PONE-D-24-29820Cancer Risk and Mortality Among People with Multiple Sclerosis: A Population-Based Study in Isfahan, IranPLOS ONE

Dear Dr. Shaygannejad,

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Mohammad Reza Fattahi, M.D., M.P.H.

Academic Editor

PLOS ONE

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Additional Editor Comments:

Thank you for your work on this important study. The integration of MS and cancer registration systems in Isfahan and also in all Iran adds significant value to understanding the incidence and risk factors for cancer among patients with MS. However, several areas of the manuscript require clarification and revision, as detailed in the reviewer comments. Addressing these will strengthen your paper, particularly in terms of the study’s methodology, data accuracy, and the inclusion of relevant references.

I encourage you to consider the reviewers' suggestions carefully, as they will help refine your work and enhance its impact on the field.

Best regards,

[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: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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

Reviewer #3: 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

Reviewer #3: 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 Authors,

Thank you for your valuable research. I have a few minor comments to improve the quality of the study:

Abstract:

1. I recommend including the mean duration of MS diagnosis in the characteristics of patients in the Results section of the abstract.

2. Please specify which cancers are more prevalent among males and which are more prevalent among females.

Methods:

1. Could you explain why the MS National Registry of Iran was not used to study MS risks among all MS patients in Isfahan for your study? Using the registry for identifying MS patients might have provided more precise data for your study.

Results:

1. As previously mentioned, please include the mean duration of MS in the Results section under "Demographic Characteristics of People with Multiple Sclerosis."

2. Include the EDSS score and MS duration in Table 1 and change the title of Table 1 to "Demographics and Characteristics of People with Multiple Sclerosis with and without Cancer."

3. Instead of writing 'MS-only,' please write 'MS without cancer' in Table 1.

4. Include the EDSS score and MS duration in Table 2 and analyze them as the probable risk factors for cancer incidence.

5. To determine appropriate screening protocols for cancer in MS patients which is highly recommended, it is important to know the incidence of each cancer type in this population. Please add Supplementary Table 2: "Incidence of Cancer Types Among People with Multiple Sclerosis" to the main tables of the manuscript and discuss it.

Reviewer #2: This manuscript titled; Cancer Risk and Mortality Among People with Multiple Sclerosis: A Population-Based Study in Isfahan, Iran.

Many patients with multiple sclerosis face numerous challenges associated with managing a chronic illness, which may lead them to overlook early warning signs that could indicate the presence of cancer. This oversight can result in delayed cancer diagnoses, potentially leading to a higher incidence of advanced-stage cancers and increased mortality rates.

This study aims to assist neurologists and specialists in MS by highlighting the potential link between cancer and MS, and by improving patient management strategies. While the discussion provided is thorough and relevant, it lacks specific guidelines for cancer screening in this patient population. Furthermore, given the higher prevalence of women with MS who are of childbearing age, the study could offer additional insights into the challenges faced by clinicians in treating MS and addressing reproductive health considerations, especially for breast cancer among women.

Considering the noted deficiencies, the article would benefit from minor revisions to address these challenges more effectively. Additionally, the language needs refinement.

Reviewer #3: This article is well helped by the integration of MS and cancer registration systems to find the incidence rate, risk factors and mortality rate among MS patients in Isfahan.

But it has ambiguities that need to be resolved. This manuscript need Major revision for acceptance.

Below are the comments:

Title: Mortality should be written as mortality rate (in title and whole body of manuscript).

Abstract

Abstract (Background): write the goal of study before method section.

Abstract (method): please specify deputy of MUIs and other registry systems such as NMSRI.

Abstract (method): data, collected following which international protocols?

Abstract (result): insert mean age instead of average age (Also in whole body of manuscript).

Abstract (result): put per 100,000 person-years at end of sentence.

Abstract (conclusion): write 2-3 sentences summarizing the supporting points / body paragraphs and delete Further research is needed …

Introduction:

Reference 1 in nor relevant for first paragraph.

Insert relevant reference for sentence “others indicate an increased or comparable risk”.

highest MS prevalence rates for Isfahan, needs relevant reference (no reference 11).

Describe the main goal of study in last sentence.

Method:

Please insert all data sources such as National MS Registry system, if you were used in this study.

Population of Iran is more than 85milion people, you should use last national census not 2016.

Specify data collection method from PwMS in manuscript with relevant references.

What is Vice-Chancellery of MUI,?

First, you must write the full word for the first time in the text and put its abbreviation in parentheses, like central nervous system (CNS). Follow this rule throughout the whole manuscript.

You should use latest McDonald criteria not 2001 version.

Insert exact number of excluded cases for each reason such as individuals who could not be identified through their national code, those who did not participate in follow-up interviews, those with insufficient data, or those whose cancer was diagnosed prior to the onset of MS.

How many subjects were collected for interview? While you mentioned about retrospective method and collecting data from registry system, why your team had interview with subjects?

How did you calculate EDSS by interview? It is not possible. Even types of MS.

This data is not exit in MUI registry system. It is available in National MS Registry of Iran.

Reference 18 is not suitable for this method.

Result:

Average ages should be change to mean age in whole manuscript.

Incidence ratio or ratio?

The overall incidence ratio of cancer among PwMS should be calculate correctly.

oldest age groups (65-79), should be write along with.

tumor grade 9? It should be corrected.

Last paragraph of “Clinical Features of Multiple Sclerosis-Cancer Patients” is confusing.

Discussion

Discussion is too long.

Insert relevant references for last paragraph of “Cancer Incidence Among People with Multiple Sclerosis: Higher or Lower?”

No need to discuses method of cancer diagnosis.

This study's strengths are not including analysis methods, detailed consideration of various influencing factors, and high ethical and methodological standards. It is necessary to do these things.

retrospective data from specific registries may

This study's limitation is not including introduce biases and inaccuracies, limiting the generalizability of findings beyond this population, absence of a control group from the general population and Retrospective data collection risks.

Tables

The total percentage of the columns in each category must be 100%. No less and no more.

What are the column titles in tables 2 and 3?

Write all Abbreviations bellow tables such as HR.

Why, apart from the references, the statistics of other variables have not been reported?

Figure

Specify cancer duration (Year).

References

References should be update and relevant to each sentence.

You should add NMSRIs references.

The manuscript needs English editing.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Cancer and Mortality Risks Among People with Multiple Sclerosis: A Population-Based Study in Isfahan, Iran

PONE-D-24-29820R1

Dear Dr. Shaygannejad

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.

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Kind regards,

Mohammad Reza Fattahi, M.D., M.P.H.

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 #2: 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 #2: Yes

Reviewer #3: Yes

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

Reviewer #2: I Don't Know

Reviewer #3: 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 #2: Yes

Reviewer #3: 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 #2: 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 #2: Comments to the Authors:

Thank you for addressing all of my comments, I appreciate the revision made.

Reviewer #3: Greeting

In my opinion, the comments have been answered appropriately and the necessary corrections have been made.

The Manuscript entitle: Cancer and Mortality Risks Among People with Multiple Sclerosis: A Population-Based Study in Isfahan, Iran could be accepted for publication in PLOS ONE, since satisfy the PLOS ONE criteria 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 #2: No

Reviewer #3: No

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