Comments

Dear Researchers,

First of all, thank you very much for submitting your work to Technology in Cancer Research & Treatment.

These is my review of your draft entitled “Chemical Exchange Saturation Transfer MRI: What NeuroOncology Clinicians Need To Know”

1.Page 2, Line 23-28
The papers on CEST imaging with exogenous contrast agents are very very relevant. These papers can help clinicians to know exogenous contrast agents better.
(1)Farrar CT, Buhrman JS, Liu G, Kleijn A, Lamfers ML, McMahon MT, Gilad AA, Fulci G. Establishing the Lysine-rich Protein CEST Reporter Gene as a CEST MR Imaging Detector for Oncolytic Virotherapy. Radiology. 2015,275(3):746-54.
(2)Ren J, Trokowski R, Zhang S, Malloy CR, Sherry AD. Imaging the tissue distribution of glucose in livers using a PARACEST sensor. Magn Reson Med. 2008,60(5):1047-55.

2.Page 5, Line 10-19
There are many ways to obtain APT and NOE-weighted maps: magnetisation transfer ratio (MTR) asymmetry (MTRasym) and Lorentzian difference (LD), the latter of which is not mentioned in this paper and is not comprehensive enough. APT measurement is affected by nuclear overhauser effects (NOE). Therefore, to realise the full potential of APT, methods to remove or separate the NOE effect need to be developed.
Zaiss M, Schmitt B, Bachert P. Quantitative separation of CEST effect from magnetization transfer and spillover effects by Lorentzian-line-fit analysis of z-spectra. J Magn Reson. 2011 Aug;211(2):149-55. doi: 10.1016/j.jmr.2011.05.001.
For tumours, some studies found that LD amide gave greater effect sizes than MTRasym for distinguishing non-enhancing gliomas from normal-appearing white matter.
Warnert EAH, Wood TC, Incekara F, Barker GJ, Vincent AJP, Schouten J, Kros JM, van den Bent M, Smits M, Tamames JAH. Mapping tumour heterogeneity with pulsed 3D CEST MRI in non-enhancing glioma at 3 T. MAGMA. 2022,35(1):53-62. doi: 10.1007/s10334-021-00911-6.

3.Page 8, Line 2
It was noted that the authors emphasised that the rNOE signal could be minimised by using higher RF amplitudes (˃2 μT). In fact, the lowest contrast of NOE is obtained when using B1 saturation powers greater than 2 µT. However, the NOE effect can't be completely eliminated. At high B1 power (˃2 µT), the contribution of magnetisation transfer contrast (MTC) to the saturated CEST signal becomes greater than the effects of APT and NOE. High B1 power is not recommended for normal use.
(1)Wu Y, Wood TC, Arzanforoosh F, Hernandez-Tamames JA, Barker GJ, Smits M, Warnert EAH. 3D APT and NOE CEST-MRI of healthy volunteers and patients with non-enhancing glioma at 3 T. MAGMA. 2022,35(1):63-73.
(2)Deshmane A et al (2019) 3D gradient echo snapshot CEST MRI
with low power saturation for human studies at 3T. Magn Reson
Med 81(4):2412-2423.
(3)van Zijl PCM, Lam WW, Xu J, et al. Magnetization Transfer Contrast and Chemical Exchange Saturation Transfer MRI. Features and analysis of the field-dependent saturation spectrum. Neuroimage. 2018,168:222-241. doi: 10.1016/j.neuroimage.2017.04.045.

4.Page 8, Line 3
In this paper, you mentioned “ rNOE is itself an emerging MR biomarker in neuro-oncology. The details outside the scope of this review.”
Obviously such an point of view will not be completely correct. Clinical application of chemical exchange saturation transfer (CEST) can be performed with investigation of amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) effects. The use of the rNOE-CEST effect for imaging is of unique importance and this effect will have implications for imaging with APT techniques. It is important to introduce NOE to neuro-oncology clinicians. These are some of the key papers:
(1)Zhou J, Hong X, Zhao X, Gao JH, Yuan J. APT-weighted and NOE-weighted image contrasts in glioma with different RF saturation powers based on magnetization transfer ratio asymmetry analyses. Magn Reson Med. 2013,70(2):320-7. doi: 10.1002/mrm.24784.
(2)Heo HY, Zhang Y, Lee DH, Hong X, Zhou J. Quantitative assessment of amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging with extrapolated semi-solid magnetization transfer reference (EMR) signals: Application to a rat glioma model at 4.7 Tesla. Magn Reson Med. 2016,75(1):137-49. doi: 10.1002/mrm.25581.
(3)Zaiss M, Windschuh J, Paech D, et al. Relaxation-compensated CEST-MRI of the human brain at 7T: Unbiased insight into NOE and amide signal changes in human glioblastoma. Neuroimage. 2015, 15;112:180-188. doi: 10.1016/j.neuroimage.2015.02.040.
The use of NOE in oncology is also a hot topic of research. Some studies showed NOE-weighted CEST signal were correlated with prognosis and grading of high-grade glioma. The author should add this part. These are very important papers as following:
(1)Paech D, Windschuh J, Oberhollenzer J, et al. Assessing the predictability of IDH mutation and MGMT methylation status in glioma patients using relaxation-compensated multipool CEST MRI at 7.0 T. Neuro Oncol. 2018,20(12):1661-1671. doi: 10.1093/neuonc/noy073.
(2)Regnery S, Adeberg S, Dreher C, et al. Chemical exchange saturation transfer MRI serves as predictor of early progression in glioblastoma patients. Oncotarget. 2018,9(47):28772-28783. doi: 10.18632/oncotarget.25594.
(3)Heo HY, Jones CK, Hua J, et al. Whole-brain amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging in glioma patients using low-power steady-state pulsed chemical exchange saturation transfer (CEST) imaging at 7T. J Magn Reson Imaging. 2016 ,44(1):41-50. doi: 10.1002/jmri.25108.

5.Page 12, Line 3
There are many other clinical applications of CEST that the author should add. By comparing the APT signals in the area of peritumour oedema, different brain tumours can be distinguished from each other by comparing the APT signals in the area of peritumour oedema.
(1)Yu H, Lou H, Zou T, et al. Applying protein-based amide proton transfer MR imaging to distinguish solitary brain metastases from glioblastoma. Eur Radiol. 2017,27(11):4516-4524. doi: 10.1007/s00330
-017-4867-z.
(2)Jiang S, Yu H, Wang X, et al. Molecular MRI differentiation between primary central nervous system lymphomas and high-grade gliomas using endogenous protein-based amide proton transfer MR imaging at 3 Tesla. Eur Radiol. 2016,26(1):64-71. doi: 10.1007/s00330-015-3805-1.

It is well revised and can be accepted now.