Review Reports

Round 1

Reviewer 1 Report

The authors summarize milestones of medulloblastoma research including diagnostics and research. This review represents a welcome overview for the history of medulloblastoma research.

The review is highly relevant for physicians and scientists in this field. The manuscript is clear and well structurated. To my knowledge no comparable review is currently published.

I recommend to accept after minor revisions.

Comments:

Perhaps Gibson et al. 2010 Nature Letters should be included. They showed also different cellular origins for different medulloblastoma subtypes.

at page 9, line 201: the citation for Rorke et al. is missing

The right column of table 1 is difficult to read because of missing pragraphs between the rows.

Some abbrevations (CTC: page 5, line76; MRD: page 10, line 261) are missing.

The last line of figure 4 legend is missing.

There are minor grammar mistakes (compound noun (+ adjective); commas).

Author Response

• The authors are truly thankful for the expert’s supportive evaluation and all the relevant comments.

Comments:

Perhaps Gibson et al. 2010 Nature Letters should be included. They showed also different cellular origins for different medulloblastoma subtypes.

• Very welcome reference included.

at page 9, line 201: the citation for Rorke et al. is missing

• Thank you. Reference number added.

The right column of table 1 is difficult to read because of missing pragraphs between the rows.

• Lines in table 1 and all other tables were activated for better readability of the manuscript (lines may be deleted and adjusted by proof editors).

Some abbrevations (CTC: page 5, line76; MRD: page 10, line 261) are missing.

• Thank you. Abbreviations were corrected (appeared at later part of manuscript, were also corrected there).

The last line of figure 4 legend is missing.

• Although it was cited as a reference, we also added the Creative Commons license.

There are minor grammar mistakes (compound noun (+ adjective); commas).

• We corrected grammar mistakes, but expect the final proof editor will correct any remaining ones.

Reviewer 2 Report

The authors present an intriguing overview of the evolution, during the years, of diagnostic assessment of medulloblastoma, considering that such evolution has affected clinical management. The last WHO classification (21) has yet restructured the classification to allow for the incorporation of updated data about medulloblastoma biology, genomics, and clinical behavior: medulloblastomas are classified according to molecular characteristics and histologic characteristics comprising the kind of pathway activation or DNA methylation profile (Cotter JA, Hawkins C. Medulloblastoma: WHO 2021 and Beyond. Pediatr Dev Pathol. 2022 Jan-Feb;25(1):23-33. doi: 10.1177/10935266211018931). The classification still impacts on the treatment, mainly about the “high-risk” tumors (Bouffet E. Management of high-risk medulloblastoma. Neurochirurgie. 2021 Feb;67(1):61-68. doi: 10.1016/j.neuchi.2019.05.007)

 

The manuscript presents some value mainly for physicians not daily involved in the management (clinical or surgical) of patients with medulloblastoma and suggests some future directions. However, I do not fully agree that “Liquid biopsy has become a milestone in modern medicine”: despite its sure and potential value in the future, analysis of CSF cfDNA is still limited in the setting of the current clinical practice. I also suggest increasing the spectrum of references related to liquid biopsy (as Greuter L et al. The Clinical Applications of Liquid Biopsies in Pediatric Brain Tumors: A Systematic Literature Review. Cancers (Basel). 2022 May 28;14(11):2683. doi: 10.3390/cancers14112683), to reduce the rate of self-citations (as for example, are all references from 40 to 48 necessary?)

Author Response

We really thank the reviewer for the time and expert evaluation and suggestions.

We happily added the two references, one of them was just accidentally not included.

Liquid Biopsy was considered recently (Nature, Dec. 2020) as one of the “milestones” in cancer in the last two decades, therefore we added the reference. We also agree that this statement might have been misleading without this reference, since there is still a lot of room for improvement for a routine clinical use of liquid biopsy:

(timeline 2004) https://www.nature.com/immersive/d42859-020-00083-8/index.html

https://www.nature.com/articles/d42859-020-00070-z

We slightly reduced our citations in the field of atomic force microscope (AFM), but also added further references from other authors on AFM entering liquid biopsy (from 2021, 2022, 2023) to support our view, that this will be a future milestone. This may also help to fund a start-up company in this field.

Reviewer 3 Report

The Review article titled "Medulloblastoma: from TP53 mutations to molecular classification and liquid biopsy" authored by Robert Eibl and Markus Schneemann provides a comprehensive review on medulloblastoma. Comments and Suggestions for Authors are following: The article is well written and informative and I enjoyed reading it. I would like to congratulate the authors for their time and effort to produce such a high quality result.  I have the following suggestion that would add value to the manuscript. It would be really helpful to add some additional data on the epidimiology of medullobalstoma in order to in order to support the significance of diagnisis and therapy.     

Author Response

We really thank for the reviewer’s time and so supportive evaluation. We happily added the incidence and two statistical references.

Reviewer 4 Report

The review entitled "Medulloblastoma: from TP53 mutations to molecular classification and liquid biopsy" deals with a current topic of medical-scientific interest. The authors have treated the subject exhaustively and have outlined it in a clear and intuitive way for the reader. Just one note, in my opinion, a figure or a paragraph should be inserted that summarizes the so far known mutations of P53, highlighting those involved in Medulloblastoma.

Author Response

We really thank the reviewer very much for this supportive evaluation. In principle, we agree that it would be nice to have a map of all p53 mutations in medulloblastoma, and to point to potential differences of specific mutations, but this might be a very new paper, or a book. Furthermore, the current WHO classification includes only “mutated” or “wildtype” TP53, not any specific mutations. Since the other reviewers didn’t mention this point, we think the paper is complete without any extra figure.

Round 2

Reviewer 2 Report

The manuscript is now suitable for publication in the present form