Dedifferentiated Chondrosarcoma Research Articles

Comparisons of clinical characteristics, treatments, and outcomes among different pathological subtypes of chondrosarcoma in the spine.

Spinal chondrosarcoma exhibits higher invasiveness and a worse prognosis compared to chondrosarcoma in the extremities. The prognosis and therapeutic plan vary greatly among different pathological subtypes of chondrosarcoma. This study aimed to analyze the differences in clinical characteristics, molecular features, therapeutic effects, and prognostic factors among the subtypes of chondrosarcoma in the spine. A retrospective review was conducted on 205 patients with spinal chondrosarcoma. The clinical features and immunohistochemical (IHC) markers were compared among the pathological subtypes of chondrosarcoma grade 1, grade 2, grade 3, mesenchymal chondrosarcoma (MCS), dedifferentiated chondrosarcoma (DCS), and clear cell chondrosarcoma (CCCS). Chondrosarcoma grade 1/2/3 are collectively referred to as conventional chondrosarcoma (CCS) for multivariate survival analysis. Univariate and multivariate analyses were performed to investigate independent prognostic factors for overall survival (OS) and recurrence-free survival (RFS) in patients with spinal chondrosarcoma. Furthermore, independent prognostic factors for OS and RFS were identified in CCS and MCS. MCS patients were younger than the other subtypes. Patients with chondrosarcoma grade 1/2 had better OS than those with chondrosarcoma grade 3, MCS and DCS, while only chondrosarcoma grade 1 patients showed better RFS than chondrosarcoma grade 2/3, MCS and DCS patients. Ki-67 index was higher in chondrosarcoma grade 3, MCS and DCS than chondrosarcoma grade 1/2. The comparison of IHC markers further highlighted the overexpression of P53/MDM2 in MCS and DCS. Gross total resection, including en-bloc and piecemeal resection, significantly improved OS and RFS for CCS patients, while only en-bloc resection significantly improved the prognosis of MCS patients. Chemotherapy appeared to be important for the OS of MCS patients. P53/MDM2 pathway was upregulated in MCS and DCS compared to chondrosarcoma grade 1/2. Radical tumor resection is crucial for the treatment of spinal chondrosarcoma, while MCS patients require further comprehensive treatments perioperatively.

ImmunoSarc II master trial (phase II of sunitinib and nivolumab): Results from the dedifferentiated chondrosarcoma (DDCS) cohort—A GEIS, ISG and UCL study.

11506 Background: Dedifferentiated chondrosarcoma (DDCS) is a rare aggressive CS subtype with a dismal prognosis and no standard of care systemic therapy. For those with advanced, metastatic disease, retrospective chemotherapy studies demonstrate short-term median progression-free survival (PFS) of around 3 to 5.5 months. Benefit from checkpoint and tyrosine kinase inhibitors has been reported, however clinical trial data is scarce, and endpoints are not well defined, thus benchmarking outcomes is challenging. The IMMUNOSARC I master-trial exploring sunitinib plus nivolumab in multiple sarcoma subtypes, detected potential activity in DDCS leading to a specific cohort within the phase II trial IMMUNOSARC II (NCT03277924). Methods: Patients (pts) with ECOG 0-1, centrally confirmed and progressive, measurable DDCS were eligible and treated with sunitinib 37.5 mg/d for 14 days (induction phase), followed by 25 mg/d, in combination with nivolumab 240 mg every 2 weeks until progressive disease (PD) or intolerance. Imaging assessments were performed every 8 weeks. Main endpoint was 6-m PFSR with one-arm survival design (type I error α 0.05, power 0.90, H0 40%, H1 70%) and a Brookmeyer-Crowley like test was assumed with at least 14 of 23 pts required without progression at 6 months. Results: Between December 2019 and October 2023, 24 pts with a median age of 60 years (38-76) were enrolled in 7 centres. Sixteen pts (66%), were male. Pts had received a median of 1 (0-2) prior lines of therapy. In total, 23 pts were evaluable with a median follow-up of 20.1 months (95%CI: 11.6-28.6). Median PFS, according to local site assessment, was 5.6 months (95%CI: 4.5-6.7); the 6m-PFSR was 10 of 23 pts (46%); (95%CI: 23-66) and median overall survival 10.3 months (95%CI: 6.7-13.9). In 19 pts with RECIST measurable response, 5 pts (26.3%) achieved a partial response; 10 (52.6%) stable disease and 4 (21.1%) PD. End-of-treatment reasons were PD in 21 pts (87%), toxicity 1 pt (4.2%) with two pts (8.4%) ongoing. For safety population, the most relevant study drug-related G3-4 toxicities were neutropenia (20.9%), anemia (16.7%), and increased ALT (12.5%). Conclusions: Sunitinib and nivolumab demonstrated encouraging activity in advanced DDCS that did not meet the primary endpoint, but compares favourably with previous analyses of cytotoxic and targeted therapy. The combination is worthy of further exploration in conjunction with reaching a consensus on clinically meaningful endpoints in this challenging population. Translational studies to identify potential predictive biomarkers are ongoing. Clinical trial information: NCT03277924 .

