Reviewer’s report
Title: 
Small intestinal mucosal injury and its risk factors in patients with
gastrointestinal cancer who developed complicated fluoropyrimidine-induced
diarrhea
Version: 
2 
Date: 
16 Apr 2020
Reviewer's report:
Comments: 
Thank you for the opportunity to review this interesting report. The authors
retrospectively assessed fluoropyrimidine-induced small intestine injury in
patients with gastrointestinal cancers. Overall, this paper offers valuable
information for the medical literature regarding this topic. I listed below some
comments.
1. The numbers of patients in figure 1 do not add up; 503 did not develop a
complicated diarrhea and 32 developed a complicated diarrhea, while the total
number is 536. 
2. In the univariate analysis, I would separate chemotherapeutic regimens that
are known to cause gastrointestinal toxicities, such as platinum-based
(oxaliplatin and cisplatin) and VEGF (bevacizumab) from the rest of the cohort.
3. It is cumbersome to differentiate the cause of abdominal cramping in patients
with gastrointestinal cancers. Also, in the methods section, I would describe how
was the grade of diarrhea assessed in patients with diarrhea at baseline, based on
baseline number of bowel movements or multiples of normal.
4. Throughout the manuscript, I suggest modifying the statements about that
most patients with complicated diarrhea had small intestine injury to clearly
indicate that only 12 patients of the 32 had capsule endoscopy evaluation, and
among these, small intestinal involvement was common. 
5. Could the authors comment on the extent and pattern of the inflammation in
the small intestine?
6. Could the authors comment on the presence of inflammation in other parts of
the gastrointestinal tract if endoscopic evaluation was performed?
7. Was histopathological examination done in any of these patients?
8. The authors list sepsis as one of the symptoms repeatedly, but I think it would
be more appropriate to list it separately. 
9. What was the rationale behind looking for enteritis in these patients rather
than looking for injury in the entire GI tract, especially the colon and rectum
which are more commonly involved?
10. In the discussion, the authors comment on a patient who died after
developing sepsis because of severe neutropenia in addition to diarrhea. This
raises the concern for having neutropenic enterocolitis or typhlitis rather than
fluoropyrimidine-induced diarrhea. The reviewer understands the difficulty of
differentiating the two entities, particularly in the absence of histopathological
examination. However, listing the absolute neutrophil count at time of diarrhea
for the whole cohort might help for this purpose.
11. There is a typo in the discussion section, line 50-55 of page 17: "for high-
grade diarrhea for compared with infusional 5-FU". 
12. In the discussion section, the authors stated "Indeed, the present study found
that genetics did not appear to have an effect on the incidence of
fluoropyrimidine-induced diarrhea.". I am not sure if the authors have data to
support this conclusion. 
13. The authors listed conducting capsule endoscopy after improvement of the
disease as one of the limitations. Nonetheless, they did not explain why it was
not done at the same time of symptoms rather than the time of improvement. 
14. One of the most important findings of the study is that oral agents were
associated with complicated diarrhea. The authors should contemplate the reason
for this finding. Also, this should be listed under conclusion. 
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
Yes
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the
authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review is recommended, please specify what aspects
require further assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
Declaration of competing interests
Please complete a declaration of competing interests, considering the following
questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
I agree to the open peer review policy of the journal. I understand that my name
will be included on my report to the authors and, if the manuscript is accepted
for publication, my named report including any attachments I upload will be
posted on the website along with the authors' responses. I agree for my report to
be made available under an Open Access Creative Commons CC-BY license
(
http://creativecommons.org/licenses/by/4.0/
). I understand that any comments
which I do not wish to be included in my named report can be included as
confidential comments to the editors, which will not be published.
I agree to the open peer review policy of the journal
Reviewer’s report
Title: 
Small intestinal mucosal injury and its risk factors in patients with
gastrointestinal cancer who developed complicated fluoropyrimidine-induced
diarrhea
Version: 
2 
Date: 
16 Apr 2020
Reviewer's report:
Comments: 
Thank you for the opportunity to review this interesting report. The authors
retrospectively assessed fluoropyrimidine-induced small intestine injury in
patients with gastrointestinal cancers. Overall, this paper offers valuable
information for the medical literature regarding this topic. I listed below some
comments.
1. The numbers of patients in figure 1 do not add up; 503 did not develop a
complicated diarrhea and 32 developed a complicated diarrhea, while the total
number is 536. 
2. In the univariate analysis, I would separate chemotherapeutic regimens that
are known to cause gastrointestinal toxicities, such as platinum-based
(oxaliplatin and cisplatin) and VEGF (bevacizumab) from the rest of the cohort.
3. It is cumbersome to differentiate the cause of abdominal cramping in patients
with gastrointestinal cancers. Also, in the methods section, I would describe how
was the grade of diarrhea assessed in patients with diarrhea at baseline, based on
baseline number of bowel movements or multiples of normal.
4. Throughout the manuscript, I suggest modifying the statements about that
most patients with complicated diarrhea had small intestine injury to clearly
indicate that only 12 patients of the 32 had capsule endoscopy evaluation, and
among these, small intestinal involvement was common. 
5. Could the authors comment on the extent and pattern of the inflammation in
the small intestine?
6. Could the authors comment on the presence of inflammation in other parts of
the gastrointestinal tract if endoscopic evaluation was performed?
7. Was histopathological examination done in any of these patients?
8. The authors list sepsis as one of the symptoms repeatedly, but I think it would
be more appropriate to list it separately. 
9. What was the rationale behind looking for enteritis in these patients rather
than looking for injury in the entire GI tract, especially the colon and rectum
which are more commonly involved?
