-->PONE-D-26-15940-->-->Choroidal Metastasis: Impact of Primary Tumors and Age on Survival - a single center analysis. -->-->PLOS One

Dear Dr. Told,

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.

ACADEMIC EDITOR:  -->-->Marin concerns:  Better depiction of primary tumor histology; address heterogeneity in group three -->-->

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Carmelo Caldarella, Ph.D., M.D.

Academic Editor

PLOS One

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If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Additional Editor Comments:

Dear Authors, please revise your manuscript according to comments provided by the Reviewers, particularly addressing issues regarding the heterogeneity in group three and better depicting primary tumor histology

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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

Reviewer #3: No

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: No

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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: 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

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: The manuscript is very well written and a good point to make. Would accept as is, adds to the information already known for metastases and helps discuss prognosis with patients that come in with questions.

Reviewer #2: The uvea is the most common site of metastasis in the eye. For both ophthalmologist and general practitioners, this article provides highly valuable information that predicts the survival of patients with uveal mets resulting from primary tumours of the breast or lung and also relates the age of the patients at the time of uveal mets to the survival. The clinical implications of this paper are that we can better counsel our patients about their prognosis.

Reviewer #3: Fuchs and colleagues present results of a retrospective analysis of survival in patients with metastatic tumors to the choroid (CM). They found that older patient age and more than one choroidal lesion were predictors of mortality. The study is interesting in its concept as a counseling basis for patients with choroidal metastasis. However, several integral methodological flaws limits the ability to draw any solid conclusions.

Major comments:

- The major concern in the study is the lack of subtyping of the primary tumors, which is a major confounder for survival. For example, breast cancer is not a single disease but a heterogenous group of diseases. Triple negative disease has poor survival than ER/PR tumors or HER-2 enriched. Similarly, lung cancer has many subtypes with different survival patterns. The lack of incorporation of molecular subtypes introduces great bias in the results.

- The other major confounder not accounted for is the sites of extra-ocular metastasis; for example, metastatic disease to the brain carries much worse prognosis than to the bones.

- As the authors acknowledge in the limitations, group 3 is heterogenous ("Other"); each of the 12 malignancy types would carry different prognosis and grouping all types under one category is inappropriate. This third group should have been omitted.

- There was no minimum limit on follow-up duration mentioned by the authors. In that sense, patients with recent CM diagnosis were included and compared to patients with long term diagnosis, which would skew survival data.

- Details of patient symptomatology and imaging strategy are not mentioned. This is also important as many patients with end stage tumors carry asymptomatic "silent" CM. If only symptomatic patients were referred, then many patients with peripheral or small asymptomatic lesions are missed from the sample.

- Treatment details are not incorporated in the analysis. Patients who elect for best supportive care would not have similar survival rates to those who elect for palliative radiation for example.

Minor comments:

- Introduction too lengthy, unnecessary to convey the background and gap of knowledge. Irrelevant sections on incidence data of primary tumors, orbital mets, screening methods, and treatment modalities - none of which are the focus of the manuscript.

- Introduction focuses on data from Europe and not globally (readership of the audience).

- Methods: Unclear why patients with bilateral involvement only had 1 eye included (right eye). Bilateral involvement should have been incorporated as a variable for survival analysis. Also, the worse eye (larger lesion) should have been included in dimension measurements.

- Methods: imaging protocols should have been mentioned, especially since the authors report rates of imaging signs (e.g., SRF), it is thus important to mention what type of OCT protocol was used for detection of the fluid.

- Methods: US is very operator-dependent and the authors should mention if measurements were done by a single operator to avoid bias.

- Statements like "A total of 70 patients... (table 1)" belong to the Results and not Methods section.

- Results: missing data on US dimensions limit the ability to include volumetric data as a variable in the analysis.

- Results: very wide CI in Cox analysis denoting heterogeneity.

- Discussion: too lengthy.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Choroidal Metastasis: Impact of Primary Tumors and Age on Survival - a single center analysis.

PONE-D-26-15940R1

Dear Dr. Told,

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,

Carmelo Caldarella, Ph.D., M.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

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

Reviewer #1: 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

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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

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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: Very well written and good responses and changes to the comments mentioned before. Would recommend accepting as is

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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

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