Reviewer’s report
Title: 
Utility of mean platelet volume in differentiating intrahepatic
cholangiocarcinoma from hepatocellular carcinoma
Version: 
0 
Date: 
30 Dec 2021
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?
Yes - appropriate statistical analyses have been used 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: 
The authors aim to assess the utility of MPV in distinguishing ICC versus HCC.
There are a number of limitations to this observational study in terms of its
design and discussion.
REQUESTED REVISIONS: 
1. The introduction is weak and language needs working on. Authors need to
make it clearer how often there is diagnostic doubt between HCC v ICC based on
radiology (CT/MR) and conventional biomarkers (aFP/ca199) ie % needing a
biopsy for confirmation of diagnosis in their management. 
2. The selection of the training and validation cohort is very stringent. The
authors need to expand on this in the methodology and in the discussion ie how
many cases did they exclude as a consequence, the risk of overfitting, the
clinical limitations of MPV as so many physiological variables influence MPV
such as gender, smoking, medications etc.
3. No comment on whether the instrument used to measure MPV differed
between the 2 centres. No comment in discussion how sample collection and
analysis can influence MPV. The technical challenges of reproducibility in MPV
again needs to be highlighted in the discussion
4. No comment on background liver, all cases have been managed by resection
so this variable needs to be included (ie cirrhotic/fibrotic) in the analysis. As
underlying liver disease severity will be a confounding factor on MPV.
5. Result section needs to be expanded on, the authors need to highlight relevant
points from their tables. Authors need to make sure all abbreviations used are
defined and normal ranges are included for all variables measured.
6. Discussion is very weak. From the way the authors have phrased things, they
give the impression that FNA (fine needle aspirate) is the gold standard when
there is diagnostic doubt in HCC v ICC. If this is the case for the 2 centres
involved in the study, please state this here. Otherwise amend, as globally the
gold standard is tru-cut liver biopsy when there is diagnostic doubt.
The involvement of platelets in tumor biology and chronic liver disease is
extremely complex. This aspect needs to be expanded on and put into clinical
context ie a number of observational papers over the years that have commented
on MPV as a surrogate marker of cancer/inflammatory state but because of so
many aspects of disease/life style/drugs/physiology influencing MPV limits the
clinical utility of this measurement.
ADDITIONAL REQUESTS/SUGGESTIONS: 
Have highlighted main points of concerns earlier. A minor comment is the
language that makes reading sections of the manuscript difficult to read and
follow.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
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and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
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.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
Reviewer Publication Consent.
 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
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Reviewer’s report
Title: 
Utility of mean platelet volume in differentiating intrahepatic
cholangiocarcinoma from hepatocellular carcinoma
Version: 
0 
Date: 
30 Dec 2021
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?
Yes - appropriate statistical analyses have been used 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: 
The authors aim to assess the utility of MPV in distinguishing ICC versus HCC.
There are a number of limitations to this observational study in terms of its
design and discussion.
REQUESTED REVISIONS: 
1. The introduction is weak and language needs working on. Authors need to
make it clearer how often there is diagnostic doubt between HCC v ICC based on
radiology (CT/MR) and conventional biomarkers (aFP/ca199) ie % needing a
biopsy for confirmation of diagnosis in their management. 
2. The selection of the training and validation cohort is very stringent. The
authors need to expand on this in the methodology and in the discussion ie how
many cases did they exclude as a consequence, the risk of overfitting, the
clinical limitations of MPV as so many physiological variables influence MPV
such as gender, smoking, medications etc.
3. No comment on whether the instrument used to measure MPV differed
between the 2 centres. No comment in discussion how sample collection and
analysis can influence MPV. The technical challenges of reproducibility in MPV
again needs to be highlighted in the discussion
4. No comment on background liver, all cases have been managed by resection
so this variable needs to be included (ie cirrhotic/fibrotic) in the analysis. As
underlying liver disease severity will be a confounding factor on MPV.
5. Result section needs to be expanded on, the authors need to highlight relevant
points from their tables. Authors need to make sure all abbreviations used are
defined and normal ranges are included for all variables measured.
6. Discussion is very weak. From the way the authors have phrased things, they
give the impression that FNA (fine needle aspirate) is the gold standard when
there is diagnostic doubt in HCC v ICC. If this is the case for the 2 centres
involved in the study, please state this here. Otherwise amend, as globally the
gold standard is tru-cut liver biopsy when there is diagnostic doubt.
The involvement of platelets in tumor biology and chronic liver disease is
extremely complex. This aspect needs to be expanded on and put into clinical
context ie a number of observational papers over the years that have commented
on MPV as a surrogate marker of cancer/inflammatory state but because of so
many aspects of disease/life style/drugs/physiology influencing MPV limits the
clinical utility of this measurement.
ADDITIONAL REQUESTS/SUGGESTIONS: 
Have highlighted main points of concerns earlier. A minor comment is the
language that makes reading sections of the manuscript difficult to read and
follow.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
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.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
Reviewer Publication Consent.
 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
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
Utility of mean platelet volume in differentiating intrahepatic
cholangiocarcinoma from hepatocellular carcinoma
Version: 
0 
Date: 
30 Dec 2021
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?
Yes - appropriate statistical analyses have been used 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: 
The authors aim to assess the utility of MPV in distinguishing ICC versus HCC.
There are a number of limitations to this observational study in terms of its
design and discussion.
REQUESTED REVISIONS: 
1. The introduction is weak and language needs working on. Authors need to
make it clearer how often there is diagnostic doubt between HCC v ICC based on
radiology (CT/MR) and conventional biomarkers (aFP/ca199) ie % needing a
biopsy for confirmation of diagnosis in their management. 
2. The selection of the training and validation cohort is very stringent. The
authors need to expand on this in the methodology and in the discussion ie how
many cases did they exclude as a consequence, the risk of overfitting, the
clinical limitations of MPV as so many physiological variables influence MPV
such as gender, smoking, medications etc.
3. No comment on whether the instrument used to measure MPV differed
between the 2 centres. No comment in discussion how sample collection and
analysis can influence MPV. The technical challenges of reproducibility in MPV
again needs to be highlighted in the discussion
4. No comment on background liver, all cases have been managed by resection
so this variable needs to be included (ie cirrhotic/fibrotic) in the analysis. As
underlying liver disease severity will be a confounding factor on MPV.
5. Result section needs to be expanded on, the authors need to highlight relevant
points from their tables. Authors need to make sure all abbreviations used are
defined and normal ranges are included for all variables measured.
6. Discussion is very weak. From the way the authors have phrased things, they
give the impression that FNA (fine needle aspirate) is the gold standard when
there is diagnostic doubt in HCC v ICC. If this is the case for the 2 centres
involved in the study, please state this here. Otherwise amend, as globally the
gold standard is tru-cut liver biopsy when there is diagnostic doubt.
The involvement of platelets in tumor biology and chronic liver disease is
extremely complex. This aspect needs to be expanded on and put into clinical
context ie a number of observational papers over the years that have commented
on MPV as a surrogate marker of cancer/inflammatory state but because of so
many aspects of disease/life style/drugs/physiology influencing MPV limits the
clinical utility of this measurement.
ADDITIONAL REQUESTS/SUGGESTIONS: 
Have highlighted main points of concerns earlier. A minor comment is the
language that makes reading sections of the manuscript difficult to read and
follow.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
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.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
Reviewer Publication Consent.
 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
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
assistant