Title: Inflammatory Biomarker Correlations and Prognosis in High-risk Gastrointestinal
Stromal Tumor Patients: A Multicenter Retrospective Analysis
Version: 1 Date: 13 Nov 2024
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Not sure - key details are missing from the manuscript
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: Overall Impression
This is a descriptive study  of the association of preoperative  inflammatory biomarkers and
pathological findings  versus recurrence-free survival (RFS) and overall survival (OS) in patients
with high risk GIST tumors of the gut. On multivariate analysis, only two of the multiple
variables were found to be statistically significantly  associated with decreased RFS and  OS but
not treatment with inatinab. What is lacking is an explanation of how these findings will be of
therapeutic value to clinical treatment of GISTs.
What have the authors done well
The detailed analysis of presumptive predictive values is well carried out
In what ways does it not meet best practice
In terms of best practice, the real questions that the readership will ask are
1. How were the threshold values selected    2. How can we use these parameters to improve
treatment  and  3. are there any focuses biological agents. Addressing the inflammatory state
that might be tried ?  These are lacking
I have seen these other questions asked on another AJE form so I am including these here
What are the major findings
The major findings  are that after a multivariate analysis, only two of the multiple variables were
statistically significantly  associated with decreased RFS and  OS but interestingly not treatment
with inatinab.
What are the unusual or novel methods used if any
None are novel; these comparisons have been done by many others in other neoplasms and many
of the variables that are not inflammatory  markers have been evaluated before in patients with
GISTs
How does this contribute to the field
In the current state, these findings may aid the physician I predicting the future outcome of such
patients and providing patients with survival concerns, but the study does not add or address any
therapeutic implications in high risk GIST tumors  such as more aggressive chemo, radiation
therapy, new focused biological agents  for targeting the inflammatory state, etc
How could other researchers ue the information presented in their own work
This study will may provide a basis for other groups interested in ameliorating the inflammatory
state of these patients s with anti-inflammatory biological agents  addressing such things as TNF,
genomic mutations in GISTS, anti TGF beta etc
REQUESTED REVISIONS:
Are there additional revisions the authors should make-consider
1. Line 6 please reserve the use of the word “significant” for statistical uses.  Rather use words
like substantial, extensive, substantive etc.  eg also line 63,99 and elsewhere throughout the text
2.line 21 do you mean “and treatment response with imatinib”
3. Line 123 delete the phrase  “The data revealed”
4. Line 39 do you mean preoperative or even neoadjuvant use of inatinab
5.add preoperative inflammatory markers and GIST  to the key words
6. Line 50 and 121 and Table 1 change gender to sex. Gender is the phenotype while sex , the
important variable, is the genotype
7. line 82. Don’t you mean “ Our hypothesis  was that inflammatory factors affect survival in
patients with high-risk GISTs.  Our goal  was to ••• “ it is always good to add a hypothesis and
goal to any experimental paper
8. Line 89 second sentence can be deleted ;this is well described above
9. Line 95. Don’t you mean “other” malignant tumors?
10. Line 99 start a new paragraph after “failures).”
11. I do not see where you registered this study in a national or international  database. You
need to do this.
11.line 167 on did you consider looking at the Ki-67 values?
12. Line 132. Should you include a few references here
13.Line 123 were the patient data de-identified? If not why?
14. Line 144 please define PNI
15. concerning the results section-  this is disappointing -you refer the reader to the Table 1
but make no summary or point out the important variables that reached statistical significance.
Most authors would explicitly point out which variables were important and add the respective
p. values or say something like “x, x, x , and e all were associated with a decrease in survival,
while x, x, and x were associated with improved survival “. For instance, which variables were
statistically significant for RFS and which for OS. Most readers will expect this and you are
asking the readers to make their own conclusions cc the tables.
16. Table 1 it is impossible to have a p value of 0.000, similarly the percentages are only allowed
to a tenth of a percentage with the total number of patients you have (145). When I looked for the
threshold  points, such as an age of 60, a preop NLR of 2.34 etc how were these chosen? When I
look at lines 147-151 you do not explain what you mean by “enabling meaningful classification”.
