PONE-D-24-39148Selective decontamination of the digestive tract in esophagectomy and the incidence of pneumonia and anastomotic leakage. A systematic review and meta-analysisPLOS ONE

Dear Dr. Oei,

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 acknowledge the well-executed review on using selective gut decontamination (SDD) to mitigate post-esophagectomy complications, despite the suboptimal quality of input studies. They recommend enhancing the justification for a randomized controlled trial (RCT), detailing SDD protocols, and considering the impact of evolving surgical techniques on outcomes. Additionally, the reviewers suggest addressing antibiotic practices, microbial diversity changes, and potential adverse events for a more comprehensive analysis.

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We look forward to receiving your revised manuscript.

Kind regards,

Zubing Mei, MD,Ph.D

Academic Editor

PLOS ONE

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2. Thank you for stating the following in the Competing Interests section:

“M. Buise is part of an international think tank regarding minimally invasive esophagectomy which is supported by Medtronic. The other authors declare that they have no known conflicts of interest.”

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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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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: Oei and colleagues from the Netherlands present a systematic review regarding the use of selective gut decontamination for reducing pneumonia and leak after oeospahgectomy. Over the years it has been challenging to gain traction in these areas with non-operative methods, mainly because of the surgical technique has been evolving, and the highly multifactorial nature of post-oesophagectomy pneumonia / acute lung injury and leaks. Overall it seems a well-executed review and thoughtfully written. The quality of the input studies are not great but I agree some insight comes from them. I couldn’t find much typographically error. It seems the goal is to develop a randomised study targeting the microbiome to reduce risk, which I would probably support given where we are now surgically (and collaboratively)

I’ve got a few comments for the authors that when addressed would strengthen the paper;

1. The key challenge you have in justifying an RCT is that reducing these risks seems to have no bearing at all on ITU stay or LOS. In some studies both were slightly longer in SDD.

2. In the introduction please provide some description regarding SDD. Is it oral or IV? Is it one dose or a week? How does it differ to the standard ‘on-induction’ IV doses. Understood there is a partial description in table 1

3. Every centre I have worked in provides 24-48h of antibiotic coverage for the operation and immediate post-op. How does the proposed strategies differ, and how has the IV prescription been considered in the presented studies (your description of the controls could be improved)

4. Because the antibiotics regimes are not well described, it is difficult to judge the risk of adverse events like diarrhoea, c. diff, carbapenamase producing infections etc. These aren’t reported. I disagree with the line that there is very little ill-effect from SDD use.

5. The discussion could be improved by checking the oesophageal microbiome literature for how these decontamination strategies actually change diversity

6. It would be worth pointing out that with advancing surgical technique (minimally invasive surgery, sparing of the pulmonary vagal branches, two lung ventilation, ERAS, prehabilitation) many of the precipitants of PPC have been considerably decreased, so potentially aspiration may have a proportionally bigger effect on acute lung injuries than when the first of the included studies were performed.

7. Following on from the previous point, at our centre we still preformed contrast studies to check for aspiration during swallowing, and delayed gastric conduit emptying. Our pneumonia rate is low. Thus if aspiration is considered to be the pathological mechanism, it would be good to understand why it is happening and treat the cause, rather than just treat the effects. This would need to be accounted for in a subsequent randomised studies

Minor:

1. Page 3 last four lines “Bacteria may interfere…” these lines are not well balanced. Undoubtedly there will be helpful bacteria also

2. Page 12 line 14 -16 non-significant lower risk please revise this to “the risk of anastomatic leakage in randomised trials was not significantly different”.

Reviewer #2: It is currently unknown whether selective decontamination of the digestive tract (SDD) affects incidence of postoperative pneumonia and anastomotic leakage in patients undergoing esophagectomy. The authors summarized current evidence regarding SDD in patients undergoing esophagectomy. Through searching various databases, they found that although the data indicates that using SDD in patients undergoing an esophagectomy was associated with a lower incidence of postoperative pneumonia and anastomotic leakage, the available studies were not of sufficient quality to make a recommendation, given their age and risk of bias. A high-quality randomized controlled trial using standardized outcome definitions is needed to substantiate claims about SDD use in esophagectomy.

Overall, the manuscript is well-written and easy follow. A few concerns need to be addressed before publishing.

1. Did the authors include Scopus database?

2. The selection criteria should be presented in details.

3. Strength and limitations should be included in the Discussion section.

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Reviewer #1: Yes:  Stefan Antonowicz

Reviewer #2: No

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PONE-D-24-39148R1Selective decontamination of the digestive tract in esophagectomy and the incidence of pneumonia and anastomotic leakage. A systematic review and meta-analysisPLOS ONE

Dear Dr. Oei,

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.

Please response to the minor comments raised by the reviewer regarding some manuscript details.

Please submit your revised manuscript by May 23 2025 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,

Zubing Mei, MD,PH.D

Academic Editor

PLOS ONE

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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

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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

**********

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

Reviewer #1: 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

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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

**********

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: Thanks for your work

Please double-check the figure / table legends before finalising

Also please delete this sentence from the discussion which i think is non-contributory: "Among the strategies mentioned, minimally invasive surgery, ERAS, and prehabilitation are wellestablished in routine clinical practice. The anticipated beneficial effects of vagal-sparing surgical

techniques are attributed to the vagus nerve's role in modulating anti-inflammatory responses [40, 41].

Formatted: Heading 1, Line spacing: single

14

However, this technique remains contentious, and its application is currently limited to a small cohort

of patients with early-stage cancers or severe epithelial dysplasia."

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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.

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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

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[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.

Selective decontamination of the digestive tract in esophagectomy and the incidence of pneumonia and anastomotic leakage. A systematic review and meta-analysis

PONE-D-24-39148R2

Dear Dr. Oei,

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.

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Kind regards,

Zubing Mei, MD,Ph.D

Academic Editor

PLOS ONE

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