Radio-Iodide Treatment: From Molecular Aspects to the Clinical View
Round 1
Reviewer 1 Report
Brief summary:
The review presented by De la Vieja et al. is a well-written, well-organized and well-illustrated paper. It summarizes the results of original research and makes a valuable contribution to knowledge and
understanding of the molecular mechanisms underlying radio-iodide therapy in thyroid cancer. Minor revisions are requested.
Broad Comments
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The authors discuss how excess iodine triggers several responses in the thyroid. One of the pathways recently described is the regulation of the eIF4 and p70S6K signaling pathway that is dependent on mTOR. Although this pathway was studied in the context of iodinated contrast media-mediated inhibition of thyroid uptake, it appeared to be regulated in a similar way in response to circulating iodide in mice. This has been discussed in the following reference : Hichri M et al, J Clin Med, 2020, doi: 10.3390/jcm9020329.
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The authors state that “A low iodine diet will allow for low levels of iodized TG before therapy, and more TG available to be organified by radioiodine. This would consequently increase the effectiveness of the treatment.” Accordingly, an increased thyroid uptake was experimentally demonstrated, in particular by Zwarthoed C, et al. (Thyroid. 2016. doi: 10.1089/thy.2015.0652). These data highlight the importance of low iodide diet, both in euthyroid and T3-treated, rhTSH-injected mice. Extrapolated to human patients, and in the context of clinical guidelines for the preparation of differentiated thyroid cancer patients, these data indicate that low iodide diet can potentiate the efficacy of rhTSH treatment in T3-treated patients.
3. The paper discusses the fact that the isotopes that could have a minor stunning effect would be those that are not Tg-organified, such as 99mTcO4-. This assumption can be strengthened by a dedicated study which addressed the ⁹⁹mTcO₄-, auger-mediated thyroid stunning, its dosimetric requirements and associated molecular events. In brief, 99mTcO4--mediated thyroid stunning was observed in mouse thyroid, associated with a reduced level of functional NIS protein, with no significant cell death and reversible within a few days. The threshold of the absorbed dose in the thyroid required to obtain a significant stunning effect was in the range of 20 Gy, a level unlikely to be encountered in clinical practice (Cambien B. et al, PLoS One, 2014, doi: 10.1371/journal.pone.0092729).
Author Response
Response to Reviewer 1 Comments
Comments and Suggestions for Authors
Brief summary:
The review presented by De la Vieja et al. is a well-written, well-organized and well-illustrated paper. It summarizes the results of original research and makes a valuable contribution to knowledge and understanding of the molecular mechanisms underlying radio-iodide therapy in thyroid cancer. Minor revisions are requested.
Thank you very much for your comments on the article. The three articles the reviewer mentions are definitely important. All 3, and one more related, have been included in the respective sections indicated below. These works provide added value to these sections. Thank you very much for the suggestions and for the thorough review of the work.
Broad Comments
1: The authors discuss how excess iodine triggers several responses in the thyroid. One of the pathways recently described is the regulation of the eIF4 and p70S6K signaling pathway that is dependent on mTOR. Although this pathway was studied in the context of iodinated contrast media-mediated inhibition of thyroid uptake, it appeared to be regulated in a similar way in response to circulating iodide in mice. This has been discussed in the following reference: Hichri M et al, J Clin Med, 2020, doi: 10.3390/jcm9020329.
Response 1: An extensive commentary of this paper has been included given the importance of the published results for the content of the review.
Comment in: Page 5, lines 17-189
New data included in Table 2
New References included:
- Hichri, M., G. Vassaux, J. M. Guigonis, T. Juhel, F. Graslin, J. Guglielmi, T. Pourcher, and B. Cambien. "Proteomic Analysis of Iodinated Contrast Agent-Induced Perturbation of Thyroid Iodide Uptake." J Clin Med 9, no. 2 (2020).
- Vassaux, G., C. Zwarthoed, L. Signetti, J. Guglielmi, C. Compin, J. M. Guigonis, T. Juhel, O. Humbert, D. Benisvy, T. Pourcher, and B. Cambien. "Iodinated Contrast Agents Perturb Iodide Uptake by the Thyroid Independently of Free Iodide." J Nucl Med 59, no. 1 (2018): 121-26.
- Garcia, B., and P. Santisteban. "Pi3k Is Involved in the Igf-I Inhibition of Tsh-Induced Sodium/Iodide Symporter Gene Expression." Mol Endocrinol 16, no. 2 (2002): 342-52.
