High-grade Chondrosarcoma Research Articles

Genetics and Molecular Pathogenesis of the Chondrosarcoma: A Review of the Literature

The chondrosarcoma, a cartilage-forming bone tumor, presents significant clinical challenges due to its resistance to chemotherapy and radiotherapy. Surgical excision remains the primary treatment, but high-grade chondrosarcomas are prone to recurrence and metastasis, necessitating the identification of reliable biomarkers for diagnosis and prognosis. This review explores the genetic alterations and molecular pathways involved in chondrosarcoma pathogenesis. These markers show promise in distinguishing between benign enchondromas and malignant chondrosarcomas, assessing tumor aggressiveness, and guiding treatment. While these advancements offer hope for more personalized and targeted therapeutic strategies, further clinical validation of these biomarkers is essential to improve prognostic accuracy and patient outcomes in chondrosarcoma management.

The Importance of Patient Systemic Health Status in High-Grade Chondrosarcoma Prognosis: A National Multicenter Study

Background: Due to the relatively advanced age and high mortality rate of patients with high-grade chondrosarcoma (CS), it is important to holistically assess patient- and tumor characteristics in multidisciplinary team and shared decision-making with regard to treatment options. While current prognostic models include multiple tumor and treatment characteristics, the only patient characteristics that are commonly included are age and gender. Based on clinical experience, we believe that factors related to patient preoperative systemic health status such as the American Society of Anesthesiologists (ASA) score may be equally important prognostic factors for overall survival (OS). Methods: A retrospective nationwide cohort study was identified from four specialized bone sarcoma centers in The Netherlands. Patients with a primary CS grade II, III, and dedifferentiated CS were eligible. Prognostic factors including age at presentation, gender, ASA score, CVD, tobacco use, BMI, histological tumor grade, tumor size, pathological fracture, presentation after unplanned excision, type of surgery and surgical margin were evaluated. The outcome measure was OS at the time of surgery. The Kaplan–Meier methodology was employed to estimate OS; a log-rank test was used to assess the difference in survival. To study the impact of prognostic factors on OS, a multivariate Cox proportional hazard regression model was estimated. Results: In total, 249 patients were eligible for this study, and 89 were deceased at the end of follow-up. In multivariate analysis, histological grade (HR 2.247, 95% CI 1.334–3.783), ASA score III (HR 2.615, 95% CI 1.145–5.976, vs. ASA I), and age per year (HR: 1.025, 95% CI 1.004–1.045) were negatively associated with OS. No association was found between tobacco use, BMI, gender or cardiovascular disease and OS in this cohort. Pathological fracture and tumor size were only associated with OS in univariate analysis. Conclusions: This multicenter study is the first on sarcomas to include ASA in a prognostic model. Results show that ASA score as a proxy for patients’ systemic health status should be included when providing a prognosis for patients with a high-grade primary CS, besides the conventional risk factors such as tumor grade and age. Specifically, severe systemic disease (ASA score III) is a strong negative predictor. Conversely, we found no difference in OS between ASA scores I and II. These findings aid multidisciplinary team and shared decision-making with regard to these complex sarcoma patients that often require life-changing surgeries. Level of Evidence: Prognostic level III. See the instructions for authors for the complete description of levels of evidence.

Multiple pulmonary hamartomas with malignant transformation of a giant pulmonary hamartomas: a case report

Pulmonary hamartomas are the most common benign tumors of the lung, typically solitary with a diameter≤4 cm, and rarely undergo malignant transformation. We reported a case of multiple pulmonary hamartomas with malignant transformation of a giant pulmonary hamartoma (approximately 10 cm×12 cm in size). The patient was a 61-year-old female who sought medical attention for the discovery of multiple lesions in the right lung during a routine examination. Computed tomography revealed multiple soft tissue density lesions in the right lung. Surgical resection was performed to remove the lower lobe of the right lung and the lesion located in the posterior segment of the right upper lobe. The pathological results indicated that the right lower lobe lesion had undergone malignant transformation to a high-grade chondrosarcoma originating from a hamartoma, while the right upper lobe lesion remained a hamartoma. By analyzing this case together with the relevant literature, we aimed to emphasize the need for clinical awareness of the malignant potential of pulmonary hamartomas.

