Protocol for producing hyperpolarized C-bicarbonate for clinical MRI of extracellular pH in aggressive tumors.

Tumor acidosis is one of the hallmarks indicating the initiation and progression of various cancers. Here, we present a protocol for preparing a hyperpolarized (HP) C-bicarbonate tissue pH MRI imaging contrast agent to detect aggressive tumors. We describe the steps for the formulation and polarization of a precursor molecule C-glycerol carbonate (C-GLC), the post-dissolution reaction, and converting HP C-GLC to an injectable HP C-bicarbonate solution.

Distinguishing metabolic signals of liver tumors from surrounding liver cells using hyperpolarized C MRI and gadoxetate.

Purpose: To use the hepatocyte-specific gadolinium-based contrast agent gadoxetate combined with hyperpolarized (HP) [1- C]pyruvate MRI to selectively suppress metabolic signals from normal hepatocytes while preserving the signals arising from tumors.

Methods: Simulations were performed to determine the expected changes in HP C MR signal in liver and tumor under the influence of gadoxetate. CC531 colon cancer cells were implanted into the livers of five Wag/Rij rats.

Advanced Hyperpolarized C Metabolic Imaging Protocol for Patients with Gliomas: A Comprehensive Multimodal MRI Approach.

This study aimed to implement a multimodal H/HP-C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-C metabolic data. A total of 100 H/HP [1-C]-pyruvate MR examinations (104 HP-C datasets) were acquired from 42 patients according to the comprehensive multimodal glioma imaging protocol. Serial data coverage, accuracy of frequency reference, and acquisition delay were evaluated using a mixed-effects model to account for multiple exams per patient.

Hyperpolarized C metabolic imaging of the human abdomen with spatiotemporal denoising.

Purpose: Improving the quality and maintaining the fidelity of large coverage abdominal hyperpolarized (HP) C MRI studies with a patch based global-local higher-order singular value decomposition (GL-HOVSD) spatiotemporal denoising approach.

Methods: Denoising performance was first evaluated using the simulated [1- C]pyruvate dynamics at different noise levels to determine optimal k and k parameters. The GL-HOSVD spatiotemporal denoising method with the optimized parameters was then applied to two HP [1- C]pyruvate EPI abdominal human cohorts (n = 7 healthy volunteers and n = 8 pancreatic cancer patients).

Hyperpolarized [1- C] pyruvate MRSI to detect metabolic changes in liver in a methionine and choline-deficient diet rat model of fatty liver disease.

Purpose: Nonalcoholic fatty liver disease is an important cause of chronic liver disease. There are limited methods for monitoring metabolic changes during progression to steatohepatitis. Hyperpolarized C MRSI (HP C MRSI) was used to measure metabolic changes in a rodent model of fatty liver disease.

Regional quantification of cardiac metabolism with hyperpolarized [1-C]-pyruvate CMR evaluated in an oral glucose challenge.

Background: The heart has metabolic flexibility, which is influenced by fed/fasting states, and pathologies such as myocardial ischemia and hypertrophic cardiomyopathy (HCM). Hyperpolarized (HP) C-pyruvate MRI is a promising new tool for non-invasive quantification of myocardial glycolytic and Krebs cycle flux. However, human studies of HP C-MRI have yet to demonstrate regional quantification of metabolism, which is important in regional ischemia and HCM patients with asymmetric septal/apical hypertrophy.

Probing human heart TCA cycle metabolism and response to glucose load using hyperpolarized [2- C]pyruvate MRS.

Introduction: The healthy heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2- C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes.

Hyperpolarized C Metabolic MRI of Patients with Pancreatic Ductal Adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related death in the United States. However, early response assessment using the current approach of measuring changes in tumor size on computed tomography (CT) or MRI is challenging.

Purpose: To investigate the feasibility of hyperpolarized (HP) [1-C]pyruvate MRI to quantify metabolism in the normal appearing pancreas and PDA, and to assess changes in PDA metabolism following systemic chemotherapy.

Dynamic relaxometry of hyperpolarized [1- C]pyruvate MRI in the human brain and kidneys.

Purpose: This study aimed to quantify for hyperpolarized [1- C]pyruvate and metabolites in the healthy human brain and renal cell carcinoma (RCC) patients at 3 T.

Methods: Dynamic values were measured with a metabolite-specific multi-echo spiral sequence. The dynamic of [1- C]pyruvate, [1- C]lactate, and C-bicarbonate was estimated in regions of interest in the whole brain, sinus vein, gray matter, and white matter in healthy volunteers, as well as in kidney tumors and the contralateral healthy kidneys in a separate group of RCC patients.

Probing Human Heart TCA Cycle Metabolism and Response to Glucose Load using Hyperpolarized [2-C]Pyruvate MR Spectroscopy.

Introduction: The normal heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid (FA) oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes.

Regional quantification of cardiac metabolism with hyperpolarized [1-C]-pyruvate MRI evaluated in an oral glucose challenge.

Background: The heart has metabolic flexibility, which is influenced by fed/fasting states, and pathologies such as myocardial ischemia and hypertrophic cardiomyopathy (HCM). Hyperpolarized (HP) C-pyruvate MRI is a promising new tool for non-invasive quantification of myocardial glycolytic and Krebs cycle flux. However, human studies of HP C-MRI have yet to demonstrate regional quantification of metabolism, which is important in regional ischemia and HCM patients with asymmetric septal/apical hypertrophy.

Clinically Translatable Hyperpolarized C Bicarbonate pH Imaging Method for Use in Prostate Cancer.

Solid tumors such as prostate cancer (PCa) commonly develop an acidic microenvironment with pH 6.5-7.2, owing to heterogeneous perfusion, high metabolic activity, and rapid cell proliferation.

Current Methods for Hyperpolarized [1-C]pyruvate MRI Human Studies.

MRI with hyperpolarized (HP) C agents, also known as HP C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of hyperpolarized agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-C]pyruvate - by far the most commonly used agent, which sits at a key metabolic junction in glycolysis.

A metabolite specific 3D stack-of-spirals bSSFP sequence for improved bicarbonate imaging in hyperpolarized [1-C]Pyruvate MRI.

C-bicarbonate is a crucial measure of pyruvate oxidation and TCA cycle flux, but is challenging to measure due to its relatively low concentration and thus will greatly benefit from improved signal-to-noise ratio (SNR). To address this, we developed and investigated the feasibility of a 3D stack-of-spirals metabolite-specific balanced steady-state free precession (MS-bSSFP) sequence for improving the SNR and spatial resolution of dynamic C-bicarbonate imaging in hyperpolarized [1-C]pyruvate studies. The bicarbonate MS-bSSFP sequence was evaluated by simulations, phantoms studies, preclinical studies on five rats, brain studies on two healthy volunteers and renal study on one renal cell carcinoma patient.

Multiparametric Magnetic Resonance Imaging and Metabolic Characterization of Patient-Derived Xenograft Models of Clear Cell Renal Cell Carcinoma.

Patient-derived xenografts (PDX) are high-fidelity cancer models typically credentialled by genomics, transcriptomics and proteomics. Characterization of metabolic reprogramming, a hallmark of cancer, is less frequent. Dysregulated metabolism is a key feature of clear cell renal cell carcinoma (ccRCC) and authentic preclinical models are needed to evaluate novel imaging and therapeutic approaches targeting metabolism.

Improving multiparametric MR-transrectal ultrasound guided fusion prostate biopsies with hyperpolarized C pyruvate metabolic imaging: A technical development study.

Purpose: To develop techniques and establish a workflow using hyperpolarized carbon-13 ( C) MRI and the pyruvate-to-lactate conversion rate (k ) biomarker to guide MR-transrectal ultrasound fusion prostate biopsies.

Methods: The integrated multiparametric MRI (mpMRI) exam consisted of a 1-min hyperpolarized C-pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of k values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T -weighted anatomic images.

Development of specialized magnetic resonance acquisition techniques for human hyperpolarized [ C, N ]urea + [1- C]pyruvate simultaneous perfusion and metabolic imaging.

Purpose: This study aimed to develop and demonstrate the in vivo feasibility of a 3D stack-of-spiral balanced steady-state free precession(3D-bSSFP) urea sequence, interleaved with a metabolite-specific gradient echo (GRE) sequence for pyruvate and metabolic products, for improving the SNR and spatial resolution of the first hyperpolarized C-MRI human study with injection of co-hyperpolarized [1- C]pyruvate and [ C, N ]urea.

Methods: A metabolite-specific bSSFP urea imaging sequence was designed using a urea-specific excitation pulse, optimized TR, and 3D stack-of-spiral readouts. Simulations and phantom studies were performed to validate the spectral response of the sequence.

Whole-Abdomen Metabolic Imaging of Healthy Volunteers Using Hyperpolarized [1- C]pyruvate MRI.

Background: Hyperpolarized C MRI quantitatively measures enzyme-catalyzed metabolism in cancer and metabolic diseases. Whole-abdomen imaging will permit dynamic metabolic imaging of several abdominal organs simultaneously in healthy and diseased subjects.

Purpose: Image hyperpolarized [1- C]pyruvate and products in the abdomens of healthy volunteers, overcoming challenges of motion, magnetic field variations, and spatial coverage.