The poor 5-year survival rate in high-grade osteosarcoma (HOS) has not been increased significantly over the past 30 years. This work aimed to develop a radiomics nomogram for survival prediction at the time of diagnosis in HOS.In this retrospective study, an initial cohort of 102 HOS patients, diagnosed from January 2008 to March 2011, was used as the training cohort. Radiomics features were extracted from the pretreatment diagnostic computed tomography images. A radiomics signature was constructed with the lasso algorithm; then, a radiomics score was calculated to reflect survival probability by using the radiomics signature for each patient. A radiomics nomogram was developed by incorporating the radiomics score and clinical factors. A clinical model was constructed by using clinical factors only. The models were validated in an independent cohort comprising 48 patients diagnosed from April 2011 to April 2012. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. Kaplan–Meier survival analysis was performed.The radiomics nomogram showed better calibration and classification capacity than the clinical model with AUC 0.86 vs. 0.79 for the training cohort, and 0.84 vs. 0.73 for the validation cohort. Decision curve analysis demonstrated the clinical usefulness of the radiomics nomogram. A significant difference (p-value <.05; log-rank test) was observed between the survival curves of the nomogram-predicted survival and non-survival groups. The radiomics nomogram may assist clinicians in tailoring appropriate therapy.
Background: Osteosarcoma is a high-grade malignant bone neoplasm. Although the introduction of chemotherapy has reduced its mortality, more than 50% of patients develop chemoresistance and have an extremely poor prognosis due to pulmonary metastasis. Several molecular pathways contributing to osteosarcoma development and progression have recently been discovered. Various studies have addressed the genes involved in the metastasis of osteosarcoma. However, the highly complex molecular mechanisms of metastasis are still poorly understood. Recently, the decisive role of microRNAs in the regulation of molecular pathways has been uncovered. miRNAs may function as either oncogenes or tumor suppressors, depending on their target genes. miR-27a, a member of an evolutionarily conserved miRNA family, is abnormally increased in several types of cancers. It has been shown to be upregulated in osteosarcoma and plays a pro-metastatic role in osteosarcoma cell lines. However, the effects of miR-27a on osteosarcoma have not been clearly elucidated. The present study thus addressed the miR-27a sensitive mechanisms in osteosarcoma. Methods: In this study, three biological programs were used to predict whether MAP2K4 was a target of miR-27a. A specific miR-27a inhibitor was used to inhibit the endogenous activity of miR-27a in the human osteosarcoma cell line MG63. Cell proliferation, colony formation, migration and invasion assays were performed to assess the effects of miR-27a on the proliferation, metastasis and invasion of MG63 cells. The expression levels of several proteins evolved in the JNK/p38 signaling pathway were detected using western blot analysis. Results: The luciferase activity of the wild-type pGL3-MAP2K4 3'UTR vector was significantly inhibited after the miR-27a precursor or the control precursor was transfected into the MG63 cells. However, the luciferase activity was not inhibited after transfection of the mutant pGL3-MAP2K4 3'UTR vector. The inhibition of miR-27a increased the luciferase activity of the wild-type pGL3-MAP2K4 3'UTR vector after MG63 cells were transfected with the miR-27a inhibitor or the control inhibitor. Thus, MAP2K4 is a potential target of miR-27a and can be directly regulated by miR-27a. Inhibition of miR-27a significantly suppressed cell proliferation after 72 hours compared to the negative control group. Inhibition of miR-27a significantly suppressed colony formation of the MG63 cells by 39 6%. Transwell migration and invasion assays demonstrated that the number of migratory and invasive cells transfected with the miR-27a inhibitor was reduced by 63.5% and 69.1%, respectively. After transfection of the miR-27a inhibitor into the MG63 cells, the level of phospho-JNK1 and phospho-p38 increased by 25% and 29%, respectively, along with the up-regulation of MAP2K4 protein. Conclusion: This is the first study showing that miR-27a can function as an oncogene by targeting MAP2K4 in the osteosarcoma MG63 cell line. Inhibition of miR-27a increases MAP2K4 expression, which in turn inhibits cell pr...
The mechanism by which osteosarcomas metastasize is elusive, and challenges remain regarding its treatment with modalities including immunotherapy. CXCL12 is deeply involved in the process of tumor metastasis and T-cell homing, which is driven by a chemokine gradient, but healthy bones are supposed to preferentially express CXCL12. Here, we show for the first time that osteosarcomas epigenetically downregulate CXCL12 expression via DNA methyltransferase 1 (DNMT1) and consequently acquire the ability to metastasize and to impair cytotoxic T-cell homing to the tumor site. Analysis of human osteosarcoma cases further revealed that CXCL12 expression strongly correlated with overall survival. Evaluations on fresh human chemotherapy-free osteosarcoma samples also showed a positive correlation between CXCL12 concentration and the number of intratumoral lymphocytes. Critically, treatment targeting DNMT1 in immunocompetent mouse models significantly elevated expression of CXCL12 in tumors, resulting in a robust immune response and consequently eradicating early lung metastases in addition to suppressing subcutaneous tumor growth. These antitumor effects were abrogated by CXCL12-CXCR4 blockade or CD8 T-cell depletion. Collectively, our data show that CXCL12 regulation plays a significant role in both tumor progression and immune response, and targeting CXCL12 is promising for therapeutics against osteosarcoma. Epigenetic regulation of CXCL12 controls metastasis and immune response in osteosarcoma, suggesting epigenetic therapies or therapies targeting CXCL12 have potential for therapeutic intervention in osteosarcoma. .
Purpose : Chondrosarcoma with metastatic disease has a very poor prognosis. However, the prognosis and potential prognostic factors of patients with primary chondrosarcoma of bone and metastasis at presentation have not been documented because of its rarity. Therefore, we examined the prognosis of this special cohort and identify possible prognostic factors. Methods : The Surveillance, Epidemiology, and End Results (SEER) program database was used to identify patients with primary chondrosarcoma of bone and metastatic disease at diagnosis from 2000 to 2013. The prognostic analysis was performed using the Kaplan-Meier method and a Cox proportional hazards regression model. Results : The SEER database contained 264 cases. The overall survival (OS) and cancer-survival specific (CSS) rates of the entire group at 5 years were 28.4% and 31.2%, respectively. The median OS and CSS were 14.0 ± 2.5 and 17.0 ± 2.6 months, respectively. Multivariate analysis revealed that low tumor grade, surgical treatment, tumor size < 10 cm, and first primary tumor were associated with improved OS. Tumor grade, tumor size, and surgery were independent predictors of CSS. Radiation therapy had no effect on either OS or CSS. Conclusion : Among patients with primary chondrosarcoma of bone and metastasis at presentation, low tumor grade, surgical treatment, tumor size < 10 cm, and first primary tumor predict prolonged survival.
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