Preoperative prediction of histopathological grading in patients with chondrosarcoma using MRI-based radiomics with semantic features

BackgroundDistinguishing high-grade from low-grade chondrosarcoma is extremely vital not only for guiding the development of personalized surgical treatment but also for predicting the prognosis of patients. We aimed to establish and validate a magnetic resonance imaging (MRI)-based nomogram for predicting preoperative grading in patients with chondrosarcoma.MethodsApproximately 114 patients (60 and 54 cases with high-grade and low-grade chondrosarcoma, respectively) were recruited for this retrospective study. All patients were treated via surgery and histopathologically proven, and they were randomly divided into training (n = 80) and validation (n = 34) sets at a ratio of 7:3. Next, radiomics features were extracted from two sequences using the least absolute shrinkage and selection operator (LASSO) algorithms. The rad-scores were calculated and then subjected to logistic regression to develop a radiomics model. A nomogram combining independent predictive semantic features with radiomic by using multivariate logistic regression was established. The performance of each model was assessed by the receiver operating characteristic (ROC) curve analysis and the area under the curve, while clinical efficacy was evaluated via decision curve analysis (DCA).ResultsUltimately, six optimal radiomics signatures were extracted from T1-weighted imaging (T1WI) and T2-weighted imaging with fat suppression (T2WI-FS) sequences to develop the radiomics model. Tumour cartilage abundance, which emerged as an independent predictor, was significantly related to chondrosarcoma grading (p < 0.05). The AUC values of the radiomics model were 0.85 (95% CI, 0.76 to 0.95) in the training sets, and the corresponding AUC values in the validation sets were 0.82 (95% CI, 0.65 to 0.98), which were far superior to the clinical model AUC values of 0.68 (95% CI, 0.58 to 0.79) in the training sets and 0.72 (95% CI, 0.57 to 0.87) in the validation sets. The nomogram demonstrated good performance in the preoperative distinction of chondrosarcoma. The DCA analysis revealed that the nomogram model had a markedly higher clinical usefulness in predicting chondrosarcoma grading preoperatively than either the rad-score or clinical model alone.ConclusionThe nomogram based on MRI radiomics combined with optimal independent factors had better performance for the preoperative differentiation between low-grade and high-grade chondrosarcoma and has potential as a noninvasive preoperative tool for personalizing clinical plans.

Incidence and survival outcomes of patients with high-grade appendicular bone sarcoma and isolated regional lymph node metastasis: A national cohort database study

BackgroundWhile distant metastases in primary bone sarcomas have been extensively studied, the impact of isolated regional lymph node (LN) metastasis on survival remains unknown. In patients with primary bone sarcomas, we sought to assess the prevalence of isolated regional LN metastasis and the survival of this population. MethodsA total of 6651 patients with histologically-confirmed high-grade osteosarcoma, Ewing sarcoma, or chondrosarcoma were retrieved from the SEER database. We defined four subgroups for our analysis: localized disease (N0 M0), isolated regional LN metastasis (N1 M0), isolated distant metastasis (N0 M1), and combined regional LN and distant metastasis (N1 M1). Disease-specific survival (DSS) was assessed using the Kaplan-Meier method. ResultsPrevalence of isolated regional LN metastasis (N1 M0) was highest in Ewing sarcoma (27/1097; 3.3 %), followed by chondrosarcoma (18/1702; 1.4 %) and osteosarcoma (26/3740; 0.9 %). In all three histologies, patients with isolated regional LN metastasis had a worse 2-year, 5-year, and 10-year DSS than those with localized disease. Chondrosarcoma patients with isolated regional LN (N1 M0) metastasis had a significantly higher DSS in comparison to those with only distant metastasis (N0 M1) at the 5- and 10-year marks; for osteosarcoma and Ewing sarcoma, only a pattern towards higher survival was seen. Risk factors for presenting isolated regional LN metastasis included tumor location in lower-limb (OR = 2.01) or pelvis (OR = 2.49), diagnosis of Ewing sarcoma (OR = 2.98), and tumor >10 cm (OR = 1.96). ConclusionsIsolated regional LN metastases in primary bone sarcomas is an infrequent presentation associated with worse survival than localized disease. Level of evidenceIII.