Also some of the  values  have too many significant figures. Like preop PLR to the hundredths
of a point and so forth for many others
17. Discussion.  While you say that this evaluation can be used to determine improvements
in treatment, you do not suggest any- what about biological agents focused at inflammatory
pathways? Are there any focused agents you think can be evaluated  in any of your findings,
should other agents than inatinab be considered?  While I understand that several of these
inflammatory biomarkers may suggest an increased risk of recurrent disease , this is good
for outlining a more detailed follow up and giving patients potentially  predictive  survival
expectations, but to what end? Do you have any suggestions cc therapeutic possibilities based
on your study? For instance lines 310-312; this begs the question of “HOW? or what are the
implications for clinical management?
18. Limitations. Your study does not point out how  these data will or could be used clinically.
What does the future hold in terms of treatment?
19 figure 1 and 2. How many patients  are evaluated at each time point, this is quite important!
Did all the patients have complete follow up?  When I look at these figures, it looks like the
threshold values you have chosen are quite good at separating the groups so how were these
values chosen see #16 above
20. In summary it appears to this reviewer that ONLY preop NLR and mitotic  index are
predictive variables but not age as you stated on line 306.  - why did you include age here?  Were
you surprised that treatment with inatinab was not predictive and if so why ?
ADDITIONAL REQUESTS/SUGGESTIONS:
see above detailed suggestions"
Title: Inflammatory Biomarker Correlations and Prognosis in High-risk Gastrointestinal
Stromal Tumor Patients: A Multicenter Retrospective Analysis
Version: 1 Date: 13 Nov 2024
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Not sure - key details are missing from the manuscript
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: Overall Impression
This is a descriptive study  of the association of preoperative  inflammatory biomarkers and
pathological findings  versus recurrence-free survival (RFS) and overall survival (OS) in patients
with high risk GIST tumors of the gut. On multivariate analysis, only two of the multiple
variables were found to be statistically significantly  associated with decreased RFS and  OS but
not treatment with inatinab. What is lacking is an explanation of how these findings will be of
therapeutic value to clinical treatment of GISTs.
What have the authors done well
The detailed analysis of presumptive predictive values is well carried out
In what ways does it not meet best practice
In terms of best practice, the real questions that the readership will ask are
1. How were the threshold values selected    2. How can we use these parameters to improve
treatment  and  3. are there any focuses biological agents. Addressing the inflammatory state
that might be tried ?  These are lacking
I have seen these other questions asked on another AJE form so I am including these here
What are the major findings
The major findings  are that after a multivariate analysis, only two of the multiple variables were
statistically significantly  associated with decreased RFS and  OS but interestingly not treatment
with inatinab.
What are the unusual or novel methods used if any
None are novel; these comparisons have been done by many others in other neoplasms and many
of the variables that are not inflammatory  markers have been evaluated before in patients with
GISTs
How does this contribute to the field
In the current state, these findings may aid the physician I predicting the future outcome of such
patients and providing patients with survival concerns, but the study does not add or address any
therapeutic implications in high risk GIST tumors  such as more aggressive chemo, radiation
therapy, new focused biological agents  for targeting the inflammatory state, etc
How could other researchers ue the information presented in their own work
This study will may provide a basis for other groups interested in ameliorating the inflammatory
state of these patients s with anti-inflammatory biological agents  addressing such things as TNF,
genomic mutations in GISTS, anti TGF beta etc
REQUESTED REVISIONS:
Are there additional revisions the authors should make-consider
1. Line 6 please reserve the use of the word “significant” for statistical uses.  Rather use words
like substantial, extensive, substantive etc.  eg also line 63,99 and elsewhere throughout the text
2.line 21 do you mean “and treatment response with imatinib”
3. Line 123 delete the phrase  “The data revealed”
4. Line 39 do you mean preoperative or even neoadjuvant use of inatinab
5.add preoperative inflammatory markers and GIST  to the key words
6. Line 50 and 121 and Table 1 change gender to sex. Gender is the phenotype while sex , the
important variable, is the genotype
7. line 82. Don’t you mean “ Our hypothesis  was that inflammatory factors affect survival in
patients with high-risk GISTs.  Our goal  was to ••• “ it is always good to add a hypothesis and
goal to any experimental paper
8. Line 89 second sentence can be deleted ;this is well described above
9. Line 95. Don’t you mean “other” malignant tumors?
10. Line 99 start a new paragraph after “failures).”
11. I do not see where you registered this study in a national or international  database. You
need to do this.
