Junjie Ma¹, Craig R. Malloy^1,2,3, Crystal E. Harrison¹, James Ratnakar¹, Galen D. Reed⁴, Vlad G. Zaha^1,2, and Jae Mo Park^1,3,5
1Advanced Imaging Research Center, UT SOUTHWESTERN MEDICAL CENTER, Dallas, TX, United States, ²Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States, ³Radiology, UT Southwestern Medical Center, Dallas, TX, United States, ⁴GE Healthcare, Dallas, TX, United States, ⁵Electrical and Computer Engineering, UT Dallas, Richardson, TX, United States

A dual-phase ¹³C imaging sequence that acquires multi-echo images of hyperpolarized [1-¹³C]pyruvate, [1-¹³C]lactate, [1-¹³C]alanine and [¹³C]bicarbonate was implemented to acquire metabolic data at both end systole and end diastole from the human heart in a single injection. The proposed method was demonstrated in short-axis and long-axis ventricle views.

Travis Salzillo¹, Vimbai Mawoneke², Joseph Weygand², Akaanksh Shetty², Joy Gumin³, Niki Zacharias², Seth Gammon², David Piwnica-Worms², Gregory Fuller⁴, Christopher Logothetis⁵, Frederick Lang³, and Pratip Bhattacharya^2
1Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States, ²Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, United States, ³Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX, United States, ⁴Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, United States, ⁵Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States

Glioblastoma is an aggressive cancer with a median survival of 16 months. Thus, waiting for changes in tumor volume to determine prognosis is too slow to benefit the patient. In this study, we show that in vivo measurements of tumor metabolism with hyperpolarized magnetic resonance can detect changes more rapidly and reliably than conventional anatomic MRI throughout all stages of tumor progression. These data are supported through ex vivo metabolic profiling. Interpretation of these results demonstrate the value that hyperpolarized magnetic resonance can bring to the clinic by addressing specific challenges encountered throughout the the care of glioblastoma patients. 

Shingo Matsumoto¹, Neil J. Stewart¹, Hitomi Nakano¹, Takuya Hashimoto², and Hiroshi Hirata^1
1Information Science and Technologies, Hokkaido University, Sapporo, Japan, ²Department of Chemistry, Chiba University, Chiba, Japan

Hyperpolarized [1-¹³C]fumarate is a promising MRI biomarker for cellular necrosis, which plays an important role in various diseases and cancer treatment response. To demonstrate the feasibility of hyperpolarized MRI of [1-¹³C]fumarate metabolism using parahydrogen-induced polarization (PHIP) – a low-cost alternative to dissolution dynamic nuclear polarization (dDNP), a cost-effective synthetic pathway for high-yield production of a fumarate precursor [1-¹³C]acetylenedicarboxylate was developed. A simple hydrogenative PHIP set-up was used to generate hyperpolarized [1-¹³C]fumarate at sufficient polarization and concentration for in vivo [1-¹³C]fumarate metabolic MRS/MRI in acetaminophen-induced murine model of hepatitis.

Qianhui Dou¹, Aaron K. Grant¹, Cody K. Callahan¹, Muneeb Ahmed¹, and Leo Lee Tsai^1
1Radiology, Beth Israel Deaconess Medical Center, Boston, MA, United States

This study investigated the feasibility of hyperpolarized ¹³C (h¹³C) MRI as diagnostic tool to monitor hepatocellular carcinoma (HCC) activity. h¹³C MRI showed significant increase in pyruvate-lactate conversion and decrease in pyruvate-alanine in N1S1 HCC tumors following stimulation from nearby hepatic radiofrequency ablation, while no such changes were seen with the MCA-RH7777 HCC tumors, despite increased tumor burden or proliferation in both cell lines. The h¹³C measurements matched mRNA expression patterns of glycolysis-related genes, which were relatively lower for MCA-RH7777. h¹³C pyruvate MRI may provide insight into malignant tumor behavior but is contingent on the activity of key glycolytic regulators.

