Putative multifunctional signature of lung metastases in dedifferentiated chondrosarcoma.
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ABSTRACT:
SUBMITTER: Malchenko S
PROVIDER: S-EPMC3289931 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dedifferentiated chondrosarcoma (DDCS) is a high-grade subtype of chondrosarcoma with the bimorphic histological appearance of a conventional chondrosarcoma component with abrupt transition to a high-grade, non-cartilaginous sarcoma. DDCS can be radiographically divided into central and peripheral types. Wide resection is currently the main therapeutic option for localized DDCS. Moreover, the effectiveness of adjuvant chemotherapy remains controversial. Therefore, we performed a systematic review of available evidence to evaluate the effect of adjuvant chemotherapy on localized DDCS. The purpose was to compare the 5-year survival rate among patients treated with surgery plus adjuvant chemotherapy or surgery alone for localized DDCS. The search was conducted in PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Of the 217 studies shortlisted, 11 retrospective non-randomized studies (comprising 556 patients with localized DDCS) were selected. The 5-year survival rates were similar between the two treatment groups (28.2% (51/181) vs. 24.0% (90/375), respectively). The overall pooled odds ratio was 1.25 (95% confidence interval: 0.80-1.94; p = 0.324), and heterogeneity I2 was 2%. However, when limited to peripheral DDCS, adjuvant chemotherapy was associated with prolonged survival (p = 0.03). Due to the paucity of included studies and the absence of prospective comparative studies, no conclusions can be drawn regarding the effectiveness or ineffectiveness of adjuvant chemotherapy for localized DDCS.
| S-EPMC10813944 | biostudies-literature
Project description:BackgroundThe dedifferentiated variant of chondrosarcoma is highly aggressive and carries an especially grim prognosis. While chemotherapeutics has failed to benefit patients with dedifferentiated chondrosarcoma significantly, preclinical chemosensitivity studies have been limited by a scarcity of available cell lines. There is, therefore, an urgent need to expand the pool of available cell lines.MethodsWe report the establishment of a novel dedifferentiated chondrosarcoma cell line DDCS2, which we isolated from the primary tumor specimen of a 60-year-old male patient. We characterized its short tandem repeat (STR) DNA profile, growth potential, antigenic markers, chemosensitivity, and oncogenic spheroid and colony-forming capacity.ResultsDDCS2 showed a spindle to polygonal shape and an approximate 60-hour doubling time. STR DNA profiling revealed a unique genomic identity not matching any existing cancer cell lines within the ATCC, JCRB, or DSMZ databases. There was no detectable contamination with another cell type. Western blot and immunofluorescence assays were consistent with a mesenchymal origin, and our MTT assay revealed relative resistance to conventional chemotherapeutics, which is typical of a dedifferentiated chondrosarcoma. Under ex vivo three-dimensional (3D) culture conditions, the DDCS2 cells produced spheroid patterns similar to the well-established CS-1 and SW1353 chondrosarcoma cell lines.ConclusionOur findings confirm DDCS2 is a novel model for dedifferentiated chondrosarcoma and therefore adds to the limited pool of current cell lines urgently needed to investigate the chemoresistance within this deadly cancer.
| S-EPMC8645311 | biostudies-literature
Project description:Dedifferentiated chondrosarcoma (DDCS) is a rare subtype of chondrosarcoma, a primary cartilaginous malignant neoplasm. It accounts for up to 1-2% of all chondrosarcomas and is generally associated with one of the poorest prognoses among all chondrosarcomas with the highest risk of metastasis. The 5-year survival rates range from 7% to 24%. DDCS may develop at any age, but the average presentation age is over 50. The most common locations are the femur, pelvis humerus, scapula, rib, and tibia. The standard treatment for localised disease is surgical resection. Most patients are diagnosed in unresectable and advanced stages, and chemotherapy for localised and metastatic dedifferentiated DDCS follows protocols used for osteosarcoma.
| S-EPMC10417069 | biostudies-literature
Project description:Genome wide DNA methylation profiling of dedifferentiated chondrosarcoma samples. Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue after manual macrodissection to ensure at least 10% tumor content, followed by bisulfite converstion. All samples were processed on the Infinium 850k array and scanned using the Illumina iScan, according to the manufacturer's recommended protocol.
