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PONE-D-21-26649Thrombocytosis and Abnormal Liver Enzymes: A Trigger for Investigation of Underlying MalignancyPLOS ONE

Dear Dr. Gold,

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PLOS ONE

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I have read the journal's policy and the authors of this manuscript have the following competing interests: Eleanor Dow: Funding - Educational grants from Siemens and Abbott; Scott Jamieson: Declaration of interest - Reviewer of Scottish Referral Guidelines for Suspected Cancer

    

We note that one or more of the authors are employed by a commercial company: Siemens and Abbott

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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: I Don't Know

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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: No

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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: This is a nice study that attempts to detect patients with cancer by a simple lab analysis and that could be very helpful in GP practice. Although I consider the findings very encouraging they should be validate prospectively and probably redefining limits of platelets to gain more sensitivity.

I would like to make two simple comments;

“Analysis of the validation cohort accepted cancer diagnoses if already present at time of request”. It may me think if this would be a bias and I would like a comment about it.

Was there a trend in the number of platelets in patients with cancer? Do patients with advanced cancer had more platelets? Maybe, due to the retrospective analysis there is data about it.

Reviewer #2: Nice paper that highlights the utility of combination of readily available data to detect clinically important outcomes.

It would be worth clarifying if the control group had the same liver enzyme abnormality as the thrombocytosis group or whether this was a mixed bag of enzyme abnormalities.

The cut off of platelet count of 400 is an arbitrary reference range level for the laboratory. With so many values being in the 400 to 450 range, were other values explored such as 350 or 375?

On line 198 this refers to figure 3 not figure 2

On line 208 this refers to figure 4 not figure 3

Table 2 could be rearranged in order site of metastases is below rather than alongside the site of the advanced cancers.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-26649R1Thrombocytosis and Abnormal Liver Enzymes: A Trigger for Investigation of Underlying MalignancyPLOS ONE

Dear Dr. Gold,

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 01 2022 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,

Hsu-Heng Yen

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.

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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 #3: 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 #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: 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 #3: 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 #3: 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: (No Response)

Reviewer #3: *The authors have come with an insightful work that highlights a trigger for investigation of underlying malignancy in patients with combined unexplained thrombocytosis and deranged liver enzymes (particularly ALP). The authors have tried to absorb the salient comments forwarded by the previous reviewers. In general, the manuscript is well written, and it should be considered for publication provided that the suggested modifications both from the reviewers and academic editor(s) are taken into account. Below are the main comments for the review report.

*Introduction: line ≠69: “Thrombocytosis is the term given to an overproduction of platelets…” Megakaryocyte proliferation is not the only cause of thrombocytosis as it can also result from decreased platelet sequestration (as in the case of asplenia, for example). Therefore, the sentence should be rewritten. One option of modification is: thrombocytosis is the presence of elevated platelet count… or the word ‘usually’ should be added to the existing sentence.

*Introduction: line ≠77 & 78: tuberculosis is written separately from bacterial causes as if it were not a bacterial infection. It should be modified like: The most common clinical scenarios in which reactive thrombocytosis occurs include bacterial infections including tuberculosis…

*Regarding exclusion criteria, was there any consideration of conditions that could potentially cause raised alkaline phosphatase such as growth healing fractures, osteomalacia, hyperparathyroidism, and hyperthyroidism? I would like to hear about this.

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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 #3: Yes: Subah Abderehim Yesuf

[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.

Thrombocytosis and Abnormal Liver Enzymes: A Trigger for Investigation of Underlying Malignancy

PONE-D-21-26649R2

Dear Dr. Gold,

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.

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Kind regards,

Hsu-Heng Yen

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: