PONE-D-19-23016

Microscopic distance from tumor invasion front to serosa might be a useful predictive factor for peritoneal recurrence after curative resection of gastric cancer

PLOS ONE

Dear Dr. Yashiro,

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.

We would appreciate receiving your revised manuscript by Nov 14 2019 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Kun Yang

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 http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2.  We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

https://www.sciencedirect.com/science/article/pii/S0960740417302025?via%3Dihub

The text that needs to be addressed is in the Introduction section.

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

'This study is partially founded by KAKENHI Grant-in-Aid for Scientific Research, Nos. 18H02883(M.Y.).'

We note that you have provided funding information that is not currently declared in your Funding Statement. However, 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:

'KAKENHI Grant-in-Aid for Scientific Research, Nos. 18H02883(M.Y.).'

Additional Editor Comments (if provided):

Please see the comments below

[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?

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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #3: Yes

Reviewer #4: Yes

**********

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: The authors reported the predictive significance of microscopic distance from tumor invasion front to serosa for peritoneal recurrence in T3-stage gastric cancer. The results of this study are interesting, but I think it is natural that the deeper depth of invasion was associated with the more frequent peritoneal recurrence. In addition, authors should revise following several points to improve the content.

1. This study evaluated only T3-gastric cancer.I suggest to change the title.

"gastric cancer" to "T3-gastric cancer"

2. Why did the authors focus on the microscopic distance from the tumor invasion front to the serosa (DIFS) and E-cadherin. Please mentioned in Introduction section.

3. Please clarify the inclusion criteria. The authors should describe the study period and flow chart.

4. The authors have used the UICC/AJCC 7th edition staging manual. Please use the most current staging manual.

5. As the authors mentioned in Introduction section, we sometimes experienced peritoneal recurrence even in T1-2 cancer patients.Why T1-2 cancer was not included in this analysis? They should included T1-2 cancers in this study.

6. In this analysis, location of the tumor (Upper/Middle/Lower and Anterior/Posterior/Grater curvature side/Lesser curvature side) was not included. These factor should be included.

Reviewer #2: The authors demonstrated that short distance from the tumor invasion front to the serosa (DIFS) was an independent risk factor for peritoneal recurrence and unfavorable survival. This study may have considerable clinical implications, but there are several problems in their presentation that need to be solved:

1. Did the authors examine peritoneal washing cytology? If so, the authors should describe the result and analyze the relationship between peritoneal recurrence and cytology.

2. The authors should show the clinicopathological features in more detail in Table 1, including tumor location, type of gastrectomy, extent of lymph node dissection, and the number of the patients who underwent adjuvant chemotherapy.

3. In Material and methods section (page 5, line 77-82), the author should describe who evaluated E-cadherin IHC staining (e.g. by experienced pathologist unaware of clinical data). If possible, the authors should perform the agreement study of E-cadherin expression and show the concordance between the two pathologist.

4. The authors should discuss several limitations of this study in Discussion section.

5. Please recheck the grammar and terminology.

6. The statistical method for the multivariate analysis is unclear.

Reviewer #3: Togano, et al. investigated the risk factors of peritoneal recurrence in patients who underwent curative gastrectomy for T3 gastric cancer. They evaluated the correlation between the occurrence of peritoneal recurrence and clinicopathologic factors including distance from tumor invasion front to serosa (DIFS) and expression status of E-Cadherin, and found that lymph node metastasis and DIFS were the independent factors associated with peritoneal recurrence. This manuscript will provide very important clinical information for readers. Several changes will improve the quality of this manuscript.

1. The authors focused on the risk factors of peritoneal metastasis after curative resection for T3 gastric cancer. The title does not include the information that this study especially focused on T3 gastric cancer.

2. The follow-up period of the study cohort is very important information for readers. Besides, it is also important how these patients were followed up. The authors should provide the information on the follow-up period, timing and modality for follow-up.

3. Adjuvant chemotherapy may influence the survival of patients. Please include the information on presence or absence of adjuvant chemotherapy into the background.

4. When discussing the DIFS, the preparation of tissue section for pathology is very important information. Please provide the details of preparation for tissue section.

5. Please provide the C-statistic of the ROC curve shown in Figure 2.

6. The authors should describe the detail of multivariate analysis. How did they select the covariates?

7. The discussion seems to be poor. Please discuss why the expression of E-Cadherin did not influence the peritoneal metastasis in this study cohort, and the clinical evidence of adjuvant therapy to decrease peritoneal recurrence. Also, they should declare the limitation of this study.

Reviewer #4: Comments for the author

Decision: Minor revision

This article identified a predictive factor for peritoneal recurrence of T3 gastric cancer patients. They focused on the distance from the tumor invasion front to the serosa (DIFS) and clarified the cut off value of DIFS for the prediction of peritoneal recurrence.

Major points

1. DIFS is very important in this article. So they should describe the precise method to measure the DIFS. For example, how many did they check to confirm the invasion front. They should clarify the identification of DIFS in details.

2. They classified the patients to peritoneal recurrence and non-recurrence groups. How long did they observe those patients? They should describe the observation period.

3. The explanation of the importance of E-cadherin in gastric cancer patients is necessary.

4. DIFS and lymph node metastasis are independent predictive factors for peritoneal recurrence. So they should add subgroup analysis in T3, lymph node metastasis negative patients.

Minor points

1. In Table1, they should include DIFS and E-cadherin expression.

2. In line 189, “by H&E staining” is unnecessary.

**********

6. 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: Yes: Masayuki Watanabe

Reviewer #4: Yes: Shinichiro Hasegawa

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Microscopic distance from tumor invasion front to serosa might be a useful predictive factor for peritoneal recurrence after curative resection of T3-gastric cancer

PONE-D-19-23016R1

Dear Dr. Yashiro,

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.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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.

With kind regards,

Kun Yang

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Please change from "TS-1" to "S-1".

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

Reviewer #3: All comments have been addressed

Reviewer #4: (No Response)

**********

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

Reviewer #3: Yes

Reviewer #4: (No Response)

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: (No Response)

**********

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

Reviewer #3: Yes

Reviewer #4: (No Response)

**********

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: (No Response)

**********

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: The authors responded well to the comments and the manuscript was improved substantially. However, authors should revise the following point.

1. Change from "TS-1" to "S-1".

Reviewer #2: I think that the authors have answered appropriately reviewers’ comments point-by-point and this article is now acceptable for the PLOS ONE.

Reviewer #3: Togano, et al. investigated the risk factors of peritoneal recurrence in patients who underwent curative gastrectomy for T3 gastric cancer. They evaluated the correlation between the occurrence of peritoneal recurrence and clinicopathologic factors including distance from tumor invasion front to serosa (DIFS) and expression status of E-Cadherin, and found that lymph node metastasis and DIFS were the independent factors associated with peritoneal recurrence. The authors appropriately revised the manuscript.

Reviewer #4: (No Response)

**********

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: Yes: Masayuki Watanabe

Reviewer #4: No