Reviewer ’s report  
 
Title: The Alpha -fetoprotein Serum is still Reliable as  a Biomarker for the Surveillance of 
Hepatocellular Carcinoma in Indonesia  
 
Version: 0 Date: 10 Mar 2020  
 
Reviewer's report:  
 
This cross -sectional stud y focuses on a controversial issue: should AFP assay (with the cut -off 
value 10 ng/ml) be used in the surveillance of HCC? The sensitivity and specificity of AFP are 
the main factors to be considered in screening. In most guidelines, the use of AFP alone i s 
strongly discouraged, and its use in addition to ultrasound is controversial. However, it's very 
important because excellent screening, especially in high risk population, may lead to a better 
prognosis of HCC patients. This study not only indicated that  AFP is still reliable as a biomarker 
for the surveillance of HCC, but also provided a profile of HCC patients and high -risk patients in 
Indonesia, with positive clinical significance. The design and research method are good. The 
sample size is medium and the data from multiple centers is valid and convincing. There are 
some suggestions and issues that I need to confirm:  
 
1. The data was collected from two hospitals that participate in the HCC -based registry. 
However, this HCC -based registry was not well des cribed in this manuscript. For example, 
which population is regarded as high -risky for HCC so as to entering the registry? Is there an 
enroll criteria? Is there a flowchart for the examinations in the registry?  
 
2. Although we know the fact that AFP level o f 20 ng/mL commonly used as the upper 
limit of normal has low sensitivity (25% to 65%) for detecting HCC, it has been considered 
inadequate as the sole screening test. （Reference: El -Serag HB, Marrero JA, Rudolph L, Reddy 
KR. Diagnosis and treatment of hepa tocellular carcinoma. Gastroenterology 2008;134:1752 -63.
） 
 
In this research, the cut -off value was designated to 10 ng/ml. The authors need to explain why 
use this specific dosage as the cut -off value.  
 
3. In the discussion section, the cut -off value should be explained more clearly. Since 
AFP as a biomarker for HCC is not new, it is import to prove a certain cut -off value could 
improve both the sensitivity and specificity. Why is the cut -off 10 ng/ml most appropriate, 
comparing with the others?  
 
4. Even thou gh the multivariate logistic regression analysis was technically perfect, the 
predictive factors of AFP elevation are not very important because of the limited clinical 
applications (AFP test can get results directly). Therefore, in the discussion section,  it's better to 
modify the related content.  
 
5. Table 2 should include all HCC (−) patients (n=198).  
 
6. Both 138 days and 146 days exceed 3 months. See line 22 and 24 on page 5.  
 
7. In table 1, the number of nodules is divided into three groups. The word "Tu nggal" 
should be single.  
 
Are the methods appropriate and well described?  
If not, ple ase 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 da ta shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what a spects 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, f ees, funding, or salary 
from an organisation that may in any way gain or lose financially from the 
publi cation of this manuscript, either now or in the future?  
 
2.  Do you hold any stocks or shares in an organisation t hat 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 curr ently 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 y es to any, please give details below.  
 
I declare that I have no competing interest.  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted for publicat ion, 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 in cluded 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: The Alpha -fetoprotein Serum is still Reliable as  a Biomarker for the Surveillance of 
Hepatocellular Carcinoma in Indonesia  
 
Version: 0 Date: 10 Mar 2020  
 
Reviewer's report:  
 
This cross -sectional stud y focuses on a controversial issue: should AFP assay (with the cut -off 
value 10 ng/ml) be used in the surveillance of HCC? The sensitivity and specificity of AFP are 
the main factors to be considered in screening. In most guidelines, the use of AFP alone i s 
strongly discouraged, and its use in addition to ultrasound is controversial. However, it's very 
important because excellent screening, especially in high risk population, may lead to a better 
prognosis of HCC patients. This study not only indicated that  AFP is still reliable as a biomarker 
for the surveillance of HCC, but also provided a profile of HCC patients and high -risk patients in 
Indonesia, with positive clinical significance. The design and research method are good. The 
sample size is medium and the data from multiple centers is valid and convincing. There are 
some suggestions and issues that I need to confirm:  
 
1. The data was collected from two hospitals that participate in the HCC -based registry. 
However, this HCC -based registry was not well des cribed in this manuscript. For example, 
which population is regarded as high -risky for HCC so as to entering the registry? Is there an 
enroll criteria? Is there a flowchart for the examinations in the registry?  
 
