Current Concepts in the Treatment of Giant Cell Tumor of Bone: An Update
, Andreas F. Mavrogenis 2, Tomoya Masunaga 1, Kanya Honoki 1, Hiromasa Fujii 1, Akira Kido 3, Yasuhito Tanaka 1 and Costantino Errani 4
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Editor,
the review illustrates the clinical and pathological characteristics of GCTB tumors . Although the review describes the main treatments and surgical approaches the organization of the review is a bit confusing. The chapters are distinguished based on the primary site of GCTB, a chapter on pharmacological treatment and then metastasis. I believe that to facilitate understanding it is better to organize by anatomical pathological site including metastases and then all pharmacological treatments including the potential immunotherapy
Comments on the Quality of English LanguageDear Editor,
The review illustrates the clinical and pathological characteristics of GCTB tumors . Although the review describes the main treatments and surgical approaches the organization of the review is a bit confusing. The chapters are distinguished based on the primary site of GCTB, a chapter on pharmacological treatment, and then metastasis. I believe that to facilitate understanding it is better to organize by anatomical pathological site including metastases and then all pharmacological treatments including the potential immunotherapy
Author Response
Responses to the Reviewer
Thank you for your detailed and thoughtful comments regarding our manuscript. Our article became better thanks to you.
Comment
the review illustrates the clinical and pathological characteristics of GCTB tumors . Although the review describes the main treatments and surgical approaches the organization of the review is a bit confusing. The chapters are distinguished based on the primary site of GCTB, a chapter on pharmacological treatment and then metastasis. I believe that to facilitate understanding it is better to organize by anatomical pathological site including metastases and then all pharmacological treatments including the potential immunotherapy
Response
As you pointed out, we revised the sections in the following order: extremity, pelvis-sacrum, spine, lung metastasis, multicentric GCTB, pharmacological treatments, and malignant GCTB.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript from Tsukamoto and colleagues is a comprehensive literature review of state-of-the-art about giant cell tumor of bone. The review describes in great detail diagnostic and therapeutic protocols as well as clinical and translational studies.
The topic is of interest since, despite GCTB being rarely metastasising, it can be highly locally aggressive and lead to severe morbidities and functional joints impairment, thus negatively affecting quality of life of patients.
The manuscript is well written and organised, images are of high quality and a very useful and clear scheme depicting treatment pipeline is provided.
As a suggestion, it would be nice to add a paragraph to discuss the use of genomic profiling as supportive diagnostic tool for GCTB. Indeed, mutation of H3.3 histone is only marginally mentioned as a immunohistochemical marker for differential diagnosis. However, besides this, several other genes have been sparsely reported to be altered in GCTB, especially in those with negative staining for H3.3. For example, TP53, KRAS/HRAS, TERT mutation as well as KDM4B/KDM6A and H3K27me3 loss have been associated with the malignant progression of GCTB. Moreover, MAPK signaling pathway gene alterations and potentially targetable fusion genes (BRAF,ALK) have been also reported, suggesting the possibility to use targeted treatment options in selected cases. (10.1097/MPH.0000000000002112, 10.1046/j.1365-2559.2001.01275.x, 10.1038/s41379-021-00972-x, 10.3892/mi.2024.141).
Author Response
Responses to the Reviewer
Thank you for your detailed and thoughtful comments regarding our manuscript. Our article became better thanks to you.
Comment
The manuscript from Tsukamoto and colleagues is a comprehensive literature review of state-of-the-art about giant cell tumor of bone. The review describes in great detail diagnostic and therapeutic protocols as well as clinical and translational studies.
The topic is of interest since, despite GCTB being rarely metastasising, it can be highly locally aggressive and lead to severe morbidities and functional joints impairment, thus negatively affecting quality of life of patients.
The manuscript is well written and organised, images are of high quality and a very useful and clear scheme depicting treatment pipeline is provided.
As a suggestion, it would be nice to add a paragraph to discuss the use of genomic profiling as supportive diagnostic tool for GCTB. Indeed, mutation of H3.3 histone is only marginally mentioned as a immunohistochemical marker for differential diagnosis. However, besides this, several other genes have been sparsely reported to be altered in GCTB, especially in those with negative staining for H3.3. For example, TP53, KRAS/HRAS, TERT mutation as well as KDM4B/KDM6A and H3K27me3 loss have been associated with the malignant progression of GCTB. Moreover, MAPK signaling pathway gene alterations and potentially targetable fusion genes (BRAF,ALK) have been also reported, suggesting the possibility to use targeted treatment options in selected cases. (10.1097/MPH.0000000000002112, 10.1046/j.1365-2559.2001.01275.x, 10.1038/s41379-021-00972-x, 10.3892/mi.2024.141).
