PONE-D-19-18111

The D-dimer level predicts the postoperative prognosis in patients with non-small cell lung cancer

PLOS ONE

Dear Dr. Nakajima,

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.

(1) Description of a normal range of D-dimer

(2) Discussion about therapeutic intervention for patients with non-small cell lung cancer (NSCLC) who underwent radical surgery

(3) Discussion about the effects of surgical procedure, if any

(4) Discussion related to vascular invasion and distant metastasis

(5) Discussion related to venous thromboembolism (VTE) and prognosis

(6) Other issues pointed out by Reviewers

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PLOS ONE

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Ichiro Yoshino received honorarium from Pfizer Inc., SHIONOGI＆CO., LTD., Astellas Pharma Inc., Nippon Boehringer Ingelheim CO., Ltd., DAIICHI SANKYO COMPANY, LIMITED., Chugai Pharmaceutical Co., Ltd., ONO PHARMACEUTICAL CO., LTD., TEIJIN PHARMA LIMITED.

Takahiro Nakajima received honorarium from Olympus Corporation, AstraZeneca plc.

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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: Yes

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?

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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: The authors investigated whether D-dimer was a prognostic impactor for patients with non-small cell lung cancers. Although not that novel, the study was reliable and the analysis was appropriate.

1. What's the normal range of D-dimer in the institution?

2. Why ten patients received induction therapy?

3. Since the small number of patients in each cN group, I wonder if it would be integrated into with or without lymph node metastasis.

4. As for HDD group, any further examination or intervention has been used?

5. Did surgical procedure (Lobectomy vs sublobar resection) impact the prognosis?

Reviewer #2: This is an interesting original work, and the only necessary thing to do is to have more appropriate references, shaping a bit different discussion, and thus making more profound and comprehensive explanations for your findings. Just to mention, vascular invasion should be in this context adequately discussed, as well as the tendency of more distant metastasis in the HDD group than in the NDD group although not significant difference in the type of recurrence, as well as NSCLC with a solid tumor appearance on CT in the context of the poorer prognosis. More recent references should be used - there are several large scaled prospective studies that found that the association of high D-dimer levels with poor prognosis was independent of VTE in hematologic malignancies and solid tumors, which raised the question that D-dimer might be able to affect prognosis through a VTE independent pathway, thus pointing that D-dimer may play an important role in the tumorigenesis.

Some suggested references, among necessary to add and comment:

-Lyman GH, Khorana AA. Cancer, clots and consensus: new understanding of an old problem. J Clin Oncol. 2009; 27:4821-4826.

-Zhao J, Zhao M, Jin B, et al. Tumor response and survival in patients with advanced non-small-cell lung cancer: the predictive value of chemotherapy-induced changes in fibrinogen. BMC Cancer 2012; 12:330.

-Zhu L, Liu B, Zhao Y, Liu L, Yang C, Yang Y, Zhong H. High levels of D-dimer correlated with disease status and poor prognosis of inoperable metastatic colorectal cancer patients treated with bevacizumab. J Cancer Res Ther. 2014; 10:246-251.

-Chen Y, Yu H, Wu C, Li J, Jiao S, Hu Y, Tao H, Wu B, Li A. Prognostic value of plasma D-dimer levels in patients with small-cell lung cancer. Biomed Pharmacother. 2016; 81:210-217.

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Reviewer #1: No

Reviewer #2: No

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The D-dimer level predicts the postoperative prognosis in patients with non-small cell lung cancer

PONE-D-19-18111R1

Dear Dr. Nakajima,

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.

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With kind regards,

Masaru Katoh, M.D., Ph.D.

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

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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

**********

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

Reviewer #1: 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

**********

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. 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 author has adequately addressed all the comments. Although not that novel, the study is now acceptable 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