Unusual soft tissue metastases in a patient with chondrosarcoma: a case report.

Chondrosarcoma (CS) is the second most frequent primary malignant bone tumour, characterized by production of non-osteoid cartilage matrix. Up to more than 30% of patients with CS present distant metastases, and the lungs represent the preferred site. Hence, CS soft tissue metastases and superficial cutaneous lesions are extremely rare. We report the case of a female who developed unusual multiple soft tissue CS metastases. This patient underwent left hindquarter amputation for recurrent grade 3 chondrosarcoma of the femoral neck with extension to the pelvis approximately 4years after internal fixation with an intramedullary nail for pathological fracture of left proximal femur and subsequent total proximal femoral endoprosthetic replacement for grade 1-2 chondrosarcoma. In the following years, she underwent metastasectomy for several grade 2 pulmonary metastatic chondrosarcomas. More than 14years after the amputation, she presented with multiple unusual superficial cutaneous lesions, and a whole-body magnetic resonance imaging demonstrated multiple soft tissue foci of metastatic disease. The histology of multiple soft tissue lesions excised confirmed metastatic chondrosarcoma. Then, she underwent marginal excision of further multifocal soft tissue metastatic high-grade chondrosarcoma. Unlike the poor survival from the onset of these metastases in the other cases reported in the literature, our patient is still alive 2years after the first multiple soft tissue excision of metastatic chondrosarcoma, and approximately 20years after the diagnosis of chondrosarcoma. Soft tissue CS metastases are a rare entity with few cases described in literature. This study aims to make the reader aware of this lesser-known CS manifestation.

A CT-based radiomics nomogram for predicting histologic grade and outcome in chondrosarcoma

ObjectiveThe preoperative identification of tumor grade in chondrosarcoma (CS) is crucial for devising effective treatment strategies and predicting outcomes. The study aims to build and validate a CT-based radiomics nomogram (RN) for the preoperative identification of tumor grade in CS, and to evaluate the correlation between the RN-predicted tumor grade and postoperative outcome.MethodsA total of 196 patients (139 in the training cohort and 57 in the external validation cohort) were derived from three different centers. A clinical model, radiomics signature (RS) and RN (which combines significant clinical factors and RS) were developed and validated to assess their ability to distinguish low-grade from high-grade CS with area under the curve (AUC). Additionally, Kaplan-Meier survival analysis was applied to examine the association between RN-predicted tumor grade and recurrence-free survival (RFS) of CS. The predictive accuracy of the RN was evaluated using Harrell’s concordance index (C-index), hazard ratio (HR) and AUC.ResultsSize, endosteal scalloping and active periostitis were selected to build the clinical model. Three radiomics features, based on CT images, were selected to construct the RS. Both the RN (AUC, 0.842) and RS (AUC, 0.835) were superior to the clinical model (AUC, 0.776) in the validation set (P = 0.003, 0.040, respectively). A correlation between Nomogram score (Nomo-score, derived from RN) and RFS was observed through Kaplan-Meier survival analysis in the training and test cohorts (log-rank P < 0.050). Patients with high Nomo-score tumors were 2.669 times more likely to suffer recurrence than those with low Nomo-score tumors (HR, 2.669, P < 0.001).ConclusionsThe CT-based RN performed well in predicting both the histologic grade and outcome of CS.

