Deuterium metabolic imaging differentiates glioblastoma metabolic subtypes and detects early response to chemoradiotherapy.

Metabolic subtypes of glioblastoma 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. Here, we used 2H magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) measurements of [6,6'-2H2]glucose metabolism to identify metabolic subtypes and their responses to chemoradiotherapy in patient-derived glioblastoma xenografts in vivo. The metabolism of patient-derived cells was first characterized in vitro by measuring the oxygen consumption rate, a marker of mitochondrial TCA cycle activity, as well as the extracellular acidification rate and 2H-labeled lactate production from [6,6'-2H2]glucose, which are markers of glycolytic activity. Two cell lines representative of a glycolytic subtype and two representative of a mitochondrial subtype were identified. 2H MRS and MRSI measurements showed similar concentrations of 2H-labeled glucose from [6,6'-2H2]glucose in all four tumor models when implanted orthotopically in mice. The glycolytic subtypes showed higher concentrations of 2H-labeled lactate than the mitochondrial subtypes and normal-appearing brain tissue, whereas the mitochondrial subtypes showed more glutamate/glutamine labeling, a surrogate for TCA cycle activity, than the glycolytic subtypes and normal-appearing brain tissue. The response of the tumors to chemoradiation could be detected within 24 hours of treatment completion, with the mitochondrial subtypes showing a decrease in both 2H-labeled glutamate/glutamine and lactate concentrations and glycolytic tumors showing a decrease in 2H-labeled lactate concentration. This technique has the potential to be used clinically for treatment selection and early detection of treatment response.

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 T1 values of 2H-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'-2H2]glucose, [2H3]acetate, [2H9]choline and [2,3-2H2]fumarate have demonstrated the considerable potential of DMI for imaging tissue metabolism and cell death in vivo. The technique is evaluated here in comparison with established metabolic imaging techniques, including PET measurements of 2-deoxy-2-[18F]fluoro-d-glucose (FDG) uptake and 13C MR imaging of the metabolism of hyperpolarized 13C-labeled substrates.

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. The main aim of this study was to use an integrated tissue analysis to evaluate metabolites and expression of TOP2A and EZH2 as predictors for recurrence among radiotherapy patients. METHODS: From 90 prostate cancer patients (56 received neoadjuvant hormonal treatment), 172 transrectal ultrasound-guided (TRUS) biopsies were collected prior to radiotherapy. Metabolic profiles were acquired from fresh frozen TRUS biopsies using high resolution-magic angle spinning MRS. Histopathology and immunohistochemistry staining for TOP2A and EZH2 were performed on TRUS biopsies containing cancer cells (n = 65) from 46 patients, where 24 of these patients (n = 31 samples) received hormonal treatment. Eleven radical prostatectomy cohorts of a total of 2059 patients were used for validation in a meta-analysis. RESULTS: Among radiotherapy patients with up to 11 years of follow-up, a low level of citrate was found to predict recurrence, p = 0.001 (C-index = 0.74). Citrate had a higher predictive ability compared with individual clinical variables, highlighting its strength as a potential biomarker for recurrence. The dual upregulation of TOP2A and EZH2 was suggested as a biomarker for recurrence, particularly for patients not receiving neoadjuvant hormonal treatment, p = 0.001 (C-index = 0.84). While citrate was a statistically significant biomarker independent of hormonal treatment status, the current study indicated a potential of glutamine, glutamate and choline as biomarkers for recurrence among patients receiving neoadjuvant hormonal treatment, and glucose among patients not receiving neoadjuvant hormonal treatment. CONCLUSION: Using an integrated approach, our study shows the potential of citrate and the dual upregulation of TOP2A and EZH2 as biomarkers for recurrence among radiotherapy patients.

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

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. Following the injection of [2,3-2H2]fumarate into tumor-bearing mice, production of [2,3-2H2]malate was measured in a human cell line-derived model and in radiosensitive and radioresistant patient-derived models of glioblastoma that were treated with temozolomide followed by targeted fractionated irradiation. The increase in the [2,3-2H2]malate/[2,3-2H2]fumarate signal ratio posttreatment, which correlated with histologic assessment of cell death, was a more sensitive indicator of treatment response than diffusion-weighted and contrast agent-enhanced 1H MRI measurements, which have been used clinically to detect responses of glioblastoma to chemoradiation. Overall, early detection of glioblastoma cell death using 2H MRI of malate production from fumarate could help improve the clinical evaluation of response to chemoradiation. SIGNIFICANCE: 2H magnetic resonance imaging of labeled fumarate metabolism can detect early evidence of tumor cell death following chemoradiation, meeting a clinical need to reliably detect treatment response in glioblastoma.

Deuterium MRSI of tumor cell death in vivo following oral delivery of 2 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 2 H MRS and MRSI measurements of increased [2,3-2 H2 ]malate production following intravenous injection of [2,3-2 H2 ]fumarate. We show here that cell death can be detected with similar sensitivity following oral administration of the 2 H-labeled fumarate. METHODS: Mice with subcutaneously implanted EL4 tumors were fasted for 1 h before administration (200 µl) of [2,3-2 H2 ]fumarate (2 g/kg bodyweight) via oral gavage without anesthesia. The animals were then anesthetized, and after 30 min, tumor conversion of [2,3-2 H2 ]fumarate to [2,3-2 H2 ]malate was assessed from a series of 13 2 H spectra acquired over a period of 65 min. The 2 H spectra and 2 H spectroscopic images were acquired using a surface coil before and at 48 h after treatment with a chemotherapeutic drug (etoposide, 67 mg/kg). RESULTS: The malate/fumarate signal ratio increased from 0.022 ± 0.03 before drug treatment to 0.12 ± 0.04 following treatment (p = 0.023, n = 4). Labeled malate was undetectable in spectroscopic images acquired before treatment and increased in the tumor area following treatment. The increase in the malate/fumarate signal ratio was similar to that observed previously following intravenous administration of labeled fumarate. CONCLUSION: Orally administered [2,3-2 H2 ]fumarate can be used to detect tumor cell death noninvasively following treatment with a sensitivity that is similar to that obtained with intravenous administration.

Absolute choline tissue concentration mapping for prostate cancer localization and characterization using 3D 1 H MRSI without water-signal suppression.

PURPOSE: Until now, 1 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. METHODS: Eight prostate cancer patients scheduled for radical prostatectomy underwent multi-parametric MRI at 3 T, including 3D water-unsuppressed semi-LASER MRSI. A postprocessing algorithm was developed to remove the water signal and its artifacts and use the extracted water signal as intravoxel reference for phase and frequency correction of metabolite signals and for absolute metabolite quantification. RESULTS: Water-unsuppressed MRSI with dedicated postprocessing produced water signal and artifact-free MR spectra throughout the prostate. In all patients, the absolute choline tissue concentration was significantly higher in tumorous than in benign tissue areas (mean ± SD: 7.2 ± 1.4 vs 3.8 ± 0.7 mM), facilitating tumor localization by choline mapping. Tumor tissue levels of choline correlated better with the commonly used (choline + spermine + creatine)/citrate ratio (r = 0.78 ± 0.1) than that of citrate (r = 0.21 ± 0.06). The highest maximum choline concentrations occurred in high-risk cancer foci. CONCLUSION: This report presents the first successful water-unsuppressed MRSI of the whole prostate. The water signal enabled amelioration of spectral quality and absolute metabolite quantification. In this way, choline tissue levels were identified as tumor biomarker. Choline mapping may serve as a tool in prostate cancer localization and risk scoring in multi-parametric MRI for diagnosis and biopsy procedures.

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. Efficient methods for simulating spin dynamics and incorporating frequency selectivity are also described. METHODS: Optimized pulse sequences for polarization transfer between protons and X-nuclei and excitation pulses that eliminate J-coupling modulation were evaluated experimentally using a surface coil on phantoms, and also the detection of hyperpolarized [2-13 C]lactate in vivo in the case of J-coupling modulation-free excitation. RESULTS: The optimized polarization transfer pulses improved the SNR by ~50% with a more than twofold reduction in the B1 field, and J-coupling modulation-free excitation was achieved with a more than threefold reduction in pulse length. CONCLUSION: This process could be used to optimize any pulse when there is a need to improve the uniformity and frequency selectivity of excitation as well as to design new pulses to steer the spin system to any desired achievable state.

