Reviewer ’s report  
 
Title: Diagnostic value of alpha -fetoprotein combined with neutrophil -to-lymphocyte ratio for 
hepatocellular carcinoma  
 
Version: 0 Date: 15 Jan 2018  
 
Reviewer: Alessandro Mussa  
 
Reviewer's report:  
 
I read with interest the paper entitled "Diagnostic value of alpha -fetoprotein combined with 
neutrophil -to-lymph ocyte ratio for hepatocellular carcinoma" by Jian Hu and colleagues.  
This retrospective study evaluates the diagnostic performance of serum markers in diagnosing 
liver carcinoma. The issue is interesting, the methods are sufficiently adequate and the paper  is 
well written. However, in my opinion, the manuscript needs revision before being considered for 
publication. Some mayor methodological issues needs to be addressed.  
1) In the background section: it is important to specify that these markers are used in a context 
of screening, as in a population at risk for HCC or to discriminate benign and malignant 
liver diseases: this concept is missing in the intro of the paper.  
 
2) The two groups of patients (HCC and liver disease) need to be described better, sev eral info 
are missing. E.g. how many with hepatitis? And cirrhosis? Which stage of HCC?  
 
3) In the end of the discussion the authors state that the control group is almost only made up 
of of HBV/HCV patients only, while cirrhosis is mentioned before. This needs to be 
clarified.  
 
4) As stated in the intro, a consistent fraction of HCC cases do not secrete AFP. How many are 
they in the present HCC cohort? Does this depends upon the stage? Or the histotype?  
 
5) Are  there differences in the AUC based on the HCC  stage at diagnosis? And different 
optimal cutoffs?  
 
6) Early diagnosis is paramount as stated in the intro and in the discussion. How does this study 
help with this point? This need to be clarified. I.e. AFP/NLR do actually allow an earlier 
diagnosis?  
 
7) There is huge difference in sex distribution in HCC/control groups. How do the markers 
compare in the two groups once divided base don the sex?  
 
8) I would be of interest to provide information on the outliers, i.e. those with HCC and no 
AFP rise and those  with benign disease and elevated AFP. How many are they respectively?  
 
9) Are there marker cutoffs able to "almost certainly exlude" or "confirm" HCC? This would 
be of a certain importance in clinical practice.  
 
Comments on longitudinal evaluations should  be helpful in the discussion section. Some of those 
patients had a longitudinal evaluation of AFP/NLR? Is a rising/stationary value indicative of 
malign/benign liver disease? Several paper into the literature evaluated this issue with interesting 
results.   
 
Minor comments:  
Line 105 - "as" is missing after used in "can be used a supplementary"  
Line 137 - "performing" should be replaced by "performed"  
Are the methods appropriate and well described?  
If not, please specify what is r equired 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, ple ase 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 wh at 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 c ompeting 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 tha t 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 commen ts 
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: Diagnostic value of alpha -fetoprotein combined with neutrophil -to-lymphocyte ratio for 
hepatocellular carcinoma  
 
Version: 0 Date: 15 Jan 2018  
 
Reviewer: Alessandro Mussa  
 
Reviewer's report:  
 
I read with interest the paper entitled "Diagnostic value of alpha -fetoprotein combined with 
neutrophil -to-lymph ocyte ratio for hepatocellular carcinoma" by Jian Hu and colleagues.  
This retrospective study evaluates the diagnostic performance of serum markers in diagnosing 
liver carcinoma. The issue is interesting, the methods are sufficiently adequate and the paper  is 
well written. However, in my opinion, the manuscript needs revision before being considered for 
publication. Some mayor methodological issues needs to be addressed.  
1) In the background section: it is important to specify that these markers are used in a context 
of screening, as in a population at risk for HCC or to discriminate benign and malignant 
liver diseases: this concept is missing in the intro of the paper.  
 
2) The two groups of patients (HCC and liver disease) need to be described better, sev eral info 
are missing. E.g. how many with hepatitis? And cirrhosis? Which stage of HCC?  
 
3) In the end of the discussion the authors state that the control group is almost only made up 
of of HBV/HCV patients only, while cirrhosis is mentioned before. This needs to be 
clarified.  
 
