Reviewer’s report
Title: VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma
Version: 0 Date: 20 Dec 2018
Reviewer: Dimitrios K. Christodoulou
Reviewer's report:
This is an interesting original article investigating the role of VWF:Ag/ADAMTS13:AC ratio as a
potential  biomarker  for  early  detection  of  hepatocellular  carcinoma.  However  there  are  several
important queries that should be addressed:
BACKGROUND
- Please  define your  criteria  for "early detection"  (size?, number of lesions?  Milan  Criteria?) of
hepatocellular carcinoma in cirrhosis. 
-Please  refer  to  the  GALAD  statistical  model  for  estimating  the  likelihood  of  the  presence  of
hepatocellular carcinoma (HCC) in individual patients with chronic liver disease, which incorporates
AFP, AFP-L3 and DCP and was demonstrated to discriminate correctly patients with HCC and CLD. 
(Clinical Gastroenterology and Hepatology 2016;14:875-886)
- Please indicate the reasons why we need biomarkers for HCC surveillance in patients with chronic
liver disease/cirrhosis and not ultrasound alone (or in combination with AFP). 
-Please make a short al least reference to the European and American Guidelines for the early detection
of hepatocellular carcinoma.
METHODS
-Is this a prospective or a retrospective study? 
- Which were the inclusion and exclusion criteria? The median age of your population is 74 years old,
which raises the possibility that the patients might have co-morbidities or being under treatment.
Did any of the patients received anti-coagulants and if this was true, were they included in the study?   
- What was the reason (abnormal US? abnormal AFP? Both?) of the 41 patients to undergo DCE-CT,
DCE-MRI or DCE-US to establish the diagnosis? 
-How many of the remaining 20 cirrhotic patients developed HCC in the follow up?
-Are there any patients with HCC recurrence in your cohort? 
- Why were all patients treated with RFA?
RESULTS
-It is known that HBV patients (which represent almost 25% of the HCC population in your study) can
develop HCC without cirrhosis. How does Willebrand factor:Ag/ADAMS13:AC ratio perform in these
patients?
- Why should someone choose (are there any advantages?) the VWF:Ag/ADAMTS13:AC ratio against
AFP-L3  to  discriminate  HCC,  since  AFP-L3  has  superior  diagnostic  performance?  (Willebrand
factor:Ag/ADAMTS13:AC ratio (Cutoff value 5.5, sensitivity 87%, specificity 80%, and AUC 0.73),
alpha-fetoprotein-L3% (Cutoff value 5.7, sensitivity 96%, specificity 80%, and AUC 0.74). You can
mention if these tests are complementary or if VWF:AG/ADAMTS13 can assist in the diagnosis of
some patients where AFP-L3 fails. 
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.
Yes
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:
Acceptable
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.
None
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: VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma
Version: 0 Date: 20 Dec 2018
Reviewer: Dimitrios K. Christodoulou
Reviewer's report:
This is an interesting original article investigating the role of VWF:Ag/ADAMTS13:AC ratio as a
potential  biomarker  for  early  detection  of  hepatocellular  carcinoma.  However  there  are  several
important queries that should be addressed:
BACKGROUND
- Please  define your  criteria  for "early detection"  (size?, number of lesions?  Milan  Criteria?) of
hepatocellular carcinoma in cirrhosis. 
-Please  refer  to  the  GALAD  statistical  model  for  estimating  the  likelihood  of  the  presence  of
hepatocellular carcinoma (HCC) in individual patients with chronic liver disease, which incorporates
AFP, AFP-L3 and DCP and was demonstrated to discriminate correctly patients with HCC and CLD. 
(Clinical Gastroenterology and Hepatology 2016;14:875-886)
- Please indicate the reasons why we need biomarkers for HCC surveillance in patients with chronic
liver disease/cirrhosis and not ultrasound alone (or in combination with AFP). 
-Please make a short al least reference to the European and American Guidelines for the early detection
of hepatocellular carcinoma.
METHODS
-Is this a prospective or a retrospective study? 
- Which were the inclusion and exclusion criteria? The median age of your population is 74 years old,
which raises the possibility that the patients might have co-morbidities or being under treatment.
