Title: Endoscopic manifestation of intestinal transplant-associated microangiopathy after stem
cell transplantation
Version: 0 Date: 12 Feb 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?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
N/A - there are no statistics in this 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
While an important  topic in this limited field and beautiful histopathology of mucosal biopsies
as well as visual changes , I am left without any criteria to differentiate iTAM from GVHD or
many of the features of CMV infection. This paper  aimed to show endoscopic findings of iTAM,
but  what the histopathology shows is the same findings of GVHD,  and the authors have NOT
described how to differentiate the two entities. Moreover, they claim that some patients  had
both but never show a slide of these patients  and how they differentiated the different lesions
of each entity.
What have the authors done well
The authors picked an important topic to research and have shown beautiful endoscopic views
of the mucosa as well as the related histopathology,
In what ways does it not meet best practice
What the authors have not done is to explain how iTAM differs from GVHD and even from
CMV infection which can be an important distinction when it comes to treatment
REQUESTED REVISIONS:
Are there additional revisions the authors should make?
1. Please add the phrase “after stem cell transplantation” at the end of the title
2. Please authors, in the future label both the page numbers and the line numbers on each page
-this makes it so much easier for the reviewer and the editor to refer to a specific page and line
on the submission    From now on, I will assume that the title page number is page 1
3. Page 3 line 6. after the word “iTAM” add the phrase
"After stem cell transplantation for soft tissue malignancies  and one patient with thalassemia”
4. Page 3 line 10  add the phrase “the times of”
5 page 3 line 15 and everywhere else in the manuscript when you say the mucosa was “reddish”
do you mean “erythematous”  I think so by what it looks like, but if  you mean something else
then you will somehow need to differentiate reddish from ”erythematous.
6. Everywhere in the manuscript   ( and there are lots of them) when you give a percentage, they
all need to be rounded off —you only have 14 patients and statistically you are allowed only 2
degrees of freedom, so round off ALL the percentages in the text and the tables
7. Authors I am adding this comment after I have read your submission several times. Your
aim/goal/purpose I assume was to describe the intestinal mucosal abnormalities of patients with
iTAM after stem cell transplantation that differentiate iTAM from GVHD and CMV infection
which have many similar findings on histopathology. Here is where you should focus the reader
on the differences of iTAM from GVHD and CMV infection that you have shown in this
manuscript. This is especially important because so many (perhaps most from reading your
results and the paragraph on GHVD in the discussion) of the histological findings are the
virtually the same in each disorder; also, and your contention that some of the patients had
BOTH iTAM and GVHD means that you could find biopsy characteristic of each disorder.  In
the conclusions, it would be crucial to say how you can differentiate these disorders with an
intestinal biopsy
8. Page 4 line 15 keywords. Add the “iTAM” after the phrase “intestinal transplant associated
microangiopathy”
9. Page 5 line 15 change the word “This” to “Treatment ”
10. Page 5 last line  delete “significantly” and change to “substantially”. Save use of the word
“significantly” for statistics
10. Page 6 line 6 from the bottom.  Why not add the phrase “(fragmented red blood cells)” after
the word “schistocytes”, because not all readers will know what shistocytes mean
11. Page 7 line 14 delete “with” and change to “who eventually developed”.
12. Page 7 line 17 replace “encompassing” with “ including”
13. Page 7  3 rd line from bottom.  Replace the “and” with “and/or”
14. Page 8 line 3. Again do you mean “ erythematous” or “ reddish” if so please explain the
difference, because everyone who looks at your endoscopic photos will think “erythematous “
15. Page 8 line 6 change “was” to “ is”
16. Page 8 lines 10-16. Your manuscript really needs a photo showing what you believe is CMV
infection along with iTAM, because lines 15-16 are also signs of iTAM.  This is a real problem,
because to say that some patients had both CMV infection and iTAM is not explained how you
could differentiate the two findings. I will make the same argument for your claim for  GVHD
where again the changes you describe for GVHD are essentially the same for iTAM. THIS IS
A MAJOR PROBLEM THAT WILL NEED TO BE DESCRIBED - i.e. How to differentiate
iTAM from GVHD and CMV.
