Giant cell tumor (GCT) of bone is generally a benign tumor composed of mononuclear stromal cells and characteristic multinucleated giant cells that exhibit osteoclastic activity. It usually develops ...in long bones but can occur in unusual locations. The typical appearance is a lytic lesion with a well-defined but nonsclerotic margin that is eccentric in location, extends near the articular surface, and occurs in patients with closed physes. However, GCT may have aggressive features, including cortical expansion or destruction with a soft-tissue component. Fluid-fluid levels, consistent with secondary formation of aneurysmal bone cysts, are seen in 14% of cases. GCT can mimic or be mimicked by other benign or malignant lesions at both radiologic evaluation and histologic analysis. Rarely, GCT is associated with histologically benign lung metastases or undergoes malignant degeneration. In the past, the mainstay of treatment was surgical, primarily consisting of curettage with cement placement, with recurrence rates of 15%-25%. Recurrence is suggested by development of progressive lucency at the cement-bone interface. Other complications include pathologic fracture and postoperative infection. Denosumab, a monoclonal antibody that targets the osteoclastic activity of GCT, has produced 90% tumor necrosis in early studies, results indicative of promise as a potential adjuvant therapy.
The classification of bone neoplasms composed of small round cells is experiencing a transformation after the discovery of various gene fusion rearrangements that determine diagnosis, behavior, and ...response to therapy. We present herein 4 new cases of small round cell tumor of the bone that harbor NFATc2 rearrangements involving either EWSR1 or FUS genes. We studied the clinical presentation, pathologic features, genetics (FISH, targeted RNA sequencing) and outcome in these 4 patients. We also reviewed the literature describing similar cases. All our patients were male. The median age at diagnosis was 33.5 years. All tumors presented in long bones of the extremities as a large destructive mass with a mean size of 12.5 cm. All cases were hypercellular with prominent collagenous stroma and consisted of small to medium size round cells arranged in cords, thin trabeculae, and pseudoacinar structures. Most cases showed focal or diffuse membrane staining for CD99; whereas S100, synaptophysin and chromogranin were negative. EMA showed cytoplasmic staining in one case. Genetic studies identified EWSR1-NFATc2 fusion in 3 cases, and FUS-NFATc2 fusion in one case. Two patients were treated with neoadjuvant chemotherapy using Ewing sarcoma regimens, and surgical excision was performed on 3 patients; necrosis was minimal. Follow-up is limited; after a median follow-up of 8.7 months, one patient developed local recurrence and metastases to the lungs. Poorly differentiated round cell sarcoma with EWSR1/FUS-NFATc2 fusions are uncommon. The tumors have consistent clinical findings, morphology, and immunoprofile that in combination are distinctive and differ from that of Ewing sarcoma. Importantly, these tumors do not respond to Ewing sarcoma chemotherapy regimens.
•The classification of bone neoplasms composed of small round cells is experiencing a transformation after the discovery of various gene-fusion rearrangements that determine diagnosis, behavior, and response to therapy.•Poorly differentiated round cell sarcoma with EWSR1/FUS-NFATc2 fusions are uncommon.•EWSR1/FUS-NFATc2 tumors have consistent clinical findings, morphology, and immunoprofile that in combination are distinctive and differ from that of Ewing sarcoma.•EWSR1/FUS-NFATc2 tumors do not respond to Ewing sarcoma chemotherapy regimens.
Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-β induces the ...acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.
