PONE-D-21-23680

Impact of acute decompensation on the prognosis of patients with hepatocellular carcinoma

PLOS ONE

Dear Dr. Kondo,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

While both reviewers appreciated the usefulness of your dataset, they both have difficulties with the structure of the manuscript, a clear definition of hypothesis etc. This issues need to be improved before the manuscript can be considered further.

Please submit your revised manuscript by Sep 20 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Pavel Strnad

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: Partly

Reviewer #2: Partly

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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: No

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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: I have read the article of Kondo et al “Impact of acute decompensation on the prognosis of patients with hepatocellular carcinoma” with great interest.

It describes an important topic on prognosis of HCC patients with HCC and the impact of acute decompensation. The aim of the study was to evaluate features and the impact of AD on the prognosis of HCC patients. The authors conducted a large retrospective study with 563 patients diagnosed with HCC, stratified them into early- and intermediate/advance group and measured occurrence of AD and ACLF episodes. The authors use internationally approved definitions and statistics are adequate.

The major comment I have is that the hypothesis/aim is somewhat confusing. On one hand they state that most studies that evaluated impact of AD in cirrhosis excluded HCC patients, and therefore the impact of AD on HCC patients is unknown. On the other hand, the authors hypothesize that AD occurrence is a crucial determinant of outcomes in HCC patients, regardless of cirrhosis. This are two important different questions. The first one requires a comparison between HCC cirrhotic patients and cirrhotic patients without HCC, and compare the occurrence of AD and the impact on survival. The second question requires a comparison between HCC patients with and without cirrhosis, and evaluate the occurrence on AD and prognosis.

By performing the analyses on the whole group (including HCC with cirrhosis and without cirrhosis) but without the comparison to a group without HCC, it is difficult to interpret these results. The main finding is that AD/ACLF occurrence is related to prognosis, but this is also the case in cirrhotic patients without HCC.

In addition, different treatment strategies were used, with potential different impacts on possible occurrence of AD. How did the authors correct for this effect, it seems important to me to separate the early complications from the potential beneficial effect in the long term when evaluating the exact impact of HCC and treatment on AD occurrence? I can imagine that an early complication presenting as AD has another impact on prognosis than an AD episode occurring years after the treatment. Moreover, the characteristics of patients that are treated with chemoembolization are completely different that patients with surgical resection or systemic therapy, it is difficult to compare these patient groups directly. I can imagine that an episode of AD impact survival differently in systemic therapy (with a HCC still present in the liver) and after resection (without an HCC). Ideally, these groups should be analyzed separately.

Finally, I’m missing AD occurrence (as a total group) in the prognostic models, given the aim of the study this would also be interesting to evaluate. Why did the authors stratify for early and advanced stage in prognostic modelling? It is also possible to include this variable as a predictive in the model, this would also results in larger groups which increases the power of the analysis.

In conclusion, while the authors have a very interesting dataset, the current analyses do not adequately answer the aims of the study. My suggestion is to remove most of the underpowered subgroup analyses and to focus on a main question that they want to answer, for example occurrence of AD after HCC treatment and impact on prognosis (but then results should be presented separately per treatment and take into account the different HCC populations undergoing these treatments). In the current form it is difficult to place these results in clinical context.

Minor comments:

- Why did the authors exclude Child-pugh C patients? Or patients with performance status of 2-3?

- Was liver biopsy known in every patient? The methods sections suggests this but it is not standard to biopsy every cirrhotic patient

- The numbers of the ACLF group are too low to perform prognostic modelling.

Reviewer #2: Kondo et al. performed a retrospective study to evaluate the impact of AD and ACLF on outcome in patients with HCC. Authors were trying to identify independent factors impacting on prognosis in this cohort.

Although this topic is interesting it is a difficult to read paper mostly due to the sequence results are presented. Different types of analysis (frequency of events, prognosis, univariate analysis, multivariate analysis) and distinct subgroups are put together into paragraphs which makes it difficult to comprehend the final messages.

