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

Ross Little; Yann Jamin; Jessica K R Boult; Josephine Naish; Yvonne Watson; Susan Cheung; Katherine Holliday; Huiqi Lu; Damien Mchugh; Joely Irlam; Catharine West; Guy Betts; Garry Ashton; Andrew R. Reynolds; Satish Maddineni; Noel W Clarke; Geoff JM Parker; John Waterton; Simon P. Robinson; James O'Connor

doi:10.1148/radiol.2018171531

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

Ross Little, Yann Jamin, Jessica K R Boult, Josephine Naish, Yvonne Watson, Susan Cheung, Katherine Holliday, Huiqi Lu, Damien Mchugh, Joely Irlam, Catharine West, Guy Betts, Garry Ashton, Andrew R. Reynolds, Satish Maddineni, Noel W Clarke, Geoff JM Parker, John Waterton, Simon P. Robinson, James O'Connor

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Abstract

Intrinsic susceptibility imaging and immunohistochemistry analysis were used to validate a combined endpoint of oxygen enhancement plus MR-derived perfusion as a biomarker of tumor hypoxia in mouse and patient studies. Purpose To 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 Methods Preclinical 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. Results Tumor-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). Conclusion Intrinsic 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.

Original language	English
Pages (from-to)	739-747
Journal	Radiology
Volume	288
Issue number	3
Early online date	5 Jun 2018
DOIs	https://doi.org/10.1148/radiol.2018171531
Publication status	Published - 2018

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10.1148/radiol.2018171531

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Little, R., Jamin, Y., Boult, J. K. R., Naish, J., Watson, Y., Cheung, S., Holliday, K., Lu, H., Mchugh, D., Irlam, J., West, C., Betts, G., Ashton, G., Reynolds, A. R., Maddineni, S., Clarke, N. W., Parker, G. JM., Waterton, J., Robinson, S. P., & O'Connor, J. (2018). Mapping Hypoxia in Renal Carcinoma with Oxygen-enhanced MRI: Comparison with Intrinsic Susceptibility MRI and Pathology. Radiology, 288(3), 739-747. https://doi.org/10.1148/radiol.2018171531

@article{9bee1bdfc06d4771bcb4b149f9726973,

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

abstract = "Intrinsic susceptibility imaging and immunohistochemistry analysis were used to validate a combined endpoint of oxygen enhancement plus MR-derived perfusion as a biomarker of tumor hypoxia in mouse and patient studies. Purpose To 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 Methods Preclinical 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. Results Tumor-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). Conclusion Intrinsic 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.",

author = "Ross Little and Yann Jamin and Boult, {Jessica K R} and Josephine Naish and Yvonne Watson and Susan Cheung and Katherine Holliday and Huiqi Lu and Damien Mchugh and Joely Irlam and Catharine West and Guy Betts and Garry Ashton and Reynolds, {Andrew R.} and Satish Maddineni and Clarke, {Noel W} and Parker, {Geoff JM} and John Waterton and Robinson, {Simon P.} and James O'Connor",

year = "2018",

doi = "10.1148/radiol.2018171531",

language = "English",

volume = "288",

pages = "739--747",

journal = "Radiology",

issn = "0033-8419",

publisher = "Radiological Society of North America",

number = "3",

}

Little, R, Jamin, Y, Boult, JKR, Naish, J, Watson, Y, Cheung, S, Holliday, K, Lu, H, Mchugh, D, Irlam, J, West, C, Betts, G, Ashton, G, Reynolds, AR, Maddineni, S, Clarke, NW, Parker, GJM, Waterton, J, Robinson, SP & O'Connor, J 2018, 'Mapping Hypoxia in Renal Carcinoma with Oxygen-enhanced MRI: Comparison with Intrinsic Susceptibility MRI and Pathology', Radiology, vol. 288, no. 3, pp. 739-747. https://doi.org/10.1148/radiol.2018171531

TY - JOUR

T1 - Mapping Hypoxia in Renal Carcinoma with Oxygen-enhanced MRI

T2 - Comparison with Intrinsic Susceptibility MRI and Pathology

AU - Little, Ross

AU - Jamin, Yann

AU - Boult, Jessica K R

AU - Naish, Josephine

AU - Watson, Yvonne

AU - Cheung, Susan

AU - Holliday, Katherine

AU - Lu, Huiqi

AU - Mchugh, Damien

AU - Irlam, Joely

AU - West, Catharine

AU - Betts, Guy

AU - Ashton, Garry

AU - Reynolds, Andrew R.

AU - Maddineni, Satish

AU - Clarke, Noel W

AU - Parker, Geoff JM

AU - Waterton, John

AU - Robinson, Simon P.

AU - O'Connor, James

PY - 2018

Y1 - 2018

N2 - Intrinsic susceptibility imaging and immunohistochemistry analysis were used to validate a combined endpoint of oxygen enhancement plus MR-derived perfusion as a biomarker of tumor hypoxia in mouse and patient studies. Purpose To 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 Methods Preclinical 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. Results Tumor-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). Conclusion Intrinsic 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.

AB - Intrinsic susceptibility imaging and immunohistochemistry analysis were used to validate a combined endpoint of oxygen enhancement plus MR-derived perfusion as a biomarker of tumor hypoxia in mouse and patient studies. Purpose To 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 Methods Preclinical 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. Results Tumor-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). Conclusion Intrinsic 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.

U2 - 10.1148/radiol.2018171531

DO - 10.1148/radiol.2018171531

M3 - Article

SN - 0033-8419

VL - 288

SP - 739

EP - 747

JO - Radiology

JF - Radiology

IS - 3

ER -

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

Abstract

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