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Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides

Abstract

It remains difficult to distinguish tumor recurrence from radiation necrosis after brain tumor therapy. Here we show that these lesions can be distinguished using the amide proton transfer (APT) magnetic resonance imaging (MRI) signals of endogenous cellular proteins and peptides as an imaging biomarker. When comparing two models of orthotopic glioma (SF188/V+ glioma and 9L gliosarcoma) with a model of radiation necrosis in rats, we could clearly differentiate viable glioma (hyperintense) from radiation necrosis (hypointense to isointense) by APT MRI. When we irradiated rats with U87MG gliomas, the APT signals in the irradiated tumors had decreased substantially by 3 d and 6 d after radiation. The amide protons that can be detected by APT provide a unique and noninvasive MRI biomarker for distinguishing viable malignancy from radiation necrosis and predicting tumor response to therapy.

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Figure 1: MRI characteristics of radiation necrosis (40 Gy, 178 d after radiation; black solid arrow) in a rat.
Figure 2: Comparison of radiation necrosis and glioma by conventional MRI.
Figure 3: Comparison of radiation necrosis and glioma using APT MRI and histology.
Figure 4: Quantitative comparison of APT image intensities (in percentage change of bulk water signal intensity) for radiation necrosis and glioma.
Figure 5: Changes in APT signal intensity (in percentage change of bulk water signal intensity) for the radiated U87MG tumors as a function of time after radiation (40 Gy; before radiation, 3 d after radiation and 6 d after radiation).

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Acknowledgements

This work was supported by the US National Institutes of Health grants EB009112, EB009731 and P41 RR015241 and by the Dana Foundation, American Physicians Fellowship and Brain Tumor Funders' Collaborative. We thank J. Zhang for help in pathology experiments and M. McAllister for editorial assistance. SF188/V+ cells used in this study were a gift from J. Gallo (Temple University).

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Authors and Affiliations

Authors

Contributions

J.Z. developed the APT methodology, designed and performed most of the MRI experiments, carried out data analysis, prepared figures, wrote the manuscript and supervised the project. E.T. and E.F. designed and performed the radiation experiments and contributed to manuscript preparation. Z.W. contributed to MRI experimental work and histological analysis, contributed to manuscript preparation and provided helpful discussions on related clinical issues. B.L. performed experimental work in the tumor models and performed pathology experiments. T.Z. contributed to MRI experimental work, statistical analysis and manuscript preparation. R.G. and B.T. contributed to experimental work, especially in the tumor models, and manuscript preparation. S.W. contributed to MRI experimental work, performed histological analysis and statistical analysis, prepared some figures and contributed to manuscript preparation. K.Y. & D.-X.F. contributed to experimental work and data analysis. J.B. and J.L. contributed to experimental design and manuscript preparation and provided helpful discussions on related clinical issues. P.C.M.v.Z. developed the APT methodology, contributed to experimental design and edited the manuscript.

Corresponding author

Correspondence to Jinyuan Zhou.

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Competing interests

J.Z. and P.C.M.v.Z. are co-inventors on a patent at the US Patent and Trademark Office for the APT technology. This patent is owned and managed by Johns Hopkins University.

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Supplementary Figures 1–3, Supplementary Tables 1 and 2, Supplementary Discussion and Supplementary Methods (PDF 342 kb)

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Zhou, J., Tryggestad, E., Wen, Z. et al. Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides. Nat Med 17, 130–134 (2011). https://doi.org/10.1038/nm.2268

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