Christopher M Walker¹, Zhan Xu¹, Keith Michel¹, Gary Martinez¹, Collin J. Harlan¹, Jeremy W. Gordon², Stephanie Carlon¹, Sandra Williams¹, Freddy Gonzalez¹, Stacy Hash¹, Jerell Jones¹, Asa McCoy¹, Brandy Willis¹, Michelle Underwood¹, Andrew Day³, Moin Chariwala³, Dao Le⁴, Gregory Waligorski³, Daniel B. Vigneron², Dawid Schellingerhout⁵, Stephen Y. Lai⁶, and James A. Bankson^1
1Imaging Physics, MD Anderson Cancer Center, Houston, TX, United States, ²2. Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, San Francisco, CA, United States, ³Center for Advanced Biomedical Imaging, MD Anderson Cancer Center, Houston, TX, United States, ⁴Nuclear Medicine, MD Anderson Cancer Center, Houston, TX, United States, ⁵Nueroradiology, MD Anderson Cancer Center, Houston, TX, United States, ⁶Head and Neck Surgery, MD Anderson Cancer Center, Houston, TX, United States

This case report presents the detection of hyperpolarized lactate production in a patient with anaplastic thyroid carcinoma. Lactate signal was observed following injection of hyperpolarized pyruvate and the signal was well localized to the tumor. The normalized lactate signal was reduced eight days following the onset of systemic therapy with Pembro and Lenvatinib.

Xiaoxi Liu¹, Shuyu Tang^1,2, Xucheng Zhu^1,3, and Peder E.Z. Larson^1
1Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, ²HeartVista, Inc., Los Altos, CA, United States, ³GE Healthcare, Sunnyvale, CA, United States

Hyperpolarized ¹³C magnetic resonance imaging is a non-invasive imaging tool to assess metabolic process in-vivo that has been most commonly applied to imaging cancer and heart disease. Spiral readout, as a rapid acquisition technique, is commonly used to acquire hyperpolarized metabolic data. However, the spiral readout is sensitive to the off-resonance effect and has blurring artifacts as a result. The blurring also affects the measurement of metabolism. In this project, we investigated two off-resonance correction methods with self-estimated field maps and applied them on different anatomies.

Roozbeh Eskandari¹, Arsen Mamakhanyan¹, Michelle Saoi², Kristin L Granlund¹, Justin Cross², Craig B Thompson³, and Kayvan Rahimi Keshari^1,4
1Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, United States, ²Memorial Sloan Kettering Cancer Center, New York, NY, United States, ³Cancer Biology & Genetics Program Share, Memorial Sloan Kettering Cancer Center, New York, NY, United States, ⁴Radiology, Memorial Sloan Kettering, New York, NY, United States

Aberrations in glutaminase enzyme expression are associated with a variety of pathologies, and an in vivo probe to quantify flux through this pathway may provide a new layer of information. We developed a custom-synthesized compound, [5-13C,4,4-2H2,5-15N­]-L-Glutamine, as a hyperpolarized MRI probe for glutaminase activity. Triple labeling of glutamine and D2O solvation reduces quadrupolar relaxation and extends both T1 and T2, facilitating in vivo imaging. We were able to acquire 13C spectroscopic data on a subcutaneous PDAC xenograft murine model and detect in vivo conversion of hyperpolarized glutamine to glutamate, which permits further exploration of this imaging probe in the future. 

Joao Piraquive¹, Hongjuan Zhao², Rosalie Nolley², Robert Bok¹, James D. Brooks², Donna M. Peehl¹, John Kurhanewicz¹, and Renuka Sriram^1
1Department of Radiology and Biomedical Imaging, University of California San Francisco, University of California San Francisco, San Francisco, CA, United States, ²Department of Urology, Stanford University, Stanford, CA, United States

We demonstrated substantial morphologic and glycolytic metabolic differences using proton and hyperpolarized 13C magnetic resonance imaging, respectively between and within RCC patient derived xenografts (PDXs). Our findings showed substantial inter-PDX differences in tumor growth rates, as well as the cystic and necrotic components. Furthermore, the xenograft (XEN) established from cell lines derived from the PDX showed significant morphological differences from the parent PDX. Interestingly, upon comparison of two subsequent passages of the same PDX, we found that while the morphological similarities persisted, the glycolytic capacity was significantly increased in the latter passage, implying natural selection of the more aggressive cells.

