C]pyruvate within different kidney compartments as well as in the vasculature. While the mouse anatomy is smaller, the resolution was also sufficient to image the distribution of all compounds within kidney, vasculature, and tumor. The development of the specialized 3D sequence with compressed sensing provided improved structural and functional assessments at a high (0.003cm3) spatial and 2s temporal resolution in vivo utilizing HP 13C substrates by exploiting their long T2 values. This 1.5mm isotropic resolution is comparable to 1H imaging and application of this approach could be extended to future studies of uptake, metabolism, and perfusion in cancer and other disease models and may ultimately be of value for clinical imaging.

Background: Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer‐related death in the United States. However, early response assessment using the current approach of measuring changes in tumor size on computed tomography (CT) or MRI is challenging. Purpose: To investigate the feasibility of hyperpolarized (HP) [1‐13C]pyruvate MRI to quantify metabolism in the normal appearing pancreas and PDA, and to assess changes in PDA metabolism following systemic chemotherapy. Study Type: Prospective. Subjects: Six patients (65.0 ± 7.6 years, 2 females) with locally advanced or metastatic PDA enrolled prior to starting a new line of systemic chemotherapy. Field Strength/Sequence: 3‐T, T1‐weighted gradient echo, metabolite‐selective 13C echoplanar imaging. Assessment: Time‐resolved HP [1‐13C]pyruvate data were acquired before (N = 6) and 4‐weeks after (N = 3) treatment initiation. Pyruvate metabolism, as quantified by pharmacokinetic modeling and metabolite area‐under‐the‐curve ratios, was assessed in manually segmented PDA and normal appearing pancreas ROIs (N = 5). The change in tumor metabolism before and 4‐weeks after treatment initiation was assessed in primary PDA (N = 2) and liver metastases (N = 1), and was compared to objective tumor response defined by response evaluation criteria in solid tumors (RECIST) on subsequent CTs. Statistical Tests: Descriptive tests (mean ± standard deviation), model fit error for pharmacokinetic rate constants. Results: Primary PDA showed reduced alanine‐to‐lactate ratios when compared to normal pancreas, due to increased lactate‐to‐pyruvate or reduced alanine‐to‐pyruvate ratios. Of the three patients who received HP [1‐13C]pyruvate MRI before and 4‐weeks after treatment initiation, one patient had a primary tumor with early metabolic response (increase in alanine‐to‐lactate) and subsequent partial response according to RECIST, one patient had a primary tumor with relatively stable metabolism and subsequent stable disease by RECIST, and one patient had metastatic PDA with increase in lactate‐to‐pyruvate of the liver metastases and corresponding progressive disease according to RECIST. Data Conclusion: Altered pyruvate metabolism with increased lactate or reduced alanine was observed in the primary tumor. Early metabolic response assessed at 4‐weeks after treatment initiation correlated with subsequent objective tumor response assessed using RECIST. Level of Evidence: 2 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

PurposeEndoluminal ultrasound may serve as a minimally invasive option for delivering thermal ablation to pancreatic tumors adjacent to the stomach or duodenum. The objective of this study was to explore the basic feasibility of this treatment strategy through the design, characterization, and evaluation of proof-of-concept endoluminal ultrasound applicators capable of placement in the gastrointestinal (GI) lumen for volumetric pancreas ablation under MR guidance.MethodsTwo variants of the endoluminal applicator, each containing a distinct array of two independently powered transducers (10 × 10 mm 3.2 MHz planar; or 8 × 10 × 20 mm radius of curvature 3.3 MHz curvilinear geometries) at the distal end of a meter long flexible catheter assembly, were designed and fabricated. Transducers and circulatory water flow for acoustic coupling and luminal cooling were contained by a low-profile polyester balloon covering the transducer assembly fixture. Each applicator incorporated miniature spiral MR coils and mechanical features (guiding tips and hinges) to facilitate tracking and insertion through the GI tract under MRI guidance. Acoustic characterization of each device was performed using radiation force balance and hydrophone measurements. Device delivery into the upper GI tract, adjacent to the pancreas, and heating characteristics for treatment of pancreatic tissue were evaluated in MR-guided ex vivo and in vivo porcine experiments. MR guidance was utilized for anatomical target identification, tracking/positioning of the applicator, and MR temperature imaging (MRTI) for PRF-based multislice thermometry, implemented in the real-time RTHawk software environment.ResultsForce balance and hydrophone measurements indicated efficiencies of 48.8% and 47.8% and -3 dB intensity beam-widths of 3.2 and 1.2 mm for the planar and curvilinear transducers, respectively. Ex vivo studies on whole-porcine carcasses revealed capabilities of producing ablative temperature rise (ΔT > 15 °C) contours in pancreatic tissue 4-40 mm long and 4-28 mm wide for the planar transducer applicator (1-13 min sonication duration, ∼4 W/cm(2) applied acoustic intensity). Curvilinear transducers produced more selective heating, with a narrower ΔT > 15 °C contour length and width of up to 1-24 mm and 2-7 mm, respectively (1-7 min sonication duration, ∼4 W/cm(2) applied acoustic intensity). Active tracking of the miniature spiral coils was achieved using a Hadamard encoding tracking sequence, enabling real-time determination of each coil's coordinates and automated prescription of imaging planes for thermometry. In vivo MRTI-guided heating trials in three pigs demonstrated capability of ∼20 °C temperature elevation in pancreatic tissue at 2 cm depths from the applicator, with 5-7 W/cm(2) applied intensity and 6-16 min sonication duration. Dimensions of thermal lesions in the pancreas ranged from 12 to 28 mm, 3 to 10 mm, and 5 to 10 mm in length, width, and depth, respectively, as verified through histological analysis of tissue sections. Multiple-baseline reconstruction and respiratory-gated acquisition were demonstrated to be effective strategies in suppressing motion artifacts for clear evolution of temperature profiles during MRTI in the in vivo studies.ConclusionsThis study demonstrates the technical feasibility of generating volumetric ablation in pancreatic tissue using endoluminal ultrasound applicators positioned in the stomach lumen. MR guidance facilitates target identification, device tracking/positioning, and treatment monitoring through real-time multislice PRF-based thermometry.

N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), one of Good's buffers, was applied to pH imaging using hyperpolarized (13)C magnetic resonance spectroscopy. Rapid NMR- and MRI-based pH measurements were obtained by exploiting the sensitive pH-dependence of its (13)C chemical shift within the physiologic range.

Simple Summary: Dynamic hyperpolarized carbon-13 (HP-13C) MRI is a novel molecular imaging technique that allows for real-time in vivo imaging of glycolysis and oxidative phosphorylation using [1-13C]pyruvate as a non-radioactive and non-toxic metabolic probe. While HP-13C MRI has recently demonstrated the potential to capture Warburg-related metabolic dysregulation in patients with progressive/treatment-naïve high-grade gliomas, further improvement in methodologies is still necessary to help monitor disease status and evaluate early predictors of therapeutic response. To this end, a multimodal 1H/HP-13C MRI protocol was implemented in this study, which incorporated advanced brain tumor MR acquisitions and improved HP-13C metabolic imaging methodologies for the serial monitoring of patients with glioma over the course of clinical treatment. This study aimed to implement a multimodal 1H/HP-13C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-13C metabolic data. A total of 100 1H/HP [1-13C]-pyruvate MR examinations (104 HP-13C datasets) were acquired from 42 patients according to the comprehensive multimodal glioma imaging protocol. Serial data coverage, accuracy of frequency reference, and acquisition delay were evaluated using a mixed-effects model to account for multiple exams per patient. Serial atlas-based HP-13C MRI demonstrated consistency in volumetric coverage measured by inter-exam dice coefficients (0.977 ± 0.008, mean ± SD; four patients/11 exams). The atlas-derived prescription provided significantly improved data quality compared to manually prescribed acquisitions (n = 26/78; p = 0.04). The water-based method for referencing [1-13C]-pyruvate center frequency significantly reduced off-resonance excitation relative to the coil-embedded [13C]-urea phantom (4.1 ± 3.7 Hz vs. 9.9 ± 10.7 Hz; p = 0.0007). Significantly improved capture of tracer inflow was achieved with the 2-s versus 5-s HP-13C MRI acquisition delay (p = 0.007). This study demonstrated the implementation of a comprehensive multimodal 1H/HP-13C MR protocol emphasizing the monitoring of steady-state/dynamic metabolism in patients with glioma. [ABSTRACT FROM AUTHOR]

Background: Hyperpolarized 13C MRI quantitatively measures enzyme‐catalyzed metabolism in cancer and metabolic diseases. Whole‐abdomen imaging will permit dynamic metabolic imaging of several abdominal organs simultaneously in healthy and diseased subjects. Purpose: Image hyperpolarized [1‐13C]pyruvate and products in the abdomens of healthy volunteers, overcoming challenges of motion, magnetic field variations, and spatial coverage. Compare hyperpolarized [1‐13C]pyruvate metabolism across abdominal organs of healthy volunteers. Study Type: Prospective technical development. Subjects: A total of 13 healthy volunteers (8 male), 21–64 years (median 36). Field Strength/Sequence: A 3 T. Proton: T1‐weighted spoiled gradient echo, T2‐weighted single‐shot fast spin echo, multiecho fat/water imaging. Carbon‐13: echo‐planar spectroscopic imaging, metabolite‐specific echo‐planar imaging. Assessment: Transmit magnetic field was measured. Variations in main magnetic field (ΔB0) determined using multiecho proton acquisitions were compared to carbon‐13 acquisitions. Changes in ΔB0 were measured after localized shimming. Improvements in metabolite signal‐to‐noise ratio were calculated. Whole‐organ regions of interests were drawn over the liver, spleen, pancreas, and kidneys by a single investigator. Metabolite signals, time‐to‐peak, decay times, and mean first‐order rate constants for pyruvate‐to‐lactate (kPL) and alanine (kPA) conversion were measured in each organ. Statistical Tests: Linear regression, one‐sample Kolmogorov–Smirnov tests, paired t‐tests, one‐way ANOVA, Tukey's multiple comparisons tests. P ≤ 0.05 considered statistically significant. Results: Proton ΔB0 maps correlated with carbon‐13 ΔB0 maps (slope = 0.93, y‐intercept = −2.88, R2 = 0.73). Localized shimming resulted in mean frequency offset within ±25 Hz for all organs. Metabolite SNR significantly increased after denoising. Mean kPL and kPA were highest in liver, followed by pancreas, spleen, and kidneys (all comparisons with liver were significant). Data Conclusion: Whole‐abdomen coverage with hyperpolarized carbon‐13 MRI was feasible despite technical challenges. Multiecho gradient echo 1H acquisitions accurately predicted chemical shifts observed using carbon‐13 spectroscopy. Carbon‐13 acquisitions benefited from local shimming. Metabolite energetics in the abdomen compiled for healthy volunteers can be used to design larger clinical trials in patients with metabolic diseases. Evidence Level: 2 Technical Efficacy: Stage 1 [ABSTRACT FROM AUTHOR]

Purpose: To improve hyperpolarized 13C (HP‐13C) MRI by image denoising with a new approach, patch‐based higher‐order singular value decomposition (HOSVD). Methods: The benefit of using a patch‐based HOSVD method to denoise dynamic HP‐13C MR imaging data was investigated. Image quality and the accuracy of quantitative analyses following denoising were evaluated first using simulated data of [1‐13C]pyruvate and its metabolic product, [1‐13C]lactate, and compared the results to a global HOSVD method. The patch‐based HOSVD method was then applied to healthy volunteer HP [1‐13C]pyruvate EPI studies. Voxel‐wise kinetic modeling was performed on both non‐denoised and denoised data to compare the number of voxels quantifiable based on SNR criteria and fitting error. Results: Simulation results demonstrated an 8‐fold increase in the calculated SNR of [1‐13C]pyruvate and [1‐13C]lactate with the patch‐based HOSVD denoising. The voxel‐wise quantification of kPL (pyruvate‐to‐lactate conversion rate) showed a 9‐fold decrease in standard errors for the fitted kPL after denoising. The patch‐based denoising performed superior to the global denoising in recovering kPL information. In volunteer data sets, [1‐13C]lactate and [13C]bicarbonate signals became distinguishable from noise across captured time points with over a 5‐fold apparent SNR gain. This resulted in >3‐fold increase in the number of voxels quantifiable for mapping kPB (pyruvate‐to‐bicarbonate conversion rate) and whole brain coverage for mapping kPL. Conclusions: Sensitivity enhancement provided by this denoising significantly improved quantification of metabolite dynamics and could benefit future studies by improving image quality, enabling higher spatial resolution, and facilitating the extraction of metabolic information for clinical research. [ABSTRACT FROM AUTHOR]

Abstract Based on the expanding set of applications for hyperpolarized carbon‐13 (HP‐13C) MRI, this work aims to communicate standardized methodology implemented at the University of California, San Francisco, as a primer for conducting reproducible metabolic imaging studies of the prostate and brain. Current state‐of‐the‐art HP‐13C acquisition, data processing/reconstruction and kinetic modeling approaches utilized in patient studies are presented together with the rationale underpinning their usage. Organized around spectroscopic and imaging‐based methods, this guide provides an extensible framework for handling a variety of HP‐13C applications, which derives from two examples with dynamic acquisitions: 3D echo‐planar spectroscopic imaging of the human prostate and frequency‐specific 2D multislice echo‐planar imaging of the human brain. Details of sequence‐specific parameters and processing techniques contained in these examples should enable investigators to effectively tailor studies around individual‐use cases. Given the importance of clinical integration in improving the utility of HP exams, practical aspects of standardizing data formats for reconstruction, analysis and visualization are also addressed alongside open‐source software packages that enhance institutional interoperability and validation of methodology. To facilitate the adoption and further development of this methodology, example datasets and analysis pipelines have been made available in the supporting information. [ABSTRACT FROM AUTHOR]

Purpose: With the initiation of human hyperpolarized 13C (HP‐13C) trials at multiple sites and the development of improved acquisition methods, there is an imminent need to maximally extract diagnostic information to facilitate clinical interpretation. This study aims to improve human HP‐13C MR spectroscopic imaging through means of Tensor Rank truncation‐Image enhancement (TRI) and optimal receiver combination (ORC). Methods: A data‐driven processing framework for dynamic HP 13C MR spectroscopic imaging (MRSI) was developed. Using patient data sets acquired with both multichannel arrays and single‐element receivers from the brain, abdomen, and pelvis, we examined the theory and application of TRI, as well as 2 ORC techniques: whitened singular value decomposition (WSVD) and first‐point phasing. Optimal conditions for TRI were derived based on bias‐variance trade‐off. Results: TRI and ORC techniques together provided a 63‐fold mean apparent signal‐to‐noise ratio (aSNR) gain for receiver arrays and a 31‐fold gain for single‐element configurations, which particularly improved quantification of the lower‐SNR‐[13C]bicarbonate and [1‐13C]alanine signals that were otherwise not detectable in many cases. Substantial SNR enhancements were observed for data sets that were acquired even with suboptimal experimental conditions, including delayed (114 s) injection (8× aSNR gain solely by TRI), or from challenging anatomy or geometry, as in the case of a pediatric patient with brainstem tumor (597× using combined TRI and WSVD). Improved correlation between elevated pyruvate‐to‐lactate conversion, biopsy‐confirmed cancer, and mp‐MRI lesions demonstrated that TRI recovered quantitative diagnostic information. Conclusion: Overall, this combined approach was effective across imaging targets and receiver configurations and could greatly benefit ongoing and future HP 13C MRI research through major aSNR improvements. [ABSTRACT FROM AUTHOR]