Metabolic imaging with hyperpolarized [1-13C] pyruvate in patient-derived preclinical mouse models of breast cancer.

13C nuclear spin hyperpolarization can increase the sensitivity of detection in an MRI experiment by more than 10,000-fold. 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]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. For complete details on the use and execution of this protocol, please refer to Ros et al. (2020).

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

2H magnetic resonance spectroscopic imaging has been shown recently to be a viable technique for metabolic imaging in the clinic. We show here that 2H MR spectroscopy and spectroscopic imaging measurements of [2,3-2H2]malate production from [2,3-2H2]fumarate can be used to detect tumor cell death in vivo via the production of labeled malate. Production of [2,3-2H2]malate, following injection of [2,3-2H2]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 2H MR spectroscopy at 7 T. Malate production was also imaged in EL4 tumors using a fast 2H chemical shift imaging sequence. The malate/fumarate ratio increased from 0.016 ± 0.02 to 0.16 ± 0.14 in EL4 tumors 48 h after drug treatment (P = 0.0024, n = 3), and from 0.019 ± 0.03 to 0.25 ± 0.23 in MDA-MB-231 tumors (P = 0.0001, n = 5) and from 0.016 ± 0.04 to 0.28 ± 0.26 in Colo205 tumors (P = 0.0002, n = 5) 24 h after drug treatment. These increases were correlated with increased levels of cell death measured in excised tumor sections obtained immediately after imaging. 2H MR measurements of [2,3-2H2]malate production from [2,3-2H2]fumarate provide a potentially less expensive and more sensitive method for detecting cell death in vivo than 13C MR measurements of hyperpolarized [1,4-13C2]fumarate metabolism, which have been used previously for this purpose.

Comparison of 13 C MRI of hyperpolarized [1-13 C]pyruvate and lactate with the corresponding mass spectrometry images in a murine lymphoma model.

PURPOSE: To compare carbon-13 (13 C) MRSI of hyperpolarized [1-13 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: [1-13 C]lactate images were obtained from tumor-bearing mice, following injection of hyperpolarized [1-13 C]pyruvate, using a single-shot 3D 13 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. The correlation between [1-13 C]pyruvate and [1-13 C]lactate in the MRS images and between [12 C] and [1-13 C]lactate in the MS images were determined by means of Pearson correlation coefficients. RESULTS: [1-13 C]lactate images generated by MS imaging were significantly correlated with the corresponding MRS images. The correlation coefficient between [1-13 C]lactate and [1-13 C]pyruvate in the MRS images was higher than between [1-13 C]lactate and [12 C]lactate in the MS images. CONCLUSION: The inhomogeneous distribution of labeled lactate observed in the MRS images was confirmed by MS imaging of the corresponding tumor sections. The images acquired using both techniques show that the rate of 13 C label exchange between the injected pyruvate and endogenous tumor lactate pool is more correlated with the rate of pyruvate delivery to the tumor cells and is less affected by the endogenous lactate concentration.

Probing hepatic metabolism of [2-13C]dihydroxyacetone in vivo with 1H-decoupled hyperpolarized 13C-MR.

