This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-13C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo 13C MR data, it is possible to evaluate the distribution of agents such as [1-13C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-13C]lactate in tumor, with the ratio of [1-13C]lactate/[1-13C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect 13C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-13C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-13C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-13C]lactate/[1-13C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

Hyperpolarized (HP) carbon 13 (13 C) MRI is an emerging molecular imaging method that allows rapid, noninvasive, and pathwayspecific investigation of dynamic metabolic and physiologic processes that were previously inaccessible to imaging. This technique has enabled real-time in vivo investigations of metabolism that are central to a variety of diseases, including cancer, cardiovascular disease, and metabolic diseases of the liver and kidney. This review provides an overview of the methods of hyperpolarization and 13 C probes investigated to date in preclinical models of disease. The article then discusses the progress that has been made in translating this technology for clinical investigation. In particular, the potential roles and emerging clinical applications of HP [1-13 C] pyruvate MRI will be highlighted. The future directions to enable the adoption of this technology to advance the basic understanding of metabolism, to improve disease diagnosis, and to accelerate treatment assessment are also detailed.

Purpose A calibrationless parallel imaging reconstruction method, termed simultaneous auto-calibrating and k-space estimation (SAKE), is presented. It is a data-driven, coil-by-coil reconstruction method that does not require a separate calibration step for estimating coil sensitivity information. Methods In SAKE, an under-sampled multi-channel dataset is structured into a single data matrix. Then the reconstruction is formulated as a structured low-rank matrix completion problem. An iterative solution that implements a projection-onto-sets algorithm with singular value thresholding is described. Results Reconstruction results are demonstrated for retrospectively and prospectively under-sampled, multi-channel Cartesian data having no calibration signals. Additionally, non-Cartesian data reconstruction is presented. Finally, improved image quality is demonstrated by combining SAKE with wavelet-based compressed sensing. Conclusion As estimation of coil sensitivity information is not needed, the proposed method could potentially benefit MR applications where acquiring accurate calibration data is limiting or not possible at all.

In order to compare in vivo metabolism between malignant gliomas and normal brain, (13)C magnetic resonance (MR) spectroscopic imaging data were acquired from rats with human glioblastoma xenografts (U-251 MG and U-87 MG) and normal rats, following injection of hyperpolarized [1-(13)C]-pyruvate. The median signal-to-noise ratio (SNR) of lactate, pyruvate, and total observed carbon-13 resonances, as well as their relative ratios, were calculated from voxels containing Gadolinium-enhanced tissue in T(1) postcontrast images for rats with tumors and from normal brain tissue for control rats. [1-(13)C]-labeled pyruvate and its metabolic product, [1-(13)C]-lactate, demonstrated significantly higher SNR in the tumor compared with normal brain tissue. Statistical tests showed significant differences in all parameters (P < .0004) between the malignant glioma tissue and normal brain. The SNR of lactate, pyruvate, and total carbon was observed to be different between the U-251 MG and U-87 MG models, which is consistent with inherent differences in the molecular characteristics of these tumors. These results suggest that hyperpolarized MR metabolic imaging may be valuable for assessing prognosis and monitoring response to therapy for patients with brain tumors.

Summary Tumor cells have an altered metabolic phenotype characterized by increased glycolysis and diminished oxidative phosphorylation. Despite the suspected importance of glycolysis in tumorigenesis, the temporal relationship between oncogene signaling, in vivo tumor formation and glycolytic pathway activity is poorly understood. Moreover, how glycolytic pathways are altered as tumors regress remains unknown. Here we use a switchable model of MYC-driven liver cancer, along with hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging (MRSI) to visualize glycolysis in de novo tumor formation and regression. LDHA abundance and activity in tumors is tightly correlated to in vivo pyruvate conversion to lactate and is rapidly inhibited as tumors begin to regress, as are numerous glycolysis pathway genes. Conversion of pyruvate to alanine predominates in pre-cancerous tissues prior to observable morphologic or histological changes. These results demonstrate that metabolic changes precede tumor formation and regression and are directly linked to the activity of a single oncogene.

Hyperpolarized 13 C MR spectroscopic imaging can detect not only the uptake of the pre-polarized molecule but also its metabolic products in vivo, thus providing a powerful new method to study cellular metabolism. Imaging the dynamic perfusion and conversion of these metabolites provides additional tissue information but requires methods for efficient hyperpolarization usage and rapid acquisitions. In this work, we have developed a time-resolved 3D MR spectroscopic imaging method for acquiring hyperpolarized 13 C data by combining compressed sensing methods for acceleration and multiband excitation pulses to efficiently use the magnetization. This method achieved a 2 sec temporal resolution with full volumetric coverage of a mouse, and metabolites were observed for up to 60 sec following injection of hyperpolarized [1-13 C]-pyruvate. The compressed sensing acquisition used random phase encode gradient blips to create a novel random undersampling pattern tailored to dynamic MR spectroscopic imaging with sampling incoherency in four (time, frequency, and two spatial) dimensions. The reconstruction was also tailored to dynamic MR spectroscopic imaging by applying a temporal wavelet sparsifying transform to exploit the inherent temporal sparsity. Customized multiband excitation pulses were designed with a lower flip angle for the [1-13 C]-pyruvate substrate given its higher concentration than its metabolic products ( Recent studies have demonstrated the feasibility and potential clinical value of metabolic imaging using injected hyperpolarized [1-13 C]-pyruvate for novel tissue characterization in vivo (1-11). With this method, the differential conversion of pyruvate to its metabolic products of lactate, alanine, and bicarbonate can be detected in vivo in sub-minute acquisition times. This is of particular value for cancer imaging in which this metabolic profile has been shown to distinguish normal and diseased tissues in preclinical animal models (3-9). This metabolic imaging method has also been used to monitor myocardium reperfusion in the heart following ischemia (11,12).The high signal enhancement of hyperpolarized agents in vivo has been made possible by the development of methods utilizing dynamic nuclear polarization (DNP) and rapid dissolution techniques that provide a Signal-to-Noise Ratio (SNR) increase of over 40,000 for [1-13 C]-pyruvate while producing an injectable solution with physiologic pH, osmolarity, and temperature (1,2). After injection of this solution, the distribution of pyruvate and its products provides metabolic information. The metabolite time courses contain additional dynamic information, such as the perfusion and uptake rate of the injected pyruvate, the duration of the metabolite signal, and the observation times of the metabolic products (13). For example, the lactate dynamics have been shown to be significantly different between tumors and normal tissues (14,15). The use of hyperpolarized agents, however, requires rapid and efficient magnetic resonance imaging techniques because ...

This study has presented the first application of hyperpolarized C metabolic imaging in patients with brain tumor and demonstrated the safety and feasibility of using hyperpolarized [1- C]pyruvate to evaluate in vivo brain metabolism. Magn Reson Med 80:864-873, 2018. © 2018 International Society for Magnetic Resonance in Medicine.

Methods for the simultaneous polarization of multiple 13 C-enriched metabolites were developed to probe several enzymatic pathways and other physiologic properties in vivo, using a single intravenous bolus. A new method for polarization of 13 C sodium bicarbonate suitable for use in patients was developed, and the co-polarization of 13 C sodium bicarbonate and [1-13 C]pyruvate in the same sample was achieved, resulting in high solution state polarizations (15.7% and 17.6%, respectively) and long spin-lattice relaxation times (T 1 ) (46.7s and 47.7s respectively at 3T). Consistent with chemical shift anisotropy dominating the T 1 relaxation of carbonyls, T 1 values for 13 C bicarbonate and [1-13 C]pyruvate were even longer at 3T (49.7s and 67.3s, respectively). Co-polarized 13 C bicarbonate and [1-13 C] pyruvate were injected into normal mice and a murine prostate tumor model at 3T. Rapid equilibration of injected hyperpolarized 13 C sodium bicarbonate with 13 C CO 2 allowed calculation of pH on a voxel by voxel basis, and simultaneous assessment of pyruvate metabolism with cellular uptake and conversion of [1-13 C] pyruvate to its metabolic products. Initial studies in a Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model demonstrated higher levels of hyperpolarized lactate and lower pH within tumor, relative to surrounding benign tissues and to the abdominal viscera of normal controls. There was no significant difference observed in the tumor lactate/pyruvate ratio obtained after the injection of co-polarized 13 C bicarbonate and [1-13 C] pyruvate or polarized [1-13 C]pyruvate alone. The technique was extended to polarize four 13 C labelled substrates potentially providing information on pH, metabolism, necrosis and perfusion, namely [1-13 C]pyruvic acid, 13 C sodium bicarbonate, [1,4-13 C]fumaric acid, and 13 C urea with high levels of solution polarization (17.5, 10.3, 15.6 and 11.6%, respectively) and spin-lattice relaxation values similar to those recorded for the individual metabolites. These studies demonstrated the feasibility of simultaneously measuring in vivo pH and tumor metabolism using nontoxic, endogenous species, and the potential to extend the multi-polarization approach to include up to four Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access