[EXSCINDED]

PONE-D-19-17840

Clinicopathologic and prognostic significance of tumor-associated macrophages in patients with hepatocellular carcinoma: a meta-analysis

PLOS ONE

Dear Mr Xu,

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.

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Kind regards,

Jung Weon Lee, Ph.D.

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: In the manuscript presented by Ding et al., authors aimed to perform a meta-analysis on the prognostic impact of tumor-associated macrophages (TAM) in patients with hepatocellular carcinoma (HCC). More particularly, by including 20 observational articles and 4297 patients, they indicate that elevated levels of CD68+, CD204+ and CD206+ TAMs infiltration predict for worse overall survival. By contrast, a high infiltration of CD169+ TAMs is associated with an improved survival.

In summary, this is an interesting analysis on the prognostic value of TAMs in HCC. There are no major issues regarding this manuscript as the topic addressed is of clinical relevance and the authors used a meaningful set of methods to corroborate their findings. Overall the analyses are well presented. There, are, however a few shortcomings as mentioned successive mainly aiming to improve the significance of the discussion section.

Minor points of improvement:

1. Abstract section: Acronyms IT (intratumor) and PT (peritumor) should be given at their first appearance in the text.

2. Introduction section: As not all readers will be closely familiar with the different CD markers, a brief introduction should be provided in this section.

3. Authors stated (Abstract section): “Our findings suggested that TAMs could serve as prognostic biomarkers and therapeutic targets in hepatocellular carcinoma”. The therapeutic aspect should be included in the discussion section (see references 4, 7).

4. Discussion section: There a number of meta-analyses available on the impact of TAMs in other tumor entities. Thus, authors should briefly discuss their results in the light of these analyses (e.g Troiano G, et al. Prognostic Oral Oncol 2019;93:66-75, Mei J, et al. Oncotarget 2016;7:34217-28).

Reviewer #2: Ding & Tan et al have presented a systematic review of prognostic roles of tumor-associated macrophages (TAMs) in patients with hepatocellular carcinoma (HCC) based on published studies. They performed meta-analysis using standard statistical methods and concluded that TAMs can be used as potential targets for HCC. The study is in accordance to standard meta-analysis studies and topic is relevant and new.

I have few queries:

1. Few typing errors in the manuscript, example in Fig 1 legend description, "10 styudied"

2. Did authors take into consideration to avoid studies that published the same subjects or overlapping groups of subjects that appeared in different studies under duplicate publications?

3. For data abstraction how many reviewers were involved to score the quality of the studies using the same quality instrument? Were the results compared between the reviewers?

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Reviewer #1: No

Reviewer #2: No

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Clinicopathologic and prognostic significance of tumor-associated macrophages in patients with hepatocellular carcinoma: a meta-analysis

PONE-D-19-17840R1

Dear Dr. Xu,

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

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Jung Weon Lee, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: (No Response)

Reviewer #2: (No Response)

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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