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Browsing by Subject "Ewing sarcoma"
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Item Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1(Oxford University Press, 2021-08-14) Nicholas, Taylor R.; Metcalf, Stephanie A.; Greulich, Benjamin M.; Hollenhorst, Peter C.; Medicine, School of MedicineEwing sarcoma breakpoint region 1 (EWSR1) encodes a multifunctional protein that can cooperate with the transcription factor ERG to promote prostate cancer. The EWSR1 gene is also commonly involved in oncogenic gene rearrangements in Ewing sarcoma. Despite the cancer relevance of EWSR1, its regulation is poorly understood. Here we find that in prostate cancer, androgen signaling upregulates a 5' EWSR1 isoform by promoting usage of an intronic polyadenylation site. This isoform encodes a cytoplasmic protein that can strongly promote cell migration and clonogenic growth. Deletion of an Androgen Receptor (AR) binding site near the 5' EWSR1 polyadenylation site abolished androgen-dependent upregulation. This polyadenylation site is also near the Ewing sarcoma breakpoint hotspot, and androgen signaling promoted R-loop and breakpoint formation. RNase H overexpression reduced breakage and 5' EWSR1 isoform expression suggesting an R-loop dependent mechanism. These data suggest that androgen signaling can promote R-loops internal to the EWSR1 gene leading to either early transcription termination, or breakpoint formation.Item Clinical and radiographic presentation of pelvic sarcoma in children(EDP Sciences, 2018) Kadhim, Muayad; Oyoun, Nariman Abol; Womer, Richard B.; Dormans, John P.; Orthopaedic Surgery, School of MedicineINTRODUCTION: Pelvic sarcomas may present with vague symptoms. The aim of this study was to examine the characteristics and clinical presentations of different types of pelvic sarcoma in children. METHODS: This is a retrospective cohort study of patients up to 21 years of age with the diagnosis of pelvic sarcoma between January 2000 and June 2013. Data on demographics, tumor type and location, and clinical presentation were collected from the medical records. RESULTS: A total of 59 patients [37 males (62.7%) and 22 females (37.3%)] were examined in this study. Mean age at presentation was 11.3 ± 5 years (range 0.8-21 years). Thirty-six patients had Ewing sarcoma (61%), 9 osteosarcoma (6.8%), 4 undifferentiated sarcoma (6.8%), 2 (3.4%) rhabdomyosarcoma, 2 synovial cell sarcoma, and one (1.7%) of each fibrosarcoma, dermatofibrosarcoma, fibromyxoid sarcoma, chondrosarcoma, chordoma, and epithelioid sarcoma. Pain at presentation was reported in 41 patients, 13 mass, 8 limping, and 5 neurologic symptoms. Most of the bony tumors were painful (77%), while most of the soft tissue tumors were painless (70%). Nine patients presented with constitutional symptoms. Most patients presented within 4-12 months from symptoms beginning. Twenty-one patients (35.6%) presented with metastases (14 Ewing sarcoma, 6 osteosarcoma, and 1 synovial cell sarcoma). Pelvic radiographs showed lytic lesion in 11 patients, 4 sclerotic lesions, 6 mixed lesion, 6 had only soft tissue mass, 1 radiograph showed osteopenia, and 2 radiographs were reported normal. CONCLUSION: Ewing sarcoma was the most common pelvic sarcoma tumor in children. In most cases, pelvic sarcoma in children presented with pain mimicking other benign conditions. Some patients presented with metastatic disease with no prognostic clinical or radiographical signs or symptoms. Pelvic sarcoma should be considered a differential diagnosis as part of children work up.Item Precision Medicine Highlights Dysregulation of the CDK4/6 Cell Cycle Regulatory Pathway in Pediatric, Adolescents and Young Adult Sarcomas(MDPI, 2022-07-25) Barghi, Farinaz; Shannon, Harlan E.; Saadatzadeh, M. Reza; Bailey, Barbara J.; Riyahi, Niknam; Bijangi-Vishehsaraei, Khadijeh; Just, Marissa; Ferguson, Michael J.; Pandya, Pankita H.; Pollok, Karen E.; Medical and Molecular Genetics, School of MedicineDespite improved therapeutic and clinical outcomes for patients with localized diseases, outcomes for pediatric and AYA sarcoma patients with high-grade or aggressive disease are still relatively poor. With advancements in next generation sequencing (NGS), precision medicine now provides a strategy to improve outcomes in patients with aggressive disease by identifying biomarkers of therapeutic sensitivity or resistance. The integration of NGS into clinical decision making not only increases the accuracy of diagnosis and prognosis, but also has the potential to identify effective and less toxic therapies for pediatric and AYA sarcomas. Genome and transcriptome profiling have detected dysregulation of the CDK4/6 cell cycle regulatory pathway in subpopulations of pediatric and AYA OS, RMS, and EWS. In these patients, the inhibition of CDK4/6 represents a promising precision medicine-guided therapy. There is a critical need, however, to identify novel and promising combination therapies to fight the development of resistance to CDK4/6 inhibition. In this review, we offer rationale and perspective on the promise and challenges of this therapeutic approach.Item Sustained Complete Response to Palbociclib in a Refractory Pediatric Sarcoma With BCOR-CCNB3 Fusion and Germline CDKN2B Variant(Wolters Kluwer, 2020-04-30) Tramontana, Timothy F.; Marshall, Mark S.; Helvie, Amy E.; Schmitt, Morgan R.; Ivanovich, Jennifer; Carter, Jacquelyn L.; Renbarger, Jamie L.; Ferguson, Michael J.; Pediatrics, School of MedicineItem Targeted treatment of refractory primitive neuroectodermal tumor arising from an immature teratoma with crizotinib leading to a sustained response(Wiley, 2023-01-03) Snyder, Benjamin M.; Lion, Alex H.; Helvie, Amy E.; Marshall, Mark S.; Ferguson, Michael J.; Pediatrics, School of MedicineHere we present a case of metastatic PNET which arose from an immature teratoma that was refractory to standard Ewing sarcoma chemotherapy. This PNET was determined to have elevated levels of ALK protein via IHC. The patient was treated with crizotinib on a palliative basis with a sustained response.