General aspects:

I suggest, and this is my understanding of the manuscript, that authors make sure to address the following aspects and to put them in a more logical order:

• What is the relevance of AD and ACLF in cirrhosis with HCC (frequency and impact on prognosis)

• Is HCC and/or the stage of liver disease a factor impacting on the frequency of AD/ACLF (e.g. frequency and impact of HCC treatment related AD/ACLF, comparison with non-treatment related AD/ACLF; how many HCC related and how many AD/ACLF related deaths etc).

• Are there further independent factors impacting on patients’ outcome?

More specific aspects:

I am also missing the justification for dividing the groups upfront into early and late stage HCC. Although it is logical from the oncological point of view this paper is trying to elaborate on the decompensated cirrhosis/ACLF, which is meant to be biologically different. Authors should explain why they chose to do this subgroup analysis. I understand the results as if there are many data suggesting the severity of liver disease rather than the HCC itself as the main determinant for risk of AD/ACLF and subsequent outcome.

Why did authors include patients without cirrhosis? EASL CLIF ACLF definition requires the presence of liver cirrhosis.

At baseline, did all patients included have compensated cirrhosis?

Please explain the rational for excluding Child-C patients?

How many patients were transplanted during follow up? I understood that eligibility for transplant was no exclusion criterion.

Authors use the terms admission and hospitalisation – is that meant to be a surrogate for admission due to AD/ACLF? It is a bit confusing as admissions in general are not always due to AD/ACLF.

What is meant by curative treatment – intended to be or ultimately curative?

How many patients developed AD/ACLF as the consequence of HCC therapy? Are there factors impacting on AD/ACLF after HCC therapy?

Were all patients with viral hepatitis treated with antivirals? Any information on viral load etc? Were there differences between treated and non-treated patients?

There are too many variables in the regression analysis. For treatment and aetiology it may be useful to have only a binary variable (categorical), e.g. treatment/no treatment or viral hepatitis/others

Table 5 – Ascites, HE etc…. are no precipitating events, but complications of cirrhosis defining decompensation.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-23680R1Impact of acute decompensation on the prognosis of patients with hepatocellular carcinomaPLOS ONE

Dear Dr. Kondo,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The reviewers appreciated the modifications that you made and only minor changes were requested.

Please submit your revised manuscript by Jan 10 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Pavel Strnad

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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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 article greatly improved by the corrections made by the authors. I have still some minor comments:

- How do the authors explain that cirrhosis is not a risk factor for AD or prognosis when compared to non-cirrhotics?

- Part of the discussion is on why Albi-score and CLIF-C are associated with prognosis, but if I understand it correctly these were predictors of prognosis in the original study and not in the rebuttal. If this is the case, the authors should focus on discussion of the new predictors if they think this is needed ( ACLF, bilirubin level, HCC progression or MELD score)

- They authors suggest to perform surgical resection in patients who have HCC with preserved liver function, even at the intermediate-advanced–stage, because of the low AD incidence rate after treatment. The fact that AD is low in the resection group can also be reflected by the relative good status of patients in this group (younger age, no portal hypertension, few comorbidities). If this is the case, it is possible that the low AD occurence in the surgical group is attributed to the patient group and not to the intervention (selection bias). Did the authors compare baseline characteristics of HCC paitents in the different groups to evaluate this? If these groups are indeed different, the authors should consider to remove this conclusion.

- Please check the manuscript for spelling errors, the word cirrhosis is spelled incorrectly in some placed (for example methods section abstract)

Reviewer #2: I would like to thank the authors for their efforts to respond to all our comments. The changes applied to the manuscript improved its quality subtantially.

Authors should go through the manuscript once more to remove some remaining typos.

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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

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Impact of acute decompensation on the prognosis of patients with hepatocellular carcinoma

PONE-D-21-23680R2

Dear Dr. Kondo,

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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Kind regards,

Pavel Strnad

Academic Editor

PLOS ONE

Additional Editor Comments (optional): Thank you for submitting you interesting work to PLoS One!

Reviewers' comments: