Peer Review History

Original SubmissionFebruary 9, 2023
Decision Letter - Robert Jeenchen Chen, Editor

PONE-D-23-03771A new scoring system with simple preoperative parameters as predictors of early recurrence of pancreatic ductal adenocarcinomaPLOS ONE

Dear Dr. Shimagaki,

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 May 11 2023 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:

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We look forward to receiving your revised manuscript.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

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

https://link.springer.com/article/10.1245/s10434-021-10866-6?

https://pubmed.ncbi.nlm.nih.gov/36338597/

https://www.sciencedirect.com/science/article/abs/pii/S1424390321005263?via%3Dihub

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Additional Editor Comments:

Please revise.

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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: No

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: To the Editors:

Thank you for the opportunity to review a manuscript entitled “A new scoring system with simple preoperative parameters as predictors of early recurrence of pancreatic ductal adenocarcinoma”.

This paper is an article which introduced the predictive score of early recurrence using the preoperative serum CA19-9, PLR, and tumor diameter. This manuscript has been reviewed. I think that it is necessary to verify whether the methodology of this statistical analysis is correct or not by statisticians. There seems to be several problem in this statistical analysis. Although the report appears to give some clinically significant information, there are several points that need to be clarified.

Reviewer #2: The study tried to make a new scoring system to predict early recurrence of PDAC. The authors tried to make it to be optimal to predict ER. These approaches were well-done. However, they did not evaluate if this scoring system is effective in other cohorts. Without this evaluation, it is hard to score this developed scoring system. Without it, this study is merely a confirmation to the clinicopathologic evaluation of PDAC reported by many groups.

The cohort used consisted of NAT (+) and NAT (-) cases. The two groups may differ clinico-pathologically and biologically (e.g., the same T factor but the cancer cell density is sometimes very different between NAT (+) and NAT (-) PDAC). If so, scoring system optimal to predict early recurrence of PDAC may be changed dependent on composition of PDAC with and without NAT in the cohort used. What do the authors think about this?

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Reviewer #1: Yes: Yusuke Yamamoto

Reviewer #2: No

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Revision 1

Answers to the Reviewer #1:

We appreciate for the thoughtful comments and suggestions. Our responses to them are as follows. We changed the manuscript accordingly.

Q1.

The title of Table 3 was “univariate and multivariate Cox regression analysis for ER”. Is this analysis really Cox regression analysis? Please check by the statisticians. If possible, please add the statisticians as one of the co-authors.

Our response to Q1:

We appreciated the reviewer’s comment and Table 3 has been modified for univariate and multivariate analysis using logistic regression analyses. We asked a statistician to review this study and included him as a co-author.

The above is described in the materials and methods section (page 10, lines 13) and in Table 3.

Q2.

In the Table 3, only four consecutive parameters were divided into two groups using the ROC analysis. I think that it will not be appropriate to divide only four consecutive parameters, and it will be preferable to divide all consecutive parameters into two groups using the ROC analysis. I recommend that these analysis will be supervised by the statisticians.

Our response to Q2:

As suggested by the reviewer, under the guidance of a statistician, all continuous parameters in Table 3 were divided into two groups using ROC analysis, followed by univariate and multivariate analysis.

The above is described in the results section (page 13, lines 5) and in Table 3.

Q3.

Authors should show the exact ER rates in every scores. I think that the ER rates of the patients with score 2 or 3, which are majority of this subjects (102 patients/153 patients), are probably similar ER rate of the entire ER rate (35%). So, this score will not actually be useful in majority of the pancreatic cancer patients.

Our response to Q3:

Using this new scoring system, the ER rate was calculated to be 0% (0 /16 patients) in the 0-point group, 16.2% (7 /36 patients) in the 1-point group, 40.7% (24 /59 patients) in the 2-point group, and 65.7% (23 /35 patients) in the 3-point group. The higher the score was, the higher the ER rate was.

The above is described in the results section (page 15, lines 1).

Q4.

The stratum-specific likelifood ratio (SSLR) indicates by how much a given diagnostic test result will increase or decrease the pretest probability of the target disorder. LR greater than 10 or less than 0.1 generates large and conclusive changes from pretest to post-test probability. Thus SSLR is estimated according to the following formula: SSLR = (x1/n1)/(x0/n0), where x1 is the number of patients in the stratum with ER; n1 is the total number of patients with ER; x0 is the number of patients in the stratum without ER; n0 is the total number of patients without ER (ref; Teasdale G, Jennett B (1974) Assessment of coma and impaired consciousness: a practical scale. Lancet 2:81–84). I recommend the authors to estimate SSLR for each score, and please prove the actual utility of this score. If the SSLR was greater than 10 or less than 0.1, this score will have the conclusive utility.

Our response to Q4:

The stratum specific likelihood ratio (SSLR) is the probability of a given test result when the disease is present, divided by the probability of the same test result when the disease is absent. We determined these ratios by means of the formula SSLR = (x1/n1)/(x0/n0), where x1 is the number of patients in the stratum with ER; n1 is the total number of patients with ER; x0 is the number of patients in the stratum without ER; n0 is the total number of patients without ER.

SSLR was calculated to be 0 in the 0-point group and 0.356 in the 1-point group, 1.257 in the 2-point group, and 3.513 in the 3-point group.

The above is described in the materials and methos section (page 10, lines 14) and the results section (page 15, lines 4).

Q5.

I recommend the authors to develop a score using each standardized variable based on the regression coefficient of the logistic regression model, because the odds ratio of each parameters of the score was greatly different. Considering their odds ratio, the equation for the scoring system had better be calculated on the assumption that a patient receives about 3-4 points for high PLR, if a patient receives 1 point for each of high CA19-9 and the tumor diameter of >3.1 cm."