OBJECTIVES: To enhance detection of the products of hyperpolarized [2-13C]dihydroxyacetone metabolism for assessment of three metabolic pathways in the liver in vivo. Hyperpolarized [2-13C]DHAc emerged as a promising substrate to follow gluconeogenesis, glycolysis and the glycerol pathways. However, the use of [2-13C]DHAc in vivo has not taken off because (i) the chemical shift range of [2-13C]DHAc and its metabolic products span over 144 ppm, and (ii) 1H decoupling is required to increase spectral resolution and sensitivity. While these issues are trivial for high-field vertical-bore NMR spectrometers, horizontal-bore small-animal MR scanners are seldom equipped for such experiments. METHODS: Real-time hepatic metabolism of three fed mice was probed by 1H-decoupled 13C-MR following injection of hyperpolarized [2-13C]DHAc. The spectra of [2-13C]DHAc and its metabolic products were acquired in a 7 T small-animal MR scanner using three purpose-designed spectral-spatial radiofrequency pulses that excited a spatial bandwidth of 8 mm with varying spectral bandwidths and central frequencies (chemical shifts). RESULTS: The metabolic products detected in vivo include glycerol 3-phosphate, glycerol, phosphoenolpyruvate, lactate, alanine, glyceraldehyde 3-phosphate and glucose 6-phosphate. The metabolite-to-substrate ratios were comparable to those reported previously in perfused liver. DISCUSSION: Three metabolic pathways can be probed simultaneously in the mouse liver in vivo, in real time,  using hyperpolarized DHAc.

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. Neural networks were created and trained with five strategies (TS-1 to TS-5). The neural network-designed RF and gradients were compared with their SLR-designed counterparts and underwent Bloch simulation and phantom imaging to investigate their performances in spin manipulations. We demonstrate a convolutional neural network (TS-5) with multi-task learning to yield both the RF pulses and the accompanying two channels of gradient waveforms that comply with the SLR design, and these design results also provide excitation spatial profiles comparable with SLR pulses in both simulation (normalized root mean square error [NRMSE] of 0.0075 ± 0.0038 over the 400 sets of testing data between TS-5 and SLR) and phantom imaging. The output RF and gradient waveforms between the neural network and SLR methods were also compared, and the joint NRMSE, with both RF and the two channels of gradient waveforms considered, was 0.0098 ± 0.0024 between TS-5 and SLR. The RF and gradients were generated on a commercially available workstation, which took ~130 ms for TS-5. In conclusion, we present a convolutional neural network with multi-task learning, trained with SLR transformation pairs, that is capable of simultaneously generating RF and two channels of gradient waveforms, given the desired spatially two-dimensional excitation profiles.

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. As a dust grain dissolves, the pockets burst and emit acoustic signals that are detected by distributed sets of external ultrasonic sensors that track the dust movement through fracture systems. The dust particles travel through locally varying fracture apertures with varying speeds and provide information about internal fracture geometry, flow paths and bottlenecks. Chattering dust particles have an advantage over chemical sensors because they do not need to be collected, and over passive tracers because the chattering dust delineates the transport path. The current laboratory work has potential to scale up to near-borehole applications in the field.

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. 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 13C 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-[18F]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.

A multi spin echo pulse sequence with optimized excitation pulses and a 3D cone readout for hyperpolarized 13 C imaging.

PURPOSE: Imaging tumor metabolism in vivo using hyperpolarized [1-13 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. METHODS: The sequence uses numerically optimized spectrally selective excitation pulses set to the resonant frequencies of pyruvate and lactate and a hyperbolic secant adiabatic refocusing pulse, all applied in the absence of slice selection gradients. The excitation pulses were designed to be resistant to the effects of B0 and B1 field inhomogeneity. The gradient readout uses a 3D cone trajectory composed of 13 cones, all fully refocused and distributed among 7 spin echoes. The maximal gradient amplitude and slew rate were set to 4 G/cm and 20 G/cm/ms, respectively, to demonstrate the feasibility of clinical translation. RESULTS: The pulse sequence gave an isotropic PSF of 2.8 mm. The excitation profiles of the optimized pulses closely matched simulations and a 46.10 ± 0.04% gain in image SNR was observed compared to a conventional Shinnar-Le Roux excitation pulse. The sequence was demonstrated with dynamic imaging of hyperpolarized [1-13 C]pyruvate and [1-13 C]lactate in vivo. CONCLUSION: The pulse sequence was capable of dynamic imaging of hyperpolarized 13 C labeled metabolites in vivo with relatively high spatial and temporal resolution and immunity to system imperfections.

Increasing the sensitivity of hyperpolarized [15 N2 ]urea detection by serial transfer of polarization to spin-coupled protons.