Junjie Ma¹, Crystal E. Harrison¹, James Ratnakar¹, Galen D. Reed², Rolf F. Schulte³, Vlad G. Zaha^1,4, Craig R. Malloy^1,4,5, and Jae Mo Park^1,5,6
1Advanced Imaging Research Center, UT SOUTHWESTERN MEDICAL CENTER, Dallas, TX, United States, ²GE Healthcare, Dallas, TX, United States, ³GE Healthcare, Munich, Germany, ⁴Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States, ⁵Radiology, UT Southwestern Medical Center, Dallas, TX, United States, ⁶Electrical and Computer Engineering, UT Dallas, Richardson, TX, United States

Multi-echo ¹³C spiral imaging sequence combined with a spectral-spatial radiofrequency pulse can measure T₂* of ¹³C-labeled metabolite signals in vivo. In this study, we measured T₂*s of hyperpolarized [1-¹³C]pyruvate and products in human heart, brain, kidney and spleen.

Jasmine Y Graham¹, Adam W Autry², Yaewon Kim², Robert A Bok², Yan Li², Peder EZ Larson^1,2, Daniel B Vigneron^1,2, and Jeremy W Gordon^2
1Bioengineering, UC San Francisco, UC Berkeley, San Francisco, CA, United States, ²Radiology and Biomedical Imaging, UC San Francisco, San Francisco, CA, United States

Utilizing a multi-resolution acquisition for hyperpolarized [1-¹³C]pyruvate brain MRI (7.5 mm in-plane for pyruvate and 15 mm in-plane resolution for lactate & bicarbonate) minimized partial volume effects from vascular pyruvate signals while maintaining the SNR of the downstream metabolites. In the healthy volunteers studied, higher resolution HP ¹³C-pyruvate multi-slice EPI images improved the quantification of kinetic rates in the brain. Selected voxels near veins and in white and gray matter showed on average >20% higher k_PL using higher resolution pyruvate images, consistent with reduced partial volume contributions from vascular HP ¹³C-pyruvate.

Vencel Somai^1,2, Felix Kreis³, Adam Gaunt¹, and Kevin M Brindle^1,4
1Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, United Kingdom, ²Department of Radiology, University of Cambridge, School of Clinical Medicine Box 218, Cambridge Biomedical Campus, Cambridge, United Kingdom, ³Department of Information Technology and Electrical Engineering, ETH Zurich, Rämistrasse 101, Zurich, Switzerland, ⁴Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom

An optimized polarization transfer pulse designed using a genetic algorithm  is presented, which has greater immunity to the effects of B₀ and B₁ field inhomogeneity and ~2 times lower peak B₁ compared to the BINEPT pulse sequence. The optimization provides a simple framework that accounts for finite pulse lengths and relaxation and outputs a shaped pulse on each frequency channel. Performance was tested on a [¹⁵N₂]urea phantom at thermal equilibrium, where the polarization transferred from protons to ¹⁵N was 1.32 times greater than that transferred using BINEPT. Partial transfer of polarization from hyperpolarized ¹⁵N to proton was also demonstrated.

Thanh Phong Lê^1,2, Lara Buscemi³, Mario Lepore⁴, Lorenz Hirt³, Jean-Noël Hyacinthe^1,5, and Mor Mishkovsky^2
1Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland, ²Laboratory of Functional and Metabolic Imaging, EPFL (Swiss Federal Institute of Technology in Lausanne), Lausanne, Switzerland, ³Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland, ⁴Center for Biomedical Imaging (CIBM), EPFL, Lausanne, Switzerland, ⁵Image Guided Intervention Laboratory, University of Geneva (UNIGE), Geneva, Switzerland

Used at low concentration in DNP sample preparations, radicals are typically chemically highly reactive species that could potentially interfere with the biochemical processes assessed in HP MR experiments. In this work, we investigate the influence of the nitroxyl radical TEMPOL on the cerebral metabolic response to a bolus of hyperpolarized [1-¹³C]lactate in a mouse model of transient ischemic stroke. Our results show that TEMPOL, administered at the same dose as when used as a polarizing agent for DNP, alters substantially the metabolic outcome of the experiment and notably results in a significantly different pyruvate labelling after hyperpolarized lactate infusion.

Andrea Capozzi¹, Jan Kilund², Magnus Karlsson², Mathilde Hauge Lerche², and Jan Henrik Ardenkjær-Larsen^2
1LIFMET, EPFL, Lausanne, Switzerland, ²Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark

Our vision is to make it possible to deliver hyperpolarized compounds to MR facilities that currently have no access to hyperpolarization technology. Today this is not the case and represents hyperpolarized-MR via dissolution Dynamic Nuclear Polarization (dDNP) main shortcoming. The reason is intrinsic in the technique and deals with the presence, in the dDNP sample, of organic free radicals necessary to generate the hyperpolarization. Herein, we demonstrate, for the first time, transportation at cryogenic temperature and remote dissolution of hyperpolarized glucose. The core idea of this project is to exploit the non-persistency of UV-induced radicals for dDNP.

Joao Piraquive¹, Shubhangi Agarwal¹, Robert Bok¹, John Kurhanewicz¹, Aras Mattis^2,3, Jaqueline Maher^3,4, Cornelius von Morze⁵, and Michael A. Ohliger^1,3
1Department of Radiology and Biomedical Imaging, University of California San Francisco, University of California San Francisco, San Francisco, CA, United States, ²Department of Pathology, University of California San Francisco, San Francisco, CA, United States, ³Liver center, University of California, San Francisco, CA, United States, ⁴Department of Medicine, University of California San Francisco, San Francisco, CA, United States, ⁵Biomedical Magnetic Resonance Laboratory, Washington University School of Medicine, St. Louis, MO, United States

Hyperpolarized ¹³C MRI was used to noninvasively detect metabolic changes in a rat model of non-alchoholic steatohepatitis. Rats were fed a methionine- and choline-deficient (MCD) diet for up to 18 weeks. In this preliminary study, we showed a significant increase in fat signal fraction and borderline-signifcant decrease in ¹³C lactate production in rats fed the MCD diet. Findings in this work suggest that HP ¹³C pyruvate can be a promising tool to monitor noninvasively the progress of fatty liver disease in patients.

Zhan Xu¹, Christopher M Walker¹, Collin J Harlan¹, Keith A Michel¹, Gary V Martinez¹, and James A Bankson^1,2
1Imaging Physics, MD Anderson Cancer Center, Houston, TX, United States, ²UT Health Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer, Houston, TX, United States

A new pharmacokinetic-model-based constrained reconstruction method CoUNFOLD is introduced for hyperpolarized 13C pyruvate imaging. This method extended classic UNFOLD method by introducing model constraint which described the signal evolution of multiple substrates. CoUNFOLD successfully accelerated the data acquisition, and the reconstruction was  implemented on single channel. An in silico experiment demonstrated the accuracy of reconstruction at a reduction factor of 2. The quantitative estimation of the conversion ratio from pyruvate to lactate was achieved with high accuracy when peak pyruvate SNR was as low as 20     

Hyeong Yeon Lee¹, Najmiddin Mamadjonov², Nguyen Trong Nguyen², Luu-Ngoc Do³, Tien Ahn Nguyen³, and Ilwoo Park^3,4,5
1Emergency Medicine, Chonnam National University Hospital, Gwangju, Korea, Republic of, ²Biomedical Science, Chonnam National University, Gwangju, Korea, Republic of, ³Radiology, Chonnam National University, Gwangju, Korea, Republic of, ⁴Radiology, Chonnam National University Hospital, Gwangju, Korea, Republic of, ⁵Artificial Intelligence Convergence, Chonnam National University, Gwangju, Korea, Republic of

This study demonstrated that hyperpolarized 13C metabolic imaging can identify the metabolic changes within 1 hour of return of spontaneous circulation in rodent model of ventricular fibrillation-induced cardiac arrest. Brain histology performed at 72 hours after ROSC showed marked difference in the levels of neuronal death and reactive astrocyte change between the cardiac arrest model and sham control. The results from this study suggest that this new metabolic imaging technique may provide a unique and noninvasive imaging biomarker for assessing functional changes at early stage of post ROSC and warrant further investigation.

Minjie Zhu¹, Stephen DeVience², and Dirk Mayer^1
1University of Maryland Baltimore, Baltimore, MD, United States, ²Scalar Magnetics, LLC, Cuyahoga Falls, OH, United States

The goal of this study is to incorporate the spectral dimension into the Low Rank Plus Sparse Reconstruction algorithm with application of undersampled dynamic Hyperpolarized 13C imaging. The proposed method can be used to increase temporal and/or spatial resolution without significantly compromising image quality.