17. page 8 line 7 from bottom figure 3A does not show any reddish mucosa to my view. Maybe
change to “had lesions in the ileum with other parts of the ileum showing reddish mucosal
changes”
18. Page 8 line 4 from the bottom  see my comments on Figure 4 I  think that saying “areas
of reddish mucosa” is much more accurate. This may be important if iTAM has only areas of
reddish mucosa versus GVHD
19.page 8 line 2 from bottom please explain why indigo carmine was used; while I understand
that it is used to detect dysplasia and various stages of inflammation, why was it used here? Does
it help to differentiate CMV or GVHD and from iTAM? And if so how?
29. Page 9 in your discussion of serological markers are they Important in differenting iTAM
from GVHD or CMV infection or is diagnosing iTAM specifically?
30. Page 10 line 11. Authors you have shown one figure where you point out endothelial
swelling- is this pathognomonic for iTAM? IS it the only pathognomonic finding?
31. Page 10 somewhere here you need a paragraph describing in no uncertain terms how you can
recognize iTAM as being different from GVHD and CMV infection, because this is the primary
aim of your study and may very well be important in treatment.  This is and will be my major
criticism of this manuscript
32. Page 11 line 7 from the bottom. Round off these percentages as well; the only had 52 patients
33. page 12. This point is absolutely important, because these criteria do not fit some of
your patients, esp. the 4% level of schistocytes!   How do you interpret the difference in
your findings and theirs?  This needs to be explained up front! I would strongly suggest that
you delete the first part of lines 2 and 3 starting with “The diagnostic criteria for transpant-
associated thrombotic microangiopathy established by” and replace it with the following
sentences: “The differentiation of iTAM from GVHD and CMV infections is crucially important
clinically. The International working of the European Group for Bone Marrow Transplantation
attempted to establish diagnostic criteria for the diagnosis of transplant-associated thrombotic
microangiopathy. Their criteria included” and fill in from here on the text starting on line 4 after
the word “include”   and then use the rest of the text. then for the next sentence, start it with
“Unfortunately” on line 7. This part of your discussion is what the clinicians want to know about
the differences between iTAM, GVHD, and CMV infection.
34. Page 12 line 9 add the word “only” after the word “from” —- note the reader here is left
without any real insight into what you have shown on your histology slides  and serologic
evaluation that allow the authors to make these diagnoses and for you  the reader to interpret
your submission in a way that they can use to diagnose iTAM and to differentiate it from GVHD
and CMV. So clearly spell out the differences of iTAM and GVHD and CMV infection.
35. table 2 add the word “Eventual” before “Outcome”
36. Overall summary: Authors you write very nicely-congratulations. But after reading this
several times, I cannot tell from your submission how you can differentiate iTaM fromGVHD
on histopathology. As you say, both have erythema, erosions, ulcers, and villus  atrophy! Does
one need to see endothelial swelling and other small vessel  abnormalities in the submucosa?
ADDITIONAL REQUESTS/SUGGESTIONS:
see above
Title: Endoscopic manifestation of intestinal transplant-associated microangiopathy after stem
cell transplantation
Version: 0 Date: 12 Feb 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?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
N/A - there are no statistics in this 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
While an important  topic in this limited field and beautiful histopathology of mucosal biopsies
as well as visual changes , I am left without any criteria to differentiate iTAM from GVHD or
many of the features of CMV infection. This paper  aimed to show endoscopic findings of iTAM,
but  what the histopathology shows is the same findings of GVHD,  and the authors have NOT
described how to differentiate the two entities. Moreover, they claim that some patients  had
both but never show a slide of these patients  and how they differentiated the different lesions
of each entity.
What have the authors done well
The authors picked an important topic to research and have shown beautiful endoscopic views
of the mucosa as well as the related histopathology,
In what ways does it not meet best practice
What the authors have not done is to explain how iTAM differs from GVHD and even from
CMV infection which can be an important distinction when it comes to treatment
REQUESTED REVISIONS:
Are there additional revisions the authors should make?
1. Please add the phrase “after stem cell transplantation” at the end of the title
2. Please authors, in the future label both the page numbers and the line numbers on each page
-this makes it so much easier for the reviewer and the editor to refer to a specific page and line
on the submission    From now on, I will assume that the title page number is page 1
3. Page 3 line 6. after the word “iTAM” add the phrase
"After stem cell transplantation for soft tissue malignancies  and one patient with thalassemia”
4. Page 3 line 10  add the phrase “the times of”
5 page 3 line 15 and everywhere else in the manuscript when you say the mucosa was “reddish”
do you mean “erythematous”  I think so by what it looks like, but if  you mean something else
then you will somehow need to differentiate reddish from ”erythematous.
6. Everywhere in the manuscript   ( and there are lots of them) when you give a percentage, they
all need to be rounded off —you only have 14 patients and statistically you are allowed only 2
degrees of freedom, so round off ALL the percentages in the text and the tables
7. Authors I am adding this comment after I have read your submission several times. Your
aim/goal/purpose I assume was to describe the intestinal mucosal abnormalities of patients with
iTAM after stem cell transplantation that differentiate iTAM from GVHD and CMV infection
which have many similar findings on histopathology. Here is where you should focus the reader
on the differences of iTAM from GVHD and CMV infection that you have shown in this
manuscript. This is especially important because so many (perhaps most from reading your
results and the paragraph on GHVD in the discussion) of the histological findings are the
virtually the same in each disorder; also, and your contention that some of the patients had
BOTH iTAM and GVHD means that you could find biopsy characteristic of each disorder.  In
the conclusions, it would be crucial to say how you can differentiate these disorders with an
intestinal biopsy
8. Page 4 line 15 keywords. Add the “iTAM” after the phrase “intestinal transplant associated
microangiopathy”
9. Page 5 line 15 change the word “This” to “Treatment ”
10. Page 5 last line  delete “significantly” and change to “substantially”. Save use of the word
“significantly” for statistics
10. Page 6 line 6 from the bottom.  Why not add the phrase “(fragmented red blood cells)” after
the word “schistocytes”, because not all readers will know what shistocytes mean
11. Page 7 line 14 delete “with” and change to “who eventually developed”.
12. Page 7 line 17 replace “encompassing” with “ including”
13. Page 7  3 rd line from bottom.  Replace the “and” with “and/or”
14. Page 8 line 3. Again do you mean “ erythematous” or “ reddish” if so please explain the
difference, because everyone who looks at your endoscopic photos will think “erythematous “
15. Page 8 line 6 change “was” to “ is”
16. Page 8 lines 10-16. Your manuscript really needs a photo showing what you believe is CMV
infection along with iTAM, because lines 15-16 are also signs of iTAM.  This is a real problem,
because to say that some patients had both CMV infection and iTAM is not explained how you
could differentiate the two findings. I will make the same argument for your claim for  GVHD
where again the changes you describe for GVHD are essentially the same for iTAM. THIS IS
A MAJOR PROBLEM THAT WILL NEED TO BE DESCRIBED - i.e. How to differentiate
iTAM from GVHD and CMV.
17. page 8 line 7 from bottom figure 3A does not show any reddish mucosa to my view. Maybe
change to “had lesions in the ileum with other parts of the ileum showing reddish mucosal
changes”
18. Page 8 line 4 from the bottom  see my comments on Figure 4 I  think that saying “areas
of reddish mucosa” is much more accurate. This may be important if iTAM has only areas of
reddish mucosa versus GVHD
19.page 8 line 2 from bottom please explain why indigo carmine was used; while I understand
that it is used to detect dysplasia and various stages of inflammation, why was it used here? Does
it help to differentiate CMV or GVHD and from iTAM? And if so how?
29. Page 9 in your discussion of serological markers are they Important in differenting iTAM
from GVHD or CMV infection or is diagnosing iTAM specifically?
30. Page 10 line 11. Authors you have shown one figure where you point out endothelial
swelling- is this pathognomonic for iTAM? IS it the only pathognomonic finding?
31. Page 10 somewhere here you need a paragraph describing in no uncertain terms how you can
recognize iTAM as being different from GVHD and CMV infection, because this is the primary
aim of your study and may very well be important in treatment.  This is and will be my major
criticism of this manuscript
32. Page 11 line 7 from the bottom. Round off these percentages as well; the only had 52 patients
33. page 12. This point is absolutely important, because these criteria do not fit some of
your patients, esp. the 4% level of schistocytes!   How do you interpret the difference in
your findings and theirs?  This needs to be explained up front! I would strongly suggest that
you delete the first part of lines 2 and 3 starting with “The diagnostic criteria for transpant-
associated thrombotic microangiopathy established by” and replace it with the following
sentences: “The differentiation of iTAM from GVHD and CMV infections is crucially important
clinically. The International working of the European Group for Bone Marrow Transplantation
attempted to establish diagnostic criteria for the diagnosis of transplant-associated thrombotic
microangiopathy. Their criteria included” and fill in from here on the text starting on line 4 after
the word “include”   and then use the rest of the text. then for the next sentence, start it with
“Unfortunately” on line 7. This part of your discussion is what the clinicians want to know about
the differences between iTAM, GVHD, and CMV infection.