2. Although we know the fact that AFP level o f 20 ng/mL commonly used as the upper 
limit of normal has low sensitivity (25% to 65%) for detecting HCC, it has been considered 
inadequate as the sole screening test. （Reference: El -Serag HB, Marrero JA, Rudolph L, Reddy 
KR. Diagnosis and treatment of hepa tocellular carcinoma. Gastroenterology 2008;134:1752 -63.
） 
 
In this research, the cut -off value was designated to 10 ng/ml. The authors need to explain why 
use this specific dosage as the cut -off value.  
 
3. In the discussion section, the cut -off value should be explained more clearly. Since 
AFP as a biomarker for HCC is not new, it is import to prove a certain cut -off value could 
improve both the sensitivity and specificity. Why is the cut -off 10 ng/ml most appropriate, 
comparing with the others?  
 
4. Even thou gh the multivariate logistic regression analysis was technically perfect, the 
predictive factors of AFP elevation are not very important because of the limited clinical 
applications (AFP test can get results directly). Therefore, in the discussion section,  it's better to 
modify the related content.  
 
5. Table 2 should include all HCC (−) patients (n=198).  
 
6. Both 138 days and 146 days exceed 3 months. See line 22 and 24 on page 5.  
 
7. In table 1, the number of nodules is divided into three groups. The word "Tu nggal" 
should be single.  
 
Are the methods appropriate and well described?  
If not, ple ase 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 da ta shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what a spects 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, f ees, funding, or salary 
from an organisation that may in any way gain or lose financially from the 
publi cation of this manuscript, either now or in the future?  
 
2.  Do you hold any stocks or shares in an organisation t hat 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 curr ently 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 y es to any, please give details below.  
 
I declare that I have no competing interest.  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted for publicat ion, 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 in cluded 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: The Alpha -fetoprotein Serum is still Reliable as  a Biomarker for the Surveillance of 
Hepatocellular Carcinoma in Indonesia  
 
Version: 0 Date: 10 Mar 2020  
 
Reviewer's report:  
 
This cross -sectional stud y focuses on a controversial issue: should AFP assay (with the cut -off 
value 10 ng/ml) be used in the surveillance of HCC? The sensitivity and specificity of AFP are 
the main factors to be considered in screening. In most guidelines, the use of AFP alone i s 
strongly discouraged, and its use in addition to ultrasound is controversial. However, it's very 
important because excellent screening, especially in high risk population, may lead to a better 
prognosis of HCC patients. This study not only indicated that  AFP is still reliable as a biomarker 
for the surveillance of HCC, but also provided a profile of HCC patients and high -risk patients in 
Indonesia, with positive clinical significance. The design and research method are good. The 
sample size is medium and the data from multiple centers is valid and convincing. There are 
some suggestions and issues that I need to confirm:  
 
1. The data was collected from two hospitals that participate in the HCC -based registry. 
However, this HCC -based registry was not well des cribed in this manuscript. For example, 
which population is regarded as high -risky for HCC so as to entering the registry? Is there an 
enroll criteria? Is there a flowchart for the examinations in the registry?  
 
2. Although we know the fact that AFP level o f 20 ng/mL commonly used as the upper 
limit of normal has low sensitivity (25% to 65%) for detecting HCC, it has been considered 
inadequate as the sole screening test. （Reference: El -Serag HB, Marrero JA, Rudolph L, Reddy 
KR. Diagnosis and treatment of hepa tocellular carcinoma. Gastroenterology 2008;134:1752 -63.
） 
 
In this research, the cut -off value was designated to 10 ng/ml. The authors need to explain why 
use this specific dosage as the cut -off value.  
 
3. In the discussion section, the cut -off value should be explained more clearly. Since 
AFP as a biomarker for HCC is not new, it is import to prove a certain cut -off value could 
improve both the sensitivity and specificity. Why is the cut -off 10 ng/ml most appropriate, 
comparing with the others?  
 
4. Even thou gh the multivariate logistic regression analysis was technically perfect, the 
predictive factors of AFP elevation are not very important because of the limited clinical 
applications (AFP test can get results directly). Therefore, in the discussion section,  it's better to 
modify the related content.  
 
5. Table 2 should include all HCC (−) patients (n=198).  
 
6. Both 138 days and 146 days exceed 3 months. See line 22 and 24 on page 5.  
 
7. In table 1, the number of nodules is divided into three groups. The word "Tu nggal" 
should be single.  
 
Are the methods appropriate and well described?  
If not, ple ase 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 da ta shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what a spects 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, f ees, funding, or salary 
from an organisation that may in any way gain or lose financially from the 
publi cation of this manuscript, either now or in the future?  
 
2.  Do you hold any stocks or shares in an organisation t hat 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 curr ently 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 y es to any, please give details below.  
 
I declare that I have no competing interest.  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted for publicat ion, 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 in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant