Wound complications following surgery to the lymph nodes: A protocol for a systematic review and meta-analysis.

BACKGROUND: Malignancies that spread to the lymph nodes may be identified through surgical biopsy, and treatment of metastatic disease may be through lymph node dissection. These surgeries, however, may be associated with significant adverse outcomes, particularly wound complications, the true incidence of which remains unknown. Multiple studies have reported their individual rates of complications in isolation. The aim of this study will be to systematically evaluate data that presents the incidence of wound complications in patients undergoing these surgeries.
METHODS: We have designed and registered a protocol for a systematic review and meta-analysis of studies presenting incidence data. We will search MEDLINE, EMBASE and CENTRAL for relevant articles. Meta-analysis will be undertaken to synthesise an overall incidence of surgical site infection, wound dehiscence, haematoma and seroma. Subgroup analyses will investigate the effects of anatomical location, primary malignancy and study design on pooled incidence. Risk of bias will be evaluated for each included study using bespoke tools matched to the study design. DISCUSSION: The results of this study will provide the incidence of wound complications and secondary complications following lymph node surgery. This will directly impact upon the consent process, and may influence the nature of future research studies aimed at reducing post-operative complications.

Background

Sentinel lymph node biopsy (SLNB) was developed in the early 1990s and became the standard diagnostic tool for evaluating metastasis to the lymph node and staging malignancy [1]. A positive SLNB, indicating the spread of malignancy to the regional nodes, may indicate the need for axillary (ALND) or inguinal (ILND) block dissection, where the entire lymph node basin is removed [1,2]. These complete dissections continue to be a staple in managing metastatic disease, even though their efficacy is still heavily debated [1-3].

Block dissection may be indicated for malignancy of the breast, malignant melanoma and other cutaneous malignancies, and urogenital cancers. However, a number of factors dispose these surgeries to an increased rate of post-operative complications, which may result in a reduced quality of life [2]. Wound complications constitute some of the major adverse outcomes following lymph node surgery, regardless of the site of the dissection. These complications are not limited to surgical site infections and also include wound dehiscence, delayed wound healing, seroma and hematoma [4].

A recent case series of 244 ILNDs reported at least one wound complication in 51.2% (n = 124) of participants. 29.8%, 21.5% and 5% of the total population developed wound infections, seroma and hematomas, respectively, and irrespective of patient and operative factors [3].

A myriad of interventions for reducing rates of wound complications following surgery have been described in the literature and have been adopted to varying degrees. To assess the potential impact of these interventions, an estimate of the true incidence of complications following surgery to the lymph nodes is required.

Study objectives

The aim of this study is to identify the incidence of wound complications following biopsy and dissection of the axillary or inguinal lymph nodes, and further identify the rate of secondary complications. The PICO framework for this review is as follows:

Population–any adult undergoing surgery to the lymph nodes in the axilla or groin for the purposes of diagnosing or treating cancer.

Intervention and Control–As this is a study of proportions, no specific intervention or control are being examined. The procedures of interest are lymph node biopsy or completion lymphadenectomy.

Outcome–The outcome of interest is one of four wound complications, namely surgical site infection, seroma, haematoma or wound dehiscence.

Methods

Systematic review registration

The protocol has been registered with PROSPERO International Prospective Register of Systematic Reviews (registration number CRD42021239530). This protocol is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) (See ) [5]. This review will be conducted in accordance with the Cochrane Handbook for Systematic Review of Interventions [6].

Search strategy and information sources

MEDLINE, EMBASE and CENTRAL are the primary literature sources searched for original studies published, in English language, from inception to the date searches are conducted. The search strings to be used for the database searches have been included in the and has been designed in conjunction with an information search specialist. Additionally, the reference lists of all included studies will be searched manually to identify any additional studies that fulfil the inclusion criteria.

Inclusion and exclusion criteria

Randomized and non-randomized studies that report wound complications (wound infections, wound dehiscence, seroma and hematoma) following axillary or inguinal lymph node biopsy or dissection for adult patients (age ≥18) with malignancy will be included. The diagnostic, therapeutic or prophylactic nature of the LND will not be taken into account when including the studies.

Case series with a sample size of less than 20 patients will be excluded. All commentaries, case reports, conference abstracts, literature overviews, literature reviews and meta-analyses, secondary analyses for previously published articles and non-English studies will be excluded. However the reference lists of relevant review articles will be hand-searched for articles missing from the original searches.

