Dear Dr. Sakai,

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Kind regards,

Mohammad Mofatteh, PhD, MPH, MSc, PGCert, BSc (Hons), MB BCh (c)

Academic Editor

PLOS ONE

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Additional Editor Comments :

Please submit an updated version after major revisions.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: N/A

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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Reviewer #1: Whilst I appreciate the effort, this is a very small and retrospective study with all the attendant problems that accompany this format. There are potentially many confounders that could affect your results and the only way to answer your question is to perform a proper RCT with standardised perioperative analgesia. Perhaps study something that has actually been shown to reduce pain e.g. ketamine. The study was conducted more than 10 years ago which is a big delay in publication - techniques may even have changed over this time. Your perioperative opioid doses are much to low to cause OIH or hyperalgesia. Propofol, if anything, will reduce postoperative pain.

Reviewer #2: Dear Authors, thank you for the opportunity to review your study.

This study addresses an important clinical issue regarding PPBCS prevention. It investigates the association between anesthetic management and the incidence of PPBCS.

In my opinion, there are aspects that need clarification and concepts that need improvement.

- It would be appropriate to include among the study's limitations the fact that it is a retrospective and observational study, which inherently limits the ability to establish causality. (minor review).

- Data were collected in a period of time when trunk blocks were not yet taken into account as part of standard clinical practice. Many of them such as Erector Spine Plane block (ESP) and Serratus Plane Block had not even been formally described at the time. It would be appropriate to specify this into discussion. (major review)

- The classification of PPBCS into 'no,' 'mild,' and 'moderate-to-severe' pain is based on NRS scores, but the choice of cut-off values is not well justified. Clarifying the rationale for NRS cut-offs would be advisable. (major review)

- There is no mention of preoperative pain assessments or how other chronic pain conditions were accounted for. Specify if this was an exclusion criteria (minor review).

- Specify whether the study protocol was drafted in relation to the Declaration of Helsinki. (minor review).

Reviewer #3: Congratulations on this retrospective study, the manuscript is very well written and easy to follow. variability in retrospective clinical studies is hard to controlled by limitations are clearly recognized and stated. Please see some comments:

Abstract:

Line 44 and 45: I would recommend to eliminate the sentence that reads "pectoral nerve block showed a tendency to reduce...". I think the p value is far away from significance enough that this statement may be misleading. As the authors stated in the discussion the number of blocks performed in this study population was very low. Low enough that in my opinion precludes from any statistically interpretation. I would recommend to match the abstract conclusion closer to the one used in Line 232.

Introduction:

Line 56: the definition of PPBCS appears to be inconsistent or lacking throughout the literature. Could the authors define what was considered "persistent pain"in this study? Was it more than 6 months after surgery? I think it should be more clearly explained

Statistical analyses:

Line 116: How was normality assessed?

Was there a sample size calculation performed at any point during the analysis to assess which variables may be underpowered?

Discussion:

Line 242 and 243: Can you please re-write this sentence? It reads awkward

Also I think it should be "this difference may depend..."

Line 260-261: I would rephrase this statement. I do not think this study can proof or disproof that intraoperative opioid use can cause persistent pain since the majority of patients did receive opioids. There was no control opioid-free population to compare.

Line 280 and 281: I do not think you can conclude for sure that the difference was not statistically significant because of the limited number without running at the analysis with bigger numbers. It may be, but you cannot predict factors such as inter-individual variability that could make the results same or even less significant with a larger population.

Sorry, I could not assess fig 1 since it was showing black for me

Reviewer #4: The review of the manuscripts"Effects of anesthetic management on persistent pain after breast cancer surgery"

Thank you foy my opportunity of reviewing.

The author have described that the association of perioperative factors, including anesthetic management, with the subsequent incidence and intensity of PPBCS.

Although this study is interesting,but there is serious concern.

Sincerely,

Major concern:

#1:Study period

This study was conducted in 2014.

This was more than 10 years ago, and I think that technological advances such as anesthetic drugs and blocks have had a significant impact during that time. I think this is a serious limitation of the study.

�2:Block

The author concluded that the PECS block might have a preventive effect on the development of PPBCS.

However, there are no details regarding the PECS block. (For example, which PECS1, PECS2, or both?, which local anesthetic used,? and who blocked?).

If information is available, it should be provided.

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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

Reviewer #3: No

Reviewer #4: No

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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.

Effects of anesthetic management on persistent pain after breast cancer surgery

PONE-D-25-08461R1

Dear Dr. Sakai,

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,

Dr. Mohammad Mofatteh, PhD, MPH, MSc, PGCert, BSc (Hons), MB BCh BAO (c)

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Congratulations.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: (No Response)

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

The PLOS Data policy

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #2: I have reviewed the revised manuscript and the authors' responses to the reviewers' comments. I am substantially satisfied with the revisions and the point-by-point responses provided. The authors have addressed the major concerns raised in my previous review.

Reviewer #3: Thanks for addressing all my comments. I think the manuscript, especially the discussion reads much better after all the edits.

Reviewer #4: Dear author,

It seems that the comments in "Word" remain(Page 13,line 224). Did you check it carefully before submitting ?

Careless resubmission may result in your submission being rejected, even if the content is fine.

So I strongly recommend that you check it carefully before submission.

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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 #2: No

Reviewer #3: No

Reviewer #4: No

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