PONE-D-21-26827The impact of background liver disease on the long-term prognosis of very-early-stage HCC after ablation therapyPLOS ONE

Dear Prof. Namiki Izumi,

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Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript submitted by Takaura et al. describes the long-term prognosis of hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA) at a very early stage (the Barcelona Clinical Liver Cancer classification stage 0). Specifically, Achieving sustained virological response (SVR) in hepatitis C was essential for further prognosis improvement. I think this manuscript still has some problems, as indicated below.

Methods

Are there any exclusion criteria?

The authors should describe the detail of the RFA procedure, such as approach, device, or protocol.

The ethics approval number should be clearly stated.

I could not find anything about informed consent.

Results

The authors should describe the success rate, frequency of complications, and degree of safety margin for RFA.

In Table 1, the range of tumor diameter is listed as 8-20 mm. This study focused on very early-stage HCC with a single lesion measuring less than 20 mm.

Was there any effect of post-treatment on overall survival (OS)?

Discussion

In general, liver function is an important prognostic factor for HCC. The authors should consider that modified albumin-bilirubin was not extracted as an independent factor contributing to OS.

In this study, was there a statistically significant difference in the changes in liver function between the HCV SVR group and the HCV non-SVR group?

Reviewer #2: In this manuscript, authors investigated the impact of the background liver disease on long-term prognosis in the BCLC stage 0 HCC treated with RFA, with a particular focus on the role of active HCV infection.

They report that active HCV infection was an independent factor influencing the prognosis of patients with the early small HCC treated with RFA.

This study is interesting and addresses an important issue. On the other hand, there are some concerns. an important issue. On the other hand, there are some concerns.

1) The study period for the inclusion of patients is quite long, from 1999 to 2010. Since the advancement of medicine in this long period, OS and RFS may differ between patients who were included earlier and those who were included more recently, and such differences may affect the study results. Therefore, authors better show and/or describe the impact of the inclusion period of the patients.

2) In relation to 1), in the era of IFN therapies, many patients could not achieve SVR. If so, is it possible that most of the HCC patients with active HCV infection participated in the early days of this study?

3) What is a suspected mechanism for the improvement of survival in HCV-HCC patients with SVR ? Did anti-HCV therapy decrease the HCC recurrence rate? Or did anti-HCV therapy have an impact on the maintaining liver functional reserve in HCC therapy? The authors should compare the clinical course of liver function in those with and without SVR.

4) In Figure 3 and 4, the OS and RFS of HBV, NBNC and HCV-SVR also should be separately demonstrated.

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Reviewer #1: No

Reviewer #2: No

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The impact of background liver disease on the long-term prognosis of very-early-stage HCC after ablation therapy

PONE-D-21-26827R1

Dear Prof. Namiki Izumi,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Tatsuo Kanda, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional): Authors reported that the long-term prognosis of very early-stage HCC (BCLC stage 0) was favorable and that the importance of sustained virological responce is very importnat for the prognosis of hepatitis C virus associated-HCC at very early stage and RFA-treatment. Thank you for giving me the opportunity of reviewing this wonderful manuscript.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript submitted by Takaura et al. describes the long-term prognosis of hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA) at a very early stage (the Barcelona Clinical Liver Cancer classification stage 0). The authors correctly understood the points raised and made the appropriate corrections. This paper is a significant contribution.

Reviewer #2: All concerns have been adequately addressed and corrected in the revised manuscript.

Therefore, the manuscript is now considered to be suitable for publication.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No