10. In the discussion, the authors comment on a patient who died after
developing sepsis because of severe neutropenia in addition to diarrhea. This
raises the concern for having neutropenic enterocolitis or typhlitis rather than
fluoropyrimidine-induced diarrhea. The reviewer understands the difficulty of
differentiating the two entities, particularly in the absence of histopathological
examination. However, listing the absolute neutrophil count at time of diarrhea
for the whole cohort might help for this purpose.
11. There is a typo in the discussion section, line 50-55 of page 17: "for high-
grade diarrhea for compared with infusional 5-FU". 
12. In the discussion section, the authors stated "Indeed, the present study found
that genetics did not appear to have an effect on the incidence of
fluoropyrimidine-induced diarrhea.". I am not sure if the authors have data to
support this conclusion. 
13. The authors listed conducting capsule endoscopy after improvement of the
disease as one of the limitations. Nonetheless, they did not explain why it was
not done at the same time of symptoms rather than the time of improvement. 
14. One of the most important findings of the study is that oral agents were
associated with complicated diarrhea. The authors should contemplate the reason
for this finding. Also, this should be listed under conclusion. 
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
Yes
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the
authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review is recommended, please specify what aspects
require further assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
Declaration of competing interests
Please complete a declaration of competing interests, considering the following
questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
I agree to the open peer review policy of the journal. I understand that my name
will be included on my report to the authors and, if the manuscript is accepted
for publication, my named report including any attachments I upload will be
posted on the website along with the authors' responses. I agree for my report to
be made available under an Open Access Creative Commons CC-BY license
(
http://creativecommons.org/licenses/by/4.0/
). I understand that any comments
which I do not wish to be included in my named report can be included as
confidential comments to the editors, which will not be published.
I agree to the open peer review policy of the journal
Please review this paper.
user
Reviewer’s report
Title: 
Small intestinal mucosal injury and its risk factors in patients with
gastrointestinal cancer who developed complicated fluoropyrimidine-induced
diarrhea
Version: 
2 
Date: 
16 Apr 2020
Reviewer's report:
Comments: 
Thank you for the opportunity to review this interesting report. The authors
retrospectively assessed fluoropyrimidine-induced small intestine injury in
patients with gastrointestinal cancers. Overall, this paper offers valuable
information for the medical literature regarding this topic. I listed below some
comments.
1. The numbers of patients in figure 1 do not add up; 503 did not develop a
complicated diarrhea and 32 developed a complicated diarrhea, while the total
number is 536. 
2. In the univariate analysis, I would separate chemotherapeutic regimens that
are known to cause gastrointestinal toxicities, such as platinum-based
(oxaliplatin and cisplatin) and VEGF (bevacizumab) from the rest of the cohort.
3. It is cumbersome to differentiate the cause of abdominal cramping in patients
with gastrointestinal cancers. Also, in the methods section, I would describe how
was the grade of diarrhea assessed in patients with diarrhea at baseline, based on
baseline number of bowel movements or multiples of normal.
4. Throughout the manuscript, I suggest modifying the statements about that
most patients with complicated diarrhea had small intestine injury to clearly
indicate that only 12 patients of the 32 had capsule endoscopy evaluation, and
among these, small intestinal involvement was common. 
5. Could the authors comment on the extent and pattern of the inflammation in
the small intestine?
6. Could the authors comment on the presence of inflammation in other parts of
the gastrointestinal tract if endoscopic evaluation was performed?
7. Was histopathological examination done in any of these patients?
8. The authors list sepsis as one of the symptoms repeatedly, but I think it would
be more appropriate to list it separately. 
9. What was the rationale behind looking for enteritis in these patients rather
than looking for injury in the entire GI tract, especially the colon and rectum
which are more commonly involved?
10. In the discussion, the authors comment on a patient who died after
developing sepsis because of severe neutropenia in addition to diarrhea. This
raises the concern for having neutropenic enterocolitis or typhlitis rather than
fluoropyrimidine-induced diarrhea. The reviewer understands the difficulty of
differentiating the two entities, particularly in the absence of histopathological
examination. However, listing the absolute neutrophil count at time of diarrhea
for the whole cohort might help for this purpose.
11. There is a typo in the discussion section, line 50-55 of page 17: "for high-
grade diarrhea for compared with infusional 5-FU". 
12. In the discussion section, the authors stated "Indeed, the present study found
that genetics did not appear to have an effect on the incidence of
fluoropyrimidine-induced diarrhea.". I am not sure if the authors have data to
support this conclusion. 
13. The authors listed conducting capsule endoscopy after improvement of the
disease as one of the limitations. Nonetheless, they did not explain why it was
not done at the same time of symptoms rather than the time of improvement. 
14. One of the most important findings of the study is that oral agents were
associated with complicated diarrhea. The authors should contemplate the reason
for this finding. Also, this should be listed under conclusion. 
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
Yes
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the
authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review is recommended, please specify what aspects
require further assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
Declaration of competing interests
Please complete a declaration of competing interests, considering the following
questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests.
I agree to the open peer review policy of the journal. I understand that my name
will be included on my report to the authors and, if the manuscript is accepted
for publication, my named report including any attachments I upload will be
posted on the website along with the authors' responses. I agree for my report to
be made available under an Open Access Creative Commons CC-BY license
(
http://creativecommons.org/licenses/by/4.0/
). I understand that any comments
which I do not wish to be included in my named report can be included as
confidential comments to the editors, which will not be published.
I agree to the open peer review policy of the journal
assistant