Study selection

Three stages have been outlined for the study selection. Search results will be uploaded to Rayyan [7], a bespoke web and mobile app for conducting systematic reviews, and titles and abstracts screened by two reviewers acting independently. Following this, full-text articles will be retrieved and examined, and assessed against the inclusion/exclusion criteria by the same two reviewers. Finally, the additional studies from the references of selected studies will be screened. Any discrepancy between reviewers will be resolved by discussion with a third reviewer, and any further discrepancy or disagreement will be put to consensus between all authors. Study inclusion and exclusion, and the reasons for exclusion at the full-text stage, will be reported using a standardised PRISMA flow-diagram [8].

Primary and secondary outcomes

The primary outcome is the incidence of wound complications at 30 days, defined as infection, dehiscence, seroma or hematoma following surgery to the axillary or inguinal lymph nodes. Where data allows, each complication will be examined individually. Where the data is available, secondary outcomes will include the use of postoperative antibiotics within 30 postoperative days (not including antibiotic prophylaxis), the incidence of return to theatre for postoperative complications within 30 days and 30-day mortality.

Study designs

It is anticipated that the searches will return studies that are either randomised intervention studies, non-randomised intervention studies, and observational/cross sectional studies reporting incidence data. In order to achieve the best possible estimate, all three study types will be considered for analysis. Where a study has multiple arms (such as an interventional study), each arm will be considered within the analysis independently.

Data extraction

Three reviewers will extract the data from the full-text articles independently, using a standardized electronic data extraction sheet designed for this systematic review. The extraction sheet will be designed in Microsoft Excel and any disagreements will be resolved by discussion with the third reviewer.

Where possible, the following information will be extracted from the individual papers: (first author, publication year, country where data was collected from, study design, journal), (number of patients included, number of males and females, mean or median age with standard deviation, comorbidities, site of SLNB or LND), (number of wound infections, wound dehiscence, seroma, hematoma, mortality) and (number of reoperations for any wound complication, antibiotic use, and 30-day mortality).

If there is missing data, the respective authors will be contacted if the email address has been provided in the article.

Assessment of risk of bias of included studies

The risk of bias will be assessed at the study level by two reviewers independently, and discrepancies will be resolved in the same fashion as used for study inclusion/exclusion. The risk of bias tool used will be a risk of bias tool specifically designed for prevalence studies [9].

Data analysis and synthesis

The extracted data will be pooled and combined statistically to assess the primary and secondary outcomes. For the primary outcome of the study, wound complications will be presented as a crude incidence estimate expressed in percentages with 95% confidence intervals, for each individual complication (total four analyses). We will use a generalised linear mixed model (GLMM) to synthesis proportions and present the results with a forest plot. GLMMs are considered to be superior to traditional two step methods with either logit or double arcsine transformations [10,11]. As a sensitivity analysis, a random effects meta-analysis using the Freeman-Tukey double arcsine transformation will also be undertaken and presented as supplementary material. Heterogeneity will be evaluated using the I statistic test, and interpretation will be according to that provided in the Cochrane Handbook [6]. An I statistic of over 75% (indicating considerable heterogeneity) will prompt us to explore the heterogeneity by way of meta-analyses by subgroup.

A funnel plot will be produced to examine the effect of publication bias, or small study effects, if more than 10 studies are included in the analysis [12].

Additional analyses

Where possible, separate subgroup analysis will be undertaken to assess the effects of important potential confounding factors upon the primary outcomes, including study design, the nature of the primary malignancy (skin, breast, urogenital, etc), the effect of the site of procedure (axillary vs inguinal surgery) and the effect of the type of procedure (biopsy vs block dissection). No meta-regression analyses are planned at this stage, as we anticipate significant statistical and clinical heterogeneity between groups.

Discussion

Surgery to the lymph nodes is common, and as worldwide rates of malignancy increase, it is likely the frequency at which these procedures are undertaken also will rise. This review will aim to identify the incidence of significant complications, which will inform the consent and decision-making process on an individual level, and may be used to direct future research studies to improve outcomes on a population level.

In this paper we have outlined a protocol for a systematic review and meta-analysis, in line with current best-practice guidelines that recommend the pre-publication of protocols such as this. Any deviations from this protocol will be reported in the final manuscript, and search strategies, results, data extraction and analyses will be held in an open-access repository. Dissemination will be through presentation at national meetings/conferences, and through robust peer-reviewed publication.

We anticipate limitations in the review, in the form of heterogenous data and a wide variance in reported rates of complications. Data on surgical site infection is difficult to collect, and there is no consensus on the definition of outcomes such as surgical site infection [13]. We aim to overcome this by placing no restrictions on definitions used, and taking the data presented in individual studies as being valid.

In summary, we have presented the protocol for a wide-ranging systematic review that aims to provide further insight into the incidence of significant complications following common surgical procedures.

PRISMA-P 2015 checklist for ‘wound complications following surgery to the lymph nodes: A protocol for a systematic review and meta-analysis’.

(DOCX)

Click here for additional data file.

Search strategy for ‘wound complications following surgery to the lymph nodes: A protocol for a systematic review and meta-analysis’.

(DOCX)

Click here for additional data file.

30 Jun 2021

PONE-D-21-12899

Wound Complications Following Surgery to the Lymph Nodes: A protocol for a systematic review and meta-analysis

PLOS ONE

Dear Dr. Joshua P Totty,

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 submit your revised manuscript by Aug 14 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.

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:  http://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,

Paolo Aurello

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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 and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for the opportunity to review this article. It is a well planned and structured meta-analysis. However authors declerated that results will be undertaken after the registration of the protocol on PROSPERO. Evaluating an article without the Results section is quite confusing. It would be appropriate to re-evaluate after the process and the article are completed.

**********

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

[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.

19 Jul 2021

13th July 2021

Dear Editors,

Thank you for your review of our manuscript, Wound Complications Following Surgery to the Lymph Nodes: A protocol for a systematic review and meta-analysis.

We were confused by the content of the review. In the review, the article is deemed to meet the criteria for publication (The reviewer’s responses to all questions is “Yes”). It clearly states that the manuscript is a protocol, and was submitted as such during the submission process. However, the reviewer has refused to accept the article, citing “Evaluating an article without the Results section is quite confusing. It would be appropriate to re-evaluate after the process and the article are completed.”

We feel the reviewer has not understood that the article is a review protocol, rather mistaking it for a half completed systematic review. As such, we have no substantial changes to make based on the reviewers comments.

Please find our responses to each individual point:

Editors Comments:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Amended and updated. Thanks.

2. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

Data availability applies to the completed review. As this submission is a study protocol, no data will be generated and therefore the submission should not be withheld. Full data in a repository will be provided with the completed review in a separate submission. Thanks

3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Amended and Updated. Thanks.

Reviewer’s Comments:

Thank you for the opportunity to review this article. It is a well planned and structured meta-analysis. However authors declerated that results will be undertaken after the registration of the protocol on PROSPERO. Evaluating an article without the Results section is quite confusing. It would be appropriate to re-evaluate after the process and the article are completed.

Thank you for your comments. The protocol is registered on PROSPERO and the registration information is contained within the manuscript. This is a study protocol and as such no results have been generated. Publishing protocols is deemed good practice and is practiced by the Cochrane Collaboration. Results will be available in due course once the study has been completed, and will be submitted to an appropriate peer reviewed journal.

As per your email of 14th July, please amend the funding statement to “The authors received no specific funding for this work.”

We have resubmitted the article with some formatting changes as requested by the journal. We fail to understand, based on this review, why our article would be rejected for PLOS ONE: Protocols, when there was no significant criticism of the protocol we presented. We hope to receive your response in a timely fashion.

Kind regards,

Joshua Totty

MBBS, PGCertRes, MRCS, MD, FHEA

Registrar in Plastic and Reconstructive Surgery (ST3) - Hull University Teaching Hospitals NHS Trust

Yorkshire and Humber Deanery

NIHR Clinical Lecturer in Plastic Surgery

Hull York Medical School

Submitted filename: Reply to Reviewers.docx

Click here for additional data file.

2 Sep 2021

PONE-D-21-12899R1

Wound Complications Following Surgery to the Lymph Nodes: A protocol for a systematic review and meta-analysis

PLOS ONE

Dear Dr.  Joshua P Totty

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.