34. Page 12 line 9 add the word “only” after the word “from” —- note the reader here is left
without any real insight into what you have shown on your histology slides  and serologic
evaluation that allow the authors to make these diagnoses and for you  the reader to interpret
your submission in a way that they can use to diagnose iTAM and to differentiate it from GVHD
and CMV. So clearly spell out the differences of iTAM and GVHD and CMV infection.
35. table 2 add the word “Eventual” before “Outcome”
36. Overall summary: Authors you write very nicely-congratulations. But after reading this
several times, I cannot tell from your submission how you can differentiate iTaM fromGVHD
on histopathology. As you say, both have erythema, erosions, ulcers, and villus  atrophy! Does
one need to see endothelial swelling and other small vessel  abnormalities in the submucosa?
ADDITIONAL REQUESTS/SUGGESTIONS:
see above
Please review this paper.
user
Title: Endoscopic manifestation of intestinal transplant-associated microangiopathy after stem
cell transplantation
Version: 0 Date: 12 Feb 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?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
N/A - there are no statistics in this 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
While an important  topic in this limited field and beautiful histopathology of mucosal biopsies
as well as visual changes , I am left without any criteria to differentiate iTAM from GVHD or
many of the features of CMV infection. This paper  aimed to show endoscopic findings of iTAM,
but  what the histopathology shows is the same findings of GVHD,  and the authors have NOT
described how to differentiate the two entities. Moreover, they claim that some patients  had
both but never show a slide of these patients  and how they differentiated the different lesions
of each entity.
What have the authors done well
The authors picked an important topic to research and have shown beautiful endoscopic views
of the mucosa as well as the related histopathology,
In what ways does it not meet best practice
What the authors have not done is to explain how iTAM differs from GVHD and even from
CMV infection which can be an important distinction when it comes to treatment
REQUESTED REVISIONS:
Are there additional revisions the authors should make?
1. Please add the phrase “after stem cell transplantation” at the end of the title
2. Please authors, in the future label both the page numbers and the line numbers on each page
-this makes it so much easier for the reviewer and the editor to refer to a specific page and line
on the submission    From now on, I will assume that the title page number is page 1
3. Page 3 line 6. after the word “iTAM” add the phrase
"After stem cell transplantation for soft tissue malignancies  and one patient with thalassemia”
4. Page 3 line 10  add the phrase “the times of”
5 page 3 line 15 and everywhere else in the manuscript when you say the mucosa was “reddish”
do you mean “erythematous”  I think so by what it looks like, but if  you mean something else
then you will somehow need to differentiate reddish from ”erythematous.
6. Everywhere in the manuscript   ( and there are lots of them) when you give a percentage, they
all need to be rounded off —you only have 14 patients and statistically you are allowed only 2
degrees of freedom, so round off ALL the percentages in the text and the tables
7. Authors I am adding this comment after I have read your submission several times. Your
aim/goal/purpose I assume was to describe the intestinal mucosal abnormalities of patients with
iTAM after stem cell transplantation that differentiate iTAM from GVHD and CMV infection
which have many similar findings on histopathology. Here is where you should focus the reader
on the differences of iTAM from GVHD and CMV infection that you have shown in this
manuscript. This is especially important because so many (perhaps most from reading your
results and the paragraph on GHVD in the discussion) of the histological findings are the
virtually the same in each disorder; also, and your contention that some of the patients had
BOTH iTAM and GVHD means that you could find biopsy characteristic of each disorder.  In
the conclusions, it would be crucial to say how you can differentiate these disorders with an
intestinal biopsy
8. Page 4 line 15 keywords. Add the “iTAM” after the phrase “intestinal transplant associated
microangiopathy”
