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.

Data Format Standardization and DICOM Integration for Hyperpolarized C MRI.

Hyperpolarized (HP) C MRI has shown promise as a valuable modality for measurements of metabolism and is currently in human trials at 15 research sites worldwide. With this growth it is important to adopt standardized data storage practices as it will allow sites to meaningfully compare data. In this paper we (1) describe data that we believe should be stored and (2) demonstrate pipelines and methods that utilize the Digital Imaging and Communications in Medicine (DICOM) standard.

Data Format Standardization and DICOM Integration for Hyperpolarized C MRI.

Hyperpolarized (HP) C MRI has shown promise as a valuable modality for in vivo measurements of metabolism and is currently in human trials at 15 research sites worldwide. With this growth, it is important to adopt standardized data storage practices as it will allow sites to meaningfully compare data. In this paper, we (1) describe data that we believe should be stored and (2) demonstrate pipelines and methods that utilize the Digital Imaging and Communications in Medicine (DICOM) standard.

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).

New Horizons in Hyperpolarized C MRI.

Hyperpolarization techniques significantly enhance the sensitivity of magnetic resonance (MR) and thus present fascinating new directions for research and applications with in vivo MR imaging and spectroscopy (MRI/S). Hyperpolarized C MRI/S, in particular, enables real-time non-invasive assessment of metabolic processes and holds great promise for a diverse range of clinical applications spanning fields like oncology, neurology, and cardiology, with a potential for improving early diagnosis of disease, patient stratification, and therapy response assessment. Despite its potential, technical challenges remain for achieving clinical translation.

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.

Monitoring response to a clinically relevant IDH inhibitor in glioma-Hyperpolarized C magnetic resonance spectroscopy approaches.

Background: Mutant isocitrate dehydrogenase (IDHmut) catalyzes 2-hydroxyglutarate (2HG) production and is considered a therapeutic target for IDHmut tumors. However, response is mostly associated with inhibition of tumor growth. Response assessment via anatomic imaging is therefore challenging.

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.

Parallel detection of chemical reactions in a microfluidic platform using hyperpolarized nuclear magnetic resonance.

The sensitivity of NMR may be enhanced by more than four orders of magnitude dissolution dynamic nuclear polarization (dDNP), potentially allowing real-time, analysis of chemical reactions. However, there has been no widespread use of the technique for this application and the major limitation has been the low experimental throughput caused by the time-consuming polarization build-up process at cryogenic temperatures and fast decay of the hyper-intense signal post dissolution. To overcome this limitation, we have developed a microfluidic device compatible with dDNP-MR spectroscopic imaging methods for detection of reactants and products in chemical reactions in which up to 8 reactions can be measured simultaneously using a single dDNP sample.

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.

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.

Multi-parametric hyperpolarized C/H imaging reveals Warburg-related metabolic dysfunction and associated regional heterogeneity in high-grade human gliomas.

Background: Dynamic hyperpolarized (HP)-C MRI has enabled real-time, non-invasive assessment of Warburg-related metabolic dysregulation in glioma using a [1-C]pyruvate tracer that undergoes conversion to [1-C]lactate and [C]bicarbonate. Using a multi-parametric H/HP-C imaging approach, we investigated dynamic and steady-state metabolism, together with physiological parameters, in high-grade gliomas to characterize active tumor.

Methods: Multi-parametric H/HP-C MRI data were acquired from fifteen patients with progressive/treatment-naïve glioblastoma [prog/TN GBM, IDH-wildtype (n = 11)], progressive astrocytoma, IDH-mutant, grade 4 (G4A, n = 2) and GBM manifesting treatment effects (n = 2).

A user independent denoising method for x-nuclei MRI and MRS.

Purpose: X-nuclei (also called non-proton MRI) MRI and spectroscopy are limited by the intrinsic low SNR as compared to conventional proton imaging. Clinical translation of x-nuclei examination warrants the need of a robust and versatile tool improving image quality for diagnostic use. In this work, we compare a novel denoising method with fewer inputs to the current state-of-the-art denoising method.

Model-constrained reconstruction accelerated with Fourier-based undersampling for hyperpolarized [1- C] pyruvate imaging.

Purpose: Model-constrained reconstruction with Fourier-based undersampling (MoReFUn) is introduced to accelerate the acquisition of dynamic MRI using hyperpolarized [1- C]-pyruvate.

Methods: The MoReFUn method resolves spatial aliasing using constraints introduced by a pharmacokinetic model that describes the signal evolution of both pyruvate and lactate. Acceleration was evaluated on three single-channel data sets: a numerical digital phantom that is used to validate the accuracy of reconstruction and model parameter restoration under various SNR and undersampling ratios, prospectively and retrospectively sampled data of an in vitro dynamic multispectral phantom, and retrospectively undersampled imaging data from a prostate cancer patient to test the fidelity of reconstructed metabolite time series.

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.