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BACKGROUND: Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone tumour with a poor prognosis and no effective treatment. Because changes in DNA methylation play critical roles in DDCS, we explored the roles that DNA methylation plays in oncogenesis to potentially identify an effective epigenetic treatment. METHODS: We identified genes downregulated in DDCS vs. conventional chondrosarcoma (CCS) due to DNA methylation using in silico analysis. The results were validated in DDCS clinical samples, and the molecular functions of the genes of interest were investigated in multiple chondrosarcoma cell lines (NDCS-1, SW1353, and OUMS-27). The therapeutic effect of decitabine, a DNA methyltransferase inhibitor, was evaluated in vitro and in vivo. RESULTS: PRKCZ was specifically downregulated by DNA methylation in DDCS. Overexpression of PRKCZ decreased the proliferation of NDCS-1 and SW1353 cells. PRKCZ directly bound to and activated ATM, which was followed by phosphorylation of CHK2 and subsequent apoptosis. Decitabine increased PRKCZ expression through de-methylating the promoter region of PRKCZ, which activated the ATM/CHK2 pathway and inhibited cell proliferation by inducing apoptosis. CONCLUSIONS: Increased DNA methylation and reduced expression of PRKCZ prevents apoptosis via inactivation of the ATM/CHK2 pathway in DDCS. Decitabine-induced expression of PRKCZ represents a promising therapy for DDCS.

Denosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker regarding tumor ossification of GCTB has not been elucidated. In this study, we investigated the relationship between Wnt/β-catenin signaling and the ossification of GCTB and evaluated whether endogenous nuclear β-catenin expression predicted denosumab-induced bone formation in GCTB. Genuine patient-derived primary GCTB tumor stromal cells exhibited osteoblastic characteristics. Identified osteoblastic markers and nuclear β-catenin translocation were significantly upregulated via differentiation induction and were inhibited by treating with Wnt signaling inhibitor, GGTI-286, or selective Rac1-LEF inhibitor, NSC23766. Furthermore, we reviewed the endogenous ossification and nuclear β-catenin translocation of 86 GCTB clinical samples and elucidated that intra-tumoral ossification was significantly associated with the nuclear translocation. Three-dimensional quantitative analyses (n = 13) of tumoral CT images have revealed that the nuclear β-catenin translocation of naïve GCTB samples was significantly involved with the denosumab-induced tumor ossification. Our findings suggest a close relationship between the nuclear β-catenin translocation and the osteoblastic differentiation of GCTB. Investigations of the nuclear β-catenin in naïve GCTB samples may provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment.

BackgroundDenosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker in terms of post-administration ossification of the tumors has not been elucidated. The aims of this study were to investigate the relationship between Wnt/β-catenin signaling and the ossification of GCTB and to evaluate whether endogenous nuclear β-catenin expression predicted denosumab-induced bone formation in GCTB. MethodsWe established cultures of patient-derived primary GCTB stromal cells (pGCTB-SCs) and assessed the osteoblastic characteristics of pGCTB-SCs using cytochemical staining, optical density method (405 nm), and immunocytochemistry. Several mRNA expressions of osteoblastic markers (ALP, collagen type Ⅰ alpha 1 (COL1A1), integrin-binding sialoprotein (IBSP), runt-related transcription factor2 (RUNX2), and bone gamma-carboxyglutamate protein (BGLAP) was also investigated using quantitative real-time PCR (qRT-PCR) analysis. The impact on nuclear β-catenin translocation (NBT) by differentiation-induction was evaluated using Western blotting and immunocytochemistry. Wnt signaling inhibitor, GGTI-286, and selective Rac1 inhibitor, NSC23766, were added with OGM to evaluate the essential role of NBT. Furthermore, the distribution of endogenous NBT and the relationship with the tumoral ossification were assessed. Its predictability for the ossification in GCTB was also evaluated using a nuclear β-catenin labeling index (NBLI) of clinical samples (n = 86) and quantitative analyses of CT images.ResultspGCTB-SCs significantly expressed the osteoblastic markers with osteogenic medium (OGM) in a time-dependent manner (P < 0.0001, vs. vehicle). NBT was upregulated within 12 hours after OGM treatment. In addition, decreasing NBT by treatment with 40μM GGTI-286 significantly abolished the osteoblastic differentiation of pGCTB-SCs (P < 0.0001, vs. OGM). The selective Rac1 inhibitor, NSC23766, also suppressed the OGM-induced osteoblastic differentiation and NBT in pGCTB-SCs. Furthermore, in GCTB clinical samples, the NBTs were significantly associated with the tumor ossification following denosumab treatment (P = 0.003 for entire and peripheral tumor, and P = 0.02 for intra-tumor of GCTB) as well as endogenous intra-tumoral ossification. ConclusionsIn summary, our findings suggest a close relationship between the NBT and the osteoblastic differentiation of GCTB. Investigations of NBTs in naïve GCTB samples will provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment.

Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. Isocitrate dehydrogenase (IDH) mutations, which are detected in ~50% of chondrosarcoma patients, contribute to malignant transformation by catalyzing the production of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Mutant IDH inhibitors are therefore potential novel anticancer drugs in IDH mutant tumors. Here, we examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma.

Background Soft tissue sarcomas arise in the deep sites of the buttocks and lower extremities. Since a tourniquet is not applied during surgery for soft tissue sarcomas at such sites, excessive intraoperative blood loss may occur. Various devices, including LigaSure™ (Medtronic, Dublin, Ireland), are used as electrothermal bipolar vessel sealers. However, its clinical relevance in soft tissue sarcomas surgery remains unclear. This study aimed to assess the effectiveness of LigaSure™ in soft tissue sarcomas surgery. Methods This study included 168 patients who underwent surgeries for soft tissue sarcomas in the deep sites in the buttocks and lower extremities between January 2004 and March 2018. The primary outcome was intraoperative blood loss, and secondary outcomes were surgery duration, wound complications, perioperative haemoglobin concentrations and intraoperative blood transfusion. To reduce selection biases, propensity score matching was applied. We defined the matched cases wherein LigaSure™ was used as the ‘using group’ and the other matched cases as the ‘non-using group’. Outcomes were compared between both groups. Results From each group, 35 cases were selected using propensity score matching. The intraoperative blood loss was significantly smaller statistically in the using group (181.5 ± 240.4 ml vs. 394.7 ± 547.3 ml, respectively; P = 0.041). The duration of operation was longer in the using group (189.9 ± 97.6 min vs. 140.6 ± 75.7 min, respectively; P = 0.007). There were no significant differences in other outcomes. Conclusion By using LigaSure™ for soft tissue sarcomas occurring in the buttocks and lower extremities, we observed a trade-off between reduced intraoperative blood loss and longer operative time.

Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs), however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94–18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10–0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin.

We present the case of an 80-year-old man with a tumor recurrence on his right arm 6 years after initial treatment. The lateral aspect of the elbow joint, involving overlaying skin, muscles, tendons, joint capsule, lateral collateral ligament complex, the lateral 1/3 of the capitellum, and lateral epicondyle of humerus were excised in the tumor resection. Intraoperative assessment revealed multidirectional instability of the elbow, and joint stabilization was needed. Because the lateral epicondyle was resected, graft placement in an anatomical position was impossible to carry out. Therefore, non-anatomical reconstruction of lateral ulnar collateral ligament with palmaris longus tendon graft was performed. The skin was reconstructed using an antegrade pedicled radial forearm flap. For wrist extension reconstruction, the pronator quadratus tendon was transferred to the extensor carpi radialis brevis tendon. One year after the operation, elbow range of motion was 5–130°. The patient remains symptom free. The Mayo elbow performance score is good. The Musculoskeletal Tumor Society rating score is excellent. To our knowledge, this is the first report of an elbow lateral ulnar collateral ligament reconstruction after tumor resection.