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Purpose Dynamic magnetic resonance spectroscopic imaging of hyperpolarized 13C-labeled cell substrates has enabled the investigation of tissue metabolism in vivo. Currently observation of these hyperpolarized substrates is limited mainly to 13C detection. We describe here an imaging pulse sequence that enables proton observation by using polarization transfer from the hyperpolarized 13C nucleus to spin-coupled protons. Methods The pulse sequence transfers 13C hyperpolarization to 1H using a modified reverse insensitive nuclei enhanced by polarization transfer (INEPT) sequence that acquires a fully refocused echo. The resulting hyperpolarized 1H signal is acquired using a 2D echo-planar trajectory. The efficiency of polarization transfer was investigated using simulations with and without T1 and T2 relaxation of both the 1H and 13C nuclei. Results Simulations showed that 1H detection of the hyperpolarized 13C nucleus in lactate should increase significantly the signal-to-noise ratio when compared with direct 13C detection at 3T. However the advantage of 1H detection is expected to disappear at higher fields. Dynamic 1H images of hyperpolarized [1-13C]lactate, with a spatial resolution of 1.25 × 1.25 mm2, were acquired from a phantom injected with hyperpolarized [1-13C]lactate and from tumors in vivo following injection of hyperpolarized [1-13C]pyruvate. Conclusions The sequence allows 1H imaging of hyperpolarized 13C-labeled substrates in vivo. Magn Reson Med 79:741-747, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. [ABSTRACT FROM AUTHOR]

Single‐shot echo planar imaging (EPI), which allows an image to be acquired using a single excitation pulse, is used widely for imaging the metabolism of hyperpolarized 13C‐labelled metabolites in vivo as the technique is rapid and minimizes the depletion of the hyperpolarized signal. However, EPI suffers from Nyquist ghosting, which normally is corrected for by acquiring a reference scan. In a dynamic acquisition of a series of images, this results in the sacrifice of a time point if the reference scan involves a full readout train with no phase encoding. This time penalty is negligible if an integrated navigator echo is used, but at the cost of a lower signal‐to‐noise ratio (SNR) as a result of prolonged T2* decay. We describe here a workflow for hyperpolarized 13C EPI that requires no reference scan. This involves the selection of a ghost‐containing background from a 13C image of a single metabolite at a single time point, the identification of phase correction coefficients that minimize signal in the selected area, and the application of these coefficients to images acquired at all time points and from all metabolites. The workflow was compared in phantom experiments with phase correction using a 13C reference scan, and yielded similar results in situations with a regular field of view (FOV), a restricted FOV and where there were multiple signal sources. When compared with alternative phase correction methods, the workflow showed an SNR benefit relative to integrated 13C reference echoes (>15%) or better ghost removal relative to a 1H reference scan. The residual ghosting in a slightly de‐shimmed B0 field was 1.6% using the proposed workflow and 3.8% using a 1H reference scan. The workflow was implemented with a series of dynamically acquired hyperpolarized [1‐13C]pyruvate and [1‐13C]lactate images in vivo, resulting in images with no observable ghosting and which were quantitatively similar to images corrected using a 13C reference scan. [ABSTRACT FROM AUTHOR]

Methylglyoxal is a faulty metabolite. It is a ubiquitous by-product of glucose and amino acid metabolism that spontaneously reacts with proximal amino groups in proteins and nucleic acids, leading to impairment of their function. The glyoxalase pathway evolved early in phylogeny to bring about rapid catabolism of methylglyoxal, and an understanding of the role of methylglyoxal and the glyoxalases in many diseases is beginning to emerge. Metabolic processing of methylglyoxal is very rapid in vivo and thus notoriously difficult to detect and quantify. Here we show that 13C nuclei in labeled methylglyoxal can be hyperpolarized using dynamic nuclear polarization, providing 13C nuclear magnetic resonance signal enhancements in the solution state close to 5,000-fold. We demonstrate the applications of this probe of metabolism for kinetic characterization of the glyoxalase system in isolated cells as well as mouse brain, liver and lymphoma in vivo. Shishmarev et al. use rapid dissolution dynamic nuclear polarization to monitor glyoxalase activity in a non-invasive manner using nuclear magnetic resonance spectroscopy. They apply their method to monitor and quantify metabolism of methylglyoxal in human red blood cells and mouse tissues. [ABSTRACT FROM AUTHOR]

Hyperpolarized MRI with 13C‐labeled metabolites has enabled metabolic imaging of tumors in vivo. The heterogeneous nature of tumors and the limited lifetime of the hyperpolarization require high resolution, both temporally and spatially. We describe two sequences that make more efficient use of the 13C polarization than previously described single‐shot 3D sequences. With these sequences, the target metabolite resonances were excited using spectral‐spatial pulses and the data acquired using spiral readouts from a series of echoes created using a fast‐spin‐echo sequence employing adiabatic 180° pulses. The third dimension was encoded with blipped gradients applied in an interleaved order to the echo train. Adiabatic inversion pulses applied in the absence of slice selection gradients allowed acquisition of signal from odd echoes, formed by unpaired adiabatic pulses, as well as from even echoes. The sequences were tested on tumor‐bearing mice following intravenous injection of hyperpolarized [1‐13C]pyruvate. [1‐13C] pyruvate and [1‐13C] lactate images were acquired in vivo with a 4 × 4 × 2 cm3 field of view and a 32 × 32 × 16 matrix, leading to a nominal resolution of 1.25 × 1.25 × 1.25 mm3 and an effective resolution of 1.25 × 1.25 × 4.5 mm3 when the z‐direction point spread function was taken into account. The acquisition of signal from more echoes also allowed for an improvement in the signal‐to‐noise ratio for resonances with longer T2 relaxation times. The pulse sequences described here produced hyperpolarized 13C images with improved resolution and signal‐to‐noise ratio when compared with similar sequences described previously. We describe two pulse sequences that make more efficient use of 13C hyperpolarization than similar sequences described previously. The sequences excite target metabolites using spectral‐spatial pulses and acquire data using spiral readouts from a series of fast spin echoes formed by adiabatic 180° pulses and that encode the third dimension with blipped gradients in an interleaved order. The adiabatic 180° pulses were applied without slice selection gradients, allowing signal acquisition from both odd and even echoes. [ABSTRACT FROM AUTHOR]

PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER + breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized 13 C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[ 18 F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance., Competing Interests: Declaration of Interests The hyperpolarizer is on loan from GE Healthcare (GEH) and is the subject of a research agreement between the University of Cambridge, Cancer Research UK, and GEH. K.M.B holds patents with GEH on some aspects of deoxyribonucleoprotein (DNP) technology and is a consultant for Sotio a.s. C.C. reports receiving speakers' bureau honoraria from Illumina, is a member of the AstraZeneca (AZ) External Science Panel, and has research grants from Roche, Genentech, AZ, and Servier that are administered by the University of Cambridge. R.D.B reports receiving speakers’ bureau honoraria from Novartis and Roche/Genentech; commercial research grants from Genentech, AZ, and Boehringer-Ingelheim; and commercial research support from AZ. M.O. reports receiving speakers' bureau honoraria from Roche and is a consultant/advisory board member for Roche, GlaxoSmithKline, and Puma Biotechnology. S.C.L. is an advisory board member for AZ, Cergentis, IBM, Pfizer, and Roche and received institutional research support from Agendia, AZ, Eurocept Pharmaceuticals, Genentech, Novartis, Pfizer, Roche, Tesaro, and Immunomedics. In addition, S.C.L. received institutional non-financial support from Genentech, Novartis, Roche, Tesaro, and Immunomedics and other institutional support from AZ, Pfizer, Cergentis, IBM, and Bayer outside of this study. P.R. has received consultation fees from Novartis, AZ, and Foundation Medicine and institutional research funds from Grail Inc, Novartis, and Illumina. M.S. has received research funds from Puma Biotechnology, Daiichi-Sankio, Immunomedics, Targimmune, and Menarini Ricerche; is a cofounder of Medendi Medical Travel; and serves on the advisory board of Menarini Ricerche., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Dynamic magnetic resonance spectroscopic imaging of hyperpolarized 13 C-labeled cell substrates has enabled the investigation of tissue metabolism in vivo. Currently observation of these hyperpolarized substrates is limited mainly to 13 C detection. We describe here an imaging pulse sequence that enables proton observation by using polarization transfer from the hyperpolarized 13 C nucleus to spin-coupled protons., Methods: The pulse sequence transfers 13 C hyperpolarization to 1 H using a modified reverse insensitive nuclei enhanced by polarization transfer (INEPT) sequence that acquires a fully refocused echo. The resulting hyperpolarized 1 H signal is acquired using a 2D echo-planar trajectory. The efficiency of polarization transfer was investigated using simulations with and without T 1 and T 2 relaxation of both the 1 H and 13 C nuclei., Results: Simulations showed that 1 H detection of the hyperpolarized 13 C nucleus in lactate should increase significantly the signal-to-noise ratio when compared with direct 13 C detection at 3T. However the advantage of 1 H detection is expected to disappear at higher fields. Dynamic 1 H images of hyperpolarized [1- 13 C]lactate, with a spatial resolution of 1.25 × 1.25 mm 2 , were acquired from a phantom injected with hyperpolarized [1- 13 C]lactate and from tumors in vivo following injection of hyperpolarized [1- 13 C]pyruvate., Conclusions: The sequence allows 1 H imaging of hyperpolarized 13 C-labeled substrates in vivo. Magn Reson Med 79:741-747, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., (© 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Single-shot echo planar imaging (EPI), which allows an image to be acquired using a single excitation pulse, is used widely for imaging the metabolism of hyperpolarized 13 C-labelled metabolites in vivo as the technique is rapid and minimizes the depletion of the hyperpolarized signal. However, EPI suffers from Nyquist ghosting, which normally is corrected for by acquiring a reference scan. In a dynamic acquisition of a series of images, this results in the sacrifice of a time point if the reference scan involves a full readout train with no phase encoding. This time penalty is negligible if an integrated navigator echo is used, but at the cost of a lower signal-to-noise ratio (SNR) as a result of prolonged T 2 * decay. We describe here a workflow for hyperpolarized 13 C EPI that requires no reference scan. This involves the selection of a ghost-containing background from a 13 C image of a single metabolite at a single time point, the identification of phase correction coefficients that minimize signal in the selected area, and the application of these coefficients to images acquired at all time points and from all metabolites. The workflow was compared in phantom experiments with phase correction using a 13 C reference scan, and yielded similar results in situations with a regular field of view (FOV), a restricted FOV and where there were multiple signal sources. When compared with alternative phase correction methods, the workflow showed an SNR benefit relative to integrated 13 C reference echoes (>15%) or better ghost removal relative to a 1 H reference scan. The residual ghosting in a slightly de-shimmed B 0 field was 1.6% using the proposed workflow and 3.8% using a 1 H reference scan. The workflow was implemented with a series of dynamically acquired hyperpolarized [1- 13 C]pyruvate and [1- 13 C]lactate images in vivo, resulting in images with no observable ghosting and which were quantitatively similar to images corrected using a 13 C reference scan., (© 2017 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

The 'omics revolution is facilitating a personalized approach to improving outcome by refining diagnosis, staging, treatment, and monitoring of hepatocellular carcinoma. Furthermore, the promise of being able to target a range of specific tumor drivers at a molecular level offers exciting new therapy prospects for a disease that is notoriously difficult to treat. We provide a unique perspective combining our understanding of the molecular mechanisms of hepatocellular carcinoma development with the potential of circulating tumor cells and radiogenomics to change the drivers of decision-making used in current practice.