Developing oxygen-enhanced magnetic resonance imaging as a prognostic biomarker of radiation response

Abstract

Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI) techniques were evaluated as potential non-invasive predictive biomarkers of radiation response. Semi quantitative blood-oxygen level dependent (BOLD) and tissue oxygen level dependent (TOLD) contrast, and quantitative responses of relaxation rates (ΔR1 and ΔR2*) to an oxygen breathing challenge during hypofractionated radiotherapy were applied. OE-MRI was performed on subcutaneous Dunning R3327-AT1 rat prostate tumors (n = 25) at 4.7 T prior to each irradiation (2Fx15 Gy) to the gross tumor volume. Response to radiation, while inhaling air or oxygen, was assessed by tumor growth delay measured up to four times the initial irradiated tumor volume (VQT). Radiation-induced hypoxia changes were confirmed using a double hypoxia marker assay. Inhaling oxygen during hypofractionated radiotherapy significantly improved radiation response. A correlation was observed between the difference in the 2nd and 1st ΔR1 (ΔΔR1) and VQT for air breathing rats. The TOLD response before the 2nd fraction showed a moderate correlation with VQT for oxygen breathing rats. The correlations indicate useful prognostic factors to predict tumor response to hypofractionation and could readily be applied for patient stratification and personalized radiotherapy treatment planning.

The effect of flow on blood oxygen level dependent (R*2) MRI of orthotopic lung tumors

“…Tissues were placed in liquid nitrogen and formalin. Slides for hematoxylin and eosin (H&E) were fixed in 4% paraformaldehyde, rinsed, and then subjected to a progressive staining line containing Leica SelecTech reagents (Hematoxylin 560 and Alcoholic Eosin‐Y 515; Leica Biosystems, Wetzlar, Germany) according to well‐established standard protocols . At the time of imaging, multiple 1600 × 1200 pixel subfields were acquired to cover the entire tumor and surrounding tissue at 10× objective magnification on a Nikon E600 compound photomicroscope (Nikon USA, Melville, NY) equipped with epifluorescence and bright‐field illumination, an Applied Scientific Instruments x‐y‐z motorized stage (Applied Scientific Instruments, Eugene, OR), and a Nikon DS‐Fi2 CCD camera.…”

Assessing Tumor Oxygenation for Predicting Outcome in Radiation Oncology: A Review of Studies Correlating Tumor Hypoxic Status and Outcome in the Preclinical and Clinical Settings

“…Prostate tumors that are well reoxygenated during pure oxygen breathing before radiotherapy display a significantly larger regrowth delay than low responders to hyperoxia (92). Combined BOLD and TOLD contrasts were also recently assessed in Dunning rat prostate tumors and were shown to be useful prognostic factors for predicting tumor response to hypofractionation (121). However, these results remain preliminary and need to be further investigated.…”

Fast and sensitive dynamic oxygen‐enhanced MRI with a cycling gas challenge and independent component analysis

“…Linnik et al reported excellent correlation between percentage of “negative AUC OE ” ( O 2 ‐negative) voxels and percentage of hypoxic areas in the highly vascular preclinical U87MG tumor xenografts . A second approach for differentiating between viable but hypoxic regions and unperfused dead tissues, is to combine OE‐MRI with W acquisition and the BOLD effect to classify regions that show both effects. Excess oxygen in the blood will induce changes in Hb saturation, which alter the resulting in a robust measure of areas with functioning vasculature.…”

“…To help understand the oxygen dynamics in tumors, including the effect of hemoglobin with T mapping, fitting exponential recovery and decay curves to the extracted oxygen response curves may provide additional insights as originally proposed by Losert et al in the brain . In a promising study, White et al has shown that OE‐MRI may be very relevant in developing prognostic factors to predict tumor response to hypofractionation by stratifying tumors that may benefit from oxygen breathing during irradiation . Featherstone et al have recently explored pre‐clinical datasets using feature‐extraction and clustering analysis and this may prove fruitful in understanding the behavior of subregions within a tumor microenvironment .…”

“…32 In a promising study, White et al has shown that OE-MRI may be very relevant in developing prognostic factors to predict tumor response to hypofractionation by stratifying tumors that may benefit from oxygen breathing during irradiation. 14 Featherstone et al have recently explored pre-clinical datasets using feature-extraction and clustering analysis and this may prove fruitful in understanding the behavior of subregions within a tumor microenvironment. 39 Future work to evaluate the utility of dOE-MRI will ultimately depend on its context-dependent validation as a relevant measure of tumor hypoxia to dynamically characterize the clinically relevant oxygen status of tumors, relating this information to treatment sensitivities and outcomes.…”