Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors present a study based on the analysis of publicly available RNA sequencing data identified chitinase-3-like 1 (CHI3L1) as a potential immunotherapy target in chordoma. They then go on to use RNA-based analysis and ELISA on chordoma cell lines and human tumor specimens, to demonstrate elevated CHI3L1 expression in chordoma cells compared with notochordal precursors, further with higher expression in primary tumors than in recurrent samples. These findings suggest that CHI3L1 may contribute to chordoma tumorigenesis and holds promise as a biomarker and therapeutic target.   

-the paper has a relatively limited sample set of 4 primary and 3 recurrent chordomas, why not broaden the data to see if this is more consistent across tumors. 

-it would be good to confirm this in a separate group of clival chordomas

-did the CHI3L1 correlate with clinical course or where there any radiographic biomarkers that may serve as correlates for its expression like contrast enhancement.  

 

Author Response

Thank you very much for taking the time to review this manuscript. Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Chitinase-3-like protein 1 (CHI3L1), a chitinase-like glycoprotein, is secreted by cancer cells and various inflammatory cells including macrophages and neutrophils. A correlation between CHI3L1 expression and the prognosis of different solid malignant tumours has been discussed in recent literature.

 To address the importance of CHI3L1 for chordoma pathogenesis and prognosis, this study analysed tumour tissue samples from chordoma patients, assessing primary tumours and recurrences separately. Fresh tissue was analysed by RNA-seq and formalin-fixed paraffin-embedded (FFPE) tissue by Nanostring. Furthermore commercially available chordoma cell lines were investigated. The applied methods are performed thoroughly. The results show most importantly a differential expression of the CHI3L1 gene in primary chordoma tissue compared with recurrences, which revealed a considerably lower expression. This was also observed in the commercial chordoma cell lines where primary chordoma cell lines exhibited significantly more CHI3L1 mRNA expression than the recurrent chordoma (U-CH1) cell line.

 These results are innovative as this is the first thoroughly performed methodical study on CHI3L1 expression in chordoma. The differential expression between primary tumours and recurrences is of particular interest. The limited number of investigated cases does not diminish the importance as it is challenging to obtain higher numbers of cases including primaries and recurrences from such an ultrarare malignant tumour as chordoma.

 There are some minor suggestions for improvement:

It would be interesting to know if the clinical cases are all conventional chordomas or if there are poorly differentiated or dedifferentiated chordomas among them.

 What is the time difference between primary tumours and recurrences? Are the recurrences short-term or long-term? If such data were available they would provide useful additional information.

 Discussion (lane 331-332): The authors state that these findings provide initial evidence of the importance of CHI3L1 as a molecular marker in early tumourigenesis. This should be discussed in more detail, particularly whether it is considered a marker for early detection of chordoma following suspicious radiological findings.

 Some studies have found a positive correlation between elevated serum levels of CHI3L1 and a poor prognosis of solid tumours while others have revealed negative results. The potential oncologic usefulness of CHI3L1 as a diagnostic tool, prognosis predictor and predictor of therapy response should be discussed further.

 

 

 

 

Author Response

Thank you very much for taking the time to review this manuscript. Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript concerns basic research in oncology, means chordoma tracing and  treatment. Chordoma is a tumor with slow growth, low malignant potential, and a certain degree of invasiveness. Unlike some tumors, chordoma has been largely resistant to conventional radiotherapy and chemotherapy. Unfortunatelly the location makes significant surgical morbidity as treated operationally. A some hope is looking in proton therapy
and carbon ion therapy. Due to its low division index, chemotherapy has low efficacy. The aim of the research is targeted at chordoma. Given these poor therapeutic conditions, the manuscript presented raises high medical expectations. 

In the introduction, it is worth elaborating on the reasons for the low effectiveness of chemotherapy and the difficult availability of proton therapy for patients with chordoma. The authors use modern scientific methods. The results are reliable and clearly presented. The discussion is based on references to current literature on biomarkers and immunotherapy.

Medicine needs badly an immunoglobuline effective in systemic treatment of chordoma and other low mitotic index malignancies. The paper is important and interesting, and I wish the authors continued success in their research.

Author Response

Thank you very much for taking the time to review this manuscript. Please see the attachment.

Author Response File: Author Response.pdf