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In Vivo (Athens, Greece) 2023Chondrogenic tumors are benign, intermediate or malignant neoplasms showing cartilaginous differentiation. In 2012, we reported a mesenchymal chondrosarcoma carrying a...
BACKGROUND/AIM
Chondrogenic tumors are benign, intermediate or malignant neoplasms showing cartilaginous differentiation. In 2012, we reported a mesenchymal chondrosarcoma carrying a t(1;5)(q42;q32) leading to an IRF2BP2::CDX1 fusion gene. Here, we report a second chondrogenic tumor carrying an IRF2BP2::CDX1 chimera.
CASE REPORT
Radiological examination of a 41 years old woman showed an osteolytic lesion in the os pubis with a large soft tissue component. Examination of a core needle biopsy led to the diagnosis chondromyxoid fibroma, and the patient was treated with curettage. Microscopic examination of the specimen showed a tumor tissue in which a pink-bluish background matrix was studded with small spindled to stellate cells without atypia, fitting well the chondromyxoid fibroma diagnosis. Focally, a more cartilage-like appearance was observed with cells lying in lacunae and areas with calcification. G-banding analysis of short-term cultured tumor cells yielded the karyotype 46,XX,der(1)inv(1)(p33~34q42) add(1)(p32)?ins(1;?)(q42;?),del(5)(q31),der(5)t(1;5)(q42;q35)[12]/46,XX[3]. RT-PCR together with Sanger sequencing showed the presence of two IRF2BP2::CDX1 chimeric transcripts in which exon 1 of the IRF2BP2 reference sequence NM_182972.3 or NM_001077397.1 was fused to exon 2 of CDX1. Both chimeras were predicted to code for proteins containing the zinc finger domain of IRF2BP2 and homeobox domain of CDX1.
CONCLUSION
IRF2BP2::CDX1 chimera is recurrent in chondrogenic tumors. The data are still too sparse to conclude whether it is a hallmark of benign or malignant tumors.
Topics: Female; Humans; Adult; Genes, Homeobox; Interferon Regulatory Factor-2; Homeodomain Proteins; Exons; Tumor Cells, Cultured; Bone Neoplasms; Fibroma; DNA-Binding Proteins; Transcription Factors
PubMed: 37905608
DOI: 10.21873/invivo.13352 -
Cureus Sep 2023Mesenchymal chondrosarcomas are extremely rare and aggressive tumors that primarily affect patients between the ages of 20 and 30. These neoplasms are typically found in...
Mesenchymal chondrosarcomas are extremely rare and aggressive tumors that primarily affect patients between the ages of 20 and 30. These neoplasms are typically found in the lower limbs and cranial region. Their occurrence within soft tissues is exceedingly rare, and the initial presentation often includes immediate metastatic dissemination. Given the extraordinarily low prevalence of extraskeletal mesenchymal chondrosarcoma, treatment approaches remain non-standardized. Surgical resection combined with neoadjuvant chemotherapy or radiotherapy is the most commonly favored strategy by medical teams. In this case report, we present the case of a 72-year-old patient with no specific medical history, who presented with a non-metastatic extraskeletal mesenchymal chondrosarcoma located in the popliteal fossa. The therapeutic intervention encompassed surgical resection followed by adjuvant radiotherapy. After 18 months of follow-up period, there was no evidence of local recurrence or distant metastases. The disparity between the patient's clinical characteristics and the existing medical literature may provide new insights into understanding this neoplastic entity.