Did any of the patients received anti-coagulants and if this was true, were they included in the study?   
- What was the reason (abnormal US? abnormal AFP? Both?) of the 41 patients to undergo DCE-CT,
DCE-MRI or DCE-US to establish the diagnosis? 
-How many of the remaining 20 cirrhotic patients developed HCC in the follow up?
-Are there any patients with HCC recurrence in your cohort? 
- Why were all patients treated with RFA?
RESULTS
-It is known that HBV patients (which represent almost 25% of the HCC population in your study) can
develop HCC without cirrhosis. How does Willebrand factor:Ag/ADAMS13:AC ratio perform in these
patients?
- Why should someone choose (are there any advantages?) the VWF:Ag/ADAMTS13:AC ratio against
AFP-L3  to  discriminate  HCC,  since  AFP-L3  has  superior  diagnostic  performance?  (Willebrand
factor:Ag/ADAMTS13:AC ratio (Cutoff value 5.5, sensitivity 87%, specificity 80%, and AUC 0.73),
alpha-fetoprotein-L3% (Cutoff value 5.7, sensitivity 96%, specificity 80%, and AUC 0.74). You can
mention if these tests are complementary or if VWF:AG/ADAMTS13 can assist in the diagnosis of
some patients where AFP-L3 fails. 
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.
Yes
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:
Acceptable
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.
None
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: VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma
Version: 0 Date: 20 Dec 2018
Reviewer: Dimitrios K. Christodoulou
Reviewer's report:
This is an interesting original article investigating the role of VWF:Ag/ADAMTS13:AC ratio as a
potential  biomarker  for  early  detection  of  hepatocellular  carcinoma.  However  there  are  several
important queries that should be addressed:
BACKGROUND
- Please  define your  criteria  for "early detection"  (size?, number of lesions?  Milan  Criteria?) of
hepatocellular carcinoma in cirrhosis. 
-Please  refer  to  the  GALAD  statistical  model  for  estimating  the  likelihood  of  the  presence  of
hepatocellular carcinoma (HCC) in individual patients with chronic liver disease, which incorporates
AFP, AFP-L3 and DCP and was demonstrated to discriminate correctly patients with HCC and CLD. 
(Clinical Gastroenterology and Hepatology 2016;14:875-886)
- Please indicate the reasons why we need biomarkers for HCC surveillance in patients with chronic
liver disease/cirrhosis and not ultrasound alone (or in combination with AFP). 
-Please make a short al least reference to the European and American Guidelines for the early detection
of hepatocellular carcinoma.
METHODS
-Is this a prospective or a retrospective study? 
- Which were the inclusion and exclusion criteria? The median age of your population is 74 years old,
which raises the possibility that the patients might have co-morbidities or being under treatment.
Did any of the patients received anti-coagulants and if this was true, were they included in the study?   
- What was the reason (abnormal US? abnormal AFP? Both?) of the 41 patients to undergo DCE-CT,
DCE-MRI or DCE-US to establish the diagnosis? 
-How many of the remaining 20 cirrhotic patients developed HCC in the follow up?
-Are there any patients with HCC recurrence in your cohort? 
- Why were all patients treated with RFA?
RESULTS
-It is known that HBV patients (which represent almost 25% of the HCC population in your study) can
develop HCC without cirrhosis. How does Willebrand factor:Ag/ADAMS13:AC ratio perform in these
patients?
- Why should someone choose (are there any advantages?) the VWF:Ag/ADAMTS13:AC ratio against
AFP-L3  to  discriminate  HCC,  since  AFP-L3  has  superior  diagnostic  performance?  (Willebrand
factor:Ag/ADAMTS13:AC ratio (Cutoff value 5.5, sensitivity 87%, specificity 80%, and AUC 0.73),
alpha-fetoprotein-L3% (Cutoff value 5.7, sensitivity 96%, specificity 80%, and AUC 0.74). You can
mention if these tests are complementary or if VWF:AG/ADAMTS13 can assist in the diagnosis of
some patients where AFP-L3 fails. 
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.
Yes
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:
Acceptable
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.
None
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