Purpose Adenoid cystic carcinomas (ACCs) represent a heterogeneous group of chemotherapy refractory tumors, with a subset demonstrating an aggressive phenotype. We investigated the molecular ...underpinnings of this phenotype and assessed the Notch1 pathway as a potential therapeutic target. Methods We genotyped 102 ACCs that had available pathologic and clinical data. Notch1 activation was assessed by immunohistochemistry for Notch1 intracellular domain. Luciferase reporter assays were used to confirm Notch1 target gene expression in vitro. The Notch1 inhibitor brontictuzumab was tested in patient-derived xenografts from patients with ACC and in a patient with ACC who was enrolled in a phase I study. Results NOTCH1 mutations occurred predominantly (14 of 15 patients) in the negative regulatory region and Pro-Glu-Ser-Thr-rich domains, the same two hotspots seen in T-cell acute lymphoblastic leukemias, and led to pathway activation in vitro. NOTCH1-mutant tumors demonstrated significantly higher levels of Notch1 pathway activation than wild-type tumors on the basis of Notch1 intracellular domain staining ( P = .004). NOTCH1 mutations define a distinct aggressive ACC subgroup with a significantly higher likelihood of solid subtype ( P < .001), advanced-stage disease at diagnosis ( P = .02), higher rate of liver and bone metastasis ( P ≤ .02), shorter relapse-free survival (median, 13 v 34 months; P = .01), and shorter overall survival (median 30 v 122 months; P = .001) when compared with NOTCH1 wild-type tumors. Significant tumor growth inhibition with brontictuzumab was observed exclusively in the ACC patient-derived xenograft model that harbored a NOTCH1 activating mutation. Furthermore, an index patient with NOTCH1-mutant ACC had a partial response to brontictuzumab. Conclusion NOTCH1 mutations define a distinct disease phenotype characterized by solid histology, liver and bone metastasis, poor prognosis, and potential responsiveness to Notch1 inhibitors. Clinical studies targeting Notch1 in a genotype-defined ACC subgroup are warranted.
Highlights • LINC00161 was induced by cisplatin in ostesarcoma cells. • Elevated LINC00161 enhanced cisplatin-induced apoptosis and reduced chemoresistance. • LINC00161 acted as a miR-645 sponge and ...inhibited its activity. • LINC00161 upregulated IFIT2 expression via miR-645. • LINC00161 sensitized ostesarcoma cell to cisplatin-induced apoptosis through regulation of the miR-645-IFIT2 axis.
Bone cancer pain Jimenez-Andrade, Juan Miguel; Mantyh, William G.; Bloom, Aaron P. ...
Annals of the New York Academy of Sciences,
June 2010, Letnik:
1198, Številka:
1
Journal Article
Recenzirano
Odprti dostop
In the United States, cancer is the second most common cause of death and it is expected that about 562,340 Americans will have died of cancer in 2009. Bone cancer pain is common in patients with ...advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone. Once tumors metastasize to bone, they are a major cause of morbidity and mortality as the tumor induces significant skeletal remodeling, fractures, pain, and anemia. Currently, the factors that drive cancer pain are poorly understood. However, several recently introduced models of bone cancer pain, which closely mirror the human condition, are providing insight into the mechanisms that drive bone cancer pain and guide the development of mechanism‐based therapies to treat the cancer pain. Several of these mechanism‐based therapies have now entered human clinical trials. If successful, these therapies have the potential to significantly enlarge the repertoire of modalities that can be used to treat bone cancer pain and improve the quality of life, functional status, and survival of patients with bone cancer.
This article reviews the cause, clinical presentation, diagnostic methods, and management of osteosarcoma, the most common primary bone tumor and third most common cancer among children and ...adolescents. In the 1970s, the introduction of adjuvant chemotherapy following tumor resection improved overall 10-year survival from 30% to about 50% of patients. However, since that change in management strategy, the survival rate has since plateaued, with no improvement in overall 10-year survival since the 1990s. A better understanding of this disease is the first step to help improve these numbers.
Bone metastases represent an important complication of malignant tumours. Despite improvement in surgical techniques and advances in systemic therapies, management of patients with bone metastatic ...disease remains a powerful cornerstone for the radiation oncologist. The primary goal of radiation therapy is to provide pain relief, preserving patient's quality of life.
Bone sarcomas are tumours belonging to the family of mesenchymal tumours and constitute a highly heterogeneous tumour group. The three main bone sarcomas are osteosarcoma, Ewing sarcoma and ...chondrosarcoma each subdivided in diverse histological entities. They are clinically characterised by a relatively high morbidity and mortality, especially in children and adolescents. Although these tumours are histologically, molecularly and genetically heterogeneous, they share a common involvement of the local microenvironment in their pathogenesis. This review gives a brief overview of their specificities and summarises the main therapeutic advances in the field of bone sarcoma.
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