PubMed: 37900409
DOI: 10.7759/cureus.45974 -
Journal of Cancer Research and Clinical... Dec 2023Sarcomas are a diverse group of malignant neoplasms of mesenchymal origin. They develop rarely, but due to poor prognosis, they are a challenging and significant... (Review)
Review
Sarcomas are a diverse group of malignant neoplasms of mesenchymal origin. They develop rarely, but due to poor prognosis, they are a challenging and significant clinical problem. Currently, available therapeutic options have very limited activity. A better understating of sarcomas' pathogenesis may help develop more effective therapies in the future. The Sonic hedgehog (Shh) signaling pathway is involved in both embryonic development and mature tissue repair and carcinogenesis. Shh pathway inhibitors are presently used in the treatment of basal cell carcinoma. Its increased activity has been demonstrated in many sarcomas, including osteosarcoma, Ewing sarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, and malignant rhabdoid tumor. In vitro studies have demonstrated the effectiveness of inhibitors of the Hedgehog pathway in inhibiting proliferation in those sarcomas in which the components of the pathway are overexpressed. These results were confirmed by in vivo studies, which additionally proved the influence of Shh pathway inhibitors on limiting the metastatic potential of sarcoma cells. However, until now, the efficacy of sarcomas treatment with Shh pathway inhibitors has not been established in clinical trials. The reason for that may be the non-canonical activation of the pathway or interactions with other signaling pathways, such as Wnt or Notch. In this review, we present the Shh signaling pathway's role in the pathogenesis of sarcomas, including both canonical and non-canonical signaling. We also propose how this knowledge could be potentially translated into clinics.
Topics: Humans; Hedgehog Proteins; Sarcoma; Sarcoma, Ewing; Osteosarcoma; Bone Neoplasms
PubMed: 37815662
DOI: 10.1007/s00432-023-05441-3 -
Cancers Sep 2023Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the... (Review)
Review
Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the standard treatment for localized MCS is only surgical resection, and there are no established treatment guidelines for patients with advanced and metastatic MCS. Due to the low incidence of MCS, the pathology of these tumors is still unknown, and other therapeutic options are lacking. Some studies show the potential role of the PDGF/PPI3K/AKT, PKC/RAF/MEK/ERK, and pRB pathways, and BCL2 overexpression in the pathogenesis of MCS. These findings provide an opportunity to use protein kinases and BCL2 inhibitors as potential therapy in MCS. In this review, we summarize the current knowledge about MCS diagnosis and treatment options. We show the immunological and molecular biomarkers used in the diagnosis of MCS. In addition, we discuss the known prognostic and predictive factors in MCS. Finally, we present the novel trends, including targeted therapies and ongoing clinical trials using protein kinase inhibitors and the death receptor 5 (DR5) agonist, which may be the focus of future MCS treatment studies.
PubMed: 37760551
DOI: 10.3390/cancers15184581 -
Journal of Neurosurgery. Case Lessons Aug 2023Mesenchymal chondrosarcoma (MCS) is an aggressive subtype of chondrosarcoma that occurs extremely rarely in the central nervous system. Patients often present with pain...
BACKGROUND
Mesenchymal chondrosarcoma (MCS) is an aggressive subtype of chondrosarcoma that occurs extremely rarely in the central nervous system. Patients often present with pain or sensorimotor deficits, and resection is considered the gold standard. The role of adjuvant radiation and/or chemotherapy is largely unknown.
OBSERVATIONS
A 22-year-old male presented with a 4-month history of progressive back and bilateral leg pain. He underwent imaging workup with magnetic resonance imaging of the lumbar spine and was found to have an intradural, extramedullary, heterogeneously enhancing mass spanning the L4-5 vertebral levels. Intraoperatively, a lobular, partially calcified mass with a ventral dural attachment displacing the nerve roots laterally was observed. The mass was removed en bloc, and the patient later underwent adjuvant radiotherapy, with no evidence of recurrence 2 years following surgery.
LESSONS
Spinal MCS is extremely rare and often presents with a more aggressive course than conventional chondrosarcoma. Radiological diagnosis is challenging, as the tumor mimics different pathologies. The presence of calcifications, heterogeneous enhancement, and a more rapid clinical course as well as the presence of HEY1::NCOA2 gene fusion, which can be detected by surrogate immunohistochemistry, aids in diagnosis. Resection is the standard of care, and adjuvant radiation may be considered to reduce local recurrence, although further studies are warranted.
PubMed: 37728306
DOI: 10.3171/CASE23317 -
Cancer Medicine Sep 2023We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs)...
Real-world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study.
