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) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response. Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors. http://cancerres.aacrjournals.org/content/canres/78/14/3755/F1.large.jpg .

Highlights d HP pyruvate can be safely infused multiple times and measures reproducible kinetics d Tumors with increased Gleason grades had increased levels of hyperpolarized lactate d Regions of high HP lactate correlated with elevated monocarboxylate transporter 1

Dissolution dynamic nuclear polarization (DNP) enables the metabolism of hyperpolarized 13C‐labelled molecules, such as the conversion of [1‐13C]pyruvate to [1‐13C]lactate, to be dynamically and non‐invasively imaged in tissue. Imaging of this exchange reaction in animal models has been shown to detect early treatment response and correlate with tumour grade. The first human DNP study has recently been completed, and, for widespread clinical translation, simple and reliable methods are necessary to accurately probe the reaction in patients. However, there is currently no consensus on the most appropriate method to quantify this exchange reaction. In this study, an in vitro system was used to compare several kinetic models, as well as simple model‐free methods. Experiments were performed using a clinical hyperpolarizer, a human 3 T MR system, and spectroscopic imaging sequences. The quantitative methods were compared in vivo by using subcutaneous breast tumours in rats to examine the effect of pyruvate inflow. The two‐way kinetic model was the most accurate method for characterizing the exchange reaction in vitro, and the incorporation of a Heaviside step inflow profile was best able to describe the in vivo data. The lactate time‐to‐peak and the lactate‐to‐pyruvate area under the curve ratio were simple model‐free approaches that accurately represented the full reaction, with the time‐to‐peak method performing indistinguishably from the best kinetic model. Finally, extracting data from a single pixel was a robust and reliable surrogate of the whole region of interest. This work has identified appropriate quantitative methods for future work in the analysis of human hyperpolarized 13C data. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

Purpose To deploy clinically, a combined parallel imaging compressed sensing method with coil compression that achieves a rapid image reconstruction, and assess its clinical performance in contrast-enhanced abdominal pediatric MRI. Materials and Methods With IRB approval and informed patient consent/assent, 29 consecutive pediatric patients were recruited. Dynamic contrast-enhanced MRI was acquired on a 3T scanner using a dedicated 32-channel pediatric coil and a 3D SPGR sequence, with pseudo-random undersampling at a high acceleration (R=7.2). Undersampled data were reconstructed with three methods: a traditional parallel imaging method and a combined parallel imaging compressed sensing method with and without coil compression. The three sets of images were evaluated independently and blindly by two radiologists at one siting, for overall image quality and delineation of anatomical structures. Wilcoxon tests were performed to test the hypothesis that there was no significant difference in the evaluations, and inter-observer agreement was analyzed. Results Fast reconstruction with coil compression did not deteriorate image quality. The mean score of structural delineation of the fast reconstruction was 4.1 on a 5-point scale, significantly better (P<0.05) than traditional parallel imaging (mean score 3.1). Fair to substantial inter-observer agreement was reached in structural delineation assessment. Conclusion A fast combined parallel imaging compressed sensing method is feasible in a pediatric clinical setting. Preliminary results suggest it may improve structural delineation over parallel imaging.

We report metabolic images of 13C, following injection of a bolus of of hyperpolarized [1-13C] pyruvate in a live rat. The data were acquired on a clinical scanner, using custom coils for volume transmission and array reception. Proton blocking of all carbon resonators enabled proton anatomic imaging with the system body coil, to allow for registration of anatomic and metabolic images, for which good correlation was achieved, with some anatomic features (kidney and heart) clearly visible in a carbon image, without reference to the corresponding proton image. Parallel imaging with sensitivity encoding was used to increase the spatial resolution in the SI direction of the rat. The signal to noise ratio in was in some instances unexpectedly high in the parallel images; variability of the polarization among different trials, plus partial volume effects, are noted as a possible cause of this.

Purpose MRI is increasingly used to scan pregnant patients. We investigated the effect of 3 Tesla (T) two-port radiofrequency (RF) shimming in anatomical pregnant women models. Theory and Methods RF shimming improves B1+ uniformity, but may at the same time significantly alter the induced current distribution and result in large changes in both the level and location of the absorbed RF energy. In this study, we evaluated the electrothermal exposure of pregnant women in the third, seventh, and ninth month of gestation at various imaging landmarks in RF body coils, including modes with RF shimming. Results Although RF shimmed configurations may lower the local RF exposure for the mother, they can increase the thermal load on the fetus. In worst-case configurations, whole-body exposure and local peak temperatures—up to 40.8°C—are equal in fetus and mother. Conclusions Two-port RF shimming can significantly increase the fetal exposure in pregnant women, requiring further research to derive a very robust safety management. For the time being, restriction to the CP mode, which reduces fetal SAR exposure compared with linear-horizontal polarization modes, may be advisable. Results from this study do not support scanning pregnant patients above the normal operating mode.

Hyperpolarised magnetic resonance imaging (HP 13C-MRI) is an emerging clinical technique to detect [1-13C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1-13C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1-13C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP 13C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1-13C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP 13C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments.