Pathology and Molecular Biology of Melanoma
, Mihai Cenariu 5 and Diana Cenariu 6,*
Round 1
Reviewer 1 Report
This manuscript summarizes the current knowledge about the mutations affecting melanoma development and progression. This manuscript would benefit from a thorough language editing. Some sections are very difficult to understand (i.e from lines 118 to 146; 158-11; 176-182). Furthermore, many references are missing and many are not appropriately used. In overall, this manuscript would need to be restructured and reorganized. The links between genetic/somatic mutations and melanoma aggressiveness, tumor microenvironment composition and immune contexture as well as response (or resistance) to treatments are clearly missing. Adding this information would improve significantly the quality of this manuscript and would be very informative to the readers.
Specific comments:
The mutations (germline or somatic) should be linked to the efficacy of treatments (with reference to the published clinical trials).
Combination therapies are not mentioned despite the fact that there are the future of melanoma treatments. On example (among many that could be cited) is the recently FDA approved anti-PD-1+anti-LAG-3 combination.
The authors mentioned oncolytic viruses without describing T-VEC, a FDA-approved oncolytic virus for melanoma treatment.
Tyrosinase is also a marker used in pathology (IHC) for the diagnostic of melanoma.
Genetics of melanoma section: There are two paragraphs on MC1R that are separated by a section describing CDK4. Those two paragraphs need to be reconciliated. Similar comments for other genes. For example, many proteins involved in the MAPK signaling cascade are found mutated in melanoma. The authors should consider grouping those proteins together and creating a sub heading to describe this pathway. Similarly, the authors could create a subheading encompassing all the proteins regulating the cell cycle. Surprisingly, PTEN and Tert are not described in this section and should be added in the revised version of the manuscript. Within this section, there is a description of MMPS and other proteins that participate in the ECM remodeling and the metastatic dissemination of tumor cells. Those paragraphs should be removed from this section and included in Section 2 "The biology of melanoma dissemination".
This manuscript needs to be edited by a native English speaker.
Author Response
Dear editor,
Thank you very much for reviewing our manuscript. We appreciate the tremendous effort and time the reviewers devoted to improve our manuscript. We sincerely feel that their thoughtful comments have further strengthened the manuscript. In the revised manuscript, revisions to the manuscript are indicated in red font. We hope that our responses to the reviewers’ comments and the revisions made to the manuscript satisfy all questions and concerns.
With my best regards
Diana Cenariu, PhD
Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
Author Response File: 
Author Response.pdf
Reviewer 2 Report
This is an interesting review of melanoma, focusing on the disease's biology and diagnostics, but paying special attention to the genetic aspects of this serious disease. Although the signaling pathways involved are mentioned, the role of these pathways in the evolution of melanoma is not detailed. Also, the authors did not approach the aspects of superior chromatin organization and epigenetics, which certainly affects gene expression and may be very important when considering "Somatic mutations".
A formal aspect, which is not very significant, but which interferes and hinders reading is that fonts of different sizes appear in the text on lines 118-170, 176-183, and 186-187. There are also some errors in parentheses, which require proofreading.
Author Response
Dear editor,
Thank you very much for reviewing our manuscript. We appreciate the tremendous effort and time the reviewers devoted to improve our manuscript. We sincerely feel that their thoughtful comments have further strengthened the manuscript. In the revised manuscript, revisions to the manuscript are indicated in red font. We hope that our responses to the reviewers’ comments and the revisions made to the manuscript satisfy all questions and concerns.
With my best regards
Diana Cenariu, PhD
Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
Author Response File: Author Response.pdf
Reviewer 3 Report
- the amout of literature cited (28 titles) is far too low for a review, especially for the actively researched melanoma field. A lot of facts are devoid of a proper citation
- It is strongly advised to add some schemes or tables to summarize the data from the paper's sections and to make it easier for a reader to understand
- In the section on germline, as well as somatic mutations, more information on the nature of the mentioned mutations (i.e. loss of function, activation, etc.) should be provided
- Local conclusions should be added to the paper's sections
- Na analysis of the existing challenges of the melanoma diagnosis is provided
Author Response
Dear editor,
Thank you very much for reviewing our manuscript. We appreciate the tremendous effort and time the reviewers devoted to improve our manuscript. We sincerely feel that their thoughtful comments have further strengthened the manuscript. In the revised manuscript, revisions to the manuscript are indicated in red font. We hope that our responses to the reviewers’ comments and the revisions made to the manuscript satisfy all questions and concerns.
With my best regards
Diana Cenariu, PhD
Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
I would like to thank the authors for their revised manuscripts. While the quality of the manuscript has been improved, I would suggest adding figures and/or a tables. For example, a table summarizing the markers for melanoma diagnosis as well as a table listing the somatic and genetic mutations associated with disease prevalence and prognosis would be helpful. Alternatively, a figure representing a melanoma cell with the different pathways found altered could be helpful.
This manuscript would benefit from having increased citations for original research articles.
Minor comment: MMP are matrix metalloproteinases and not gelatinases (line 226)
Author Response
Dear editor,
Thank you very much for reviewing our manuscript. We appreciate the tremendous effort and time the reviewers devoted to improve our manuscript. We sincerely feel that their thoughtful comments have further strengthened the manuscript. In the revised manuscript, revisions to the manuscript are indicated in red font. We hope that our responses to the reviewers’ comments and the revisions made to the manuscript satisfy all questions and concerns.
With my best regards
Diana Cenariu, PhD
Reviewer 3 Report
At the moment, the paper seems to be for the most part a compilation of (many) other reviews. To make it into a substantial contribution to the field, some analysis should be added. It could be either a set of tables summing up the genetic alterations and druggable targets, or at least a section discussing the discrepancies in the available literature and pointing to the major existing problems.
Author Response
Dear editor,
Thank you very much for reviewing our manuscript. We appreciate the tremendous effort and time the reviewers devoted to improve our manuscript. We sincerely feel that their thoughtful comments have further strengthened the manuscript. In the revised manuscript, revisions to the manuscript are indicated in red font. We hope that our responses to the reviewers’ comments and the revisions made to the manuscript satisfy all questions and concerns.
With my best regards
Diana Cenariu, PhD
Author Response File: Author Response.pdf
Round 3
Reviewer 1 Report
II would like to thank the authors for their revised manuscript. I am happy to endorse the publication of this manuscript.
Reviewer 3 Report
The points were addressed.