OBJECTIVES
We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra-skeletal mesenchymal CS (ESMC).
METHODS
After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.
RESULTS
From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12-76); median starting dose was 60 mg for CABO (n = 37, range 40-60) and 120 mg for REGO (n = 29, range 40-160). Twenty-eight (42.4%) patients required dose reduction: hand-foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7-13.1); 13.4 months (n = 18, 95% CI 3.4-27.2), 8.1 (n = 4, 95% CI 4.1-9.3) and 18.2 (n = 5, 95% CI (10.4-na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8-5), 3.9 (n = 18, 95% CI 2.1-5.9), 5.53 (n = 4. 95% CI 2.13-NA) and 11.4 (n = 5, 95% CI 1.83-14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis.
CONCLUSION
Our real-world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research.
Topics: Humans; Adult; Child; Adolescent; Young Adult; Middle Aged; Aged; Tyrosine Kinase Inhibitors; Neoplasm Recurrence, Local; Canada; Bone Neoplasms; Sarcoma; Sarcoma, Ewing; Osteosarcoma; Chondrosarcoma; Retrospective Studies; Soft Tissue Neoplasms
PubMed: 37724607
DOI: 10.1002/cam4.6515 -
BMC Cancer Sep 2023Cancer cells are characterized by changes in cell cytoskeletal architecture and stiffness. Despite advances in understanding the molecular mechanisms of musculoskeletal...
BACKGROUND
Cancer cells are characterized by changes in cell cytoskeletal architecture and stiffness. Despite advances in understanding the molecular mechanisms of musculoskeletal cancers, the corresponding cellular mechanical properties remain largely unexplored. The aim of this study was to investigate the changes in cellular stiffness and the associated cytoskeleton configuration alterations in various musculoskeletal cancer cells.
METHODS
Cell lines from five main sarcoma types of the musculoskeletal system (chondrosarcoma, osteosarcoma, Ewing sarcoma, fibrosarcoma and rhabdomyosarcoma) as well as their healthy cell counterparts (chondrocytes, osteoblasts, mesenchymal stem cells, fibroblasts, skeletal muscle cells) were subjected to cell stiffness measurements via atomic force microscopy (AFM). Biochemical and structural changes of the cytoskeleton (F-actin, β-tubulin and actin-related protein 2/3) were assessed by means of fluorescence labelling, ELISA and qPCR.
RESULTS
While AFM stiffness measurements showed that the majority of cancer cells (osteosarcoma, Ewing sarcoma, fibrosarcoma and rhabdomyosarcoma) were significantly less stiff than their corresponding non-malignant counterparts (p < 0.001), the chondrosarcoma cells were significant stiffer than the chondrocytes (p < 0.001). Microscopically, the distribution of F-actin differed between malignant entities and healthy counterparts: the organisation in well aligned stress fibers was disrupted in cancer cell lines and the proteins was mainly concentrated at the periphery of the cell, whereas β-tubulin had a predominantly perinuclear localization. While the F-actin content was lower in cancer cells, particularly Ewing sarcoma (p = 0.018) and Fibrosarcoma (p = 0.023), this effect was even more pronounced in the case of β-tubulin for all cancer-healthy cell duos. Interestingly, chondrosarcoma cells were characterized by a significant upregulation of β-tubulin gene expression (p = 0.005) and protein amount (p = 0.032).
CONCLUSION
Modifications in cellular stiffness, along with structural and compositional cytoskeleton rearrangement, constitute typical features of sarcomas cells, when compared to their healthy counterpart. Notably, whereas a decrease in stiffness is typically a feature of malignant entities, chondrosarcoma cells were stiffer than chondrocytes, with chondrosarcoma cells exhibiting a significantly upregulated β-tubulin expression. Each Sarcoma entity may have his own cellular-stiffness and cytoskeleton organisation/composition fingerprint, which in turn may be exploited for diagnostic or therapeutic purposes.
