Specialized computational methods for denoising, B correction, and kinetic modeling in hyperpolarized C MR EPSI studies of liver tumors.

Purpose: To develop a novel post-processing pipeline for hyperpolarized (HP) C MRSI that integrates tensor denoising and correction to measure pyruvate-to-lactate conversion rates (k ) in patients with liver tumors.

Methods: Seven HP C MR scans of progressing liver tumors were acquired using a custom C surface transmit/receive coil and the echo-planar spectroscopic imaging (EPSI) data analysis included B correction, tensor rank truncation, and zero- and first-order phase corrections to recover metabolite signals that would otherwise be obscured by spectral noise as well as a correction for inhomogeneous transmit ( ) using a map aligned to the coil position for each patient scan. Processed HP data and corrected flip angles were analyzed with an inputless two-site exchange model to calculate k .

Resistance to Androgen Deprivation Leads to Altered Metabolism in Human and Murine Prostate Cancer Cell and Tumor Models.

Currently, no clinical methods reliably predict the development of castration-resistant prostate cancer (CRPC) that occurs almost universally in men undergoing androgen deprivation therapy. Hyperpolarized (HP) C magnetic resonance imaging (MRI) could potentially detect the incipient emergence of CRPC based on early metabolic changes. To characterize metabolic shifts occurring upon the transition from androgen-dependent to castration-resistant prostate cancer (PCa), the metabolism of [U-C]glucose and [U-C]glutamine was analyzed by nuclear magnetic resonance spectroscopy.

Modeling hyperpolarized lactate signal dynamics in cells, patient-derived tissue slice cultures and murine models.

Determining the aggressiveness of renal cell carcinoma (RCC) noninvasively is a critical part of the diagnostic workup for treating this disease that kills more than 15,000 people annually in the USA. Recently, we have shown that not only the amount of lactate produced, as a consequence of the Warburg effect, but also its efflux out of the cell, is a critical marker of RCC aggressiveness and differentiating RCCs from benign renal tumors. Enzymatic conversions can now be measured in situ with hyperpolarized (HP) C magnetic resonance (MR) on a sub-minute time scale.

Characterization of serial hyperpolarized C metabolic imaging in patients with glioma.

Background: Hyperpolarized carbon-13 (HP-C) MRI is a non-invasive imaging technique for probing brain metabolism, which may improve clinical cancer surveillance. This work aimed to characterize the consistency of serial HP-C imaging in patients undergoing treatment for brain tumors and determine whether there is evidence of aberrant metabolism in the tumor lesion compared to normal-appearing tissue.

Methods: Serial dynamic HP [1-C]pyruvate MRI was performed on 3 healthy volunteers (6 total examinations) and 5 patients (21 total examinations) with diffuse infiltrating glioma during their course of treatment, using a frequency-selective echo-planar imaging (EPI) sequence.

Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures.

Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-C]pyruvate to [1-C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa.

Hyperpolarized C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study.

Background: Hyperpolarized (HP) C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera.

Kinetic Modeling of Hyperpolarized Carbon-13 Pyruvate Metabolism in the Human Brain.

Kinetic modeling of the in vivo pyruvate-to-lactate conversion is crucial to investigating aberrant cancer metabolism that demonstrates Warburg effect modifications. Non-invasive detection of alterations to metabolic flux might offer prognostic value and improve the monitoring of response to treatment. In this clinical research project, hyperpolarized [1-C] pyruvate was intravenously injected in a total of 10 brain tumor patients to measure its rate of conversion to lactate ( k ) and bicarbonate ( k ) via echo-planar imaging.

Pulse sequence considerations for quantification of pyruvate-to-lactate conversion k in hyperpolarized C imaging.

Hyperpolarized C MRI takes advantage of the unprecedented 50 000-fold signal-to-noise ratio enhancement to interrogate cancer metabolism in patients and animals. It can measure the pyruvate-to-lactate conversion rate, k , a metabolic biomarker of cancer aggressiveness and progression. Therefore, it is crucial to evaluate k reliably.

Translation of Carbon-13 EPI for hyperpolarized MR molecular imaging of prostate and brain cancer patients.

Purpose: To develop and translate a metabolite-specific imaging sequence using a symmetric echo planar readout for clinical hyperpolarized (HP) Carbon-13 ( C) applications.

Methods: Initial data were acquired from patients with prostate cancer (N = 3) and high-grade brain tumors (N = 3) on a 3T scanner. Samples of [1- C]pyruvate were polarized for at least 2 h using a 5T SPINlab system operating at 0.

Investigation of analysis methods for hyperpolarized 13C-pyruvate metabolic MRI in prostate cancer patients.

MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1- C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion.

Spatio-Temporally Constrained Reconstruction for Hyperpolarized Carbon-13 MRI Using Kinetic Models.

We present a method of generating spatial maps of kinetic parameters from dynamic sequences of images collected in hyperpolarized carbon-13 magnetic resonance imaging (MRI) experiments. The technique exploits spatial correlations in the dynamic traces via regularization in the space of parameter maps. Similar techniques have proven successful in other dynamic imaging problems, such as dynamic contrast enhanced MRI.

Molecular detection of inflammation in cell models using hyperpolarized C-pyruvate.

The detection and treatment monitoring of inflammatory states remain challenging in part due to the multifactorial mechanisms of immune activation and spectrum of clinical manifestations. Currently, diagnostic strategies tend to be subjective and limited quantitative tools exist to monitor optimal treatment strategies. Pro-inflammatory M1 polarized macrophages exhibit a distinct metabolic glycolytic phenotype compared to the continuum of M2 polarization states.

