Deuterium MRI of serine metabolism in mouse models of glioblastoma.

Purpose: Serine is a major source of one-carbon units needed for the synthesis of nucleotides and the production of intramitochondrial nicotinamide adenine dinucleotide phosphate (NADPH), and it plays an important role in cancer cell proliferation. The aim of this study was to develop a deuterium (H) MRS imaging method for imaging tumor serine metabolism.

Methods: Sequential (H) spectra and spectroscopic images were used to monitor the metabolism of [2,3,3-H]serine in patient-derived glioblastoma cells in vitro and in tumors obtained by their orthotopic implantation in mouse brain.

Deuterium Metabolic Imaging Differentiates Glioblastoma Metabolic Subtypes and Detects Early Response to Chemoradiotherapy.

Unlabelled: Metabolic subtypes of glioblastoma (GBM) have different prognoses and responses to treatment. Deuterium metabolic imaging with 2H-labeled substrates is a potential approach to stratify patients into metabolic subtypes for targeted treatment. In this study, we used 2H magnetic resonance spectroscopy and magnetic resonance spectroscopic imaging (MRSI) measurements of [6,6'-2H2]glucose metabolism to identify metabolic subtypes and their responses to chemoradiotherapy in patient-derived GBM xenografts in vivo.

Metabolic imaging with deuterium labeled substrates.

Deuterium metabolic imaging (DMI) is an emerging clinically-applicable technique for the non-invasive investigation of tissue metabolism. The generally short T values of H-labeled metabolites in vivo can compensate for the relatively low sensitivity of detection by allowing rapid signal acquisition in the absence of significant signal saturation. Studies with deuterated substrates, including [6,6'-H]glucose, [H]acetate, [H]choline and [2,3-H]fumarate have demonstrated the considerable potential of DMI for imaging tissue metabolism and cell death in vivo.

Imaging Glioblastoma Response to Radiotherapy Using 2H Magnetic Resonance Spectroscopy Measurements of Fumarate Metabolism.

Unlabelled: Early detection of tumor cell death in glioblastoma following treatment with chemoradiation has the potential to distinguish between true disease progression and pseudoprogression. Tumor cell death can be detected noninvasively in vivo by imaging the production of [2,3-2H2]malate from [2,3-2H2]fumarate using 2H magnetic resonance (MR) spectroscopic imaging. We show here that 2H MR spectroscopy and spectroscopic imaging measurements of [2,3-2H2]fumarate metabolism can detect tumor cell death in orthotopically implanted glioblastoma models within 48 hours following the completion of chemoradiation.

Deuterium MRSI of tumor cell death in vivo following oral delivery of H-labeled fumarate.

Purpose: There is an unmet clinical need for direct and sensitive methods to detect cell death in vivo, especially with regard to monitoring tumor treatment response. We have shown previously that tumor cell death can be detected in vivo from H MRS and MRSI measurements of increased [2,3- H ]malate production following intravenous injection of [2,3- H ]fumarate. We show here that cell death can be detected with similar sensitivity following oral administration of the H-labeled fumarate.

Prediction of recurrence from metabolites and expression of TOP2A and EZH2 in prostate cancer patients treated with radiotherapy.

Background: The dual upregulation of TOP2A and EZH2 gene expression has been proposed as a biomarker for recurrence in prostate cancer patients to be treated with radical prostatectomy. A low tissue level of the metabolite citrate has additionally been connected to aggressive disease and recurrence in this patient group. However, for radiotherapy prostate cancer patients, few prognostic biomarkers have been suggested.

Genetic algorithm-based optimization of pulse sequences.

Purpose: The performance of pulse sequences in vivo can be limited by fast relaxation rates, magnetic field inhomogeneity, and nonuniform spin excitation. We describe here a method for pulse sequence optimization that uses a stochastic numerical solver that in principle is capable of finding a global optimum. The method provides a simple framework for incorporating any constraint and implementing arbitrarily complex cost functions.

Absolute choline tissue concentration mapping for prostate cancer localization and characterization using 3D H MRSI without water-signal suppression.

Purpose: Until now, H MRSI of the prostate has been performed with suppression of the large water signal to avoid distortions of metabolite signals. However, this signal can be used for absolute quantification and spectral corrections. We investigated the feasibility of water-unsuppressed MRSI in patients with prostate cancer for water signal-mediated spectral quality improvement and determination of absolute tissue levels of choline.

Metabolic imaging with hyperpolarized [1-C] pyruvate in patient-derived preclinical mouse models of breast cancer.

C nuclear spin hyperpolarization can increase the sensitivity of detection in an MRI experiment by more than 10,000-fold. C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized C label exchange between injected [1-C]pyruvate and the endogenous tumor lactate pool can be used clinically to assess tumor grade and response to treatment. We describe here an experimental protocol for using this technique in patient-derived and established cell line xenograft models of breast cancer in the mouse.

Monitoring tumor cell death in murine tumor models using deuterium magnetic resonance spectroscopy and spectroscopic imaging.

H magnetic resonance spectroscopic imaging has been shown recently to be a viable technique for metabolic imaging in the clinic. We show here that H MR spectroscopy and spectroscopic imaging measurements of [2,3-H]malate production from [2,3-H]fumarate can be used to detect tumor cell death in vivo via the production of labeled malate. Production of [2,3-H]malate, following injection of [2,3-H]fumarate (1 g/kg) into tumor-bearing mice, was measured in a murine lymphoma (EL4) treated with etoposide, and in human breast (MDA-MB-231) and colorectal (Colo205) xenografts treated with a TRAILR2 agonist, using surface-coil localized H MR spectroscopy at 7 T.

Comparison of C MRI of hyperpolarized [1- C]pyruvate and lactate with the corresponding mass spectrometry images in a murine lymphoma model.