X-rays radiomics-based machine learning classification of atypical cartilaginous tumour and high-grade chondrosarcoma of long bones

Atypical cartilaginous tumour (ACT) and high-grade chondrosarcoma (CS) of long bones are respectively managed with active surveillance or curettage and wide resection. Our aim was to determine diagnostic performance of X-rays radiomics-based machine learning for classification of ACT and high-grade CS of long bones. This retrospective, IRB-approved study included 150 patients with surgically treated and histology-proven lesions at two tertiary bone sarcoma centres. At centre 1, the dataset was split into training (n=71 ACT, n=24 high-grade CS) and internal test (n=19 ACT, n=6 high-grade CS) cohorts, respectively, based on the date of surgery. At centre 2, the dataset constituted the external test cohort (n=12 ACT, n=18 high-grade CS). Manual segmentation was performed on frontal view X-rays, using MRI or CT for preliminary identification of lesion margins. After image pre-processing, radiomic features were extracted. Dimensionality reduction included stability, coefficient of variation, and mutual information analyses. In the training cohort, after class balancing, a machine learning classifier (Support Vector Machine) was automatically tuned using nested 10-fold cross-validation. Then, it was tested on both the test cohorts and compared to two musculoskeletal radiologists' performance using McNemar's test. Five radiomic features (3 morphology, 2 texture) passed dimensionality reduction. After tuning on the training cohort (AUC=0.75), the classifier had 80%, 83%, 79% and 80%, 89%, 67% accuracy, sensitivity, and specificity in the internal (temporally independent) and external (geographically independent) test cohorts, respectively, with no difference compared to the radiologists (p≥0.617). X-rays radiomics-based machine learning accurately differentiates between ACT and high-grade CS of long bones. AIRC Investigator Grant.

A retrospective external validation study of the Birmingham Atypical Cartilage Tumour Imaging Protocol (BACTIP) for the management of solitary central cartilage tumours of the proximal humerus and around the knee.

This study aimed to externally validate the Birmingham Atypical Cartilage Tumour Imaging Protocol (BACTIP) recommendations for differentiation/follow-up of central cartilage tumours (CCTs) of the proximal humerus, distal femur, and proximal tibia and to propose BACTIP adaptations if the results provide new insights. MRIs of 123 patients (45 ± 11years, 37 men) with an untreated CCT with MRI follow-up (n = 62) or histopathological confirmation (n = 61) were retrospectively/consecutively included and categorised following the BACTIP (2003-2020 / Ghent University Hospital/Belgium). Tumour length and endosteal scalloping differences between enchondroma, atypical cartilaginous tumour (ACT), and high-grade chondrosarcoma (CS II/III/dedifferentiated) were evaluated. ROC-curve analysis for differentiating benign from malignant CCTs and for evaluating the BACTIP was performed. For lesion length and endosteal scalloping, ROC-AUCs were poor and fair-excellent, respectively, for differentiating different CCT groups (0.59-0.69 versus 0.73-0.91). The diagnostic performance of endosteal scalloping and the BACTIP was higher than that of lesion length. A 1° endosteal scalloping cut-off differentiated enchondroma from ACT + high-grade chondrosarcoma with a sensitivity of 90%, reducing the potential diagnostic delay. However, the specificity was 29%, inducing overmedicalisation (excessive follow-up). ROC-AUC of the BACTIP was poor for differentiating enchondroma from ACT (ROC-AUC = 0.69; 95%CI = 0.51-0.87; p = 0.041) and fair-good for differentiation between other CCT groups (ROC-AUC = 0.72-0.81). BACTIP recommendations were incorrect/unsafe in five ACTs and one CSII, potentially inducing diagnostic delay. Eleven enchondromas received unnecessary referrals/follow-up. Although promising as a useful tool for management/follow-up of CCTs of the proximal humerus, distal femur, and proximal tibia, five ACTs and one chondrosarcoma grade II were discharged, potentially inducing diagnostic delay, which could be reduced by adapting BACTIP cut-off values. Mostly, Birmingham Atypical Cartilage Tumour Imaging Protocol (BACTIP) assesses central cartilage tumours of the proximal humerus and the knee correctly. Both when using the BACTIP and when adapting cut-offs, caution should be taken for the trade-off between underdiagnosis/potential diagnostic delay in chondrosarcomas and overmedicalisation in enchondromas. • This retrospective external validation confirms the Birmingham Atypical Cartilage Tumour Imaging Protocol as a useful tool for initial assessment and follow-up recommendation of central cartilage tumours in the proximal humerus and around the knee in the majority of cases. • Using only the Birmingham Atypical Cartilage Tumour Imaging Protocol, both atypical cartilaginous tumours and high-grade chondrosarcomas (grade II, grade III, and dedifferentiated chondrosarcomas) can be misdiagnosed, excluding them from specialist referral and further follow-up, thus creating a potential risk of delayed diagnosis and worse prognosis. • Adapted cut-offs to maximisedetection of atypical cartilaginous tumours and high-grade chondrosarcomas, minimiseunderdiagnosis and reduce potential diagnostic delay in malignant tumours but increase unnecessary referral and follow-up of benign tumours.