Chondrosarcoma evaluation using hematein-based x-ray staining and high-resolution 3D micro-CT: a feasibility study

BackgroundChondrosarcomas are rare malignant bone tumors diagnosed by analyzing radiological images and histology of tissue biopsies and evaluating features such as matrix calcification, cortical destruction, trabecular penetration, and tumor cell entrapment.MethodsWe retrospectively analyzed 16 cartilaginous tumor tissue samples from three patients (51-, 54-, and 70-year-old) diagnosed with a dedifferentiated chondrosarcoma at the femur, a moderately differentiated chondrosarcoma in the pelvis, and a predominantly moderately differentiated chondrosarcoma at the scapula, respectively. We combined a hematein-based x-ray staining with high-resolution three-dimensional (3D) microscopic x-ray computed tomography (micro-CT) for nondestructive 3D tumor assessment and tumor margin evaluation.ResultsWe detected trabecular entrapment on 3D micro-CT images and followed bone destruction throughout the volume. In addition to staining cell nuclei, hematein-based staining also improved the visualization of the tumor matrix, allowing for the distinction between the tumor and the bone marrow cavity. The hematein-based staining did not interfere with further conventional histology. There was a 5.97 ± 7.17% difference between the relative tumor area measured using micro-CT and histopathology (p = 0.806) (Pearson correlation coefficient r = 0.92, p = 0.009). Signal intensity in the tumor matrix (4.85 ± 2.94) was significantly higher in the stained samples compared to the unstained counterparts (1.92 ± 0.11, p = 0.002).ConclusionsUsing nondestructive 3D micro-CT, the simultaneous visualization of radiological and histopathological features is feasible.Relevance statement3D micro-CT data supports modern radiological and histopathological investigations of human bone tumor specimens. It has the potential for being an integrative part of clinical preoperative diagnostics.Key points• Matrix calcifications are a relevant diagnostic feature of bone tumors.• Micro-CT detects all clinically diagnostic relevant features of x-ray-stained chondrosarcoma.• Micro-CT has the potential to be an integrative part of clinical diagnostics.Graphical

Can the Cartilaginous Thickness Determine the Risk of Malignancy in Pelvic Cartilaginous Tumors, and How Accurate is the Preoperative Biopsy of These Tumors?

Can the Cartilaginous Thickness Determine the Risk of Malignancy in Pelvic Cartilaginous Tumors, and How Accurate is the Preoperative Biopsy of These Tumors?

