NAMPT enhances LOX expression and promotes metastasis in human chondrosarcoma cells by inhibiting miR-26b-5p synthesis.

Chondrosarcoma is a malignant bone tumor that emerges from abnormalities in cartilaginous tissue and is related with lung metastases. Nicotinamide phosphoribosyltransferase (NAMPT) is an adipocytokine reported to enhance tumor metastasis. Our results from clinical samples and the Gene Expression Omnibus data set reveal that NAMPT levels are markedly higher in chondrosarcoma patients than in normal individuals. NAMPT stimulation significantly increased lysyl oxidase (LOX) production in chondrosarcoma cells. Additionally, NAMPT increased LOX-dependent cell migration and invasion in chondrosarcoma by suppressing miR-26b-5p generation through the c-Src and Akt signaling pathways. Overexpression of NAMPT promoted chondrosarcoma metastasis to the lung in vivo. Furthermore, knockdown of LOX counteracted NAMPT-facilitated metastasis. Thus, the NAMPT/LOX axis presents a novel target for treating the metastasis of chondrosarcoma.

Development of Injectable Thermosensitive Nanocomposite Hydrogel for Ratiometric Drug Delivery to Treat Drug Resistant Chondrosarcoma In Vivo.

Chondrosarcoma(CS), a prevalent primary malignant bone tumor, frequently exhibits chemotherapy resistance attributed to upregulated anti-apoptosis pathways such as the Bcl-2 family. In this manuscript, a new strategy is presented to augment chemosensitivity and mitigate systemic toxicity by harnessing a nano-enabled drug delivery hydrogel platform. The platform utilizes "PLGA-PEG-PLGA", an amphiphilic triblock copolymer combining hydrophilic polyethylene glycol (PEG) and hydrophobic polylactide glycolide (PLGA) blocks, renowned for its properties conducive to crafting a biodegradable, temperature-sensitive hydrogel. This platform is tailored to encapsulate a ratiometrically designed dual-loaded liposomes containing a first-line chemo option for CS, Doxorubicin (Dox), plus a calculated amount of small molecule inhibitor for anti-apoptotic Bcl-2 pathway, ABT-737. In vitro and in vivo evaluations demonstrate successful Bcl-2 suppression, resulting in the restoration of Dox sensitivity, evident through impeded tumor growth and amplified necrosis rates at the tumor site. This delivery system showcases remarkable thermal responsiveness, injectability, and biodegradability, all finely aligned with the clinical demands of CS treatment. Collectively, this study introduces a transformative avenue for tackling drug resistance in CS chemotherapy, offering significant clinical potential.

CHRNA6 RNA In Situ Hybridization Is a Useful Tool for the Diagnosis of Extraskeletal Myxoid Chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is an uncommon mesenchymal neoplasm characteristically composed of uniform-appearing round to spindle-shaped cells with eosinophilic cytoplasm and abundant myxoid extracellular matrix. Although the majority of cases harbor a pathognomonic t(9;22) translocation that fuses EWSR1 with the orphan nuclear receptor NR4A3, there are less common variants that partner NR4A3 with TAF15, TCF12, or TFG. By immunohistochemistry, EMC has features of both cartilaginous and neuroendocrine differentiation, as evidenced by inconsistent expression of S100 protein and synaptophysin or INSM1, respectively, in a subset of cases. Given the limitations of available immunohistochemical stains for the diagnosis of EMC, we analyzed genome-wide gene expression microarray data to identify candidate biomarkers based on differential expression in EMC in comparison with other mesenchymal neoplasms. This analysis pointed to CHRNA6 as the gene with the highest relative expression in EMC (96-fold; P = 8.2 × 10-26) and the only gene with >50-fold increased expression in EMC compared with other tumors. Using RNA chromogenic in situ hybridization, we observed strong and diffuse expression of CHRNA6 in 25 cases of EMC, including both EWSR1-rearranged and TAF15-rearranged variants. All examined cases of histologic mimics were negative for CHRNA6 overexpression; however, limited CHRNA6 expression, not reaching a threshold of >5 puncta or 1 aggregate of chromogen in >25% of cells, was observed in 69 of 685 mimics (10.1%), spanning an array of mesenchymal tumors. Taken together, these findings suggest that, with careful interpretation and the use of appropriate thresholds, CHRNA6 RNA chromogenic in situ hybridization is a potentially useful ancillary histologic tool for the diagnosis of EMC.