Hikari A. I. Yoshihara¹, Arnaud Comment^2,3, and Juerg Schwitter^4,5
1Laboratory for Functional and Metabolic Imaging, Institute of Physics, Swiss Federal Institute of Technology, Lausanne (EPFL), Lausanne, Switzerland, ²Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom, ³General Electric Healthcare, Chalfont St Giles, United Kingdom, ⁴Division of Cardiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland, ⁵Cardiac MR Center, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland

Labeled metabolites of hyperpolarized 1-¹³C pyruvate, including aspartate, malate and fumarate are detected in the rat kidney in vivo, indicating the possibility of detecting gluconeogenic flux. Pyruvate-to-bicarbonate conversion in the fasted rat liver is a marker of PEP-CK flux. Fasting resulted in lower bicarbonate and higher aspartate in the kidney. Conversely, treatment with the PEP-CK inhibitor 3-MPA did not affect bicarbonate production but did yield a lower normalized aspartate signal, with a 12-fold reduction in fasted rats. Renal pyruvate-to-bicarbonate conversion is therefore largely attributable to pyruvate hydrogenase flux, while pyruvate-to-aspartate conversion is a potential marker of renal gluconeogenesis.

Aditya Jhajharia¹, Sui Seng Tee¹, Maninder Singh¹, Sausan Jaber², Binny Bhandary³, Brian Polster², Ronald B. Gartenhaus^3,4, Kavita Bhalla³, and Dirk Mayer^1
1Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States, ²Department of Anesthesiology, University of Maryland, Baltimore, MD, United States, ³Department of Medicine, University of Maryland, Baltimore, MD, United States, ⁴Veterans Administration Medical Center, Baltimore, MD, United States

Ataxia-telangiectasia mutated (ATM) kinase regulates critical metabolic processes of B-cell lymphoid malignancies. Diffuse large B-cell lymphoma (DLBCL) is clinically a very aggressive tumor subtype. This study investigates the role of ATM in metabolism. Oxygen consumption rate measurements showed decreased respiration in DLBCL cells lacking ATM. MRS of hyperpolarized [1-¹³C]pyruvate in DLBCL line HLY that were either wild-type or had ATM knocked down showed increased conversion of hyperpolarized pyruvate to lactate in HLY cells lacking ATM. These results indicate that deregulation of mitochondrial structure/function due to ATM deficiency results in metabolic changes and may contribute to the development of cancer.

Martin Grashei¹, Carolin Kitzberger², Jason G. Skinner¹, Sandra Sühnel¹, Geoffrey J. Topping¹, Elisabeth Bliemsrieder¹, Christian Hundshammer¹, Katja Steiger³, Peter J. Nelson⁴, Rainer Glaß⁵, Wolfgang Weber¹, Christine Spitzweg², and Franz Schilling^1
1Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany, ²Medizinische Klinik und Poliklinik IV-Campus Großhadern, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany, ³Department of Pathology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany, ⁴Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany, ⁵Neurosurgical Research University Clinics, Ludwig-Maximilians-University Munich and Walter-Brendel-Centre of Experimental Medicine, Munich, Germany

A novel treatment approach for glioblastoma is based on mesenchymal stem cell (MSC)-mediated gene therapies whereby cell accumulation can be influenced by the tumor microenvironment. Here, we demonstrate the ability to image pH, metabolic pyruvate-lactate conversion and hypoxia in glioblastoma using hyperpolarized [1,5-¹³C₂,3,6,6,6-D₄]zymonic acid-MRSI, [1-¹³C]pyruvate-MRI and [¹⁸F]FMISO-PET as predictors for hypoxia-targeted sodium-iodide-symporter (NIS)-expression of tumor-infiltrating MSCs assessed by ¹²⁴I-PET. Observed hypoxia (SUV_mean = 0.49±0.05) was confirmed by histology and occurred together with increased lactate-production (AUC_mean = 1.14±0.17) and mild acidification (pH_mean = 7.34±0.02). This shows to be a suitable environment for NIS-MSC-activity, thereby allowing efficient therapy.