11.line 167 on did you consider looking at the Ki-67 values?
12. Line 132. Should you include a few references here
13.Line 123 were the patient data de-identified? If not why?
14. Line 144 please define PNI
15. concerning the results section-  this is disappointing -you refer the reader to the Table 1
but make no summary or point out the important variables that reached statistical significance.
Most authors would explicitly point out which variables were important and add the respective
p. values or say something like “x, x, x , and e all were associated with a decrease in survival,
while x, x, and x were associated with improved survival “. For instance, which variables were
statistically significant for RFS and which for OS. Most readers will expect this and you are
asking the readers to make their own conclusions cc the tables.
16. Table 1 it is impossible to have a p value of 0.000, similarly the percentages are only allowed
to a tenth of a percentage with the total number of patients you have (145). When I looked for the
threshold  points, such as an age of 60, a preop NLR of 2.34 etc how were these chosen? When I
look at lines 147-151 you do not explain what you mean by “enabling meaningful classification”.
Also some of the  values  have too many significant figures. Like preop PLR to the hundredths
of a point and so forth for many others
17. Discussion.  While you say that this evaluation can be used to determine improvements
in treatment, you do not suggest any- what about biological agents focused at inflammatory
pathways? Are there any focused agents you think can be evaluated  in any of your findings,
should other agents than inatinab be considered?  While I understand that several of these
inflammatory biomarkers may suggest an increased risk of recurrent disease , this is good
for outlining a more detailed follow up and giving patients potentially  predictive  survival
expectations, but to what end? Do you have any suggestions cc therapeutic possibilities based
on your study? For instance lines 310-312; this begs the question of “HOW? or what are the
implications for clinical management?
18. Limitations. Your study does not point out how  these data will or could be used clinically.
What does the future hold in terms of treatment?
19 figure 1 and 2. How many patients  are evaluated at each time point, this is quite important!
Did all the patients have complete follow up?  When I look at these figures, it looks like the
threshold values you have chosen are quite good at separating the groups so how were these
values chosen see #16 above
20. In summary it appears to this reviewer that ONLY preop NLR and mitotic  index are
predictive variables but not age as you stated on line 306.  - why did you include age here?  Were
you surprised that treatment with inatinab was not predictive and if so why ?
ADDITIONAL REQUESTS/SUGGESTIONS:
see above detailed suggestions"
Please review this paper.
user
Title: Inflammatory Biomarker Correlations and Prognosis in High-risk Gastrointestinal
Stromal Tumor Patients: A Multicenter Retrospective Analysis
Version: 1 Date: 13 Nov 2024
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Not sure - key details are missing from the manuscript
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: Overall Impression
This is a descriptive study  of the association of preoperative  inflammatory biomarkers and
pathological findings  versus recurrence-free survival (RFS) and overall survival (OS) in patients
with high risk GIST tumors of the gut. On multivariate analysis, only two of the multiple
variables were found to be statistically significantly  associated with decreased RFS and  OS but
not treatment with inatinab. What is lacking is an explanation of how these findings will be of
therapeutic value to clinical treatment of GISTs.
What have the authors done well
The detailed analysis of presumptive predictive values is well carried out
In what ways does it not meet best practice
In terms of best practice, the real questions that the readership will ask are
1. How were the threshold values selected    2. How can we use these parameters to improve
treatment  and  3. are there any focuses biological agents. Addressing the inflammatory state
that might be tried ?  These are lacking
I have seen these other questions asked on another AJE form so I am including these here
What are the major findings
The major findings  are that after a multivariate analysis, only two of the multiple variables were
statistically significantly  associated with decreased RFS and  OS but interestingly not treatment
with inatinab.
