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American Family Physician Aug 2018Primary bone cancers include osteosarcoma, Ewing sarcoma, and chondrosarcoma. They account for less than 1% of diagnosed cancers each year and are associated with... (Review)
Review
Primary bone cancers include osteosarcoma, Ewing sarcoma, and chondrosarcoma. They account for less than 1% of diagnosed cancers each year and are associated with significant morbidity and mortality. Timely diagnosis is challenging because of late patient presentation, nonspecific symptoms that mimic common musculoskeletal injuries, and low suspicion by physicians. Plain radiography is the preferred diagnostic test. Radiographic suspicion of a bone malignancy should prompt quick referral to a cancer center for multidisciplinary care. Osteosarcoma, the most common bone cancer, most often occurs in children and adolescents. It typically develops in the metaphysis of long bones, specifically the distal femur, proximal tibia, and proximal humerus. Metastasis to the lungs is common. Use of neoadjuvant and adjuvant chemotherapy, in combination with surgery, has improved survival rates to nearly 80% for patients with localized disease, and 90% to 95% of patients do not require limb amputation. Ewing sarcoma is the second most common bone cancer and is similar to osteosarcoma in terms of presenting symptoms, age at occurrence, and treatment. Prognosis for osteosarcoma and Ewing sarcoma depends on the presence of metastasis, which lowers the five-year survival rate to 20% to 30%. Chondrosarcoma is the rarest bone cancer, primarily affecting adults older than 40 years. Survival rates are higher because most of these tumors are low-grade lesions.
Topics: Age Factors; Bone Neoplasms; Chondrosarcoma; Early Detection of Cancer; Humans; Neoplasm Staging; Osteosarcoma; Patient Care Management; Patient Selection; Prognosis; Sarcoma, Ewing
PubMed: 30215968
DOI: No ID Found -
Pathology Oncology Research : POR Oct 2020Ewing sarcoma is a rare tumor developed in bone and soft tissues of children and teenagers. This entity is biologically led by a chromosomal translocation, typically... (Review)
Review
Ewing sarcoma is a rare tumor developed in bone and soft tissues of children and teenagers. This entity is biologically led by a chromosomal translocation, typically including EWS and FLI1 genes. Little is known about Ewing sarcoma predisposition, although the role of environmental factors, ethnicity and certain polymorphisms on Ewing sarcoma susceptibility has been studied during the last few years. Its prevalence among cancer predisposition syndromes has also been thoroughly examined. This review summarizes the available evidence on predisposing factors involved in Ewing sarcoma susceptibility. On the basis of these data, an integrated approach of the most influential factors on Ewing sarcoma predisposition is proposed.
Topics: Bone Neoplasms; Genetic Predisposition to Disease; Humans; Polymorphism, Single Nucleotide; Proto-Oncogene Protein c-fli-1; RNA-Binding Protein EWS; Sarcoma, Ewing
PubMed: 31656020
DOI: 10.1007/s12253-019-00765-3 -
Journal of Orthopaedic Science :... Mar 2015Ewing sarcoma (ES) is rare in Japanese people, and only 30-40 patients develop the disease annually. To diagnose ES, molecular techniques that aim to detect... (Review)
Review
Ewing sarcoma (ES) is rare in Japanese people, and only 30-40 patients develop the disease annually. To diagnose ES, molecular techniques that aim to detect characteristic fusion genes are commonly used in combination with conventional histological and immunohistochemical examinations. The treatment strategy for ES is characterized by multi-disciplinary collaboration between pediatric oncologists, medical oncologists, radiation oncologists, and orthopedic surgeons. In recent years, numerous large-scale national or international multi-institutional studies of ES have been performed. Pre- and postoperative intensive systemic chemotherapy with multiple anticancer drugs is the standard treatment method for ES. Depending on the obtained surgical margin, postoperative radiation might also be performed. If preoperative radiological examinations indicate that surgical excision would be difficult, preoperative radiation can be administered. As the treatment outcomes of ES have improved, late complications and secondary malignancies have become a problem. After treatment, patients with ES require very long-term follow-up in order to detect secondary malignancies and growth-related musculoskeletal complications.