Response
As you pointed out, we added the following sentence in the “10. Genomic profiling” section; “H3F3A encodes the H3.3 protein. GCTB has the following genetic characteristics: Mutations in H3F3A are highly specific to GCTB, with the G34W mutation being the most common [1,178]. The H3.3 G34W mutation is specific for GCTB, and almost all histological mimics lack it [3–5]. Loss of H3.3K36me3 in mutant H3.3 alters the deposition of repressive H3K27me3 that marks intergenic to genic regions beyond the H3.3 region. This modification promotes other chromatin marks and aberrant transcription, altering the cell fate of mesenchymal progenitor cells and preventing differentiation [179]. Previous studies have shown that H3F3A mutations are also detected in malignant GCTB [4,180]. However, some malignant GCTBs are found to be H3F3A negative, even if the paired GCTB components are found to be H3F3A mutation positive [166,172,180]. Other reports suggested that TP53 mutations, KRAS/HRAS mutations, TERT mutations, KDM4B/KDM6A loss, or H3K27me3 loss were associated with malignant progression of GCTB [181–183]. Furthermore, genetic alterations in the MAPK signaling pathway and potential target fusion genes (BRAF, ALK) have also been reported in malignant GCTB lacking H3F3A mutations. It has been suggested that targeted therapy may be effective in such cases [184].”
Reviewer 3 Report
Comments and Suggestions for AuthorsThe aim is to update the current therapeutic paradigm for GCTB.
L48, describe method section. How did you collect and select your literature? How did you consider the level of evidence?
L48, Is your study design narrative review? Define it.
L521, describe discussion section. What is the difference between this and previous REVIEWs?
L521, describe research implication.
Author Response
Responses to the Reviewer
Thank you for your detailed and thoughtful comments regarding our manuscript. Our article became better thanks to you.
Comment
The aim is to update the current therapeutic paradigm for GCTB.
L48, describe method section. How did you collect and select your literature? How did you consider the level of evidence?
Response
As you pointed out, we added the following sentence in the “Methods” section; “We searched for “giant cell tumor of bone” on PubMed, mainly extracted important articles from the literature from January 2021 to March 2024, and described their contents to update the review article published in 2021 [11]. Regarding the literature related to reconstruction after en bloc resection (EBR) of GCTB of the distal radius, which was not included in the previously published review [11], we cited and described many of the articles published before 2021. Therefore, this review is a narrative review.”
Since this is a narrative review, there is no need to evaluate the evidence for each study. The only RCT was “155. Yue, J.; Sun, W.; Li, S. Denosumab versus Zoledronic Acid in Cases of Surgically Unsalvageable Giant Cell Tumor of Bone: A Randomized Clinical Trial. J. Bone Oncol. 2022, 35, 100441.”. Only that study received a ``High'' according to GRADE criteria; the others received a ``low'' or ``very low'' according to GRADE.
Comment
L48, Is your study design narrative review? Define it.
Response
Yes, it is. We added the following sentence in the “Methods” section; “Therefore, this review is a narrative review.”
Comment
L521, describe discussion section. What is the difference between this and previous REVIEWs?
L521, describe research implication.
Response
We added the following sentence in the “Research implication” section; “Denosumab treatment prior to curettage should be considered in patients with GCTB of the extremity who are Campanacci stage 3 and for whom joint preservation is difficult, although the risk of local recurrence may be increased. Even if recurrence occurs, re-curettage may allow joint preservation. For GCTB of the proximal humerus, en bloc resection and reverse shoulder arthroplasty may be a good indication because function remains the same compared to curettage. Denosumab therapy (every 3 months) is a good option for inoperable GCTBs of the pelvis, spine, and sacrum, as well as for growing lung metastases, and is effective when repeated after discontinuation due to complications.”
Reviewer 4 Report
Comments and Suggestions for AuthorsThe authors review the treatment of GCTB. The manuscript is well written, however, I have some concerns to discuss.
-What type of review is this, narrative or systematic?
-The authors have published extensively in the literature on GCTB, but what are the new findings of this review?
Author Response
Responses to the Reviewer
Thank you for your detailed and thoughtful comments regarding our manuscript. Our article became better thanks to you.
Comment
The authors review the treatment of GCTB. The manuscript is well written, however, I have some concerns to discuss.
-What type of review is this, narrative or systematic?
Response
It is narrative. We added the following sentence in the “Methods” section; “Therefore, this review is a narrative review.”
Comment
-The authors have published extensively in the literature on GCTB, but what are the new findings of this review?
Response
New findings have been added to the research implication section. We added the following sentence in the “Research implication” section; “Denosumab treatment prior to curettage should be considered in patients with GCTB of the extremity who are Campanacci stage 3 and for whom joint preservation is difficult, although the risk of local recurrence may be increased. Even if recurrence occurs, re-curettage may allow joint preservation. For GCTB of the proximal humerus, en bloc resection and reverse shoulder arthroplasty may be a good indication because function remains the same compared to curettage. Denosumab therapy (every 3 months) is a good option for inoperable GCTBs of the pelvis, spine, and sacrum, as well as for growing lung metastases, and is effective when repeated after discontinuation due to complications.”
Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsThank you for revision.
No comments
Reviewer 4 Report
Comments and Suggestions for AuthorsThe authors replied well, so the manuscript is suitable for publication.