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.

OBJECTIVES: 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. METHODS: MRIs of 123 patients (45 ± 11 years, 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. RESULTS: 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. CONCLUSION: 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. CLINICAL RELEVANCE STATEMENT: 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. KEY POINTS: • 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 maximise detection of atypical cartilaginous tumours and high-grade chondrosarcomas, minimise underdiagnosis and reduce potential diagnostic delay in malignant tumours but increase unnecessary referral and follow-up of benign tumours.

Evaluation of cranial nerve involvement in chordomas and chondrosarcomas: a retrospective imaging study.

PURPOSE: Cranial nerve involvement (CNI) influences the treatment strategies and prognosis of head and neck tumors. However, its incidence in skull base chordomas and chondrosarcomas remains to be investigated. This study evaluated the imaging features of chordoma and chondrosarcoma, with a focus on the differences in CNI. METHODS: Forty-two patients (26 and 16 patients with chordomas and chondrosarcomas, respectively) treated at our institution between January 2007 and January 2023 were included in this retrospective study. Imaging features, such as the maximum diameter, tumor location (midline or off-midline), calcification, signal intensity on T2-weighted image, mean apparent diffusion coefficient (ADC) values, contrast enhancement, and CNI, were evaluated and compared using Fisher's exact test or the Mann-Whitney U-test. The odds ratio (OR) was calculated to evaluate the association between the histological type and imaging features. RESULTS: The incidence of CNI in chondrosarcomas was significantly higher than that in chordomas (63% vs. 8%, P < 0.001). An off-midline location was more common in chondrosarcomas than in chordomas (86% vs. 13%; P < 0.001). The mean ADC values of chondrosarcomas were significantly higher than those of chordomas (P < 0.001). Significant associations were identified between chondrosarcomas and CNI (OR = 20.00; P < 0.001), location (OR = 53.70; P < 0.001), and mean ADC values (OR = 1.01; P = 0.002). CONCLUSION: The incidence of CNI and off-midline location in chondrosarcomas was significantly higher than that in chordomas. CNI, tumor location, and the mean ADC can help distinguish between these entities.

Subungual melanoma with cartilaginous differentiation: Molecular insights.

Melanoma's rare capacity to undergo heterologous differentiation can create significant diagnostic challenges. The molecular mechanisms underlying this phenomenon are not well understood. We present an unusual case of subungual melanoma exhibiting extensive cartilaginous differentiation and provide insights into its molecular and cytogenomic features. Histopathologically, the tumor was predominantly composed of nodules of malignant cartilage in association with a smaller population of nested epithelioid to rhabdoid cells. Immunohistochemically, the tumor cells in both components were positive for S100, SOX10, and PRAME, and were negative for Melan-A and HMB-45. Molecular analysis by whole exome DNA sequence did not detect any pathogenic variants in genes commonly implicated in melanoma. Additional analysis by SNP chromosomal microarray revealed a complex genome characterized by numerous chromosomal losses and gains, including a homozygous deletion of the CDKN2A locus and a heterozygous deletion of the locus containing EXT2, a tumor suppressor implicated in hereditary multiple osteochondromas and secondary chondrosarcomas. This case underscores the importance of recognizing cartilaginous differentiation as a rare manifestation of melanoma, particularly at subungual sites, and suggests that at least some of these melanomas may be driven by non-canonical molecular pathways.

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

BACKGROUND: Distinguishing 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. METHODS: Approximately 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). RESULTS: Ultimately, 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. CONCLUSION: The 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.

Extra-skeletal intracranial mesenchymal chondrosarcoma: systematic-literature review.