Topics: Bone Neoplasms; Combined Modality Therapy; Humans; Neoplasms, Second Primary; Sarcoma, Ewing
PubMed: 25691401
DOI: 10.1007/s00776-014-0687-z -
Cancer Discovery Nov 2021Cancer cells must overcome anoikis (detachment-induced death) to successfully metastasize. Using proteomic screens, we found that distinct oncoproteins upregulate IL1...
Cancer cells must overcome anoikis (detachment-induced death) to successfully metastasize. Using proteomic screens, we found that distinct oncoproteins upregulate IL1 receptor accessory protein (IL1RAP) to suppress anoikis. IL1RAP is directly induced by oncogenic fusions of Ewing sarcoma, a highly metastatic childhood sarcoma. IL1RAP inactivation triggers anoikis and impedes metastatic dissemination of Ewing sarcoma cells. Mechanistically, IL1RAP binds the cell-surface system X transporter to enhance exogenous cystine uptake, thereby replenishing cysteine and the glutathione antioxidant. Under cystine depletion, IL1RAP induces cystathionine gamma lyase (CTH) to activate the transsulfuration pathway for cysteine synthesis. Therefore, IL1RAP maintains cyst(e)ine and glutathione pools, which are vital for redox homeostasis and anoikis resistance. IL1RAP is minimally expressed in pediatric and adult normal tissues, and human anti-IL1RAP antibodies induce potent antibody-dependent cellular cytotoxicity of Ewing sarcoma cells. Therefore, we define IL1RAP as a new cell-surface target in Ewing sarcoma, which is potentially exploitable for immunotherapy. SIGNIFICANCE: Here, we identify cell-surface protein IL1RAP as a key driver of metastasis in Ewing sarcoma, a highly aggressive childhood sarcoma. Minimal expression in pediatric and adult normal tissues nominates IL1RAP as a promising target for immunotherapy...
Topics: Adult; Anoikis; Cell Line, Tumor; Child; Humans; Interleukin-1 Receptor Accessory Protein; Proteomics; Receptors, Interleukin-1; Sarcoma, Ewing
PubMed: 34021002
DOI: 10.1158/2159-8290.CD-20-1690 -
Deutsches Arzteblatt International Jun 2023Osteosarcoma and Ewing's sarcoma in children and adolescents require age-specific interdisciplinary diagnosis and treatment to achieve optimal therapeutic outcomes.
BACKGROUND
Osteosarcoma and Ewing's sarcoma in children and adolescents require age-specific interdisciplinary diagnosis and treatment to achieve optimal therapeutic outcomes.
METHODS
The diagnosis and treatment of malignant bone tumors in childhood and adolescence are presented in the light of publications retrieved by a selective search, pertinent guidelines, and the authors' extensive experience in an interdisciplinary cancer center.
RESULTS
Bone sarcomas make up approximately 5% of all malignancies in children and adolescents; the most common types are Ewing's sarcoma and osteosarcoma. Patients are often not referred to a specialized center until long after the onset of symptoms, as they and their physicians rarely consider the possibility of a bone tumor, and the symptoms are often trivialized. Bone pain of unknown origin, swelling, and functional limitations should be investigated with conventional x-rays. Lesions of unclear origin should be biopsied after a meticulous clinical and radiologic evaluation. Multimodal treatment consists of neo - adjuvant chemotherapy, limb-preserving resection if possible, and radiotherapy where indicated. In multicenter studies, patients with osteosarcoma achieve event-free survival in 64% of cases if their disease is localized, and 28% if it is metastatic; the corresponding figures for patients with Ewing's sarcoma are 80% and 27%, respectively.
CONCLUSION
With implementation of the current treatment recommendations, most children and adolescents with malignant bone tumors can be treated successfully with curative intent. These patients should be referred to a sarcoma center for diagnosis and treatment.
