Mapping Hypoxia in Renal Carcinoma with Oxygen-enhanced MRI: Comparison with Intrinsic Susceptibility MRI and Pathology

Abstract

PurposeTo cross-validate T1-weighted oxygen-enhanced (OE) MRI measurements of tumor hypoxia with intrinsic susceptibility MRI measurements and to demonstrate the feasibility of translation of the technique for patients.Materials and MethodsPreclinical studies in nine 786–0-R renal cell carcinoma (RCC) xenografts and prospective clinical studies in eight patients with RCC were performed. Longitudinal relaxation rate changes (∆R1) after 100% oxygen inhalation were quantified, reflecting the paramagnetic effect on tissue protons because of the presence of molecular oxygen. Native transverse relaxation rate (R2*) and oxygen-induced R2* change (∆R2*) were measured, reflecting presence of deoxygenated hemoglobin molecules. Median and voxel-wise values of ∆R1 were compared with values of R2* and ∆R2*. Tumor regions with dynamic contrast agent–enhanced MRI perfusion, refractory to signal change at OE MRI (referred to as perfused Oxy-R), were distinguished from perfused oxygen-enhancing (perfused Oxy-E) and nonperfused regions. R2* and ∆R2* values in each tumor subregion were compared by using one-way analysis of variance.ResultsTumor-wise and voxel-wise ∆R1 and ∆R2* comparisons did not show correlative relationships. In xenografts, parcellation analysis revealed that perfused Oxy-R regions had faster native R2* (102.4 sec–1 vs 81.7 sec–1) and greater negative ∆R2* (−22.9 sec–1 vs −5.4 sec–1), compared with perfused Oxy-E and nonperfused subregions (all P < .001), respectively. Similar findings were present in human tumors (P < .001). Further, perfused Oxy-R helped identify tumor hypoxia, measured at pathologic analysis, in both xenografts (P = .002) and human tumors (P = .003).ConclusionIntrinsic susceptibility biomarkers provide cross validation of the OE MRI biomarker perfused Oxy-R. Consistent relationship to pathologic analyses was found in xenografts and human tumors, demonstrating biomarker translation.Published under a CC BY 4.0 license.Online supplemental material is available for this article.

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

“…Using an IAUGC 60 map from DCE‐MRI as a mask to obtain Oxy‐R fractions O’Connor et al showed good correlation with the histological hypoxic fraction . In more recent work, Little et al showed oxygen enhancement in tumors with a histological hypoxic fraction as high as 43% and this translated very well to a study of six renal cell carcinoma patients. 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 .…”

“…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.…”

Oxygen‐sensitive MRI assessment of tumor response to hypoxic gas breathing challenge

“…Necrotic regions have been identified using diffusion methods (ADC and IVIM) based on the intrinsic tissue water properties or DCE MRI based on the intravenous infusion of gadolinium contrast agents . BOLD contrast has been compared to the non‐model‐based DCE parameters and showed similar capability of imaging vasculature and revealing intratumoral heterogeneity .…”

“…Necrotic regions have been identified using diffusion methods (ADC and IVIM) based on the intrinsic tissue water properties 66,67 or DCE MRI based on the intravenous infusion of gadolinium contrast agents. 8,68,69 BOLD contrast has been compared to the non-model-based DCE parameters and showed similar capability of imaging vasculature 48 and revealing intratumoral heterogeneity. 63,70 Potential advantages of using BOLD response to classify intratumoral heterogeneity include: 1) BOLD response relates directly to tumor oxygenation 36 ; 2) BOLD measurements can be interleaved with TOLD measurements for a single gas breathing intervention, avoiding the need for an additional scanning sequence such as DCE or IVIM; 3) avoiding the need for exogenous gadolinium contrast agents, which have become controversial for routine use.…”

Evaluating Imaging Biomarkers of Acquired Resistance to Targeted EGFR Therapy in Xenograft Models of Human Head and Neck Squamous Cell Carcinoma

“…Tumor hypoxia is a well-established cause of treatment resistance, adversely affects the prognosis of HNSCC ( 21 , 22 ), and moderates the expression and activation of EGFR ( 26 ). Both intrinsic susceptibility and oxygen-enhanced MRI are being actively exploited for spatially mapping tumor hypoxia in vivo ( 36 , 45 , 48 – 50 ). Oxygen inhalation induced a reduction in of both CAL R and CAL S xenografts, a consequence of a reduction in paramagnetic deoxyhaemoglobin in perfused tumor blood vessels.…”