Technique development of 3D dynamic CS-EPSI for hyperpolarized C pyruvate MR molecular imaging of human prostate cancer.

Purpose: The purpose of this study was to develop a new 3D dynamic carbon-13 compressed sensing echoplanar spectroscopic imaging (EPSI) MR sequence and test it in phantoms, animal models, and then in prostate cancer patients to image the metabolic conversion of hyperpolarized [1- C]pyruvate to [1- C]lactate with whole gland coverage at high spatial and temporal resolution.

Methods: A 3D dynamic compressed sensing (CS)-EPSI sequence with spectral-spatial excitation was designed to meet the required spatial coverage, time and spatial resolution, and RF limitations of the 3T MR scanner for its clinical translation for prostate cancer patient imaging. After phantom testing, animal studies were performed in rats and transgenic mice with prostate cancers.

Detection of Bacteria-Specific Metabolism Using Hyperpolarized [2-C]Pyruvate.

The differentiation of bacterial infection from other causes of inflammation is difficult in clinical practice and is critical where patient outcomes rely heavily on early interventions. In addition to physical exam and laboratory markers, several imaging modalities are frequently employed, but these techniques generally target the host immune response, rather than the living microorganisms themselves. Here, we describe a method to detect bacteria-specific metabolism using hyperpolarized (HP) C magnetic resonance spectroscopy.

Development of methods and feasibility of using hyperpolarized carbon-13 imaging data for evaluating brain metabolism in patient studies.

Purpose: Hyperpolarized C metabolic imaging is a non-invasive imaging modality for evaluating real-time metabolism. The purpose of this study was to develop and implement experimental strategies for using [1-C]pyruvate to probe metabolism for patients with brain tumors and other neurological diseases.

Methods: The C RF coils and pulse sequences were tested in a phantom and were performed using a 3T whole body scanner.

Sensitivity enhancement for detection of hyperpolarized C MRI probes with H spin coupling introduced by enzymatic transformation in vivo.

Purpose: Although H spin coupling is generally avoided in probes for hyperpolarized (HP) C MRI, enzymatic transformations of biological interest can introduce large C- H couplings in vivo. The purpose of this study was to develop and investigate the application of H decoupling for enhancing the sensitivity for detection of affected HP C metabolic products.

Methods: A standalone H decoupler system and custom concentric C/ H paddle coil setup were integrated with a clinical 3T MRI scanner for in vivo C MR studies using HP [2- C]dihydroxyacetone, a novel sensor of hepatic energy status.

Separation of extra- and intracellular metabolites using hyperpolarized (13)C diffusion weighted MR.

This work demonstrates the separation of extra- and intracellular components of glycolytic metabolites with diffusion weighted hyperpolarized (13)C magnetic resonance spectroscopy. Using b-values of up to 15,000smm(-2), a multi-exponential signal response was measured for hyperpolarized [1-(13)C] pyruvate and lactate. By fitting the fast and slow asymptotes of these curves, their extra- and intracellular weighted diffusion coefficients were determined in cells perfused in a MR compatible bioreactor.

Non-invasive differentiation of benign renal tumors from clear cell renal cell carcinomas using clinically translatable hyperpolarized C pyruvate magnetic resonance.

Localized renal tumors are increasingly detected incidentally at imaging. Conventional imaging cannot reliably differentiate the 20% of these tumors that are benign from malignant renal cell carcinomas (RCCs), leading to unnecessary surgical resection and resulting morbidity associated with surgery. Here, we investigated hyperpolarized C pyruvate metabolism in live patient-derived renal tumor tissue slices using a novel magnetic resonance (MR) -compatible bioreactor platform.

Application of Good's buffers to pH imaging using hyperpolarized (13)C MRI.

N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), one of Good's buffers, was applied to pH imaging using hyperpolarized (13)C magnetic resonance spectroscopy. Rapid NMR- and MRI-based pH measurements were obtained by exploiting the sensitive pH-dependence of its (13)C chemical shift within the physiologic range.

Real-time measurement of hyperpolarized lactate production and efflux as a biomarker of tumor aggressiveness in an MR compatible 3D cell culture bioreactor.

We have developed a 3D cell/tissue culture bioreactor compatible with hyperpolarized (HP) (13)C MR and interrogated HP [1-(13)C]lactate production and efflux in human renal cell carcinoma (RCC) cells. This platform is capable of resolving intracellular and extracellular HP lactate pools, allowing the kinetic measurement of lactate production and efflux in the context of cancer aggressiveness and response to therapy. HP (13)C MR studies were performed on three immortalized human renal cell lines: HK2, a normal renal proximal tubule cell line from which a majority of RCCs arise, UMRC6, a cell line derived from a localized RCC, and UOK262, an aggressive and metastatic RCC.

Metabolic response of prostate cancer to nicotinamide phophoribosyltransferase inhibition in a hyperpolarized MR/PET compatible bioreactor.

Background: Metabolic shifts in disease are of great interest for the development of novel therapeutics. In cancer treatment, these therapies exploit the metabolic phenotype associated with oncogenesis and cancer progression. One recent strategy involves the depletion of the cofactors needed to maintain the high rate of glycolysis seen with the Warburg effect.

Handheld electromagnet carrier for transfer of hyperpolarized carbon-13 samples.

Purpose: Hyperpolarization of carbon-13 ((13) C) nuclei by dissolution dynamic nuclear polarization increases signal-to-noise ratio (SNR) by >10,000-fold for metabolic imaging, but care must be taken when transferring hyperpolarized (HP) samples from polarizer to MR scanner. Some (13) C substrates relax rapidly in low ambient magnetic fields. A handheld electromagnet carrier was designed and constructed to preserve polarization by maintaining a sufficient field during sample transfer.