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Co-imaging of the tumor oxygenation and metabolism using electron paramagnetic resonance imaging and 13-C hyperpolarized magnetic resonance imaging before and after irradiation.

ABSTRACT: To examine the relationship between local oxygen partial pressure and energy metabolism in the tumor, electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) with hyperpolarized [1-13C] pyruvate were performed. SCCVII and HT29 solid tumors implanted in the mouse leg were imaged by EPRI using OX063, a paramagnetic probe and 13C-MRI using hyperpolarized [1-13C] pyruvate. Local partial oxygen pressure and pyruvate metabolism in the two tumor implants were examined. The effect of a single dose of 5-Gy irradiation on the pO2 and metabolism was also investigated by sequential imaging of EPRI and 13C-MRI in HT29 tumors. A phantom study using tubes filled with different concentration of [1-13C] pyruvate, [1-13C] lactate, and OX063 at different levels of oxygen confirmed the validity of this sequential imaging of EPRI and hyperpolarized 13C-MRI. In vivo studies revealed SCCVII tumor had a significantly larger hypoxic fraction (pO2 < 8 mmHg) compared to HT29 tumor. The flux of pyruvate-to-lactate conversion was also higher in SCCVII than HT29. The lactate-to-pyruvate ratio in hypoxic regions (pO2 < 8 mmHg) 24 hours after 5-Gy irradiation was significantly higher than those without irradiation (0.76 vs. 0.36) in HT29 tumor. The in vitro study showed an increase in extracellular acidification rate after irradiation. In conclusion, co-imaging of pO2 and pyruvate-to-lactate conversion kinetics successfully showed the local metabolic changes especially in hypoxic area induced by radiation therapy.

SUBMITTER: Matsuo M

PROVIDER: S-EPMC5982751 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Co-imaging of the tumor oxygenation and metabolism using electron paramagnetic resonance imaging and 13-C hyperpolarized magnetic resonance imaging before and after irradiation.

Matsuo Masayuki M Kawai Tatsuya T Kishimoto Shun S Saito Keita K Munasinghe Jeeva J Devasahayam Nallathamby N Mitchell James B JB Krishna Murali C MC

Oncotarget 20180518 38

To examine the relationship between local oxygen partial pressure and energy metabolism in the tumor, electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) with hyperpolarized [1-13C] pyruvate were performed. SCCVII and HT29 solid tumors implanted in the mouse leg were imaged by EPRI using OX063, a paramagnetic probe and 13C-MRI using hyperpolarized [1-13C] pyruvate. Local partial oxygen pressure and pyruvate metabolism in the two tu ...[more]

PMID: 29861855

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Project description:BackgroundOptimal treatment selection for localized renal tumors is challenging because of their variable biologic behavior and limitations in the preoperative assessment of tumor aggressiveness. The authors investigated the emerging hyperpolarized (HP) 13 C magnetic resonance imaging (MRI) technique to noninvasively assess tumor lactate production, which is strongly associated with tumor aggressiveness.MethodsEleven patients with renal tumors underwent HP 13 C pyruvate MRI before surgical resection. Tumor 13 C pyruvate and 13 C lactate images were acquired dynamically. Five patients underwent 2 scans on the same day to assess the intrapatient reproducibility of HP 13 C pyruvate MRI. Tumor metabolic data were compared with histopathology findings.ResultsEight patients had tumors with a sufficient metabolite signal-to-noise ratio for analysis; an insufficient tumor signal-to-noise ratio was noted in 2 patients, likely caused by poor tumor perfusion and, in 1 patient, because of technical errors. Of the 8 patients, 3 had high-grade clear cell renal cell carcinoma (ccRCC), 3 had low-grade ccRCC, and 2 had chromophobe RCC. There was a trend toward a higher lactate-to-pyruvate ratio in high-grade ccRCCs compared with low-grade ccRCCs. Both chromophobe RCCs had relatively high lactate-to-pyruvate ratios. Good reproducibility was noted across the 5 patients who underwent 2 HP 13 C pyruvate MRI scans on the same day.ConclusionsThe current results demonstrate the feasibility of HP 13 C pyruvate MRI for investigating the metabolic phenotype of localized renal tumors. The initial data indicate good reproducibility of metabolite measurements. In addition, the metabolic data indicate a trend toward differentiating low-grade and high-grade ccRCCs, the most common subtype of renal cancer.Lay summaryRenal tumors are frequently discovered incidentally because of the increased use of medical imaging, but it is challenging to identify which aggressive tumors should be treated. A new metabolic imaging technique was applied to noninvasively predict renal tumor aggressiveness. The imaging results were compared with tumor samples taken during surgery and showed a trend toward differentiating between low-grade and high-grade clear cell renal cell carcinomas, which are the most common type of renal cancers.

Project description:In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium (3He) and xenon (129Xe) gases have reached the stage where they are under study in clinical research. HP 129Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129Xe gas exchange into lung tissue and blood, HP 129Xe MRI is attracting new attention. In parallel, HP 13C and 15N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-13C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13C and 15N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into (1) a brief introduction, (2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, (3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, (4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study: (5) metabolic pathways in cancer and cardiac disease and (6) lung function in both pre-clinical and clinical research studies, concluding with (7) some future directions and challenges, and (8) an overall summary.

Project description:Lipopolysaccharide (LPS) is a commonly used agent for induction of neuroinflammation in preclinical studies. Upon injection, LPS causes activation of microglia and astrocytes, whose metabolism alters to favor glycolysis. Assessing in vivo neuroinflammation and its modulation following therapy remains challenging, and new noninvasive methods allowing for longitudinal monitoring would be highly valuable. Hyperpolarized (HP) 13 C magnetic resonance spectroscopy (MRS) is a promising technique for assessing in vivo metabolism. In addition to applications in oncology, the most commonly used probe of [1-13 C] pyruvate has shown potential in assessing neuroinflammation-linked metabolism in mouse models of multiple sclerosis and traumatic brain injury. Here, we aimed to investigate LPS-induced neuroinflammatory changes using HP [1-13 C] pyruvate and HP 13 C urea. 2D chemical shift imaging following simultaneous intravenous injection of HP [1-13 C] pyruvate and HP 13 C urea was performed at baseline (day 0) and at days 3 and 7 post-intracranial injection of LPS (n = 6) or saline (n = 5). Immunofluorescence (IF) analyses were performed for Iba1 (resting and activated microglia/macrophages), GFAP (resting and reactive astrocytes) and CD68 (activated microglia/macrophages). A significant increase in HP [1-13 C] lactate production was observed at days 3 and 7 following injection, in the injected (ipsilateral) side of the LPS-treated mouse brain, but not in either the contralateral side or saline-injected animals. HP 13 C lactate/pyruvate ratio, without and with normalization to urea, was also significantly increased in the ipsilateral LPS-injected brain at 7 days compared with baseline. IF analyses showed a significant increase in CD68 and GFAP staining at 3 days, followed by increased numbers of Iba1 and GFAP positive cells at 7 days post-LPS injection. In conclusion, we can detect LPS-induced changes in the mouse brain using HP 13 C MRS, in alignment with increased numbers of microglia/macrophages and astrocytes. This study demonstrates that HP 13 C spectroscopy has substantial potential for providing noninvasive information on neuroinflammation.

Dataset Information

Co-imaging of the tumor oxygenation and metabolism using electron paramagnetic resonance imaging and 13-C hyperpolarized magnetic resonance imaging before and after irradiation.

Publications

Co-imaging of the tumor oxygenation and metabolism using electron paramagnetic resonance imaging and 13-C hyperpolarized magnetic resonance imaging before and after irradiation.

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