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/ß-catenin, and TGF-ß, 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.

Imaging Aspects of Enchondromas in Pediatric Patients.

Enchondromas are benign tumors located primarily in long bones, some of which can be accidentally discovered during imaging exams conducted for other pathologies. These benign cartilaginous tumors are hard to differentiate from low grade chondrosarcomas, which require periodic follow ups. The purpose of this study was to identify the incidence of enchondromas in pediatric patients, to determine medical imaging criteria (Computed Tomography-CT and Magnetic Resonance Imaging-MRI) in order to differentiate enchondromas from other atypical cartilaginous tumors, and to identify a potential correlation between imaging aspects and clinical signs. The aim of this study was to review imaging findings of enchondromas in children.

Genetics and epigenetics in conventional chondrosarcoma with focus on non-coding RNAs.

The detection of mutations of isocitrate dehydrogenase 1 and 2 (IDH 1/2) as tumor driver genes in chondromas and chondrosarcomas more than ten years ago was a first major step for better understanding the molecular carcinogenenesis of these rare mesenchymal tumors. Within the TCA cycle, wild-typ IDH1/2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). IDH mutations catalyze the production of a non-physiological metabolite, D-2hydroxyglutarate (D-2HG) from α-KG. D-2HG can inhibit the class of α-KG-dependent enzymes by binding competitively to its receptor. Important enzyme families, such as the Ten-Eleven Translocation (TET) family of 5-methylcytosine hydroxylases and the Jumonji family of histone lysine demethylases are α-KG dependent. Many of the TET and Jumonji family-dependent enzymes regulate epigenetic factors, such as DNA methylation, histone modification, and nucleosome remodeling, underscoring the central role of the epigenome in cancer development. When D-2HG acts with these enzymes instead α-KG their functions will be in disarray with heavily hypermethylated DNA and dysregulations in histone metylation. NcRNAs have increasingly been described as a cornerstone of cancer development. Therefore this review describes exemplarily the oncogenic functions of miRNAs in chondrosarcoma in more detail. Particularly in chondrosarcomas additional carcinogenic features are aquired by interactions of ncRNAs with α-KG-dependent epigenetic regulators. Distinct ncRNAs, miRNAs and lncRNAs alike, are involved in deregulating important cellular signalling pathways and thus contributing further to malignant transformation and development of malignant cellular traits in these rare mesenchymal tumors. This review specially empasizes the complex interactions between the world of ncRNAs and genetics and epigenetics.

Distinct Roles of Glutamine Metabolism in Benign and Malignant Cartilage Tumors With IDH Mutations.

Enchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant, respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. In contrast, pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden partially because glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study demonstrates that glutamine metabolism plays different roles in tumor initiation and cancer maintenance. Supplementation of α-ketoglutarate and inhibiting GLS may provide a therapeutic approach to suppress enchondroma and chondrosarcoma tumor growth, respectively. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Enchondromatosis and Growth Plate Development.

PURPOSE OF REVIEW: Enchondroma is a common cartilage benign tumor that develops from dysregulation of chondrocyte terminal differentiation during growth plate development. Here we provide an overview of recent progress in understanding causative mutations for enchondroma, dysregulated signaling and metabolic pathways in enchondroma, and the progression from enchondroma to malignant chondrosarcoma. RECENT FINDINGS: Several signaling pathways that regulate chondrocyte differentiation are dysregulated in enchondromas. Somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) are the most common findings in enchondromas. Mechanisms including metabolic regulation, epigenetic regulation, and altered signaling pathways play a role in enchondroma formation and progression. Multiple pathways regulate growth plate development in a coordinated manner. Deregulation of the process can result in chondrocytes failing to undergo differentiation and the development of enchondroma.

The epidemiology, surgical management, and impact of margins in skull and mandibular osseous-site tumors.

