PONE-D-22-33926Role of intrapulmonary lymph nodes in patients with NSCLC and visceral pleural invasion. The VPI 1314 multicenter registry study protocolPLOS ONE

Dear Dr. Minervini,

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,

Ming-Ching Lee

Academic Editor

PLOS ONE

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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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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

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?

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

Reviewer #3: Yes

Reviewer #4: Yes

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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: This is a well-written study protocol to retrospectively investigate the incidence of intraoperative lymph node metastasis and the association between intraoperative lymph node metastasis and visceral pleural invasion. Based on the recently revealed significant study results regarding sublobar resection (JCOG0802, CALGB140503), the use of sublobar resection has been increasing and is expected to increase further. To determine the extent of resection (sublobar resection or lobectomy), the presence of lymph node metastasis (occult lymph node metastasis) would be essential. Therefore, the results of this study will be of great importance to all thoracic surgeons. Vaghjiani et al. investigated occult lymph node metastasis in patients with clinical stage I lung cancer and found one-third of occult metastases located in intrapulmonary lymph nodes (Vaghjiani et al. J Thorac Oncol 2020). The findings of Vaghjiani’s study would be related to this study, which should be described in the Introduction or Discussion.

Reviewer #2: I red with interest the proposed protocol. It is well written ad focused on an actual and interesting matter regaradin lung cancer staging.

however, I have some criticisms that need author clarification.

1) which kind of lymphadenectomy are you planning for this study? for the study purpose I suggesto to insert a radical mediastinal dissection with almost 3 mediastinal nodal station dissected.

2) why do you prefer a zip file for data collection? Maybe for multicentric studies a web based dataset software is more fit.

Reviewer #3: the main issue I find is that unlike N2-nodes or even 10/11 nodes; the 12-14 nodes represent mainly the quality that is yielded from the pathology. Then becomes the issue of heterogeneity; as most centrest under report 12-14 nodes - compared to 11 nodes. So that is an insight into possible major bias. Thus; for reasoning - keep intrapulmonary nodes independent and other N1 nodes as divided.

Reviewer #4: Sample size: the formula for the prevalence estimation is not readable. Need justification of the allowable error. What is the 5-year survival rate? Will the cohort have enough events (298) during the study time?

Statistical analysis:

Should be “univariable” and “multivariable” instead of “univariate” and “multivariate”.

Which covariates will be included in the multivariable logistic regression?

What subgroups will be created for the KM analysis?

What if the non-informative censoring assumption is violated?

Need justification to use the RF for imputation? Will this imputation be used for outcome measures or covariates? Imputation will bring bias and a good approach requires a careful evaluation of the missing data mechanism and methods for imputation.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Ilkka Ilonen

Reviewer #4: No

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Role of intrapulmonary lymph nodes in patients with NSCLC and visceral pleural invasion. The VPI 1314 multicenter registry study protocol

PONE-D-22-33926R1

Dear Dr. Minervini,

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,

Ming-Ching Lee

Academic 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 #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #3: Yes

Reviewer #4: 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: I appreciate that the authors revised their paper appropriately. I do not have any further comments.

Reviewer #2: The authors answered clearly to my comments. I think this is an interesting protocol and I', courious to see their results.

Reviewer #3: all concerns are addressed satisfactorilrly. I wish all the best to the authors and to the project presented

Reviewer #4: All my concerns were addressed.

The statistical section is acceptable.

I think the protocol is good for publication.

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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

Reviewer #3: No

Reviewer #4: No

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