High-Grade Chondrosarcoma of Mandibular Molar Region- A Case Report and Review of Literature

Chondrosarcomas are malignant tumors of cartilaginous origin with only 5-10% reported in the head and neck region. Intraorally it has higher incidence of occurrence in anterior maxilla followed by posterior mandible. The 5-year survival and metastases rates are adversely affected by the grade of tumor, which necessitates its early diagnosis. Histopathology and immunohistochemistry are vital for its accurate diagnosis. Chondrosarcomas being radio-and chemoresistant are treated surgically although adjuvant radiotherapy helps in prevention of local recurrences. A case of high-grade chondrosarcoma of the mandibular molar region is presented, along with pertinent review of literature.

High-Grade Chondrosarcoma of Nasal Septum-A Rare Case Report and Review of Literature

Chondrosarcoma of the nasal septum is a rare malignancy. Since 1927 to date, 69 cases of chondrosarcoma of nasal septum have been reported. In addition to the 70th case, we reported here. Mostly chondrosarcoma is present on the ends of long bones and 5-10% in the head-neck region. In our case, 50 years old female presented a bilateral nasal obstruction, and a biopsy was sent for nasal mass. Histomorphology suggested high-grade chondrosarcoma, which is positive for S-100 immunohistochemistry. Early intervention through radiology and biopsy will manage the patient with chondrosarcoma.

Intravoxel Incoherent Motion and Dynamic Contrast-Enhanced Magnetic Resonance Imaging Can Differentiate Between Atypical Cartilaginous Tumors and High-Grade Chondrosarcoma: Correlation With Histological Vessel Characteristics.

To differentiate between atypical cartilaginous tumors and high-grade chondrosarcoma of the major long bones using intravoxel incoherent motion (IVIM) and Dynamic Contrast-Enhanced magnetic resonance imaging (DCE-MRI), and explore the correlation of quantitative parameters with hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and microvessel density (MVD). Between September 2016 and March 2022, 35 patients (17 atypical cartilaginous tumors, 18 high-grade chondrosarcoma) underwent MRI examination and pathological confirmation at our hospital. First, IVIM-derived parameters ( D , D* , and f ), and DCE-MRI parameters ( Ktrans , Kep , and V e ) were measured, and intraclass correlation efficient (ICC) and Mann-Whitney U test were performed. Second, receiver-operating characteristic curve analysis was performed to evaluate the diagnostic performance. Finally, Spearman's correlation analysis was performed between the quantitative parameters of IVIM-DWI and DCE-MRI and the immunohistochemical factors HIF-1α, VEGF, and MVD in chondrosarcoma tissue. D in atypical cartilaginous tumors was significantly higher than that in high-grade chondrosarcoma ( P = 0.003), whereas D* , Ktrans , and K ep in atypical cartilaginous tumors were significantly lower than those in high-grade chondrosarcoma (all P < 0.001). Ktrans demonstrated the highest area under the curve (AUC) of 0.979. The D* , Ktrans , and K ep were positively correlated with HIF-1α, VEGF, and MVD (all P < 0.001), whereas D had no correlation with HIF-1α, VEGF, and MVD ( P = 0.113, 0.077, 0.058, respectively). The IVIM-DWI quantitative parameters ( D , D* ) and DCE-MRI quantitative parameters ( Ktrans , Kep ) are helpful to differentiate between atypical cartilaginous tumors and high-grade chondrosarcoma and could be imaging biomarkers to reflect the expressions of HIF-1α, VEGF, and angiogenesis of chondrosarcoma.