OBJECTIVE: The aim of the study was to characterize the epidemiology and treatment outcomes of head and neck (HN) osseous-site tumors. METHODS: Descriptive analyses and multivariate Cox regressions were performed to analyze the effect of surgery on overall survival (OS) utilizing the National Cancer Database (2004-2016). RESULTS: Of 2449 tumors, surgery was utilized in 84.5% of cases. OS was worse in osteosarcoma (5-year OS: 53.4% [SE: 2.5%]) compared with cartilage tumors (5-year OS: 84.6% [SE: 1.8%]) (log-rank P < .001). Treatment regimens that included surgery were associated with improved OS on multivariate analysis (hazard ratio [HR] 0.495 [95% CI: 0.366-0.670]). Positive margins were found in 40.8% of cases, and associated with decreased OS in osteosarcomas (HR 1.304 [0.697-2.438]). CONCLUSION: Treatment that included surgery was associated with an increased OS within our cohort of HN osseous-site tumors, although the rates of positive margins were >40%. These findings may be limited by inherent selection bias in the database.

[Cartilage tumors: morphology, genetics, and current aspects of target therapy]. / Knorpeltumoren: Morphologie, Genetik und Basisaspekte der Targettherapie.

Cartilage tumors are a heterogeneous group of mesenchymal tumors whose common characteristic is the formation of a chondroblastic differentiated groundsubstance by the tumor cells. The basic features of their histological classification were already developed in the 1940s and supplemented by further entities in the following decades. Only in the past 10-15 years have fundamental new insights been gained through molecular genetic analysis. So, osteochondromas are characterized by alterations in the EXT1 and EXT2 genes. The description of mutations of isocitrate dehydrogenase 1 and 2 (IDH 1 and 2) in chondromas and chondrosarcomas is particularly important. The mesenchymal chondrosarcoma is characterized by a fusion of the HEY1-NCOA2 genes. The molecular genetic alterations characteristic for the individual tumor entities are first of all an essential supplement for the differential diagnosis of radiologically and histologically difficult cases. They also provide the basis for the establishment of molecular target therapies for malignant chondrogenic tumors. This applies in particular to conventional chondrosarcoma, for which all approaches to chemo- and radiotherapy have proven to be ineffective. However, the use of target therapies is still in its beginnings.

Chondromyxoid Fibroma of the Pelvis: Institutional Case Series With a Focus on Distinctive Features.

Chondromyxoid fibroma (CMF) is a relatively uncommon benign bone tumor of cartilaginous differentiation. The primary pitfall in the histopathologic diagnosis of CMF is confusion with a high-grade chondrosarcoma, owing to the atypical stellate and spindled cells set within a chondromyxoid background. CMF is particularly challenging to diagnose within the pelvis, where clinical suspicion for chondrosarcoma is high and benign lesions may grow to a large size to occupy the pelvic bones. In our practice, we noted this difficulty in several consecutive cases, especially when older patients presented with CMF within the pelvis. This prompted an institutional retrospective case review of all CMF within the pelvis. In 10 cases, we found overall that CMF of pelvis occurred in an older age range (mean age = 48.6 years), was larger in size (mean size = 6.0 cm), and showed a higher rate of soft tissue extension (50%) as compared with prior reports of nonpelvic CMF. Typical histologic features of CMF were seen in all cases; however, a high frequency of dystrophic calcification (50%) and necrosis (30%) was observed. Of interest, these aggregate demographic, radiologic, and histologic findings are all consistent with a benign neoplasm that has grown undetected within the pelvis over a long period of time. Recognition of these differences between pelvic CMF and tumors involving other sites will aid in avoiding misdiagnosis of this uncommon entity.

Orthopaedic tumors: What problems are we solving, and are universities and major medical centers doing enough?

Little has been published about the complexity of orthopaedic tumors compared to others tumors. The current study in the literature treated this problem in terms of classification, surgical intervention and impact on the patient. In this article, factors risks of tumors will be we identified. A strategy based on three dimensional simulations will be explained in order to improve the clinical trials.