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Disease Models & Mechanisms Jun 2024Survival for children with cancer has primarily improved over the past decades due to refinements in surgery, radiation and chemotherapy. Although these general... (Review)
Review
Survival for children with cancer has primarily improved over the past decades due to refinements in surgery, radiation and chemotherapy. Although these general therapies are sometimes curative, the cancer often recurs, resulting in poor outcomes for patients. Fusion-driven pediatric soft tissue sarcomas are genetically defined by chromosomal translocations that create a chimeric oncogene. This distinctive, almost 'monogenic', genetic feature supports the generation of animal models to study the respective diseases in vivo. This Review focuses on a subset of fusion-driven pediatric soft tissue sarcomas that have transgenic animal tumor models, which includes fusion-positive and infantile rhabdomyosarcoma, synovial sarcoma, undifferentiated small round cell sarcoma, alveolar soft part sarcoma and clear cell sarcoma. Studies using the animal models of these sarcomas have highlighted that pediatric cancers require a specific cellular state or developmental stage to drive tumorigenesis, as the fusion oncogenes cause different outcomes depending on their lineage and timing of expression. Therefore, understanding these context-specific activities could identify targetable activities and mechanisms critical for tumorigenesis. Broadly, these cancers show dependencies on chromatin regulators to support oncogenic gene expression and co-opting of developmental pathways. Comparative analyses across lineages and tumor models will further provide biological and therapeutic insights to improve outcomes for these children.
Topics: Animals; Humans; Sarcoma; Disease Models, Animal; Oncogene Proteins, Fusion; Child
PubMed: 38916046
DOI: 10.1242/dmm.050704 -
The Indian Journal of Radiology &... Jul 2024Primary lung sarcoma (PLS) differs in management protocols and prognosis from the more common primary lung carcinoma (PLC). It becomes imperative to raise a high...
Primary lung sarcoma (PLS) differs in management protocols and prognosis from the more common primary lung carcinoma (PLC). It becomes imperative to raise a high index of suspicion on radiological and pathological features. The aim of this study is to highlight the variable imaging appearances of PLS compared with PLC, which impacts radiologic - pathologic correlation. A retrospective observational study of 68 patients with biopsy-proven lung tumors who underwent baseline imaging at our tertiary care cancer hospital was conducted between January 2018 and March 2022. The patient details and imaging parameters of the mass on contrast-enhanced computed tomography (CECT) were recorded and analyzed for patients with PLS and compared with PLC. Follow-up imaging was available in 9/12 PLS and 52/56 PLC patients. Among 12 patients with PLS, 5 patients had synovial sarcoma on histopathology. PLS was seen in patients with a mean age of 40.8 years; the mass showed a mean size of 13.2 cm, lower lobe (75%), parahilar (75%), hilar involvement (41.7%), oval shape (41.7%), circumscribed (25%) or lobulated (75%) margins, lower mean postcontrast attenuation of 57.3 HU, fissural extension (50%), calcification (50%), and no organ metastasis other than to the lung. PLC (56 patients) was seen in the elderly with a mean age of 54.8 years; the mass showed a mean size of 5.7 cm, irregular shape (83.9%), spiculated margins (73.2%), higher mean postcontrast attenuation (77.3 HU), chest wall infiltration (30.4%), and distant metastasis (58.9%) at baseline imaging. A statistically significant difference ( < 0.05) was seen between sarcoma and carcinoma in the mean age, size, site, shape, margins, postcontrast attenuation, presence of calcifications, fissural extension, and distant metastasis. The distinct imaging features of sarcoma help in differentiating it from carcinoma. This can also be used to corroborate with histopathology to achieve concordance and guide clinicians on further approach.
PubMed: 38912250
DOI: 10.1055/s-0043-1777834 -
European Heart Journal. Case Reports Jun 2024
PubMed: 38912120
DOI: 10.1093/ehjcr/ytae295 -
Research Square Jun 2024Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin...
Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.
PubMed: 38883782
DOI: 10.21203/rs.3.rs-4362092/v1 -
Molecular Therapy. Methods & Clinical... Jun 2024T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of...
T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients. The HLA/MAGE-A4 assays validation, biomarker data, and their relationship to covariates (demographics, cancer type, histopathology, tissue location) are reported here. HLA-A∗02 eligibility was 44.8% (2,959/6,606) in patients from 43 sites across North America and Europe. While HLA-A∗02:01 was the most frequent HLA-A∗02 allele, others (A∗02:02, A∗02:03, A∗02:06) considerably increased HLA eligibility in Hispanic, Black, and Asian populations. Overall, MAGE-A4 prevalence based on clinical trial enrollment was 26% (447/1,750) across 10 solid tumor types, and was highest in synovial sarcoma (70%) and lowest in gastric cancer (9%). The covariates were generally not associated with MAGE-A4 expression, except for patient age in ovarian cancer and histology in non-small cell lung cancer. This report shows the eligibility rate from biomarker screening for TCR T cell therapies and provides epidemiological data for future clinical development of MAGE-A4-targeted therapies.