BACKGROUND: Intracranial mesenchymal chondrosarcoma (IMC) is a rare malignant tumor in pediatric population. IMC can present as extra- or intra-axial lesion in pediatric patients, though the former is commoner causing raised intracranial pressure (ICP). Radiological diagnosis is a challenge in these cases, as is it difficult to differentiate these from other extra-axial neoplasms due to the wide differential diagnosis in pediatric population. We aim to systematically review the literature and present a rare case of extraskeletal intracranial mesenchymal chondrosarcoma treated with safe maximal resection. METHODS: A systematic review of literature was conducted in accordance with PRISMA guidelines. PubMed and Scopus databases were queried using the search terms, "primary intracranial chondrosarcoma", "extraskeletal mesenchymal chondrosarcoma", "mesenchymal chondrosarcoma" and "pediatric". Presentation, surgical management and outcome of a 15-year-old male with an extraskeletal IMC are also described. RESULTS: The search yielded 25 articles which met the inclusion criteria. These published records consisted of 33 IMC cases with mean age at presentation of 9.81 ± 5.2 years (range 2 months to 18 years). Frontal region was the commonest locations (11, 33.3%). Most common presentation was headache (14, 42.4%). All patients underwent surgical intervention: gross total resection (20, 60.6%), subtotal resection (9, 27.3%) and no extent mentioned (4, 12.1%). No adjuvant therapy was received in 15 patients (45.5%). On latest follow-up, 11 patients (33.3%) are on remission, 5 patients (15.2%) are symptom free, 3 patients (9.1%) had recurrence, 2 patients (6.1%) had metastasis and 9 patients (27.3%) expired. CONCLUSION: IMC is a rare entity in pediatric population with imaging findings which are non-characteristic leading to its diagnostic challenge. It can masquerade as other extra-axial intracranial neoplasm (meningioma or hemangiopericytoma). Combination of clinico-radiological and pathological examination can help in accurate diagnosis.  Safe Maximal resection followed by radiotherapy is the preferred treatment strategy.

Application of microwave ablation assisted degradation therapy in surgical treatment of intramedullary chondrosarcoma of extremities.

AIM: Clinical diagnosis and surgical treatment of chondrosarcoma (CS) are continuously improving. The purpose of our study is to evaluate the effectiveness of microwave ablation (MWA) assisted degradation therapy in the surgical treatment of intramedullary chondrosarcoma of the extremities, to provide a new reference and research basis for the surgical treatment of CS. METHODS: We recruited 36 patients with intramedullary CS who underwent MWA assisted extended curettage. Preoperative patient demographics and clinical data were recorded. Surgery was independently assisted by a medical team. Patients were followed up strictly and evaluated for oncological prognosis, radiological results, limb joint function, pain, and complications. RESULTS: We included 15 men and 21 women (mean age: 43.5 ± 10.1). The average length of the lesion was 8.1 ± 2.5 cm. Based on preoperative radiographic, clinical manifestations, and pathological results of puncture biopsy, 28 patients were preliminarily diagnosed with CS-grade I and eight patients with CS-grade II. No recurrence or metastasis occurred in the postoperative follow-up. The average Musculoskeletal Tumor Society score was 28.8 ± 1.0, significantly better than presurgery. Secondary shoulder periarthritis and abduction dysfunction occurred in early postoperative stage CS of the proximal humerus in some, but returned to normal after rehabilitation exercise. Secondary bursitis occurred at the knee joint in some due to the internal fixation device used in treatment; however, secondary osteoarthritis and avascular necrosis of the femoral head were not observed. Overall, oncological and functional prognoses were satisfactory. CONCLUSIONS: The application of MWA assisted degradation therapy in intramedullary CS can achieve satisfactory oncology and functional prognosis, providing a new option for the limited treatment of CS.

Complications and local recurrence of chondrosarcoma and chordoma treated by total tumor resection in thoracic and lumbar spine.

BACKGROUND: En bloc resection of spinal tumors is challenging and associated with a high incidence of complications; however, it offers the potential to reduce the risk of recurrence when a wide margin is achieved. This research aims to investigate the safety and efficacy of en bloc resection in treating thoracic and lumbar chondrosarcoma/chordoma. METHODS: Data from patients diagnosed with chondrosarcoma and chordoma in the thoracic or lumbar region, who underwent total en bloc or piecemeal resection at our institution over a 7-year period, were collected and regularly followed up. The study analyzed overall perioperative complications and compared differences in complications and local tumor recurrence between the two surgical methods. RESULTS: Seventeen patients were included, comprising 12 with chondrosarcoma and 5 with chordoma. Among them, 5 cases underwent intralesional piecemeal resection, while the remaining 12 underwent planned en bloc resection. The average surgical time was 684 min (sd = 287), and the mean estimated blood loss was 2300 ml (sd = 1599). Thirty-five complications were recorded, with an average of 2.06 perioperative complications per patient. 82% of patients (14/17) experienced at least one perioperative complication, and major complications occurred in 64.7% (11/17). Five patients had local recurrence during the follow-up, with a mean recurrence time of 16.2 months (sd = 7.2) and a median recurrence time of 20 months (IQR = 12.5). Hospital stays, operation time, blood loss, and complication rates did not significantly differ between the two surgical methods. The local recurrence rate after en bloc resection was lower than piecemeal resection, although not statistically significant (P = 0.067). CONCLUSIONS: The complication rates between the two surgical procedures were similar. Considering safety and local tumor control, en bloc resection is recommended as the primary choice for patients with chondrosarcoma/chordoma in the thoracic and lumbar regions who are eligible for this treatment.