Topics: Humans; Child; Adolescent; Sarcoma, Ewing; Osteosarcoma; Bone Neoplasms; Combined Modality Therapy
PubMed: 37097079
DOI: 10.3238/arztebl.m2023.0079 -
Pathology International Jan 2023The fifth edition of the World Health Organization classification of soft tissue and bone tumors redefined Ewing sarcoma by fusions between EWSR1/FUS and ETS family of... (Review)
Review
The fifth edition of the World Health Organization classification of soft tissue and bone tumors redefined Ewing sarcoma by fusions between EWSR1/FUS and ETS family of transcription factors, and recognized three tumor groups among Ewing-like sarcoma: CIC-rearranged sarcoma, sarcoma with BCOR genetic alterations, and round cell sarcoma with EWSR1::non-ETS fusions. Although this classification underscores the critical role of molecular genetics in the diagnosis of small round cell sarcoma, each entry is recognized as a specific entity not only because they have different genetics but because their phenotypes are distinct and reasonably robust to support the diagnosis. This review focuses on the morphological aspects of Ewing sarcoma and a subset of Ewing-like sarcomas (CIC-rearranged sarcoma, BCOR-associated sarcoma, and EWSR1::NFATC2 sarcoma) for which phenotypic characteristics have been well established. Classic histological findings, uncommon variations, and recurrent diagnostic pitfalls are addressed, along with the utility of recently developed immunohistochemical markers (NKX2.2, PAX7, ETV4, BCOR, CCNB3, and NKX3.1). Phenotypic expertise would significantly expedite the diagnostic process and complement (or sometimes outperform) genetic testing, even in well-resourced settings. Morphological knowledge plays an even more substantial role in facilities that do not have easy access to molecular testing.
Topics: Humans; Sarcoma, Ewing; Sarcoma; Sarcoma, Small Cell; Transcription Factors; Bone Neoplasms; Biomarkers, Tumor; Oncogene Proteins, Fusion
PubMed: 36484765
DOI: 10.1111/pin.13293 -
Cell Chemical Biology Aug 2022Ewing sarcoma (EWS) is a pediatric malignancy driven by the EWSR1-FLI1 fusion protein formed by the chromosomal translocation t(11; 22). The small molecule TK216 was...
Ewing sarcoma (EWS) is a pediatric malignancy driven by the EWSR1-FLI1 fusion protein formed by the chromosomal translocation t(11; 22). The small molecule TK216 was developed as a first-in-class direct EWSR1-FLI1 inhibitor and is in phase II clinical trials in combination with vincristine for patients with EWS. However, TK216 exhibits anti-cancer activity against cancer cell lines and xenografts that do not express EWSR1-FLI1, and the mechanism underlying cytotoxicity remains unresolved. We apply a forward-genetics screening platform utilizing engineered hypermutation in EWS cell lines and identify recurrent mutations in TUBA1B, encoding ⍺-tubulin, that prove sufficient to drive resistance to TK216. Using reconstituted microtubule (MT) polymerization in vitro and cell-based chemical probe competition assays, we demonstrate that TK216 acts as an MT destabilizing agent. This work defines the mechanism of cytotoxicity of TK216, explains the synergy observed with vincristine, and calls for a reexamination of ongoing clinical trials with TK216.