Our response to Q5:

We appreciate the reviewer’s comment, and added logistic regression model in the revised manuscript.

We calculated a predictive model for ER after the resection for PDAC by stepwise multiple logistic regression analysis as follows. If a patient had a high PLR, a high CA19-9, or a tumor diameter > 3.1 cm, they received 1 point each in this model.

Logit(p) = 1.6 + 1.2 × high PLR + 0.7 × high CA19-9 + 0.5 × tumor diameter > 3.1cm

The AUC, sensitivity, and specificity of our prediction model were 0.763, 85.2% and 55.6%, respectively (Figure 4, Table 2). This ER prediction model was comparable to the scoring system and was more useful than any test for identifying ER after the resection of PDAC (Table 2).

The above is described in the abstract and the results section (page 15, lines 10).

Answers to the Reviewer #2:

We appreciate for your thoughtful comments and suggestions. Our responses to the comments are as follows.

Q.

The cohort used consisted of NAT (+) and NAT (-) cases. The two groups may differ clinico-pathologically and biologically (e.g., the same T factor but the cancer cell density is sometimes very different between NAT (+) and NAT (-) PDAC). If so, scoring system optimal to predict early recurrence of PDAC may be changed dependent on composition of PDAC with and without NAT in the cohort used. What do the authors think about this?

Our response to Q:

We performed this scoring system analysis in total 153 cases combining 55 NAT cases and 98 upfront surgery cases, using parameters measured before NAT (at time of first diagnosis). As a result, the significant worse prognosis for both OS and DFS were observed in the cases with higher score (Supplementary Figure 2A-2D), which was similar to the main results (Figure 3A-3D).

We also did this scoring system analysis only in 55 cases that underwent NAT. We compared OS and DFS stratified by the prediction scoring system using parameters before and after NAT (Supplementary Figure 3A-3D). As a result, both OS and DFS tended to be worse in the cases with higher score, whether the parameters before or after NAT were used. There was no statistically significant difference due to small number of cases. These results indicated that the preoperative parameters have the same significance even if it is measured before or after preoperative chemotherapy.

The above is described in the results section (page 14, lines 9).

Attachments
Attachment
Submitted filename: Response to Referees.docx
Decision Letter - Robert Jeenchen Chen, Editor

PONE-D-23-03771R1A new scoring system with simple preoperative parameters as predictors of early recurrence of pancreatic ductal adenocarcinomaPLOS ONE

Dear Dr. Shimagaki,

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 Jul 16 2023 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,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Journal Requirements:

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.

Additional Editor Comments:

Please revise.

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

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

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

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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

**********

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

**********

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 have submitted a revised article on a new scoring system with simple preoperative parameters as predictors of early recurrence of pancreatic ductal adenocarcinoma. The data and methods have been thoroughly revised, and the results of this study have been clarified, offering important insights. I recommend making an additional correction as follows.

1. The authors have clearly demonstrated the SSLR in each score. Considering the SSLR in each score, this score will be particularly useful for patients with a score of 0 (SSLR = 0), which accounts for only 16 out of the total 153 patients. However, for the majority of patients (137 out of 153), calculating this score did not significantly alter the probability of early recurrence when compared to the overall early recurrence rate (35%). The authors should mention this limitation of the study in the limitations paragraph within the Discussion section.

Reviewer #2: The authors responded to the comment of the reviewer #2 and the revised manuscript has been improved.

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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

**********

[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.

Revision 2

Answers to the Reviewer #1:

We appreciate for the thoughtful comments and suggestions. Our responses to them are as follows. We changed the manuscript accordingly.

Q1.

The authors have clearly demonstrated the SSLR in each score. Considering the SSLR in each score, this score will be particularly useful for patients with a score of 0 (SSLR = 0), which accounts for only 16 out of the total 153 patients. However, for the majority of patients (137 out of 153), calculating this score did not significantly alter the probability of early recurrence when compared to the overall early recurrence rate (35%). The authors should mention this limitation of the study in the limitations paragraph within the Discussion section.

Our response to Q1:

We appreciated the reviewer’s comment.

We have clearly demonstrated the SSLR in each score. Considering the SSLR in each score, this score will be particularly useful for patients with a score of 0 (SSLR = 0), which accounts for only 16 out of the total 153 patients. However, for the majority of patients (137 out of 153), calculating this score did not significantly alter the probability of ER when compared to the overall ER rate (35%).

The above is described in the discussion section (page 19, lines 14).

Attachments
Attachment
Submitted filename: Response to Referees.docx
Decision Letter - Robert Jeenchen Chen, Editor

A new scoring system with simple preoperative parameters as predictors of early recurrence of pancreatic ductal adenocarcinoma

PONE-D-23-03771R2

Dear Dr. Shimagaki,

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,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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

**********

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

Reviewer #1: Yes

Reviewer #2: 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

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 #1: Yes

Reviewer #2: 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: TO THE AUTHORS:

The authors have submitted a revised article on a new scoring system with simple preoperative parameters as predictors of early recurrence of pancreatic ductal adenocarcinoma. The data and methods have been thoroughly revised, and the study's results have been well clarified.

Reviewer #2: (No Response)

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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

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Formally Accepted
Acceptance Letter - Robert Jeenchen Chen, Editor

PONE-D-23-03771R2

A new scoring system with simple preoperative parameters as predictors of early recurrence of pancreatic ductal adenocarcinoma

Dear Dr. Shimagaki:

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.

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

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Robert Jeenchen Chen

Academic Editor

PLOS ONE

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