Elevated Levels of Serum Biomarkers Associated with Damage to the CNS Neurons and Endothelial Cells Are Linked with Changes in Brain Connectivity in Breast Cancer Patients with Vestibulo-Atactic Syndrome
, Maria Pospelova 1, Varvara Krasnikova 1, Albina Makhanova 1, Samvel Tonyan 1, Yurii Krasnopeev 1, Evgeniya Kayumova 1, Elena Vasilieva 1, Aleksandr Efimtsev 1, Anatoliy Levchuk 1, Gennadiy Trufanov 1, Mark Voynov 1 and Maxim Shevtsov 1,2,*Round 1
Reviewer 1 Report
All corrections should be done before the start of publication process
There is no highlights ---should be
The abstract should be improved and contained background including the aims , Methods, Results and Conclusion
The authors used a huge a mounts of abbreviations---he should tabulate all and be detailed then abbreviate for the ordinary readers
LN/39-40---add neuroimaging , connectomes , cognitive impairment and quality life of patient to the keywords
LN/28---add registered instead of enrolled
LN/29-30----the increased levels are reasonable---what is the new about this or Novel ????
LN/36---damage to CNS neurons and endothelial ---explain with more additional data and what about the pathology of white matter that is well known in damaging in case of BC ???
LN/43---GLOBOCAN---you should detailed then abbreviate---clear this for ordinary readers and what about WHO classification for BC ???
The BC is originated from outside the brain --so what is the relation between it and cognitive impairment of the brain ????
The vulnerability of the post-breast cancer brain network to future neurodegenerative process is increased---clear this also
LN/53----more details are needed
LN/58---add reference
LN/60-61----pathogenesis is very important
LN/66---cicatrical changes---do you have any gross picture for this ?
LN/113-114---the aim of the present study should be written at the end of introduction
Introduction is very long ----be more concise and summarize
Write as Table(1):---------, Fig.(1):------------etc---apply for all
LN/155---the authors did not mention which type of BC he had detected(diagnosed)---papillary, colloid , tubular,DCI ,IBS--etc)
LN/163-167---the exclusion criteria done according to whom or why ??
The most used methodology ---without any references ???
There is no reference for the statistical analysis---why ??
There is no even one picture histologic or grossly for the tumor ??/
There is no pathological scores ???
Are there any suggested recommendations to decreased the degree of invasiveness of the surgical technique (decrease the complications) or improve the methods of diagnosis (what about the other types -tumor markers ??? )
Results should be more summarize
Discussion should be based upon debating the obtained results with those of the previous investigators results
Discussion also very long
LN/363---add reference
LN/371-373---delete --as it mentioned in materials and methods
There is no acknowledgement
The most cited references contained more than 6 authors ---why ???should be 6 at the maximum plus etal with the last ones --apply for all
We don't add etal with the reference lists unless the total number of authors exceed than 6
As volume , issue , number and pages ---all are available so no need for the link(s)---apply for all
Some cited references need to be more update
Some journal names were written abbreviated , while others were not ---why ??? same style should be ---apply for all
What a huge number of used references (57) ????
Comments for author File: 
Comments.pdf
Author Response
We would like to thank the reviewer for the provided comments. We have substantially revised the manuscript according to the raised questions. Please find the answers to the comments below.
COMMENT 1: The abstract should be improved and contained background including the aims , Methods, Results and Conclusion
ANSWER 1: Dear reviewer, we thank you for your comment. It would probably be more logical and clear to divide the abstract into sections materials, methods, results and conclusions. But, unfortunately, the MDPI editorial rules do not offer us such an opportunity.
COMMENT 2: The authors used a huge a mounts of abbreviations---he should tabulate all and be detailed then abbreviate for the ordinary readers
ANSWER 2: We have added the list of abbreviations.
COMMENT 3: LN/39-40---add neuroimaging , connectomes , cognitive impairment and quality life of patient to the keywords
ANSWER 3: We have added the suggested keywords.
COMMENT 4: LN/28---add registered instead of enrolled
ANSWER 4: We have corrected this.
COMMENT 5: LN/29-30----the increased levels are reasonable---what is the new about this or Novel ????
ANSWER 5: We novelty is in the first time evaluation of these markers in this subgroup of patients (BCS with VAS) and association with the fMRI data.
COMMENT 6: LN/36---damage to CNS neurons and endothelial ---explain with more additional data and what about the pathology of white matter that is well known in damaging in case of BC ???
ANSWER 6: We have added references.
COMMENT 7: LN/43---GLOBOCAN---you should detailed then abbreviate---clear this for ordinary readers and what about WHO classification for BC ???
ANSWER 7: We have corrected this.
COMMENT 8: The BC is originated from outside the brain --so what is the relation between it and cognitive impairment of the brain ????
ANSWER 8: We have added a clarification in the Introduction section the notion about the influence of radio- and chemotherapy for BC on the CNS.
COMMENT 9: The vulnerability of the post-breast cancer brain network to future neurodegenerative process is increased---clear this also
ANSWER 9: This was corrected.
COMMENT 10: LN/53----more details are needed
ANSWER 10: This was corrected.
COMMENT 11: LN/58---add reference
ANSWER 11: Reference was added.
COMMENT 12: LN/66---cicatrical changes---do you have any gross picture for this ?
ANSWER 12: We do not have picture of the cicatrical changes.
COMMENT 13: LN/113-114---the aim of the present study should be written at the end of introduction
ANSWER 13: We have added the description of the study purpose into the Introduction section.
COMMENT 14: Introduction is very long ----be more concise and summarize
ANSWER 14: We have revised the Introduction.
COMMENT 15: Write as Table(1):---------, Fig.(1):------------etc---apply for all
ANSWER 15: We have corrected the notion of tables and figures throughout the manuscript according to the journal rules.
COMMENT 16: LN/155---the authors did not mention which type of BC he had detected(diagnosed)---papillary, colloid , tubular,DCI ,IBS--etc)
ANSWER 16: According to the approved study protocol we did not evaluate the correlation between the detected markers, fMRI data and histology of the tumor due to the low number of patients in the study group (BC with VAS).
COMMENT 17: LN/163-167---the exclusion criteria done according to whom or why ??
ANSWER 17: We have added the reference and notion that the exclusion and inclusion criteria were approved along with a study protocol by ethical committee.
COMMENT 18: The most used methodology ---without any references ???
ANSWER 18: We added the references.
COMMENT 19: There is no even one picture histologic or grossly for the tumor ??/
ANSWER 19: We did not include the figure of the tumor as these patients were registered into this study following there discharge from the hospital.
COMMENT 20: There is no pathological scores ???
ANSWER 20: 6: According to the approved study protocol we did not evaluate the correlation between the detected markers, fMRI data and histology of the tumor due to the low number of patients in the study group (BC with VAS).
COMMENT 21: Are there any suggested recommendations to decreased the degree of invasiveness of the surgical technique (decrease the complications) or improve the methods of diagnosis (what about the other types -tumor markers ??? )
ANSWER 21: In the current study we observed the association between the serum levels of markers (ICAM-1, PECAM-1, NSE) and fMRI data in BC patients with VAS. We plan to further increase the study group to elaborate clinical recommendations.
COMMENT 22: Discussion should be based upon debating the obtained results with those of the previous investigators results
ANSWER 22: We have revised the Discussion section.
COMMENT 23: Discussion also very long
ANSWER 23: We have revised the Discussion section.
COMMENT 24: LN/363---add reference
ANSWER 24: It was added.
COMMENT 25: LN/371-373---delete --as it mentioned in materials and methods
ANSWER 25: This was corrected.
COMMENT 26: There is no acknowledgement
ANSWER 26: We added the Funding information into the Funding section but not into the Acknowledgement section.
COMMENTS 27-32: The most cited references contained more than 6 authors ---why ???should be 6 at the maximum plus etal with the last ones --apply for all.
We don't add etal with the reference lists unless the total number of authors exceed than 6
As volume , issue , number and pages ---all are available so no need for the link(s)---apply for all
Some cited references need to be more update
Some journal names were written abbreviated , while others were not ---why ??? same style should be ---apply for all
What a huge number of used references (57) ????
ANSWERS 27-32: We have revised the References section according to the journal rules.
Reviewer 2 Report
Please address the following changes:
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Line 76: Breast cancer patients who have been treated with cytotoxic agents regularly report cognitive problems. Please remove "that have been." It should be read as "Breast cancer patients treated with cytotoxic agents regularly report cognitive problems."
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Line 102: What is "con-inactivity"? I've never heard of this term before.
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Table 3: What are those numbers? Are those mean, median, or IQR? Please explain in detail. Otherwise, the readers cannot understand.
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Line 374: What do you mean by "intersections" in the sentence, "fMRI can reveal intersections between serum markers and changes in neural networks"? It is incorrect. Please rephrase.
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Line 281-4: Who has stronger functional connections? Patients with VAS or controls? Please be clear.
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In the discussion, why did the authors discuss the VBM results when your study is on functional connectivity? It is not necessary, as it can lead to confusion about structural and functional aspects of the brain, unless you present the VBM results of your study sample.
Author Response
We would like to thank the reviewer for the provided comments. We have revised the manuscript accordingly. Please find the answers to the comments below.
COMMENT 1: Line 76: Breast cancer patients who have been treated with cytotoxic agents regularly report cognitive problems. Please remove "that have been." It should be read as "Breast cancer patients treated with cytotoxic agents regularly report cognitive problems."
ANSWER 1: This was corrected.
COMMENT 2: Line 102: What is "con-inactivity"? I've never heard of this term before.
ANSWER 2: We have corrected this.
COMMENT 3: Table 3: What are those numbers? Are those mean, median, or IQR? Please explain in detail. Otherwise, the readers cannot understand.
ANSWER 3: We have clarified this. Variables are represented by medians and ranges of values (Me [25 Percentile; 75 Percentile]).
COMMENT 4: Line 374: What do you mean by "intersections" in the sentence, "fMRI can reveal intersections between serum markers and changes in neural networks"? It is incorrect. Please rephrase.
ANSWER 4: We have corrected this.
COMMENT 5: Line 281-4: Who has stronger functional connections? Patients with VAS or controls? Please be clear.
ANSWER 5: We have clarified this.
COMMENT 6: In the discussion, why did the authors discuss the VBM results when your study is on functional connectivity? It is not necessary, as it can lead to confusion about structural and functional aspects of the brain, unless you present the VBM results of your study sample.
ANSWER 6: We have modified the Discussion section accordingly.