Chondrosarcoma Resistance to Radiation Therapy: Origins and Potential Therapeutic Solutions

Chondrosarcoma is a malignant cartilaginous tumor that is particularly chemoresistant and radioresistant to X-rays. The first line of treatment is surgery, though this is almost impossible in some specific locations. Such resistances can be explained by the particular composition of the tumor, which develops within a dense cartilaginous matrix, producing a resistant area where the oxygen tension is very low. This microenvironment forces the cells to adapt and dedifferentiate into cancer stem cells, which are described to be more resistant to conventional treatments. One of the main avenues considered to treat this type of tumor is hadrontherapy, in particular for its ballistic properties but also its greater biological effectiveness against tumor cells. In this review, we describe the different forms of chondrosarcoma resistance and how hadrontherapy, combined with other treatments involving targeted inhibitors, could help to better treat high-grade chondrosarcoma.

Distinct IDH1/2-associated Methylation Profile and Enrichment of TP53 and TERT Mutations Distinguish Dedifferentiated Chondrosarcoma from Conventional Chondrosarcoma.

DDCS 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.

Classification of Chondrosarcoma: From Characteristic to Challenging Imaging Findings.

Chondrosarcomas can be classified into various forms according to the presence or absence of a precursor lesion, location, and histological subtype. The new 2020 World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone classifies chondrogenic bone tumors as benign, intermediate (locally aggressive), or malignant, and separates atypical cartilaginous tumors (ACTs) and chondrosarcoma grade 1 (CS1) as intermediate and malignant tumors. respectively. Furthermore, the classification categorizes chondrosarcomas (including ACT) into eight subtypes: central conventional (grade 1 vs. 2-3), secondary peripheral (grade 1 vs. 2-3), periosteal, dedifferentiated, mesenchymal, and clear cell chondrosarcoma. Most chondrosarcomas are the low-grade, primary central conventional type. The rarer subtypes include clear cell, mesenchymal, and dedifferentiated chondrosarcomas. Comprehensive analysis of the characteristic imaging findings can help differentiate various forms of chondrosarcomas. However, distinguishing low-grade chondrosarcomas from enchondromas or high-grade chondrosarcomas is radiologically and histopathologically challenging, even for experienced radiologists and pathologists.

Development and validation of a MRI-based combined radiomics nomogram for differentiation in chondrosarcoma.

This study aims to develop and validate the performance of an unenhanced magnetic resonance imaging (MRI)-based combined radiomics nomogram for discrimination between low-grade and high-grade in chondrosarcoma. A total of 102 patients with 44 in low-grade and 58 in high-grade chondrosarcoma were enrolled and divided into training set (n=72) and validation set (n=30) with a 7:3 ratio in this retrospective study. The demographics and unenhanced MRI imaging characteristics of the patients were evaluated to develop a clinic-radiological factors model. Radiomics features were extracted from T1-weighted (T1WI) images to construct radiomics signature and calculate radiomics score (Rad-score). According to multivariate logistic regression analysis, a combined radiomics nomogram based on MRI was constructed by integrating radiomics signature and independent clinic-radiological features. The performance of the combined radiomics nomogram was evaluated in terms of calibration, discrimination, and clinical usefulness. Using multivariate logistic regression analysis, only one clinic-radiological feature (marrow edema OR=0.29, 95% CI=0.11-0.76, P=0.012) was found to be independent predictors of differentiation in chondrosarcoma. Combined with the above clinic-radiological predictor and the radiomics signature constructed by LASSO [least absolute shrinkage and selection operator], a combined radiomics nomogram based on MRI was constructed, and its predictive performance was better than that of clinic-radiological factors model and radiomics signature, with the AUC [area under the curve] of the training set and the validation set were 0.78 (95%CI =0.67-0.89) and 0.77 (95%CI =0.59-0.94), respectively. DCA [decision curve analysis] showed that combined radiomics nomogram has potential clinical application value. The MRI-based combined radiomics nomogram is a noninvasive preoperative prediction tool that combines clinic-radiological feature and radiomics signature and shows good predictive effect in distinguishing low-grade and high-grade bone chondrosarcoma, which may help clinicians to make accurate treatment plans.