PubMed: 38872830
DOI: 10.1016/j.omtm.2024.101265 -
Radiology Case Reports Aug 2024Synovial sarcoma (SS) is an uncommon malignant tumor, ranking third in prevalence within the soft tissue sarcomas group. The vast majority of synovial sarcomas are...
Synovial sarcoma (SS) is an uncommon malignant tumor, ranking third in prevalence within the soft tissue sarcomas group. The vast majority of synovial sarcomas are present in the extremities, with only 15% developing in the retroperitoneal space. Retroperitoneal synovial sarcoma (RSS) is an infrequent case of SS, with only about 20 cases reported in the literature. Diagnosing RSS before treatment remains challenging because of its nonspecific clinical symptoms. The disease is often detected at a later stage, leading to additional damage to other organs as well as complicated and ineffective treatment. Consequently, the 5-year survival rate is only 20%-29%. This report introduces a case of RSS in a 19-year-old male patient with imaging characteristics on computed tomography (CT) and magnetic resonance (MR).
PubMed: 38872739
DOI: 10.1016/j.radcr.2024.05.029 -
International Journal of Surgery Case... Jul 2024Synovial sarcoma is a relatively common high-grade soft-tissue sarcoma. This lesion accounts for 5-10 % of soft-tissue sarcomas, which tend to appear in the limbs,...
INTRODUCTION
Synovial sarcoma is a relatively common high-grade soft-tissue sarcoma. This lesion accounts for 5-10 % of soft-tissue sarcomas, which tend to appear in the limbs, especially the lower limbs. Synovial sarcoma in the neck is rare and causes involvement of the head and neck in 6-7 % of cases. Intraosseous involvement of the mandible is rare. In this report, a rare intraosseous synovial sarcoma of the mandible is reported.
PRESENTATION OF CASE
A 29-year-old man with a complaint of painless outgrowth of the gingiva in the posterior region of the left mandible. In the intraoral examination, an exophytic, firm, smooth and well-defined lobulated mass on the alveolar ridge, extending from distal of the second premolar to mesial of the second molar, was observed. On a radiographic examination, a radiolucent lesion with an ill-defined border was seen in the left body of the mandibular with perforation of the buccal cortex. In a histological examination, immunohistochemistry confirmed synovial sarcoma. The patient underwent surgery with wide margins, and radiotherapy after surgery.
DISCUSSION
The main treatment method is surgery with a wide margin. Radiotherapy as an adjuvant treatment along with surgery is the second most common treatment method. Radiotherapy is recommended in cases of involvement of the margin of the lesion, size greater than 5 cm, and recurrence of the lesion. Chemotherapy after surgery has been used less frequently.
CONCLUSION
Surgical resection with a wide margin is the main treatment. Adjuvant radiation therapy and chemotherapy can be helpful in tumor control, especially in monophasic cases.
PubMed: 38870657
DOI: 10.1016/j.ijscr.2024.109880 -
Autoimmunity Dec 2024Rheumatoid arthritis (RA) is the predominant manifestation of inflammatory arthritis, distinguished by an increasing burden of morbidity and mortality. The intricate...
Rheumatoid arthritis (RA) is the predominant manifestation of inflammatory arthritis, distinguished by an increasing burden of morbidity and mortality. The intricate interplay of genes and signalling pathways involved in synovial inflammation in patients with RA remains inadequately comprehended. This study aimed to ascertain the role of necroptosis in RA, as along with their associations with immune cell infiltration. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to identify central genes for RA. In this study, identified total of 28 differentially expressed genes (DEGs) were identified in RA. Utilising WGCNA, two co-expression modules were generated, with one module demonstrating the strongest correlation with RA. Through the integration of differential gene expression analysis, a total of 5 intersecting genes were discovered. These 5 hub genes, namely fused in sarcoma (FUS), transformer 2 beta homolog (TRA2B), eukaryotic translation elongation factor 2 (EEF2), cleavage and polyadenylation specific factor 6 (CPSF6) and signal transducer and activator of transcription 3 (STAT3) were found to possess significant diagnostic value as determined by receiver operating characteristic (ROC) curve analysis. The close association between the concentrations of various immune cells is anticipated to contribute to the diagnosis and treatment of RA. Furthermore, the infiltration of immune cells mentioned earlier is likely to exert a substantial influence on the initiation of this disease.
Topics: Arthritis, Rheumatoid; Humans; Necroptosis; Gene Regulatory Networks; Gene Expression Profiling; Transcriptome; Computational Biology; Gene Expression Regulation; Signal Transduction; STAT3 Transcription Factor; Biomarkers; ROC Curve
PubMed: 38869013
DOI: 10.1080/08916934.2024.2358069 -
Clinical Case Reports Jun 2024Extensive studies are required to understand the behavior as well as prognosis of SS in the colorectal region. IHC staining is essential for the accurate diagnosis when...
Extensive studies are required to understand the behavior as well as prognosis of SS in the colorectal region. IHC staining is essential for the accurate diagnosis when a lesion is encountered at an unusual site.
PubMed: 38868121
DOI: 10.1002/ccr3.9062