9. Page 5 line 15 change the word “This” to “Treatment ”
10. Page 5 last line  delete “significantly” and change to “substantially”. Save use of the word
“significantly” for statistics
10. Page 6 line 6 from the bottom.  Why not add the phrase “(fragmented red blood cells)” after
the word “schistocytes”, because not all readers will know what shistocytes mean
11. Page 7 line 14 delete “with” and change to “who eventually developed”.
12. Page 7 line 17 replace “encompassing” with “ including”
13. Page 7  3 rd line from bottom.  Replace the “and” with “and/or”
14. Page 8 line 3. Again do you mean “ erythematous” or “ reddish” if so please explain the
difference, because everyone who looks at your endoscopic photos will think “erythematous “
15. Page 8 line 6 change “was” to “ is”
16. Page 8 lines 10-16. Your manuscript really needs a photo showing what you believe is CMV
infection along with iTAM, because lines 15-16 are also signs of iTAM.  This is a real problem,
because to say that some patients had both CMV infection and iTAM is not explained how you
could differentiate the two findings. I will make the same argument for your claim for  GVHD
where again the changes you describe for GVHD are essentially the same for iTAM. THIS IS
A MAJOR PROBLEM THAT WILL NEED TO BE DESCRIBED - i.e. How to differentiate
iTAM from GVHD and CMV.
17. page 8 line 7 from bottom figure 3A does not show any reddish mucosa to my view. Maybe
change to “had lesions in the ileum with other parts of the ileum showing reddish mucosal
changes”
18. Page 8 line 4 from the bottom  see my comments on Figure 4 I  think that saying “areas
of reddish mucosa” is much more accurate. This may be important if iTAM has only areas of
reddish mucosa versus GVHD
19.page 8 line 2 from bottom please explain why indigo carmine was used; while I understand
that it is used to detect dysplasia and various stages of inflammation, why was it used here? Does
it help to differentiate CMV or GVHD and from iTAM? And if so how?
29. Page 9 in your discussion of serological markers are they Important in differenting iTAM
from GVHD or CMV infection or is diagnosing iTAM specifically?
30. Page 10 line 11. Authors you have shown one figure where you point out endothelial
swelling- is this pathognomonic for iTAM? IS it the only pathognomonic finding?
31. Page 10 somewhere here you need a paragraph describing in no uncertain terms how you can
recognize iTAM as being different from GVHD and CMV infection, because this is the primary
aim of your study and may very well be important in treatment.  This is and will be my major
criticism of this manuscript
32. Page 11 line 7 from the bottom. Round off these percentages as well; the only had 52 patients
33. page 12. This point is absolutely important, because these criteria do not fit some of
your patients, esp. the 4% level of schistocytes!   How do you interpret the difference in
your findings and theirs?  This needs to be explained up front! I would strongly suggest that
you delete the first part of lines 2 and 3 starting with “The diagnostic criteria for transpant-
associated thrombotic microangiopathy established by” and replace it with the following
sentences: “The differentiation of iTAM from GVHD and CMV infections is crucially important
clinically. The International working of the European Group for Bone Marrow Transplantation
attempted to establish diagnostic criteria for the diagnosis of transplant-associated thrombotic
microangiopathy. Their criteria included” and fill in from here on the text starting on line 4 after
the word “include”   and then use the rest of the text. then for the next sentence, start it with
“Unfortunately” on line 7. This part of your discussion is what the clinicians want to know about
the differences between iTAM, GVHD, and CMV infection.
34. Page 12 line 9 add the word “only” after the word “from” —- note the reader here is left
without any real insight into what you have shown on your histology slides  and serologic
evaluation that allow the authors to make these diagnoses and for you  the reader to interpret
your submission in a way that they can use to diagnose iTAM and to differentiate it from GVHD
and CMV. So clearly spell out the differences of iTAM and GVHD and CMV infection.
35. table 2 add the word “Eventual” before “Outcome”
36. Overall summary: Authors you write very nicely-congratulations. But after reading this
several times, I cannot tell from your submission how you can differentiate iTaM fromGVHD
on histopathology. As you say, both have erythema, erosions, ulcers, and villus  atrophy! Does
one need to see endothelial swelling and other small vessel  abnormalities in the submucosa?
ADDITIONAL REQUESTS/SUGGESTIONS:
see above
assistant