Abstract CT263: Atezolizumab clinical trial biopsies reveal varied immune landscapes in clear cell sarcoma and chondrosarcoma

Abstract Introduction: Clear cell sarcoma (CCS) constitutes <1% of sarcomas and frequently presents in adolescents and young adults. Chondrosarcoma is one of the most common bone malignancies in adults, occurring as conventional chondrosarcoma (CS) or the more-aggressive dedifferentiated chondrosarcoma (dCS). There is no standard of care therapy approved for these malignancies. The activity of immune checkpoint inhibition (ICI) in alveolar soft part sarcoma, together with case reports of ICI activity in these other sarcoma subtypes, prompted us to conduct a phase 2 clinical trial of atezolizumab (atezo), in patients (pts) with advanced CCS, CS, or dCS (NCT04458922). Methods: We evaluated the effect of targeting PD-L1 with atezo upon the growth and immune landscape of CCS, CS, and dCS. Pts received intravenous atezo 1200 mg/m2 once every 21 days. Prior ICI therapy was not allowed. Tumor biopsy pairs for immuno-pharmacodynamic (IO-PD) studies were collected at baseline and on Cycle 3 Day 1(C3D1); paraffin sections were analyzed using immunofluorescence (IF) microscopy after staining with two multiplexed antibody panels (CD4/FOXP3 and PD-L1/CD8/CD3ζ pY142). Biomarker-positive cells within the tumor area and margins were quantified using image analysis algorithms. Activated cytotoxic T lymphocytes (CTLs) were defined as CD8+ CD3ζ pY142+ and reported as the percentage of the total CD8+ cell density. Results: Nine pts were enrolled per disease cohort. No RECIST objective responses were observed; accrual was closed due to futility. Median progression-free survival (PFS) was 2.66 months (range: 1.3 to 11.7) in CCS, 3.22 (range: 1.4 to 8.9) in CS, and 2.04 (range: 0.4 to 11.7) in dCS. IF microscopy of biopsy pairs from five CCS pts revealed varied immune landscapes: 4/5 C3D1 biopsies contained PD-L1+ cells, 4/5 contained CD8+ cells, and 3/5 contained activated CTLs. Immune phenotype did not generally correlate with response; however, the highest percentage of activated CTLs occurred in the CCS pt with the longest PFS and this pt showed an increase in PD-L1+ cells on treatment—consistent with target engagement of the PD-L1/PD-1 immune checkpoint. dCS biopsy pairs (N=3) also contained a range of biomarker densities that did not correlated with PFS. In dCS and CCS, on-treatment increases in the percentage of activated CTLs were accompanied by increased Treg cell density in some pts. In contrast, CS biopsies (N=5) were uniformly devoid of infiltrating immune cells. Conclusion: The tumor microenvironment of CS is an immune desert, while dCS and CCS tumors contain a range of immune cell compositions. Atezo treatment increased the percentage of activated CTLs and density of PD-L1+ cells in some tumors, but an increase in Treg cells may explain why that pharmacodynamic evidence of ICI activity (the increase in activated CTLs) was not associated with clinical response. Funded NCI Contract No. HHSN261201500003I. Citation Format: Katherine V. Ferry-Galow, Kristin K. Fino, Geraldine O'Sullivan Coyne, Nancy Moore, Elad Sharon, Melissa Burgess, James Chen, Anthony P. Conley, Elizabeth J. Davis, Priscilla Merriam, Albiruni R. Abdul Razak, Brian Van Tine, Jared C. Foster, Naoko Takebe, Christina L. Rosenberger, James H. Doroshow, Alice P. Chen, Ralph E. Parchment. Atezolizumab clinical trial biopsies reveal varied immune landscapes in clear cell sarcoma and chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT263.

Clinico-Genomic Profiling of Conventional and Dedifferentiated Chondrosarcomas Reveals TP53 Mutation to Be Associated with Worse Outcomes.

Chondrosarcomas are the most common primary bone tumor in adults. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are prevalent. We aimed to assess the clinico-genomic properties of IDH mutant versus IDH wild-type (WT) chondrosarcomas as well as alterations in other genes. We included 93 patients with conventional and dedifferentiated chondrosarcoma for which there were available clinical next-generation sequencing data. Clinical and genomic data were extracted and compared between IDH mutant and IDH WT chondrosarcomas and between TP53 mutant and TP53 WT chondrosarcomas. IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising in the extremities, associated with higher age at diagnosis, and more common in dedifferentiated chondrosarcomas compared with grades 1-3 conventional chondrosarcoma. There was no difference in survival based on IDH mutation in univariate and multivariate analyses. TP53 mutation was the next most prevalent (41.9%) and is associated with worse overall survival and metastasis-free survival in both univariate and multivariate analyses. TP53 mutation was also associated with higher risk of recurrence following curative-intent surgery and worse survival among patients that presented with de novo metastatic disease. IDH mutations are prevalent in chondrosarcoma though were not associated with survival outcomes in this cohort. TP53 mutations were the next most common alteration and were associated with worse outcomes.

Dedifferentiated Chondrosarcoma from Molecular Pathology to Current Treatment and Clinical Trials.

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.

Establishment and characterization of a novel dedifferentiated chondrosarcoma cell line, SMU-DDCS, harboring an IDH1 mutation.

Dedifferentiated chondrosarcoma (DDCS) is a high-grade subtype with a bi-morphic histological appearance of a conventional chondrosarcoma component and it can abruptly transition to a high-grade non-cartilaginous sarcoma. To better understand the biological features of DDCSs and to help develop new therapies, a novel DDCS cell line, SMU-DDCS, was established. Tissue from an open biopsy of a tumor resected from a 75-year-old patient was subjected to primary culture. The cell line was established and authenticated by assessing DNA microsatellite short tandem repeats. The cells maintained in monolayer cultures exhibited constant growth, spheroid formation, and high invasive capacity. Out of the four mice inoculated with SMU-DDCS cells, tumors developed in three mice after 2weeks. R132C mutation was found in the IDH1 but not the IDH2 genomic DNA sequence of SMU-DDCS cells. SMU-DDCS cells exhibited low chemosensitivity to doxorubicin, methotrexate, and cisplatin. This SMU-DDCS cell line harboring an IDH1 mutation will be a useful tool for investigating DDCS development and for evaluating novel therapeutic agents against it.

A Retrospective Multi-Institutional Cohort Analysis of Clinical Characteristics and Outcomes in Dedifferentiated Chondrosarcoma.

Dedifferentiated 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. We 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. Seventy-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. DDCS 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.

Differentiated chondrosarcoma, variants of transformation of the sarcomatous component of the tumor

Introduction. It is generally accepted that dedifferentiated chondrosarcomas are a result of transformation of low-grade (grade I and II) malignant chondrosarcomas into sarcoma with marked signs of cellular and tissue anaplasia with more aggressive clinical progression. Morphological examination of dedifferentiated chondrosarcomas allows to detect presence of pre-existent low-grade malignant chondrosarcoma tissue. Dedifferentiated chondrosarcomas comprise about 10 % of all chondrosarcomas. Most frequently, this tumor is located in the femur, pelvic bones, and humerus. A common clinical complication of dedifferentiated chondrosarcomas is pathological fracture. This disease is characterized by more aggressive progression with unfavorable prognosis compared to conventional types of chondrosarcomas.Aim. To study in detail the data of laboratory, clinical, radiological and morphological examinations of patients with different chondrosarcoma types for refinement of the algorithm of dedifferentiated chondrosarcoma examination and diagnosis.Materials and methods. Between 2008 and 2022, data of 160 patients with chondrosarcomas of varying locations and differentiation were analyzed. Diagnosis of “cartilaginous tumor” was made in all patients after clinical and radiological exams, as well as preoperative biopsy. Diagnosis of “dedifferentiated chondrosarcoma” was made in 30 patients. Radiological exam included several methods (X-ray, X-ray computed tomography, and magnetic resonance imaging) and modes of patient examination. Morphological diagnosis included routine techniques of histological analysis with gentle decalcification and subsequent immunohistochemical (PD-L1, PU-1, CD8, CD20, Ki67, CD34) and genetic analyses (IDH1/IDH2).Results. Among 160 patients, preoperative biopsy verified the diagnosis of “dedifferentiated chondrosarcoma” only in 6 patients. In 4 patients, the possibility of chondrosarcoma transformation into poorly differentiated sarcoma of non-cartilaginous structure was suspected. At the stage of postoperative material examination, diagnosis of “dedifferentiated chondrosarcoma” was confirmed in 4 patients with suspicion of more malignant tumor transformation and newly made in 20 more patients. Female patients were a little more common (19/11). Mean patient age was 59 years. Pathological fracture at the preoperative stage was observed in 6 patients. In almost one third of the cases (36 %), decreased differentiation of chondrosarcoma compared to preoperative biopsy was observed. It is important for management of these patients that in approximately 13 % of chondrosarcoma cases, recurrence with decreased tumor differentiation is observed.Conclusion. Radical surgical resection remains the standard treatment of chondrosarcoma as the effectiveness of radio- and chemotherapy is limited though it remains important in dedifferentiated type of the disease. These circumstances lead to the use of tumor immunotherapy targeted at the search for potential use of the immune response for recognition and killing of various malignant cells including dedifferentiated chondrosarcoma. Consequently, a promising research direction is determination of the significance of tumor-associated macrophages, as well as tumor-infiltrating lymphocytes as antitumor factors and biomarkers affecting clinical and morphological characteristics of oncological diseases.