What are the unusual or novel methods used if any
None are novel; these comparisons have been done by many others in other neoplasms and many
of the variables that are not inflammatory  markers have been evaluated before in patients with
GISTs
How does this contribute to the field
In the current state, these findings may aid the physician I predicting the future outcome of such
patients and providing patients with survival concerns, but the study does not add or address any
therapeutic implications in high risk GIST tumors  such as more aggressive chemo, radiation
therapy, new focused biological agents  for targeting the inflammatory state, etc
How could other researchers ue the information presented in their own work
This study will may provide a basis for other groups interested in ameliorating the inflammatory
state of these patients s with anti-inflammatory biological agents  addressing such things as TNF,
genomic mutations in GISTS, anti TGF beta etc
REQUESTED REVISIONS:
Are there additional revisions the authors should make-consider
1. Line 6 please reserve the use of the word “significant” for statistical uses.  Rather use words
like substantial, extensive, substantive etc.  eg also line 63,99 and elsewhere throughout the text
2.line 21 do you mean “and treatment response with imatinib”
3. Line 123 delete the phrase  “The data revealed”
4. Line 39 do you mean preoperative or even neoadjuvant use of inatinab
5.add preoperative inflammatory markers and GIST  to the key words
6. Line 50 and 121 and Table 1 change gender to sex. Gender is the phenotype while sex , the
important variable, is the genotype
7. line 82. Don’t you mean “ Our hypothesis  was that inflammatory factors affect survival in
patients with high-risk GISTs.  Our goal  was to ••• “ it is always good to add a hypothesis and
goal to any experimental paper
8. Line 89 second sentence can be deleted ;this is well described above
9. Line 95. Don’t you mean “other” malignant tumors?
10. Line 99 start a new paragraph after “failures).”
11. I do not see where you registered this study in a national or international  database. You
need to do this.
11.line 167 on did you consider looking at the Ki-67 values?
12. Line 132. Should you include a few references here
13.Line 123 were the patient data de-identified? If not why?
14. Line 144 please define PNI
15. concerning the results section-  this is disappointing -you refer the reader to the Table 1
but make no summary or point out the important variables that reached statistical significance.
Most authors would explicitly point out which variables were important and add the respective
p. values or say something like “x, x, x , and e all were associated with a decrease in survival,
while x, x, and x were associated with improved survival “. For instance, which variables were
statistically significant for RFS and which for OS. Most readers will expect this and you are
asking the readers to make their own conclusions cc the tables.
16. Table 1 it is impossible to have a p value of 0.000, similarly the percentages are only allowed
to a tenth of a percentage with the total number of patients you have (145). When I looked for the
threshold  points, such as an age of 60, a preop NLR of 2.34 etc how were these chosen? When I
look at lines 147-151 you do not explain what you mean by “enabling meaningful classification”.
Also some of the  values  have too many significant figures. Like preop PLR to the hundredths
of a point and so forth for many others
17. Discussion.  While you say that this evaluation can be used to determine improvements
in treatment, you do not suggest any- what about biological agents focused at inflammatory
pathways? Are there any focused agents you think can be evaluated  in any of your findings,
should other agents than inatinab be considered?  While I understand that several of these
inflammatory biomarkers may suggest an increased risk of recurrent disease , this is good
for outlining a more detailed follow up and giving patients potentially  predictive  survival
expectations, but to what end? Do you have any suggestions cc therapeutic possibilities based
on your study? For instance lines 310-312; this begs the question of “HOW? or what are the
implications for clinical management?
18. Limitations. Your study does not point out how  these data will or could be used clinically.
What does the future hold in terms of treatment?
19 figure 1 and 2. How many patients  are evaluated at each time point, this is quite important!
Did all the patients have complete follow up?  When I look at these figures, it looks like the
threshold values you have chosen are quite good at separating the groups so how were these
values chosen see #16 above
20. In summary it appears to this reviewer that ONLY preop NLR and mitotic  index are
predictive variables but not age as you stated on line 306.  - why did you include age here?  Were
you surprised that treatment with inatinab was not predictive and if so why ?
ADDITIONAL REQUESTS/SUGGESTIONS:
see above detailed suggestions"
assistant