PONE-D-23-43229The observational EURACAN prospective clinical registry dedicated to epithelioid hemangioendothelioma:  the protocol of an international and collaborative effort on an ultra-rare entityPLOS ONE

Dear Dr. Trama,

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.

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ACADEMIC EDITOR: This is an important field of research and your protocol is fairly good. Add  a sentence in the protocol describing  the procedures in case of protocol deviations and  justify why a 6 months update and not one year. Please find bellow the reccomendations of reviewer 1 and  please answer the questions .

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Cristina Deppermann Fortes, PhD

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://doi.org/10.1371/journal.pone.0283071

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

3. Thank you for stating the following in the Competing Interests section:

“Anna Maria Frezza declares institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics.

Alexia Bertuzzi declares support for attending meeting and/or travels from Pharmamar and Istituto Gentili; support for scientific activities from Istituto Gentili.

Antonella Brunello declares consulting fees or serving on advisory boards for Eli Lilly, Roche, GSK, Eisai, Pharmamar, Boehringer Ingelheim, Deciphera; payment or honoraria for educational events by GSK and Pharmamar; travel grants by Pharmamar, Istituto Gentili.

Giacomo G. Baldi declares consulting fees from Eli Lilly, Pharmamar, AboutEvents; honoraria from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai, IstitutoGentili; support for attending meetings and/or travels from Novartis, Pharmamar, Eli Lilly; participation on the advisory board from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai.

Paolo G. Casali declares institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics.

Virginia Ferraresi declares consultancy fees or honoraria from PharmaMar, Boehringer Ingelheim, Gentili e Serb Pharmaceuticals.

Matilde Ingrosso reports institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics.

Laura Monteleone reports institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics.

Johanna Szkandera reports participation in advisory boards or invited speaker fees for PharmaMar, Bayer, Roche, Lilly, Amgen; travel expenses coverage from PharmaMar, Roche, Lilly, Amgen, Bristol Myers Squibb; research funding from PharmaMar, Roche, Eisai.

Bruno Vincenzi reports consulting fees from Eisai, Lilly, Bayer, Deciphera, PharmaMar, Blueprint, Pfizer, GSK, Accord, Abbott and research support from PharmaMar, Novartis, Lilly

Silvia Stacchiotti declares advisory board roles with Bayer, Boehringer, Daiichi, Ikena, Nec Oncology, Pharma Essentia, Regeneron, Servier; invited speaker roles for Bayer, Boehringer, Gentili, Pharmamar; institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics.

Carlo Cicala, Lorenzo D’Ambrosio, Angelo Paolo Dei Tos, Alessandro Gronchi, Nadia Hindi, Robin Jones, Iwona Lugowska, Julia Ketzer, Anna Mariuk-Jarema, Andrea Napolitano, Andri Papakonstantinou, Sandro Pasquali, Marta Sbaraglia, Federico Scolari, Elisa Crotti, Irene Benzonelli, Jean-Yves Blay, Christophe Bouvier, Javier Martin Broto, Hugh Leonard, Ninna Aggerholm-Pedersen, Andri Papakonstantinou, Giuseppe Bianchi, Federica Zuccheri, Paolo Baili, Simone Bonfarnuzzo, Domenico Campanacci, Armelle Dufresne, Sebastian Bauer, Serena Bazzurri, Stefano Gabellini, Claudia Giani, Vincenzo Giannusa, Melissa Gil-Sanjines, Teresa Grassani, Paolo Lasalvia, Stefan Lindskog, Salvatore Vizzaccaro, Nils Dieckmann, Alessandro Mazzocca, Andrei Ivanescu, Giuseppe Badalamenti, Carlo Morosi, Stephanie Elston, Kyetil Boye, Francesca Nardozza, Elisabetta Neri, Maria Nilsson and Annalisa Trama declares no conflict of interest.”

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4. 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 (if provided):

This is an important field of research and your protocol is fairly good.The authors should add in the protocol that any deviations from the protocol has to be ammended with justifications and reviewed by the local the ethical committee.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: No

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The study represents an observational registry-based cohort study which includes new pathological and molecularly confirmed diagnosis of EHE, starting from the 1st December 2023, with an estimated completion date of December 2033. The study represents the first effort of this kind, being joined by 21 sarcoma reference centers across EU and UK, spanning 10 countries. It has a projected combined accrual of 100 cases/tear. The goal is to collect full details on patients and disease features, treatment and outcome, according to common clinical practice guidelines developed and shared with all the contributing centers.

This effort is highly laudable and will be the first STARTER international registry, fully dedicated to an ultra-rare sarcoma such as EHE, which will serve as an example for other sarcomas.

One point that the authors may want to clarify or add relates to the semi-annual updates – if one particular systemic regimen has shown encouraging results in few patients – is there a mechanism in place to inform the other contributors? Meaning, can this registry serve as an interactive/active platform and have a feedback mechanism for the data analysis, not only at the end of the 10 years of observation.

Second point, a mandatory 6-monthly update is requested from the participating sites. Why only 6 month and not 1 year – as most EHE have an indolent behavior, with some multifocal liver or even lung EHE, showing no changes for years.

There are many EHE registry objectives listed. However, among prognostic and predictive factors will be important to add under the molecular features: NGS findings when available, such as secondary hits: CDKN2A/B deletion. TERT promoter mutations, etc.

Minor comments: mostly rephrasing and typos

- ‘peculiar molecular and pathologic features’ – replace ‘peculiar’ with ‘distinctive’ – in the Abstract intro as well as from the 1st sentence in the Introduction

- delete word ‘extremely’ before variable clinical behavior in the Abstract intro

- fix typo: ‘Centres’ with ‘centers’ in abstract settings, 2nd page intro and discussion

Intro: use italics for gene names and update nomenclature for gene fusions ‘-‘ replace with ‘::’

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Reviewer #1: No

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The observational EURACAN prospective clinical registry dedicated to epithelioid hemangioendothelioma:  the protocol of an international and collaborative effort on an ultra-rare entity

PONE-D-23-43229R1

Dear Dr. Annalisa Trama,

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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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,

Cristina Deppermann Fortes, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Please add clearly the objectives of the Registry and state its limitations as suggested by the reviewer. 

Reviewers' comments:

The study represents an observational registry-based cohort study which includes new pathological and molecularly confirmed diagnosis of EHE, starting from the 1st December 2023, with an estimated completion date of December 2033. The study represents the first effort of this kind, being joined by 21 sarcoma reference centers across EU and UK, spanning 10 countries. It has a projected combined accrual of 100 cases/tear. The goal is to collect full details on patients and disease features, treatment and outcome, according to common clinical practice guidelines developed and shared with all the contributing centers.

This effort is highly laudable and will be the first STARTER international registry, fully dedicated to an ultra-rare sarcoma such as EHE, which will serve as an example for other sarcomas.

One point that the authors may want to clarify or add relates to the semi-annual updates – if one particular systemic regimen has shown encouraging results in few patients – is there a mechanism in place to inform the other contributors? Meaning, can this registry serve as an interactive/active platform and have a feedback mechanism for the data analysis, not only at the end of the 10 years of observation.

Second point, a mandatory 6-monthly update is requested from the participating sites. Why only 6 month and not 1 year – as most EHE have an indolent behavior, with some multifocal liver or even lung EHE, showing no changes for years.

There are many EHE registry objectives listed. However, among prognostic and predictive factors will be important to add under the molecular features: NGS findings when available, such as secondary hits: CDKN2A/B deletion. TERT promoter mutations, etc.

Minor comments: mostly rephrasing and typos

- ‘peculiar molecular and pathologic features’ – replace ‘peculiar’ with ‘distinctive’ – in the Abstract intro as well as from the 1st sentence in the Introduction

- delete word ‘extremely’ before variable clinical behavior in the Abstract intro

- fix typo: ‘Centres’ with ‘centers’ in abstract settings, 2nd page intro and discussion

Intro: use italics for gene names and update nomenclature for gene fusions ‘-‘ replace with ‘::’