2023-01-01 | GSE214180 | GEO
Project description:BackgroundDedifferentiated chondrosarcoma is a rare, highly malignant tumor with a poor survival. There are many confusing issues concerning the imaging feature that can facilitate early diagnosis and the factors that might be related to outcomes.MethodsTwenty-three patients with dedifferentiated chondrosarcoma confirmed by pathology were retrospectively reviewed from 2008 to 2015. The patients' clinical information, images from radiographs (n = 17), CT (n = 19), and MRI (n = 17), histological features, treatment and prognosis were analyzed.ResultsThere were 12 males and 11 females, and the mean age was 50.39 years old. Fourteen cases affected the axial bone (pelvis, spine), and 9 cases involved the appendicular bone. Seven (41.17%), 9 (47.36), and 12 (66.66%) lesions showed a biphasic nature on radiograph, CT and MRI, respectively. Of the lesions, 17.39% (4/23) were accompanied by pathological fractures. Histologically, the cartilage component was considered histological Grade1 in 12 patients and Grade 2 in 11 patients. The dedifferentiated component showed features of osteosarcoma in 8 cases, malignant fibrous histiocytoma in3 cases, myofibroblastic sarcoma in 1 case and spindle cell sarcoma in 11cases. Twenty-two cases were treated with surgical resection, and 17 cases achieved adequate (wide or radical) surgical margin. In 8 cases, surgery was combined with adjuvant chemotherapy. The overall median survival time was nine months; 17.4% of patients survived to five years.ConclusionAxial bone location, lung metastasis at diagnosis, inadequate surgical margin, incorrect diagnosis before surgery and pathological fractures was related to poorer outcome. Pre- or postoperative chemotherapy had no definitively effect on improved survival.
| S-EPMC5354284 | biostudies-literature
Project description:Background:Dedifferentiated chondrosarcoma (DC) is an extremely uncommon malignant bone tumor with dismal survival outcomes. The purpose of this study was to investigate whether the preoperative neutrophil/lymphocyte ratio (NLR) has the ability to predict overall survival (OS) in DC patients. Materials and Methods:Twenty-three DC patients with surgical resection were retrospectively reviewed between 2008 and 2015. The clinical pathological information and survival data were collected for analysis. The cut-off point for NLR was defined by receiver operating curve (ROC). The impact of NLR level on OS between two groups was compared using Kaplan-Meier curves with the Log-rank test. The association between NLR and OS was calculated by univariate and multivariate Cox proportional models. Results:From the ROC analysis, the optimal NLR cut-off point was 3.11. Patients with high NLR had a worse OS than low NLR (p = 0.003, Log-rank test). In univariate analysis, a significant association was observed between high NLR and poor OS (Hazard ratio (HR) 4.62, 95% confidence interval (CI) 1.48-14.34, p = 0.008). After adjustment of co-variables, high NLR had more than 4 times the risk of mortality (HR 4.01, 95% CI 1.12-14.26, p = 0.032). Conclusion:Preoperative NLR in peripheral blood is an easily accessible and cost-effective prognostic biomarker in DC patients. A prospective study with large sample size is warranted.
| S-EPMC7425651 | biostudies-literature
Project description:BackgroundDedifferentiated chondrosarcoma (DDCS) is a rare subset of chondrosarcoma. It is an aggressive neoplasm characterized by a high rate of recurrent and metastatic disease with overall poor outcomes. Systemic therapy is often used to treat DDCS; however, the optimal regimen and timing are not well defined, with current guidelines recommending following osteosarcoma protocols.MethodsWe conducted a multi-institutional retrospective analysis of clinical characteristics and outcomes of patients with DDCS. Between 1 January 2004 and 1 January 2022, the databases from five academic sarcoma centers were reviewed. Patient and tumor factors, including age, sex, tumor size, site, location, the treatments rendered, and survival outcomes, were collected.ResultsSeventy-four patients were identified and included in the analysis. Most patients presented with localized disease. Surgical resection was the mainstay of therapy. Chemotherapy was used predominantly in the metastatic setting. Partial responses were low (n = 4; 9%) and occurred upon treatment with doxorubicin with cisplatin or ifosfamide and single-agent pembrolizumab. For all other regimens, stable disease was the best response. Prolonged stable disease occurred with the use of pazopanib and immune checkpoint inhibitors.ConclusionsDDCS has poor outcomes and conventional chemotherapy has limited benefit. Future studies should focus on defining the possible role of molecularly targeted therapies and immunotherapy in the treatment of DDCS.