Biology and Management of High-Grade Chondrosarcoma: An Update on Targets and Treatment Options.

This review provides an overview of histopathology, clinical presentation, molecular pathways, and potential new systemic treatments of high-grade chondrosarcomas (CS), including grade 2−3 conventional, dedifferentiated, and mesenchymal CS. The diagnosis of CS combines radiological and histological data in conjunction with patient clinical presentations. Conventional CS is the most frequent subtype of CS (85%) and represents about 25% of primary bone tumors in adults; they can be categorized according to their bone location into central, peripheral, and periosteal chondrosarcomas. Central and peripheral CS differ at the molecular level with either IDH1/2 mutations or EXT1/2 mutations, respectively. CDKN2A/B deletions are also frequent in conventional CS, as well as COL2A1 mutations. Dedifferentiated CS develops when low-grade conventional CS transforms into a high-grade sarcoma and most frequently exhibits features of osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. Their molecular characteristics are similar to conventional CS. Mesenchymal CS is a totally different pathological entity exhibiting recurrent translocations. Their clinical presentation and management are different too. The standard treatment of CSs is wide en-bloc resection. CS are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in an attempt to achieve local control in unresectable tumors. Chemotherapy is possibly effective in mesenchymal chondrosarcoma and is of uncertain value in dedifferentiated chondrosarcoma. Due to resistance to standard anticancer agents, the prognosis is poor in patients with metastatic or unresectable chondrosarcomas. Recently, the refined characterization of the molecular profile, as well as the development of new treatments, allow new therapeutic options for these rare tumors. The efficiency of IDH1 inhibitors in other malignancies suggests that these inhibitors will be part of IDH1/2 mutated conventional CS management soon. Other treatment approaches, such as PIK3-AKT-mTOR inhibitors, cell cycle inhibitors, and epigenetic or immune modulators based on improving our understanding of CS molecular biology, are emerging.

MicroRNA-631 Resensitizes Doxorubicin-Resistant Chondrosarcoma Cells by Targeting Apelin

Chondrosarcoma is the second most common type of bone cancer. Surgical resection is the best choice for clinical treatment. High-grade chondrosarcoma is destructive and is more possible to metastasis, which is difficult to remove using surgery. Doxorubicin (Dox) is the most commonly used chemotherapy drug in the clinical setting; however, drug resistance is a major obstacle to effective treatment. In the present study, we compared Dox-resistant SW1353 cells to their parental cells using RNA sequencing (RNA-Seq). We found that the apelin (APLN) pathway was highly activated in resistant cells. In addition, tissue array analysis also showed that APLN was higher in high-grade tissues compared to low-grade tissues. APLN is a member of the adipokine family, which is a novel secreted peptide with multifunctional and biological activities. Previously, studies have shown that inhibition of the APLN axis may have a therapeutic benefit in cancers. However, the role of APLN in chondrosarcoma is completely unclear, and no related studies have been reported. During in vitro experiments, APLN was also observed to be highly expressed and secreted in Dox-resistant cells. Once APLN was knocked down, it could effectively improve its sensitivity to Dox. We also explored possible upstream regulatory microRNAs (miRNAs) of APLN through bioinformatics tools and the results disclosed that miR-631 was the most likely regulator of APLN. Furthermore, the expression of miR-631 was lower in the resistant cells, but overexpression of miR-631 in the Dox-resistant cell lines significantly increased the Dox sensitivity. These results were also observed in another chondrosarcoma cell line, JJ012 cells. Taken together, these findings will provide rationale for the development of drug resistance biomarkers and therapeutic strategies for APLN pathway inhibitors to improve the survival of patients with chondrosarcoma.