Combining morphological and functional imaging parameters to diagnose primary bone neoplasms in the skull base, spine and sacrum.

PURPOSE: Morphological magnetic resonance (MR) and computed tomography (CT) features are used in combination with histology for diagnosis and treatment selection of primary bone neoplasms. Isolated functional MRI parameters have shown potential in diagnosis. Our goal is to facilitate diagnosis of primary bone neoplasms of the skull base, mobile spine and sacrum, by a comprehensive approach, combining morphological and functional imaging parameters. MATERIALS AND METHODS: Pre-treatment MR of 80 patients with histologically proven diagnosis of a primary bone neoplasm of the skull base, mobile spine and sacrum were retrospectively analyzed for morphological and functional MRI parameters. Functional parameters were measured in 4 circular regions of interest per tumor placed on non-adjacent scan slices. Differences in values of functional parameters between different histologies were analyzed with Dunn's test. RESULTS: Chordomas were the predominant histology (60.0%). Most neoplasms (80.0%) originated in the midline and had geographical (78.2%) bone destruction. Amorphous-type calcification (pre-existing bone) was seen only in chordomas. Homogeneous contrast enhancement pattern was seen only in chondrosarcoma and plasmacytoma. Ktrans and Kep were significantly lower in both chordoma, and chondrosarcoma compared to giant cell tumor of the bone (p = 0.006 - 0.011), and plasmacytoma (p = 0.004 - 0.014). Highest diffusion-weighted MRI apparent diffusion coefficient (ADC) values corresponded to chondrosarcoma and were significantly higher to those of chordoma (p = 0.008). CONCLUSION: We identified the most discriminating morphological parameters and added functional MR parameters based on histopathological features that are useful in making a confident diagnosis of primary bone neoplasms in the skull base, mobile spine and sacrum.

Treatment strategy in laryngeal chondrosarcoma: a multicenter study of 43 cases.

PURPOSE: Laryngeal chondrosarcoma is a rare tumor that mostly affects the cricoid cartilage. The aim of this study was to compare outcomes between the various treatments of this pathology as there are no official guidelines for this pathology. METHODS: A retrospective analysis of the pathology database of nine French tertiary care centers was conducted. Outcomes of patients treated by total laryngectomy were compared with those treated by more conservative approaches (endoscopic debulking, median thyrotomy, partial laryngectomy). Two Kaplan-Meier survival analyses were performed: one to assess the overall survival rate and the other to assess laryngeal preservation over time. RESULTS: A total of 43 patients were enrolled: 12 with total laryngectomy as the initial treatment, and 31 who initially underwent laryngeal-preserving treatment. With conservative treatment, laryngeal function was preserved in 96% and 75% of patients at 1 and 5 years, respectively. Conservative treatment did not reduce the overall survival rate. CONCLUSION: These results suggest that laryngeal preservation should be considered as the initial treatment in cases of laryngeal chondrosarcoma.

The stimulation of exosome generation by visfatin polarizes M2 macrophages and enhances the motility of chondrosarcoma.

Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Extracellular vesicles called exosomes are primarily used as mediators of intercellular signal transmission to control tumor metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with exosome generation in chondrosarcoma motility remains undetermined. Our results found that overexpressing visfatin augments the production of exosomes from chondrosarcoma cells. Visfatin-treated chondrosarcoma exosomes educate macrophage polarization towards the M2 but not M1 phenotype. Interestingly, M2 macrophages polarized by exosomes return to chondrosarcoma cells to facilitate cell motility. According to these findings, chondrosarcoma cells emit more exosomes when treated with visfatin. The stimulation of exosome generation by visfatin polarizes M2 macrophages and enhances the motility of chondrosarcoma.

MicroRNAs as Prognostic Biomarkers and Therapeutic Targets in Chondrosarcoma.

Chondrosarcoma, the second most common primary malignant bone tumor, originates from cartilaginous tissue and accounts for almost 20% of all primary bone tumors. The management of chondrosarcoma remains challenging due to its diverse clinical course and prognosis, which can range from benign to highly aggressive with a huge risk of metastasis. Emerging research has demonstrated the importance of microRNA (miRNA) dysregulation in the pathogenesis of chondrosarcoma. MiRNAs are small, noncoding RNA molecules that play an essential role in gene expression regulation by targeting specific messenger RNAs (mRNAs) for degradation or translational repression. This article provides an extensive review of current miRNA research in chondrosarcoma, focusing on diagnostic strategies, cell cycle regulation, drug resistance, biomarkers of progression, and stem cell phenotype. We will examine recent studies identifying differentially expressed miRNAs in chondrosarcoma compared to normal cartilage tissue, exploring their potential as diagnostic and prognostic biomarkers. Furthermore, we will discuss the role of miRNAs in regulating cell cycle progression and their potential as therapeutic targets to overcome drug resistance. We will also investigate the prospective utility of miRNAs as biomarkers of progression and their role in modulating the stem cell phenotype of chondrosarcoma cells. This article offers a comprehensive analysis of current miRNA research in chondrosarcoma, focusing on its potential as diagnostic and prognostic biomarkers, therapeutic targets, and regulators of disease progression. By integrating the latest discoveries in this field, we aim to contribute to the development of novel approaches to the prevention, diagnosis, and treatment of chondrosarcoma, ultimately enhancing patient outcomes.

DNA-PKcs Inhibition Sensitizes Human Chondrosarcoma Cells to Carbon Ion Irradiation via Cell Cycle Arrest and Telomere Capping Disruption.

In order to overcome the resistance to radiotherapy in human chondrosarcoma cells, the prevention from efficient DNA repair with a combined treatment with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor AZD7648 was explored for carbon ion (C-ion) as well as reference photon (X-ray) irradiation (IR) using gene expression analysis, flow cytometry, protein phosphorylation, and telomere length shortening. Proliferation markers and cell cycle distribution changed significantly after combined treatment, revealing a prominent G2/M arrest. The expression of the G2/M checkpoint genes cyclin B, CDK1, and WEE1 was significantly reduced by IR alone and the combined treatment. While IR alone showed no effects, additional AZD7648 treatment resulted in a dose-dependent reduction in AKT phosphorylation and an increase in Chk2 phosphorylation. Twenty-four hours after IR, the key genes of DNA repair mechanisms were reduced by the combined treatment, which led to impaired DNA repair and increased radiosensitivity. A time-dependent shortening of telomere length was observed in both cell lines after combined treatment with AZD7648 and 8 Gy X-ray/C-ion IR. Our data suggest that the inhibition of DNA-PKcs may increase sensitivity to X-rays and C-ion IR by impairing its functional role in DNA repair mechanisms and telomere end protection.

Visfatin Facilitates VEGF-D-Induced Lymphangiogenesis through Activating HIF-1α and Suppressing miR-2277-3p in Human Chondrosarcoma.

Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Lymphangiogenesis plays an essential role in cancer metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with VEGF-D generation and lymphangiogenesis in chondrosarcoma remains undetermined. Our results from clinical samples reveal that VEGF-D levels are markedly higher in chondrosarcoma patients than in normal individuals. Visfatin stimulation promotes VEGF-D-dependent lymphatic endothelial cell lymphangiogenesis. We also found that visfatin induces VEGF-D production by activating HIF-1α and reducing miR-2277-3p generation through the Raf/MEK/ERK signaling cascade. Importantly, visfatin controls chondrosarcoma-related lymphangiogenesis in vivo. Therefore, visfatin is a promising target in the treatment of chondrosarcoma lymphangiogenesis.

IDH-negative chondrosarcoma with metachronous dedifferentiation only in the metastatic site-A diagnostic pitfall.