| S-EPMC10177459 | biostudies-literature
Project description:Dedifferentiated chondrosarcoma (DDCS) is a rare high-grade chondrosarcoma characterized by a well-differentiated chondrosarcoma (WDCS) component that abruptly transitions to a high-grade, noncartilaginous sarcomatous component. To date, the molecular pathogenesis of DDCS and its distinction from conventional chondrosarcoma remain poorly understood. By targeted sequencing, we examined the mutational and copy-number profiles of 18 DDCS, including macrodissected WDCS components, compared with 55 clinically sequenced conventional chondrosarcomas. In conjunction with publicly available external data, we analyzed the methylation and expression profiles of 34 DDCS and 94 conventional chondrosarcomas. Isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 (IDH1/IDH2) mutations were present in 36% conventional chondrosarcomas and 71% DDCS. Compared with conventional chondrosarcomas, DDCS had higher frequencies of TP53 and TERT promoter mutations and CDKN2A/B copy-number losses. Paired analysis of macrodissected WDCS and the high-grade components revealed TERT promoter mutations as early events. Despite phenotypic similarities, the percentage of genome with copy-number alterations in DDCS was significantly lower than that in other high-grade sarcomas. Differential methylation analysis revealed reduction of IDH1/IDH2-associated global hypermethylation characteristically seen in conventional chondrosarcoma and a distinct methylation profile in DDCS. The WDCS and high-grade components in DDCS showed similar methylation profiles. These CpG sites were associated with upregulated expression of genes involved in G2-M checkpoints and E2F targets. Genomic profiling revealed enrichment of TP53, TERT promoter, and CDKN2A/B alterations in DDCS. Integrated methylation and gene expression analysis revealed distinct IDH1/IDH2-associated methylation and transcriptional profiles as early events in DDCS, which may underlie the pathogenesis of dedifferentiation in chondrosarcomas.SignificanceDDCS is a rare, high-grade chondrosarcoma with a dismal prognosis. About 50%-80% of DDCS harbor IDH1/IDH2 mutations. We uncover a significant alteration of IDH-associated methylation profile in DDCS, which we propose is key to the progression to dedifferentiation. In this context, the potential effect of the use of IDH inhibitors is unclear but important to address, as clinical trials of selective IDH1 inhibitors showed worse outcome in DDCS.
| S-EPMC10013202 | biostudies-literature
Project description:Bone morphogenetic protein receptors (BMPRs) are multifunctional proteins; they have indispensible roles in the process of BMP signaling. However, their function in dedifferentiated chondrosarcoma is uncertain. It has been reported that BMPR2 is associated with chondrosarcoma. Moreover, the detection of BMPR2 is more frequent in dedifferentiated chondrosarcomas (DDCS) than in conventional chondrosarcomas (CCS). BMPR2, phospho-SMAD1/5 (pSMAD1/5), and runt-related transcription factor 2 (RUNX2) expressions were found to be associated with the pathological grades of chondrosarcoma and could be a promising target of treatment outcome. Moreover, BMPR2 was found to induce the RUNX2 expression via pSmad1/5. Knockdown of BMPR2 and pSmad1/5 results in the downregulation of RUNX2 expression in DDCS cells, while the upregulation of BMPR2 and Smad1/5 in CCS cells leads to increased RUNX2 expression. The luciferase reporter gene assay suggested that BMPR2 can induce the RUNX2 expression at the transcriptional level. By chromatin immunoprecipitation (ChIP) and electrophoresis mobility shift assay (EMSA), it was found that pSmad1/5 combined directly to RUNX2. The in vivo tumorigenicity assay in mice showed that the inhibition of BMPR2 or Smad1/5 in DDCS cell line reduced tumor growth, while the upregulation of BMPR2 or Smad1/5 in CCS cell line increased tumor growth. Furthermore, a BMPR signaling inhibitor, LDN-193189, was introduced to investigate its role as a potential drug to treat DDCS. Taken together, the present-study results suggest that BMPR2-pSmad1/5 signaling pathway has an important role in regulating not only the RUNX2 expression but also the tumorigenesis of DDCS.
| S-EPMC4937734 | biostudies-literature
Project description:Chondrosarcoma is the second most common primary malignant bone tumor. In this multicenter study, we sought to evaluate the disease-specific survival (DSS) and disease-free survival (DFS), and prognostic factors in patients with dedifferentiated chondrosarcoma (DDCS) or grade 3 chondrosarcoma (G3CS) in Japan. We retrospectively investigated the treatment outcomes and prognostic factors in 62 patients with DDCS and 19 patients with G3CS at 15 institutions participating in the Japanese Musculoskeletal Oncology Group. We also clarified significant clinicopathological factors for oncological outcomes. In surgery for primary lesions aimed at cure, a histologically negative margin (R0) was obtained in 93% (14/15) of patients with G3CS and 100% (49/49) of patients with DDCS. The 5-year DSS was 18.5% in patients with DDCS and 41.7% in patients with G3CS (p = 0.13). Local control was obtained in 80% (12/15) and 79.6% (39/49) of patients with G3CS and DDCS in the primary lesion after surgery with a wide surgical margin, respectively. In multivariate analysis, stage and no treatment/palliative treatment for the primary lesion were independent prognostic factors for DSS of DDCS, and age and no treatment/palliative treatment for DSS of G3CS. The 5-year DFS rate was 22.8% in 26 patients with DDCS who did not receive adjuvant chemotherapy, and 21.4% in 14 patients who received adjuvant chemotherapy. The prognosis of DDCS remains poor, although R0 resection was carried out in most cases. Effective and/or intensive chemotherapeutic regimens or agents should be considered or developed for patients with high-grade chondrosarcoma, particularly for those with DDCS.
| S-EPMC9277248 | biostudies-literature