Association of FBXW11 levels with tumor development and prognosis in chondrosarcoma.

The E3 ubiquitin ligase FBXW11 exerts an oncogenic or tumor suppressive function in a cellular context-dependent manner. However, the clinical significance and biological role of FBXW11 in chondrosarcoma have not been clearly characterized. This study focuses on the expression profile, prognostic value and biological function of FBXW11 in chondrosarcoma. FBXW11 expression was analyzed by qRT-PCR and Western blot in six cases of chondrosarcoma specimens and the matched adjacent non-tumor tissues. The expression profile and prognostic value of FBXW11 were investigated in sixty-three cases of chondrosarcoma patients. Cell viability, colony formation, migration, invasion and apoptosis assays were further detected in SW1353 chondrosarcoma cells with restored FBXW11 expression. Downregulation of FBXW11 was remarkably detected in human chondrosarcoma specimens compared with the corresponding non-tumor tissues and benign cartilage tumors. Downregulated FBXW11 expression significantly correlated with high-grade chondrosarcoma and poor prognosis. Furthermore, FBXW11 was identified as an independent prognostic factor for the overall survival of chondrosarcoma patients. Restored expression of FBXW11 significantly suppressed chondrosarcoma cell growth and induced apoptosis. These findings establish that FBXW11 was markedly downregulated and recognized as an independent prognostic factor for patients with chondrosarcoma, and restored FBXW11 expression can suppress chondrosarcoma growth and induce apoptosis, highlighting a novel biological marker and potential therapeutic target against chondrosarcoma.

Bone sarcoma follow-up; a nationwide analysis of oncological events after initial treatment

AimFollow-up strategies for high-grade bone sarcomas have been optimized to facilitate early detection of local recurrence and distant metastasis. The ideology is that early detection enables early treatment presuming better survival. However, the clinical value for each individual patient remains questionable. This study aims to evaluate oncological events after initial treatment in order to assess current follow-up strategies for high-grade bone sarcomas in the Netherlands. Patients and MethodsA retrospective cohort study was conducted based on a national registry. All cases were retrieved from the Netherlands Cancer Registry. Our study consisted of 393 patients treated between 2007 and 2011 with complete follow-up data. Baseline characteristics were analysed for all entities. Local recurrence and distant metastasis was analysed along with overall survival for high-grade chondrosarcoma, high-grade osteosarcoma, Ewing sarcoma and chordoma. ResultsMedian follow-up was 8,3 years for high-grade chondrosarcoma, 4,9 for high-grade osteosarcoma, 3,8 for Ewing sarcoma and 7,5 for chordoma. Median time to local recurrence and distant metastasis was 1,2 years for high-grade osteosarcoma and 1,5 years for Ewing sarcoma. For high-grade osteosarcoma with localized disease at presentation, 0.09 new distant metastatic events per patient per year were seen after five years of follow-up with 11,1 patients needed to follow-up for any event. Five-year overall survival was 60,0% for high-grade chondrosarcoma, 50,0% for high-grade osteosarcoma, 45,3% for Ewing sarcoma and 71,4% for chordoma. ConclusionsThis nationwide study shows a plateau in local recurrences and distant metastatic events after four years of treatment for patients with high-grade osteosarcoma and Ewing sarcoma. Due to a lack of reliable evidence however, we were not able to provide additional guidance on follow-up intervals and duration. Collaborative research with larger groups is needed in order to provide a solid scientific recommendation for follow-up in the heterogenous patient population with bone sarcoma.