PURPOSE: Hyperpolarized 15 N-labeled molecules have been proposed as imaging agents for investigating tissue perfusion and pH. However, the sensitivity of direct 15 N detection is limited by the isotope's low gyromagnetic ratio. Sensitivity can be increased by transferring 15 N hyperpolarization to spin-coupled protons provided that there is not significant polarization loss during transfer. However, complete polarization transfer would limit the temporal window for imaging to the order of the proton T1 (2-3 s). To exploit the long T1 offered by storing polarization in 15 N and the higher sensitivity of 1 H detection, we have developed a pulse sequence for partial polarization transfer. METHODS: A polarization transfer pulse sequence was modified to allow partial polarization transfer, as is required for dynamic measurements, and that can be implemented with inhomogeneous B1 fields, as is often the case in vivo. The sequence was demonstrated with dynamic spectroscopy and imaging measurements with [15 N2 ]urea. RESULTS: When compared to direct 15 N detection, the sequence increased the signal-to-noise ratio (SNR) by a factor of 1.72 ± 0.25, where both experiments depleted ~20% of the hyperpolarization (>10-fold when 100% of the hyperpolarization is used). Simulations with measured cross relaxation rates showed that this sequence gave up to a 50-fold increase in urea proton polarization when compared to spontaneous polarization transfer via cross relaxation. CONCLUSION: The sequence gave an SNR increase that was close to the theoretical limit and can give a significant SNR benefit when compared to direct 13 C detection of hyperpolarized [13 C]urea.

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 [2H]) MR spectroscopic imaging for quantitative mapping of tumor glycolytic flux and to assess response to chemotherapy. Materials and Methods A fast three-dimensional 2H MR spectroscopic imaging pulse sequence, with a time resolution of 10 minutes, was used to image glycolytic flux in a murine tumor model after bolus injection of D-[6,6'-2H2]glucose before and 48 hours after treatment with a chemotherapeutic agent. Tumor lactate labeling, expressed as the lactate-to-water and lactate-to-glucose signal ratios, was also assessed in localized 2H MR spectra. Statistical significance was tested with a one-sided paired t test. Results 2H MR spectroscopic imaging showed heterogeneity in glycolytic flux across the tumor and an early decrease in flux following treatment with a chemotherapeutic drug. Spectroscopy measurements on five animals showed a decrease in the lactate-to-water signal ratio, from 0.33 ± 0.10 to 0.089 ± 0.039 (P = .005), and in the lactate-to-glucose ratio, from 0.27 ± 0.12 to 0.12 ± 0.06 (P = .04), following drug treatment. Conclusion Rapidly acquired deuterium (hydrogen 2) MR spectroscopic images can provide quantitative and spatially resolved measurements of glycolytic flux in tumors that can be used to assess treatment response. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Ouwerkerk in this issue.

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 [18F]FDG uptake and MRI measurement of hyperpolarized [1-13C]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. Tumor glycolysis was assessed by injecting [1,6-13C2]glucose and measuring 13C-labeled metabolites in tumor extracts. Injection of hyperpolarized [1-13C]pyruvate induced rapid reduction in lactate labeling. This decrease, which correlated with an increase in histologic markers of cell death and preceded decrease in tumor volume, reflected reduced flux from glucose to lactate and decreased lactate concentration. However, [18F]FDG uptake and phosphorylation were maintained following treatment, which has been attributed previously to increased [18F]FDG uptake by infiltrating immune cells. Quantification of [18F]FDG uptake in flow-sorted tumor and immune cells from disaggregated tumors identified CD11b+/CD45+ macrophages as the most [18F]FDG-avid cell type present, yet they represented <5% of the cells present in the tumors and could not explain the failure of [18F]FDG-PET to detect treatment response. MRI measurement of hyperpolarized [1-13C]pyruvate metabolism is therefore a more sensitive marker of the early decreases in glycolytic flux that occur following cell death than PET measurements of [18F]FDG uptake. SIGNIFICANCE: These findings demonstrate superior sensitivity of MRI measurement of hyperpolarized [1-13C]pyruvate metabolism versus PET measurement of 18F-FDG uptake for detecting early changes in glycolysis following treatment-induced tumor cell death.