Topics: Antineoplastic Agents; Cell Line, Tumor; Child; Gene Expression Regulation, Neoplastic; Humans; Microtubules; Sarcoma, Ewing; Vincristine
PubMed: 35803262
DOI: 10.1016/j.chembiol.2022.06.002 -
Molecular Cancer Research : MCR Feb 2021Ewing sarcoma is an aggressive pediatric tumor of the bone and soft tissue. The current standard of care is radiation and chemotherapy, and patients generally lack... (Review)
Review
Ewing sarcoma is an aggressive pediatric tumor of the bone and soft tissue. The current standard of care is radiation and chemotherapy, and patients generally lack targeted therapies. One of the defining molecular features of this tumor type is the presence of significantly elevated levels of replication stress as compared with both normal cells and many other types of cancers, but the source of this stress is poorly understood. Tumors that harbor elevated levels of replication stress rely on the replication stress and DNA damage response pathways to retain viability. Understanding the source of the replication stress in Ewing sarcoma may reveal novel therapeutic targets. Ewing sarcomagenesis is complex, and in this review, we discuss the current state of our knowledge regarding elevated replication stress and the DNA damage response in Ewing sarcoma, one contributor to the disease process. We will also describe how these pathways are being successfully targeted therapeutically in other tumor types, and discuss possible novel, evidence-based therapeutic interventions in Ewing sarcoma. We hope that this consolidation will spark investigations that uncover new therapeutic targets and lead to the development of better treatment options for patients with Ewing sarcoma. IMPLICATIONS: This review uncovers new therapeutic targets in Ewing sarcoma and highlights replication stress as an exploitable vulnerability across multiple cancers.
Topics: Humans; Mutation; Oncogene Proteins, Fusion; Sarcoma, Ewing
PubMed: 33020173
DOI: 10.1158/1541-7786.MCR-20-0651 -
Cancer Gene Therapy Aug 2023Ewing sarcoma (ES) is an aggressive malignant tumor, characterized by non-random chromosomal translocations that produce fusion genes. Fusion genes and fusion protein... (Review)
Review
Ewing sarcoma (ES) is an aggressive malignant tumor, characterized by non-random chromosomal translocations that produce fusion genes. Fusion genes and fusion protein products are promising targets for gene therapy. Therapeutic approaches and strategies vary based on target molecules (nucleotides, proteins) of interest. We present an extensive literature review of active molecules for gene therapy and methods of gene therapy delivery, both of which are necessary for successful treatment.
Topics: Humans; Sarcoma, Ewing; Bone Neoplasms; Proteins; Genetic Therapy; Oncogene Proteins, Fusion
PubMed: 37037906
DOI: 10.1038/s41417-023-00615-0 -
American Society of Clinical Oncology... 2017Bone tumors make up a significant portion of noncentral nervous system solid tumor diagnoses in pediatric oncology patients. Ewing sarcoma and osteosarcoma, both with... (Review)
Review
Bone tumors make up a significant portion of noncentral nervous system solid tumor diagnoses in pediatric oncology patients. Ewing sarcoma and osteosarcoma, both with distinct clinical and pathologic features, are the two most commonly encountered bone cancers in pediatrics. Although mutations in the germline have classically been more associated with osteosarcoma, there is recent evidence germline alterations in patients with Ewing sarcoma also play a significant role in pathogenesis. Treatment advances in this patient population have lagged behind that of other pediatric malignancies, particularly targeted interventions directed at the biologic underpinnings of disease. Recent advances in biologic and genomic understanding of these two cancers has expanded the potential for therapeutic advancement and prevention. In Ewing sarcoma, directed focus on inhibition of EWSR1-FLI1 and its effectors has produced promising results. In osteosarcoma, instead of a concentrated focus on one particular change, largely due to tumor heterogeneity, a more diversified approach has been adopted including investigations of growth factors inhibitors, signaling pathway inhibitors, and immune modulation. Continuing recently made treatment advances relies on clinical trial design and enrollment. Clinical trials should include incorporation of biological findings; specifically, for Ewing sarcoma, assessment of alternative fusions and, for osteosarcoma, stratification utilizing biomarkers. Expanded cancer genomics knowledge, particularly with solid tumors, as it relates to heritability and incorporation of family history has led to early identification of patients with cancer predisposition. In these patients through application of cost-effective evidence-based screening techniques the ultimate goal of cancer prevention is becoming a realization.
Topics: Bone Neoplasms; Child; Genome, Human; Humans; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Osteosarcoma; Sarcoma, Ewing; Signal Transduction
PubMed: 28561686
DOI: 10.1200/EDBK_175378