Comparative analysis of miRNA expression in dedifferentiated and well-differentiated components of dedifferentiated chondrosarcoma

Dedifferentiated chondrosarcoma (DDCS) is a rare malignant cartilage tumor arising out of a low-grade chondrosarcoma, whereby the well-differentiated and the dedifferentiated components coexist in the same localization. DDCS has a massively increased metastatic potential in comparison to low-grade chondrosarcoma. So far, the underlying mechanisms of DDCS development and the increased malignancy are widely unknown. Targeted DNA sequencing revealed no genetic differences between both tissue components. Besides genetic events, alterations in epigenetic control may play a role in DDCS development. In this preliminary study, we have analyzed the differential miRNA expression in paired samples of both components of four primary DDCS cases and a rare lung metastasis with both components using the nCounter MAX analysis system from NanoString technologies. We identified 21 upregulated and two downregulated miRNAs in the dedifferentiated components of the primary cases. Moreover, three miRNAs were also significantly deregulated in the dedifferentiated component of the lung metastasis, supporting their possible role in DDCS development. Additionally, validated targets of the 23 deregulated miRNAs are involved in signaling pathways, like PI3K/Akt, Wnt/β-catenin, and TGF-β, as well as in cellular processes, like cell cycle regulation, apoptosis, and dedifferentiation. Further investigations are necessary to confirm and understand the role of the identified miRNAs in DDCS development.

What's New in Musculoskeletal Tumor Surgery.

What's New in Musculoskeletal Tumor Surgery.

Loss of H3K27 trimethylation in a distinct group of de-differentiated chordoma of the skull base.

De-differentiated chordoma is defined as a high-grade sarcoma lacking notochordal differentiation, which arises in association with conventional chordoma. The mechanism underlying de-differentiation remains unclear. We immunohistochemically investigated trimethylation at lysine 27 of histone 3 (H3K27me3) in nine de-differentiated chordomas. The tumours occurred at the skull base (n=5) or the sacrum (n=4) in four men and five women with a median age of 50 years. De-differentiation occurred de novo in four cases and at recurrence/metastasis in five cases. Five tumours retained H3K27me3, whereas four showed complete loss of H3K27me3 only in the de-differentiated component, while the conventional chordoma component retained H3K27me3. All the H3K27me3-negative tumours showed co-loss of dimethylation at H3K27 (H3K27me2), consistent with inactivation of polycomb repressive complex 2. Two genetically analysed H3K27me3-negative tumours harboured EED homozygous deletions. All four H3K27me3-negative de-differentiated chordomas affected the skull base of young or middle-aged women. Unlike dense proliferation of highly pleomorphic spindle or epithelioid cells in the H3K27me3-positive de-differentiated chordomas, all H3K27me3-negative tumours displayed swirling fascicles of relatively uniform spindle cells with alternating cellularity and perivascular accentuation, resembling malignant peripheral nerve sheath tumour (MPNST). Rhabdomyoblastic differentiation was present in one H3K27me3-negative tumour. We identified a novel group of de-differentiated chordomas in the skull base that lost H3K27me3/me2 only in the de-differentiated component, which was associated with EED homozygous deletion and MPNST-like histology. Our data suggest a distinct 'polycomb-type' de-differentiation pathway in chordoma, similar to a recently described de-differentiated chondrosarcoma with H3K27me3 loss.

