Oncolytic virotherapy (OV) is a promising treatment for high mortality cancers. To optimize the clinical outcome, non-invasive monitoring is essential. The goal of this work was to develop a deep-learning-based technique for quantitative and rapid molecular imaging of OV treatment response. Two CEST MR-fingerprinting protocols were sequentially implemented (105s each) and incorporated within a deep-reconstruction-network, trained to output the quantitative semi-solid and amide pool exchange parameters. The resulting molecular maps allowed early apoptosis detection in brain tumor OV mouse models. Clinical translation of CEST-MRF is demonstrated in a normal human subject and yielded parameters in good agreement with literature values.
1. Parato, K. A., Senger, D., Forsyth, P. A., and Bell, J. C. Recent progress in the battle between oncolytic viruses and tumours. Nature Reviews Cancer 2005;5(12):965.
2. Russell, S. J., Peng, K.-W., and Bell, J. C. Oncolytic virotherapy. Nature biotechnology 2012;30(7):658.
3. Ribas, A., Dummer, R., Puzanov, I., VanderWalde, A., Andtbacka, R. H., Michielin, O., Olszanski, A. J., Malvehy, J., Cebon, J., Fernandez, E., et al. Oncolytic virotherapy promotes intratumoral t cell infiltration and improves anti-pd-1 immunotherapy. Cell 2017;170(6):1109–1119.
4. Farrar, C. T., Buhrman, J. S., Liu, G., Kleijn, A., Lamfers, M. L., McMahon, M. T., Gilad, A. A., and Fulci, G. Establishing the lysine-rich protein CEST reporter gene as a CEST mr imaging detector for oncolytic virotherapy. Radiology 2015;275(3):746–754.
5. Perlman, O., Cohen O., Ito H., Nakashima, H., Chiocca, EA., Rosen MS, Farrar, CT. Sequential and deep multi-pool CEST MR fingerprinting in in-vivo tumor-bearing mice. in ISMRM Annual Meeting & Exhibition, 1090. Montreal, QC, Canada: International Society for Magnetic Resonance in Medicine; 2019.
6. Kim, M., Gillen, J., Landman, B. A., Zhou, J., and Van Zijl, P. C. Water saturation shift referencing (wassr) for chemical exchange saturation transfer (CEST) experiments. Magn Reson Med. 2009;61(6):1441–1450.
7. Schuenke, P., Windschuh, J., Roeloffs, V., Ladd, M. E., Bachert, P., and Zaiss, M. Simultaneous mapping of water shift and b1 (wasabi) - application to field-inhomogeneity correction of CEST mri data. Magn Reson Med. 2017;77(2):571–580
8. Ma, D., Gulani, V., Seiberlich, N., Liu, K., Sunshine, J. L., Duerk, J. L., and Griswold, M. A. Magnetic resonance fingerprinting. Nature 2103;495(7440):187.
9. Cohen, O., Huang, S., McMahon, M. T., Rosen, M. S., and Farrar, C. T. Rapid and quantitative chemical exchange saturation transfer (CEST) imaging with magnetic resonance fingerprinting (MRF). Magn Reson Med. 2018;80(6):2449–2463.
10. Perlman, O., Herz, K., Zaiss, M., Cohen, O., Rosen, MS., Farrar, CT. CEST MR‐Fingerprinting: Practical considerations and insights for acquisition schedule design and improved reconstruction. Magn Reson Med. 2019;00:1–17. https://doi.org/10.1002/mrm.27937
11. Cohen, O., Zhu, B., and Rosen, M. S. MR fingerprinting deep reconstruction network (DRONE). Magn Reson Med. 2018;80(3):885–894.
12. Zur, R. M., Jiang, Y., Pesce, L. L., and Drukker, K. Noise injection for training artificial neural networks: A comparison with weight decay and early stopping. Med Phys. 2009;36(10):4810–4818.
13. Roeloffs, V., Meyer, C., Bachert, P., and Zaiss, M. Towards quantification of pulsed spinlock and CEST at clinical MR scanners: an analytical interleaved saturation–relaxation (ISAR) approach. NMR in Biomedicine 2015;28(1), 40-53
14. Layton, K. J., Kroboth, S., Jia, F., Littin, S., Yu, H., Leupold, J., Nielsen, J.-F., Stöcker, T., and Zaitsev, M. Pulseq: a rapid and hardware-independent pulse sequence prototyping framework. Magn Reson Med. 2017;77(4):1544–1552.
15. Jeffrey, I. W., Bushell, M., Tilleray, V. J., Morley, S., and Clemens, M. J. Inhibition of protein synthesis in apoptosis: differential requirements by the tumor necrosis factor α family and a dna-damaging agent for caspases and the double-stranded rna-dependent protein kinase. Cancer Research 2002;62(8):2272–2280.
16. Nilsson, C., Johansson, U., Johansson, A.-C., Kågedal, K., and Öllinger, K. Cytosolic acidification and lysosomal alkalinization during tnf-α induced apoptosis in u937 cells. Apoptosis 2006;11(7):1149.
17 Stanisz, G. J., Odrobina, E. E., Pun, J., Escaravage, M., Graham, S. J., Bronskill, M. J., and Henkelman, R. M. T1, T2 relaxation and magnetization transfer in tissue at 3T. Magn Reson Med. 2005;54(3):507–512.
18. Van Zijl, P. C., Zhou, J., Mori, N., Payen, J.-F., Wilson, D., and Mori, S. Mechanism of magnetization transfer during on-resonance water saturation. a new approach to detect mobile proteins, peptides, and lipids. Magn Reson Med. 2003;49(3):440–449.