4) As stated in the intro, a consistent fraction of HCC cases do not secrete AFP. How many are 
they in the present HCC cohort? Does this depends upon the stage? Or the histotype?  
 
5) Are  there differences in the AUC based on the HCC  stage at diagnosis? And different 
optimal cutoffs?  
 
6) Early diagnosis is paramount as stated in the intro and in the discussion. How does this study 
help with this point? This need to be clarified. I.e. AFP/NLR do actually allow an earlier 
diagnosis?  
 
7) There is huge difference in sex distribution in HCC/control groups. How do the markers 
compare in the two groups once divided base don the sex?  
 
8) I would be of interest to provide information on the outliers, i.e. those with HCC and no 
AFP rise and those  with benign disease and elevated AFP. How many are they respectively?  
 
9) Are there marker cutoffs able to "almost certainly exlude" or "confirm" HCC? This would 
be of a certain importance in clinical practice.  
 
Comments on longitudinal evaluations should  be helpful in the discussion section. Some of those 
patients had a longitudinal evaluation of AFP/NLR? Is a rising/stationary value indicative of 
malign/benign liver disease? Several paper into the literature evaluated this issue with interesting 
results.   
 
Minor comments:  
Line 105 - "as" is missing after used in "can be used a supplementary"  
Line 137 - "performing" should be replaced by "performed"  
Are the methods appropriate and well described?  
If not, please specify what is r equired 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, ple ase 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 wh at 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 c ompeting 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 tha t 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 commen ts 
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: Diagnostic value of alpha -fetoprotein combined with neutrophil -to-lymphocyte ratio for 
hepatocellular carcinoma  
 
Version: 0 Date: 15 Jan 2018  
 
Reviewer: Alessandro Mussa  
 
Reviewer's report:  
 
I read with interest the paper entitled "Diagnostic value of alpha -fetoprotein combined with 
neutrophil -to-lymph ocyte ratio for hepatocellular carcinoma" by Jian Hu and colleagues.  
This retrospective study evaluates the diagnostic performance of serum markers in diagnosing 
liver carcinoma. The issue is interesting, the methods are sufficiently adequate and the paper  is 
well written. However, in my opinion, the manuscript needs revision before being considered for 
publication. Some mayor methodological issues needs to be addressed.  
1) In the background section: it is important to specify that these markers are used in a context 
of screening, as in a population at risk for HCC or to discriminate benign and malignant 
liver diseases: this concept is missing in the intro of the paper.  
 
2) The two groups of patients (HCC and liver disease) need to be described better, sev eral info 
are missing. E.g. how many with hepatitis? And cirrhosis? Which stage of HCC?  
 
3) In the end of the discussion the authors state that the control group is almost only made up 
of of HBV/HCV patients only, while cirrhosis is mentioned before. This needs to be 
clarified.  
 
4) As stated in the intro, a consistent fraction of HCC cases do not secrete AFP. How many are 
they in the present HCC cohort? Does this depends upon the stage? Or the histotype?  
 
5) Are  there differences in the AUC based on the HCC  stage at diagnosis? And different 
optimal cutoffs?  
 
6) Early diagnosis is paramount as stated in the intro and in the discussion. How does this study 
help with this point? This need to be clarified. I.e. AFP/NLR do actually allow an earlier 
diagnosis?  
 
7) There is huge difference in sex distribution in HCC/control groups. How do the markers 
compare in the two groups once divided base don the sex?  
 
8) I would be of interest to provide information on the outliers, i.e. those with HCC and no 
AFP rise and those  with benign disease and elevated AFP. How many are they respectively?  
 
9) Are there marker cutoffs able to "almost certainly exlude" or "confirm" HCC? This would 
be of a certain importance in clinical practice.  
 
Comments on longitudinal evaluations should  be helpful in the discussion section. Some of those 
patients had a longitudinal evaluation of AFP/NLR? Is a rising/stationary value indicative of 
malign/benign liver disease? Several paper into the literature evaluated this issue with interesting 
results.   
 
Minor comments:  
Line 105 - "as" is missing after used in "can be used a supplementary"  
Line 137 - "performing" should be replaced by "performed"  
Are the methods appropriate and well described?  
If not, please specify what is r equired 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, ple ase 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 wh at 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 c ompeting 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 tha t 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 commen ts 
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