Appendicular dedifferentiated chondrosarcoma: A management and survival study from the SEER database

IntroductionDedifferentiated chondrosarcoma (DDC) is an aggressive osseous neoplasm with a dismal prognosis. Treatment commonly involves limb-salvage surgery or amputation. In patients with appendicular DDC, we sought to describe demographic, clinical and treatment characteristics (1), analyze risk factors for metastasis (2) and overall death (3), and assess survival rates by treatment (4). Materials and methodsTwo-hundred-and-five patients from the SEER Database were included in our analysis. Demographic, clinical and treatment variables were analyzed. Multivariate regression was performed to identify risk factors. Survival analysis was performed using the Kaplan-Meier method. ResultsFifty-one (24.9 %) of the patients included presented metastasis at diagnosis. The most common locations were the lungs, other sites, and bone. Surgery to the primary site was more common in patients without metastasis (94.2 %) than those with (78.2 %); limb-salvage procedures were more common than amputations. Tumors >8 cm (T2) and those discontinuous (T3) were more likely to present metastasis at diagnosis (OR = 2.54, p = 0.043 and OR = 7.4, p = 0.008, respectively). Female gender was found to be a protective factor for overall death on crude analysis (OR = 0.33, p = 0.019). Metastases to sites other than the lungs (M1b) had the highest risk of overall death (OR = 49, p = 0.01). Combination of surgery and chemotherapy showed a trend towards higher overall survival in non-metastatic patients (p = 0.1069 and p = 0.1703). ConclusionsAppendicular DDC displays a high metastatic rate and low survival rates. The most common procedure is a limb-salvage surgery. Tumor size increases the risk of presenting metastases at diagnosis and female gender is a protective factor against death.

Chondroitin sulfate proteoglycan 4 expression in chondrosarcoma: A potential target for antibody-based immunotherapy.

Chondrosarcoma is a common primary bone malignancy whose phenotype increases with its histologic grade. They are relatively resistant to chemotherapy and radiation therapy limiting curative options for disseminated disease. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is highly expressed across various human cancers, including chondrosarcoma, and has restricted distribution in healthy tissues, making it an attractive target for the antibody-based therapy. CSPG4 specific chimeric antigen receptor (CAR) T cell therapies have been shown to be effective in treating other cancers such as melanoma and triple negative breast cancer. The goal of this study was to assess the prevalence of CSPG4 in human chondrosarcoma and to assess the efficacy of CSPG4 specific CAR T cells in lysing chondrosarcoma cells in vitro. Using immunohistochemistry (IHC), we stained a tissue microarray containing primary conventional and dedifferentiated chondrosarcoma from 76 patients with CSPG4 specific monoclonal antibodies (mAbs). In addition, we incubated 2 chondrosarcoma cell lines with CSPG4-targeting CAR T cells and subsequently evaluated cell survival. Our results showed medium to high expression of CSPG4 in 29 of 41 (71%) conventional chondrosarcoma tumors and in 3 of 20 (15%) dedifferentiated chondrosarcoma tumors. CSPG4 expression showed a positive association with time to metastasis and survival in both subtypes. CSPG4 CAR T treated cell lines showed a lysis of respectively >80% and 70% demonstrating CSPG4-targeted CAR T cells effective in killing CSPG4-positive chondrosarcoma tumors.

Dedifferentiated Chondrosarcoma: A Case Series and Review of the Literature.

