PONE-D-22-30499The impact of nutritional status in nivolumab-treated patients with advanced esophageal cancerPLOS ONE

Dear Dr. tsuda,

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Academic Editor

PLOS ONE

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Additional Editor Comments:

Dear Dr. Tsuda.

I inherited this manuscript from another Academic Editor. I feel sorry for you for the long period of the review process. The manuscript is about the contribution of nutritional status for the treatment of esophageal cancer with an immune checkpoint inhibitor. The results show the statistical significance and I think the data sounds intriguing to many readers. I agree to two reviewers and this manuscript is eligible to proceed to major revision.

I added my own comments below. I look forward to seeing the revision.

Best,

Kenji Fujiwara

Major concerns.

1. The results seem interesting but the numbers of patients are limited, especially in the Nivolumab group. I think the authors may be able to add more patients now. Please update it, if possible.

2. It seems rational to me that nutritional status affects the prognosis but Taxane did not show the difference. This might be the question for many readers. Could you discuss the irrelevance of nutritional status in chemotherapy in the Discussion section?

3. I agree with a reviewer about the necessity of English proofreading.

4. For the ethics statement, I understand it is difficult to get consent in a retrospective study like this. However, the authors' statement “Consent was not obtained because the data were analyzed anonymously," sounds irrational because most studies are analyzed anonymously. Please change the description. At least, the authors should describe that the ethics committee waived the requirement for informed consent.

5. From the author contributions, only two authors ran the study and nine authors did only writing–review and editing. I am surprised that only one person ran the analysis and investigation, but the contributions seem unbalanced. Please reconfirm the contributions by checking the guidelines.

https://journals.plos.org/plosone/s/authorship#loc-author-contributions

6. Introduction consists of too many paragraphs. Please reconstruct it.

7. Whether Squamous cell carcinoma or adenocarcinoma is a very interesting point in the effectiveness of treatment. The authors may add the data analyzing the prognosis separately by depending on histology or at least discuss it.

Minor concerns.

1. The names of persons and addresses are not written in capital letters sometimes in the submission system. Please adjust them.

2. Please show elaboration for the abbreviation when it first appeared. For example, “AEC” was used without description in the abstract.

3. I think PLOS ONE does not ask the authors to include a short title and authors' contribution in the title pages. Please refer to the guidelines and adjust them.

https://journals.plos.org/plosone/s/submission-guidelines

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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: Partly

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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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

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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: Dear Sir:

I have read the manuscript entitled "The impact of nutritional status in nivolumab-treated patients with advanced esophageal cancer". The study explored whether there is a correlation between nutritional status (Glasgow prognostic score, prognostic nutritional index, and neutrophil-to-lymphocyte ratio) and prognosis of advanced esophageal cancer (AEC) in patients treated with taxane or nivolumab therapy. In the nivolumab cohort (N=28), patients with good nutritional status had significantly better median overall survival than those with poor nutritional status (15.5 vs. 7.6 months, respectively, p=0.017, classified by prognostic nutritional index, 14.6 vs. 5.5 months, respectively, p=0.022, classified by Glasgow prognostic score), whereas the prognosis of the patients treated with taxane therapy was less affected by the nutritional status. This observation suggests that pretreatment nutritional status of patients with advanced esophageal cancer is a key factor for successful outcomes, especially for nivolumab treatment.

I have several comments:

1.English editing is necessary

2.As stated by the authors, the retrospective nature of this analysis and limited number of cases may have introduced potential bias of confounding factors. Also both patients with squamous cell carcinoma and adenocarcinoma were included. These two different types of histology may further bias the result. Authors should discuss this point.

3.OS could be influenced by subsequent therapy. Is it possible that in nivolumab group, patients with relatively good nutrition status may have higher chance to receive subsequent chemotherapy? On the contrary, is it possible that in taxane group, patients with either good or poor nutritional status could have similar chance to receive nivolumab after taxane due to relatively low toxicity of immunotherapy? Could authors provide information regarding subsequent therapy in both groups following failure of nivolumab or taxane? Authors should also discuss this possibility in Discussion section.

4.Is there any papers discussing about the association between nutritional status and other biomarkers predicting response to immunotherapy, such as PD-L1 expression, T cell population, inflammation gene signature, etc.? Please discuss

5.Could authors release more detailed information about the design of ENTRANCE study and explain how this study could explore this question?

Reviewer #2: Thank you for your valuable consideration.

Although the number of cases is small, it is interesting to compare the data between taxane and nivolumab regarding the relationship between nutritional status and therapeutic effect.

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Reviewer #1: Yes: Chueh-Chuan Yen

Reviewer #2: No

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Attachments

Attachment

Submitted filename: minnor comment.docx

The impact of nutritional status in nivolumab-treated patients with advanced esophageal cancer

PONE-D-22-30499R1

Dear Dr. tsuda,

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,

Kenji Fujiwara, PhD, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Dr. Tsuda.

Thank you for revising your manuscript appropriately. All reviewers and I agreed to the acceptance.

Yours sincerely,

Kenji Fujiwara

Academic editor

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

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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

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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: (No Response)

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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: As stated in my previous comment, this is a study with small sample size. So the information that could be given is limited. However, in the response letter, authors have provided a well point-to-point response for the comments. Hopefully authors could explore relevant issue in the future study with a larger sample size.

Reviewer #2: Thank you for the opportunity to peer review this wonderful study.

You have answered all the comments properly and I have nothing to point out.

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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: Yes: Chueh-Chuan Yen

Reviewer #2: Yes: Toshihiko Matsumoto

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