Kundan Thind

Mapping metabolic changes associated with early Radiation Induced Lung Injury post conformal radiotherapy using hyperpolarized 13C-pyruvate Magnetic Resonance Spectroscopic Imaging

PURPOSE Radiation Pneumonitis (RP) limits radiotherapy. Detection of early metabolic changes in the lungs associated with RP may provide an opportunity to adjust treatment before substantial toxicities occur. In this work, regional lactate-to-pyruvate signal ratio (lac/pyr) was quantified in rat lungs and heart following administration of hyperpolarized (13)C-pyruvate magnetic resonance imaging (MRI) at day 5, 10, 15 and 25-post conformal radiotherapy. These results were also compared to histology and blood analyses. METHODS The lower right lungs of 12 Sprague Dawley rats were irradiated in 2 fractions with a total dose of 18.5 Gy using a modified micro-CT system. Regional lactate and pyruvate data were acquired from three irradiated and three age-matched healthy rats at each time point on days 5, 10, 15 and 25-post radiotherapy. Arterial blood was collected from each animal prior to the (13)C-pyruvate injection and was analyzed for blood lactate concentration and arterial oxygen concentration (paO₂). Macrophage count was computed from the histology of all rat lungs. RESULTS A significant increase in lac/pyr was observed in both right and left lungs of the irradiated cohort compared to the healthy cohort for all time points. No increase in lac/pyr was observed in the hearts of the irradiated cohort compared to the hearts of the healthy cohorts. Blood lactate concentration and paO2 did not show a significant change between the irradiated and the healthy cohorts. Macrophage count in both right and left lungs was elevated for the irradiated cohort compared to the healthy cohort. CONCLUSIONS Metabolic changes associated with RP may be mapped as early as five days post conformal radiotherapy. Over the small sample size in each cohort, elevated macrophage count, consistent with early phase of inflammation was highly correlated to increases in lac/pyr in both the irradiated and unirradiated lungs. Further experiments with larger sample size may improve the confidence of this finding.

Detection of radiation induced lung injury in rats using dynamic hyperpolarized 129Xe magnetic resonance spectroscopy

PURPOSE Radiation induced lung injury (RILI) is a common side effect for patients undergoing thoracic radiation therapy (RT). RILI can lead to temporary or permanent loss of lung function and in extreme cases, death. Combining functional lung imaging information with conventional radiation treatment plans may lead to more desirable treatment plans that reduce lung toxicity and improve the quality of life for lung cancer survivors. Magnetic Resonance Imaging of the lung following inhalation of hyperpolarized(129)Xe may provide a useful nonionizing approach for probing changes in lung function and structure associated with RILI before, during, or after RT (early and late time-points). METHODS In this study, dynamic(129)Xe MR spectroscopy was used to measure whole-lung gas transfer time constants for lung tissue and red blood cells (RBC), respectively (TTr_tissue and TTr_RBC) in groups of rats at two weeks and six weeks following 14 Gy whole-lung exposure to radiation from a (60)Co source. A separate group of six healthy age-matched rats served as a control group. RESULTS TTr_tissue values at two weeks post-irradiation (51.6 ± 6.8 ms) were found to be significantly elevated (p < 0.05) with respect to the healthy control group (37.2 ± 4.8 ms). TTr_RBC did not show any significant changes between groups. TTr_tissue was strongly correlated with TTr_RBC in the control group (r = 0.9601 p < 0.05) and uncorrelated in the irradiated groups. Measurements of arterial partial pressure of oxygen obtained by arterial blood sampling were found to be significantly decreased (p < 0.05) in the two-week group (54.2 ± 12.3 mm Hg) compared to those from a representative control group (85.0 ± 10.0 mm Hg). Histology of a separate group of similarly irradiated animals confirmed the presence of inflammation due to radiation exposure with alveolar wall thicknesses that were significantly different (p < 0.05). At six weeks post-irradiation, TTr_tissue returned to values (35.6 ± 9.6 ms) that were not significantly different from baseline. CONCLUSIONS Whole-lung tissue transfer time constants for(129)Xe (TTr_tissue) can be used to detect the early phase of RILI in a rat model involving 14 Gy thoracic (60)Co exposure as early as two weeks post-irradiation. This knowledge combined with more sophisticated models of gas exchange and imaging techniques, may allow functional lung avoidance radiation therapy planning to be achievable, providing more beneficial treatment plans and improved quality of life for recovering lung cancer patients.

Detection of radiation-induced lung injury using hyperpolarized 13C magnetic resonance spectroscopy and imaging

Radiation‐induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation‐induced lung injury (2–4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized 13C‐pyruvate (pyruvate) and 13C‐lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole‐thorax irradiation (14 Gy). Lactate‐to‐pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age‐matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate‐to‐pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized 13C metabolic MR spectroscopy and imaging for detection of early radiation‐induced lung injury. Magn Reson Med 70:601–609, 2013.