Dedifferentiated chondrosarcoma (DCS) is a rare and aggressive malignancy with a poor prognosis. The purpose of this investigation was to describe our treatment and outcomes of 16 DCS patients at our institution and provide a review of the current literature. This study was a retrospective review over a consecutive twenty-year period. Data including treatment details and outcomes were recorded. A total of 16 cases from 2000 to 2018 were identified. The median age (IQR) was 62 years (52; 69) and the majority of DCS arose in the femur (50%, n=8) and pelvis (25%, n=4). Fourteen (88%) cases underwent limb salvage/wide margin resection (n=13) or intralesional surgery (n=1). For all DCS, the median survival (IQR) was 46 months (12; 140), with both a five and ten-year probability of 32.1% (95% CI, 7.3% to 57.0%). At study conclusion, 81.3% (n=13) were deceased and 18.7% (n=3) were alive. Our findings confirm the poor prognosis of DCS patients, with a five-year estimate of 32%. Together with existing literature, our data might help enable future strategic recommendation of these patients.

Clinical features and treatment outcomes of dedifferentiated and grade 3 chondrosarcoma: A multi-institutional study.

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.

IDH1 Mutation Induces HIF-1α and Confers Angiogenic Properties in Chondrosarcoma JJ012 Cells.

Chondrosarcoma is a group of primary bone cancers that arise from transformed cells of chondrocytic lineage. Tumor recurrence and metastasis are devastating for patients with chondrosarcoma since there are no effective treatment options. IDH mutations occur in over 50% of tumors from patients with conventional or dedifferentiated chondrosarcomas and represent an attractive target for therapy. However, their role in the pathogenesis of chondrosarcoma remains largely unknown. In this study, we sought to determine the association of IDH mutation and HIF-1α in chondrosarcoma. We used the chondrosarcoma JJ012 cell line and its derived CRISPR/Cas9 mutant IDH1 (IDH1mut) knockout (KO) cells. RNA-Seq data analysis revealed downregulation of several HIF-1α target genes upon loss of IDH1mut. This was associated with reduced HIF-1α levels in the IDH1mut KO cells and tumors. Loss of IDH1mut also attenuated the expression of angiogenic markers in tumor tissues and abrogated the angiogenic capacity of JJ012 cells. Moreover, we observed that exogenous expression of HIF-1α significantly promoted anchorage-independent colony-formation by IDH1mut KO cells. These results suggest IDH1 mutation confers angiogenic and tumorigenic properties of JJ012 cells by inducing HIF-1α. Thus, the HIF pathway represents a promising candidate for combinatorial regimens to target IDH1 mutated chondrosarcomas.

Methylation-mediated silencing of protein kinase C zeta induces apoptosis avoidance through ATM/CHK2 inactivation in dedifferentiated chondrosarcoma.

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. 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. 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. 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.

Can 18F-FDG PET/CT alone or combined with radiology be used to reliably grade cartilage bone neoplasms for surgical decision making?

Treatment of chondrosarcomas is grade based; intralesional curettage for grade 1 and resection for grade 2 or more. Currently used methods to determine grades before surgery are not highly accurate and create a dilemma for the surgeon. We have used a PET-CT combined with imaging to answer the following study questions: (1) Does SUVmax value from an 18F-FDG PET/CT correlate with the grade of chondrosarcoma? (2) Can a cutoff SUVmax value be used to differentiate between various grades of chondroid neoplasms with sufficient sensitivity and specificity? (3) Does SUVmax guide the clinician and add value to radiology in offering histologic grade-dependent management? SUVmax values of patients with suspected chondrosarcoma were retrospectively correlated with the final histology grade for the operated patients. Radiologic parameters and radiology aggressiveness scores (RAS) were reevaluated and tabulated. Totally 104 patients with chondroid tumors underwent 18F-FDG PET/CT assessment. In total 73 had tissue diagnosis available as a pretreatment investigation. Spearman correlation indicated that there was a significant positive association between SUVmax and the final histology grading of chondroid tumors (correlation coefficient = 0.743; P < 0.01). SUVmax cutoff of 13.3 was 88.9% sensitive and 100% specific for diagnosing dedifferentiated chondrosarcomas. An RAS cutoff value of 3 or more could diagnose IHGCS with a sensitivity of 80.7% and specificity of 93.75%. Adding an SUVmax cutoff of 3.6 improves the sensitivity to 89.5%. SUVmax value can reliably help diagnose dedifferentiated chondrosarcoma and when added to the radiology score can improve the accuracy of grading chondrosarcoma.