Topics: Humans; Sarcoma, Ewing; Tubulin; Actins; Sarcoma; Osteosarcoma; Fibrosarcoma; Rhabdomyosarcoma; Chondrosarcoma; Soft Tissue Neoplasms; Biomarkers; Bone Neoplasms
PubMed: 37700272
DOI: 10.1186/s12885-023-11375-3 -
Cytopathology : Official Journal of the... Jan 2024Mesenchymal chondrosarcoma (MC) is a rare but extremely aggressive type of chondrosarcoma distinguished by the presence of both primitive mesenchymal cells and fully...
Mesenchymal chondrosarcoma (MC) is a rare but extremely aggressive type of chondrosarcoma distinguished by the presence of both primitive mesenchymal cells and fully developed chondroid tissue. The identification of a biphasic morphology in pleural effusion, along with detection of the HEY1::NCOA2 fusion using next-generation sequencing, serve as vital indicators for an accurate diagnosis.
Topics: Humans; Chondrosarcoma, Mesenchymal; Bone Neoplasms; Immunohistochemistry; Basic Helix-Loop-Helix Transcription Factors; Cell Cycle Proteins; Pleural Effusion; High-Throughput Nucleotide Sequencing; Nuclear Receptor Coactivator 2
PubMed: 37688410
DOI: 10.1111/cyt.13296 -
JCI Insight Sep 2023Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is...
Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds. High-throughput screening (HTS) with 11,948 clinical-stage compounds was performed using a reporter cell line detecting endogenous KLF4 activation. Eighteen compounds were identified through the HTS and confirmed in a secondary screen. After testing in SW1353 chondrosarcoma cells and human chondrocytes, mocetinostat - a class I selective histone deacetylase (HDAC) inhibitor - had the best profile of biological activities. Mocetinostat upregulated cartilage signature genes in human chondrocytes, meniscal cells, and BM-derived mesenchymal stem cells, and it downregulated hypertrophic, inflammatory, and catabolic genes in those cells and synoviocytes. I.p. administration of mocetinostat into mice reduced severity of OA-associated changes and improved pain behaviors. Global gene expression and proteomics analyses revealed that regenerative and protective effects of mocetinostat were dependent on peroxisome proliferator-activated receptor γ coactivator 1-α. These findings show therapeutic and protective activities of mocetinostat against OA, qualifying it as a candidate to be used as a DMOAD.
Topics: Humans; Animals; Mice; Kruppel-Like Factor 4; Osteoarthritis; Inflammation; Histone Deacetylase Inhibitors; Bone Neoplasms
PubMed: 37681413
DOI: 10.1172/jci.insight.170513 -
Experimental and Therapeutic Medicine Sep 2023Maffucci syndrome is an extremely rare disease which can manifest symptoms as early as childhood. It is estimated that there have been <300 cases reported globally;...
Maffucci syndrome is an extremely rare disease which can manifest symptoms as early as childhood. It is estimated that there have been <300 cases reported globally; however, this number is likely to be an underestimate. Maffucci syndrome is characterized by multiple enchondromas and soft tissue hemangiomas, which can cause growth and developmental malformations. In addition to bone deformities, pathological fractures and a loss of mobility, patients with Maffucci syndrome may develop secondary central chondrosarcoma and have a higher risk of developing non-skeletal malignant tumors, such as gliomas and mesenchymal ovarian tumors. The present study provides information for clinicians about this disease through the use of imaging, physical examinations, clinical manifestations and the treatment strategy used. There is need to summarize the existing cases of this disease around the world and produce an effective framework for the diagnosis, treatment and prevention of Maffucci syndrome, in order to better understand this disease. The present study reports on a 15-year-old male diagnosed with Maffucci syndrome. . Due to the risk of malignant tumor development in the absence of effective treatment, regular and careful observation through monitoring of tumor markers and imaging studies is important for patients with Maffucci syndrome. As cases of this disease are rare and case data is limited, it is difficult to create a clear treatment plan. There is an urgent need to establish a case database of Maffucci syndrome patients and explore its pathogenesis for early diagnosis, treatment and prevention of disease.
PubMed: 37602309
DOI: 10.3892/etm.2023.12134