Detection of radiation-induced lung injury using hyperpolarized (13)C magnetic resonance spectroscopy and imaging.

Radiation‐induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation‐induced lung injury (2–4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized 13C‐pyruvate (pyruvate) and 13C‐lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole‐thorax irradiation (14 Gy). Lactate‐to‐pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age‐matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate‐to‐pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized 13C metabolic MR spectroscopy and imaging for detection of early radiation‐induced lung injury. Magn Reson Med 70:601–609, 2013.

Anatomical, functional and metabolic imaging of radiation-induced lung injury using hyperpolarized MRI.

MRI of hyperpolarized 129Xe gas and 13C‐enriched substrates (e.g. pyruvate) presents an unprecedented opportunity to map anatomical, functional and metabolic changes associated with lung injury. In particular, inhaled hyperpolarized 129Xe gas is exquisitely sensitive to changes in alveolar microanatomy and function accompanying lung inflammation through decreases in the apparent diffusion coefficient (ADC) of alveolar gas and increases in the transfer time (Ttr) of xenon exchange from the gas and into the dissolved phase in the lung. Furthermore, metabolic changes associated with hypoxia arising from lung injury may be reflected by increases in lactate‐to‐pyruvate signal ratio obtained by magnetic resonance spectroscopic imaging following injection of hyperpolarized [1‐13C]pyruvate. In this work, the application of hyperpolarized 129Xe and 13C MRI to radiation‐induced lung injury (RILI) is reviewed and results of ADC, Ttr and lactate‐to‐pyruvate signal ratio changes in a rat model of RILI are summarized. These results are consistent with conventional functional (i.e. blood gases) and histological (i.e. tissue density) changes, and correlate significantly with inflammatory cell counts (i.e. macrophages). Hyperpolarized MRI may provide an earlier indication of lung injury associated with radiotherapy of thoracic tumors, potentially allowing adjustment of treatment before the onset of severe complications and irreversible fibrosis. Copyright

Construction and evaluation of a switch‐tuned 13C ‐ 1H birdcage radiofrequency coil for imaging the metabolism of hyperpolarized 13C‐enriched compounds

To construct a switch‐tuned 13C ‐ 1H birdcage radiofrequency (RF) coil system capable of metabolic imaging of hyperpolarized 13C‐enriched metabolic probes for co‐registration with MRI morphology using protons.

Hyperpolarized choline as an MR imaging molecular probe: feasibility of in vivo imaging in a rat model.

To assess the feasibility of choline MRI using a new choline molecular probe for dynamic nuclear polarization (DNP) hyperpolarized MRI.

Longitudinal anatomical and metabolic MRI characterization of orthotopic xenograft prostate tumors in nude mice

To assess anatomic and functional magnetic resonance imaging (MRI) for monitoring of tumor volume and metabolism of orthotopic xenograft prostate cancer tumors.

Detection of radiation-induced lung injury using hyperpolarized13C magnetic resonance spectroscopy and imaging: Detection of RILI

Radiation‐induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation‐induced lung injury (2–4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized 13C‐pyruvate (pyruvate) and 13C‐lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole‐thorax irradiation (14 Gy). Lactate‐to‐pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age‐matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate‐to‐pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized 13C metabolic MR spectroscopy and imaging for detection of early radiation‐induced lung injury. Magn Reson Med 70:601–609, 2013.

TU‐A‐BRC‐06: Using Hyperpolarized 13C Magnetic Resonance Spectroscopy to Detect Radiation Induced Lung Injury at an Early Stage

Purpose: To use hyperpolarized ,13C Magnetic Resonance Spectroscopy for early detection of Radiation Induced Lung Injury (RILI) by quantifying the ratio between metabolites of , 13C‐lactate and ,13C‐pyruvateMethods: Rats were irradiated with dose of 14 Gy to the thorax region to induced RILI using a ,13Co source. The contrast agent, ,13C‐pyruvate was hyperpolarized using Dynamic Nuclear Polarization (DNP) that increases signal intensity by four orders of magnitude. It was injected into the animals two weeks post irradiation and dynamic, 13C‐spectroscopy was performed. Proton Images were acquires prior to the spectroscopy for proper localization of the thorax region. Results: A factor of more than two increase in the,13C‐lactate to,13C‐ pyruvate ratio was observed for the irradiated rats compared to the normal animals. This result supports the hypothesis that an increase in production of lactate is evident with onset of hypoxia, which is a consequence of RILI. Conclusions: Significantly higher ratio of ,13C‐lactate to ,13C‐pyruvate is seen the irradiated animals compared to the normal animals demonstrating the feasibility of using ,13C pyruvate to probe in in vivo metabolism and its use as an early market for onset of RILI.