Yours sincerely,

Paolo Aurello

Academic Editor

PLOS ONE

20 Sep 2021

Dear Editors,

As part of the appeal process, we are required to submit a response to reviewers. The entire content of the review is as follows:

“Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we have decided that your manuscript does not meet our criteria for publication and must therefore be rejected.

I am sorry that we cannot be more positive on this occasion, but hope that you appreciate the reasons for this decision.”

As you may see, there is little feedback given for us, as authors to respond to.

In the reply, you cite that the manuscript does not meet publication criteria. You do not state how, or why, it does not meet these criteria.

• The manuscript is a study protocol, which PLOS ONE advertises as publishing - see https://plos.org/protocols/

• Indeed, it is the protocol for a systematic review, which PLOS ONE does publish, as evidenced by the following articles published this month:

o https://doi.org/10.1371/journal.pone.0256596

https://doi.org/10.1371/journal.pone.0255789

• Furthermore, when the submission originally went for peer review, it was deemed to meet the criteria for publication by the reviewer (See below):

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

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

As authors we responded to the review positively and resubmitted in a timely fashion.

In summary, I do not "appreciate the reasons for this decision” and we as authors are left confused by the fact that, despite minimal changes between revisions, an article can be deemed unpublishable after 4 months of submission.

We look forward to the outcome of the appeal.

Kind regards,

Joshua Totty

MBBS, PGCertRes, MRCS, MD, FHEA

Registrar in Plastic and Reconstructive Surgery (ST3) - Hull University Teaching Hospitals NHS Trust

Yorkshire and Humber Deanery

NIHR Clinical Lecturer in Plastic Surgery

Hull York Medical School

Submitted filename: Reply to Reviewers.docx

Click here for additional data file.

4 May 2022

12 May 2022

Reply to reviewers:

1. Please note that in order to use the direct billing option the corresponding author must be affiliated with the chosen institute. Please either amend your manuscript to change the affiliation or corresponding author, or email us at plosone@plos.org with a request to remove this option.

Thank you. I can confirm that as the corresponding author I am affiliated with the University of Hull, listed in my affiliations in the manuscript.

2. Thank you for stating the following in the Funding Section of your manuscript:

“No direct funding was secured for this protocol or subsequent review. Joshua Totty is a Clinical Lecturer funded by Health Education England (HEE) / National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care.”

We note that you have provided funding information within the funding Section that is not currently declared in your Funding Statement. Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

“The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Thank you. The funding statement should read “No direct funding was secured for this protocol or subsequent review. Joshua Totty is a Clinical Lecturer funded by Health Education England (HEE) / National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care”

3. 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.

Thank you. I can confirm the reference list is up to date.

Reviewer #2: The protocol is well presented with appropriate details. Authors have mentioned the aim of the study. It would be more clearer if there is any mention on the study objectives and what are the specific review questions. These could be spelt clearly before describing the methods. Systematic reviews and protocols generally have the eligibility criteria mentioned in the PICO framework (also mentioned in the PRISMA-P). The authors need to mention this in the protocol.

We thank the reviewer for their comments. We have updated and amended the manuscript as suggested, with the addition of a section titled “study objectives”, including a PICO framework, before the methods section.

Submitted filename: Reply to reviewers.docx

Click here for additional data file.

21 Jul 2022

Wound Complications Following Surgery to the Lymph Nodes: A protocol for a systematic review and meta-analysis

PONE-D-21-12899R3

Dear Dr. Totty,

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Carla Pegoraro

Division Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 #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 #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The protocol is presented well. The population included is still broad without any specific category. All adults, with any primary site malignancy, any stage, any duration of malignancy, any co-morbid conditions, any cancer treatment group etc. Authors need to bear this in mind when you pool the data and genenralise the outcome. Sub-group analysis will be very valuable. Lines 124, 125 mentions the primary outcomes as wound complications at 30 days. This 30 days criteria has not come up anywhere in the background and methodology. The word haematoma is mentioned as hematoma at several places. Need to have uniformity. Lines 109 and 110 are not relevant. Data extraction template could have been presented as appendix. The search terms, statistical analysis proposed, PRISMA check list is appropriate.

**********

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 #2: Yes: Arun Kumar Basavaraj

**********

26 Jul 2022

PONE-D-21-12899R3

Wound Complications Following Surgery to the Lymph Nodes: A protocol for a systematic review and meta-analysis

Dear Dr. Totty:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr Carla Pegoraro

Staff Editor

PLOS ONE