Purpose: To compare carbon-13 ( C) MRSI of hyperpolarized [1- C]pyruvate metabolism in a murine tumor model with mass spectrometric (MS) imaging of the corresponding tumor sections in order to cross validate these metabolic imaging techniques and to investigate the effects of pyruvate delivery and tumor lactate concentration on lactate labeling.

Methods: [1- C]lactate images were obtained from tumor-bearing mice, following injection of hyperpolarized [1- C]pyruvate, using a single-shot 3D C spectroscopic imaging sequence in vivo and using desorption electrospray ionization MS imaging of the corresponding rapidly frozen tumor sections ex vivo. The images were coregistered, and levels of association were determined by means of Spearman rank correlation and Cohen kappa coefficients as well as linear mixed models.

Multi-task convolutional neural network-based design of radio frequency pulse and the accompanying gradients for magnetic resonance imaging.

Modern MRI systems usually load the predesigned RFs and the accompanying gradients during clinical scans, with minimal adaption to the specific requirements of each scan. Here, we describe a neural network-based method for real-time design of excitation RF pulses and the accompanying gradients' waveforms to achieve spatially two-dimensional selectivity. Nine thousand sets of radio frequency (RF) and gradient waveforms with two-dimensional spatial selectivity were generated as the training dataset using the Shinnar-Le Roux (SLR) method.

Probing complex geophysical geometries with chattering dust.

The modern energy economy and environmental infrastructure rely on the flow of fluids through fractures in rock. Yet this flow cannot be imaged directly because rocks are opaque to most probes. Here we apply chattering dust, or chemically reactive grains of sucrose containing pockets of pressurized carbon dioxide, to study rock fractures.

Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER Breast Cancer.

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.

Probing hepatic metabolism of [2-C]dihydroxyacetone in vivo with H-decoupled hyperpolarized C-MR.

Objectives: To enhance detection of the products of hyperpolarized [2-C]dihydroxyacetone metabolism for assessment of three metabolic pathways in the liver in vivo. Hyperpolarized [2-C]DHAc emerged as a promising substrate to follow gluconeogenesis, glycolysis and the glycerol pathways. However, the use of [2-C]DHAc in vivo has not taken off because (i) the chemical shift range of [2-C]DHAc and its metabolic products span over 144 ppm, and (ii) H decoupling is required to increase spectral resolution and sensitivity.

A multi spin echo pulse sequence with optimized excitation pulses and a 3D cone readout for hyperpolarized C imaging.

Purpose: Imaging tumor metabolism in vivo using hyperpolarized [1- C]pyruvate is a promising technique for detecting disease, monitoring disease progression, and assessing treatment response. However, the transient nature of the hyperpolarization and its depletion following excitation limits the available time for imaging. We describe here a single-shot multi spin echo sequence, which improves on previously reported sequences, with a shorter readout time, isotropic point spread function (PSF), and better signal-to-noise ratio.

Increasing the sensitivity of hyperpolarized [ N ]urea detection by serial transfer of polarization to spin-coupled protons.

Purpose: Hyperpolarized N-labeled molecules have been proposed as imaging agents for investigating tissue perfusion and pH. However, the sensitivity of direct N detection is limited by the isotope's low gyromagnetic ratio. Sensitivity can be increased by transferring N hyperpolarization to spin-coupled protons provided that there is not significant polarization loss during transfer.

Measuring Tumor Glycolytic Flux in Vivo by Using Fast Deuterium MRI.

Background Tumor cells frequently show high rates of aerobic glycolysis, which provides the glycolytic intermediates needed for the increased biosynthetic demands of rapid cell growth and proliferation. Existing clinical methods (fluorodeoxyglucose PET and carbon 13 MRI and spectroscopy) do not allow quantitative images of glycolytic flux. Purpose To evaluate the use of deuterium (hydrogen 2 [H]) MR spectroscopic imaging for quantitative mapping of tumor glycolytic flux and to assess response to chemotherapy.

Author Correction: MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death-Dependent Changes in Glycolysis.

Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here, we assess the abilities of PET measurement of [F]FDG uptake and MRI measurement of hyperpolarized [1-C]pyruvate metabolism to detect early changes in glycolysis following treatment-induced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death.

A Single-Arm, Multicenter Validation Study of Prostate Cancer Localization and Aggressiveness With a Quantitative Multiparametric Magnetic Resonance Imaging Approach.

Objectives: The aims of this study were to assess the discriminative performance of quantitative multiparametric magnetic resonance imaging (mpMRI) between prostate cancer and noncancer tissues and between tumor grade groups (GGs) in a multicenter, single-vendor study, and to investigate to what extent site-specific differences affect variations in mpMRI parameters.

Materials And Methods: Fifty patients with biopsy-proven prostate cancer from 5 institutions underwent a standardized preoperative mpMRI protocol. Based on the evaluation of whole-mount histopathology sections, regions of interest were placed on axial T2-weighed MRI scans in cancer and noncancer peripheral zone (PZ) and transition zone (TZ) tissue.

Glyoxalase activity in human erythrocytes and mouse lymphoma, liver and brain probed with hyperpolarized C-methylglyoxal.

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.

Levels of choline-containing compounds in normal liver and liver metastases of colorectal cancer as recorded by H MRS.

Purpose: A relatively high signal for choline-containing compounds (total choline, tCho) is commonly found in H MR spectra of malignant tumors, but it is unclear if this also occurs in tumors in the liver. We evaluated the potential of the tCho signal in single voxel H MR spectra of the human liver to assess metastases of colorectal cancers.

Experiment: MR spectra of an 8 cm PRESS-localized voxel were obtained at 3 T from the livers of 12 healthy volunteers and from metastatic lesions in 20 patients in two different sessions.