- Kogai, T., S. Sajid-Crockett, L. S. Newmarch, Y. Y. Liu, and G. A. Brent. "Phosphoinositide-3-Kinase Inhibition Induces Sodium/Iodide Symporter Expression in Rat Thyroid Cells and Human Papillary Thyroid Cancer Cells." J Endocrinol 199, no. 2 (2008): 243-52.
- Zaballos, M. A., B. Garcia, and P. Santisteban. "Gbetagamma Dimers Released in Response to Thyrotropin Activate Phosphoinositide 3-Kinase and Regulate Gene Expression in Thyroid Cells." Mol Endocrinol 22, no. 5 (2008): 1183-99.
2: The authors state that “A low iodine diet will allow for low levels of iodized TG before therapy, and more TG available to be organified by radioiodine. This would consequently increase the effectiveness of the treatment.” Accordingly, an increased thyroid uptake was experimentally demonstrated, in particular by Zwarthoed C, et al. (Thyroid. 2016. doi: 10.1089/thy.2015.0652). These data highlight the importance of low iodide diet, both in euthyroid and T3-treated, rhTSH-injected mice. Extrapolated to human patients, and in the context of clinical guidelines for the preparation of differentiated thyroid cancer patients, these data indicate that low iodide diet can potentiate the efficacy of rhTSH treatment in T3-treated patients.
Response 2: Indeed, the work mentioned by the reviewer shows that a low iodine diet increases iodine uptake. Although the work is done in euthyroid mice, not in the tumoral cell context, the results support the statement of the article, therefore the comment of the results of said article has been included in the review.
Comment in page 6, lines 224-230
New reference included:
- Zwarthoed, C., K. Chatti, J. Guglielmi, M. Hichri, C. Compin, J. Darcourt, G. Vassaux, D. Benisvy, T. Pourcher, and B. Cambien. "Single-Photon Emission Computed Tomography for Preclinical Assessment of Thyroid Radioiodide Uptake Following Various Combinations of Preparative Measures." Thyroid 26, no. 11 (2016): 1614-22.
3: The paper discusses the fact that the isotopes that could have a minor stunning effect would be those that are not Tg-organified, such as 99mTcO4-. This assumption can be strengthened by a dedicated study which addressed the ⁹⁹mTcO₄-, auger-mediated thyroid stunning, its dosimetric requirements and associated molecular events. In brief, 99mTcO4--mediated thyroid stunning was observed in mouse thyroid, associated with a reduced level of functional NIS protein, with no significant cell death and reversible within a few days. The threshold of the absorbed dose in the thyroid required to obtain a significant stunning effect was in the range of 20 Gy, a level unlikely to be encountered in clinical practice (Cambien B. et al, PLoS One, 2014, doi: 10.1371/journal.pone.0092729).
Response 3: Thanks again for the comment and for contributing with a relevant work to the content of the review.
Comment in page 13, lines 533-535
New reference included:
- Cambien, B., P. R. Franken, A. Lamit, T. Mauxion, P. Richard-Fiardo, J. Guglielmi, L. Crescence, B. Mari, T. Pourcher, J. Darcourt, M. Bardies, and G. Vassaux. "(9)(9)Mtco(4)--, Auger-Mediated Thyroid Stunning: Dosimetric Requirements and Associated Molecular Events." PLoS One 9, no. 3 (2014): e92729
Reviewer 2 Report
The review is well written and gives an update on the molecular biology underlying radioidine treatment in thyroid cancer. I have no major issue. There are only minor typos/mistakes to correct:
page 3 line 99 "physiology-The main." maybe the bar is an error..
page 7, line 257 Noth1 is maybe Notch1?
please spell out the acronym of ROS species the first time is used (reactive oxygen species).
Author Response
Response to Reviewer 2 Comments
Comments and Suggestions for Authors
The review is well written and gives an update on the molecular biology underlying radioidine treatment in thyroid cancer. I have no major issue. There are only minor typos/mistakes to correct:
Thank you very much for your comments on the article. All three typos have been corrected in the new version. Thank you very much for the suggestions and for the thorough review of the work.
page 3, line 99 "physiology-The main." => page 3, line 100: "physiology. The main"
page 7, line 257 Noth1 is maybe Notch1? => page 7, line 276: Notch1
please spell out the acronym of ROS species the first time is used (reactive oxygen species).
=> page 2, Figure legend in Figure 1 and in page 5, line 176.