Dedifferentiated chondrosarcoma is a subtype of chondrosarcoma with a biphasic histological appearance of a chondrosarcoma component transitioning to a high-grade, noncartilaginous sarcoma. It is particularly difficult to confirm the diagnosis when a sarcoma lacking cartilaginous component occurs at a distant location from the primary lesion. The patient was a 72-year-old woman with multiple lesions in the pelvis, lungs, and liver, 18 months after resection of grade 2 central chondrosarcoma of the sternum. Imaging showed no cartilage component in any location. Although a needle biopsy from the pelvic region confirmed the diagnosis as high-grade sarcoma without a cartilage component, it was difficult to distinguish between a new primary sarcoma and metachronous metastatic lesions from patient's known prior dedifferentiated chondrosarcoma. We therefore performed a comparative molecular analysis by whole-exome sequencing of the biopsy sample and the resected sternal central chondrosarcoma. Both lesions had no IDH1/2 mutations but shared 19 somatic mutations and wide-range chromosomal losses, indicating similar origin. This case illustrates the challenge is coupling a diagnosis of metastatic dedifferentiated chondrosarcoma when no chondroid component is evident. Our study also highlights the benefit of genomic analysis in this differential diagnosis, especially in the context of dedifferentiated chondrosarcoma lacking IDH1/2 mutations.

A novel fusion variant LSM14A::NR4A3 in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue neoplasm of uncertain lineage characterized by the pathognomonic rearrangement of the NR4A3 gene, which in most cases is fused with EWSR1. Other NR4A3 fusion partners have been described, namely TAF15, FUS, TCF12, and TGF. Some studies suggest that EMCs with non-EWSR1 variant fusion are associated with high-grade morphology and worst clinical behavior compared to EWSR1::NR4A3 tumors, supporting the potential significance of particular fusion variant in EMC. We report a case of a 34-year-old male who presented with calf EMC and subsequently developed a slowly progressive metastatic disease 3 years after diagnosis. Whole-transcriptome analysis with total RNA sequencing enabled identification of a novel fusion transcript LSM14A::NR4A3, expanding the molecular spectrum of EMC.

Novel low-grade renal spindle cell neoplasm with HEY1::NCOA2 fusion that is distinct from mesenchymal chondrosarcoma.

HEY1-NCOA2 fusion is most described in mesenchymal chondrosarcoma. This is the first case report of a primary renal spindle cell neoplasm of uncertain malignant potential with a HEY1::NCOA2 fusion identified by Fusionplex RNA-sequencing that is histologically distinct from mesenchymal chondrosarcoma. The neoplasm was identified in a 33-year-old woman without significant past medical history who underwent partial nephrectomy for an incidentally discovered renal mass. The histologic features of the mass included spindle cells with variable cellularity and monotonous bland cytology forming vague fascicles and storiform architecture within a myxoedematous and collagenous stroma with areas of calcification. The morphologic and immunophenotypic features were not specific for any entity but were most similar to low-grade fibromyxoid sarcoma. To date, the patient has not had recurrence, and the malignant potential of the neoplasm is uncertain.

TAF15::NR4A3 gene fusion identifies a morphologically distinct subset of extraskeletal myxoid chondrosarcoma mimicking myoepithelial tumors.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain differentiation predominantly arising in deep soft tissue. Its conventional morphologic appearance manifests as a relatively well-circumscribed, multilobular tumor composed of uniform short spindle-to-ovoid primitive mesenchymal cells with deeply eosinophilic cytoplasm arranged in anastomosing cords within abundant myxoid matrix. The genetic hallmark of EMC has long been considered to be pathognomonic gene rearrangements involving NR4A3, which when fused to TAF15, often have high-grade morphology with increased cellularity, moderate to severe cytologic atypia, and rhabdoid cytomorphology. Herein, we describe two cases of EMC with TAF15::NR4A3 fusion that appear morphologically distinct from both conventional and high-grade EMC. Both cases had an unusual biphasic appearance and showed diffuse positivity for p63, mimicking myoepithelial tumors. DNA methylation profiling demonstrated that both cases clearly cluster with EMC, indicating that they most likely represent morphologically distinct variants of EMC. The clinical significance and prognostic impact of this morphologic variance remains to be determined. Molecular testing, including DNA methylation profiling, can help to confirm the diagnosis and avoid confusion with mimics; it adds another layer of data to support expanding the morphologic spectrum of EMC.