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Jia K, Cao L, Yu Y, Jing D, Wu W, Van Tine BA, Shao Z. Signaling pathways and targeted therapies in Ewing sarcoma. Pharmacol Ther 2025; 266:108765. [PMID: 39622389 DOI: 10.1016/j.pharmthera.2024.108765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 12/08/2024]
Abstract
Ewing sarcoma, the second most prevalent malignant bone tumor with potential occurrence in soft tissues, exhibits a high level of aggressiveness, primarily afflicting children and adolescents. It is characterized by fusion proteins arising from chromosomal translocations. The fusion proteins induce aberrations in multiple signaling pathways and molecules, constituting a key event in oncogenic transformation. While diagnostic and therapeutic modalities have advanced in recent decades and multimodal treatments, including surgery, radiotherapy, and chemotherapy, have significantly improved survival of patients with localized tumors, patients with metastatic tumors continue to face poor prognoses. There persists a pressing need for novel alternative treatments, yet the translation of our understanding of Ewing sarcoma pathogenesis into improved clinical outcomes remains a critical challenge. Here, we provide a comprehensive review of Ewing sarcoma, including fusion proteins, various signaling pathways, pivotal pathogenetic molecules implicated in its development, and associated targeted therapies and immunotherapies. We summarize past endeavors, current advancements, and deliberate on limitations and future research directions. It is envisaged that this review will furnish novel insights into prospective treatment avenues for Ewing sarcoma.
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Affiliation(s)
- Ke Jia
- Department of Orthopaedics, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Li Cao
- Department of Orthopaedics, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Washington University School of Medicine, St Louis, MO, USA.
| | - Yihan Yu
- Department of Orthopaedics, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Doudou Jing
- Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China.
| | - Wei Wu
- Department of Orthopaedics, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | | | - Zengwu Shao
- Department of Orthopaedics, Union hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Lyvannak S, Sereyleak B, Kakazu M, Bisiphan H, Jarzembowski J, Camitta B. Pyrites: A Rectal Mass. J Pediatr Hematol Oncol 2024; 46:446-447. [PMID: 39028189 DOI: 10.1097/mph.0000000000002900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 05/13/2024] [Indexed: 07/20/2024]
Affiliation(s)
| | | | - Mariko Kakazu
- Japan Heart Children's Medical Center, Kandal, Cambodia
| | - Hor Bisiphan
- Japan Heart Children's Medical Center, Kandal, Cambodia
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Özdenoğlu FY, Ödemiş DA, Erciyas SK, Tunçer ŞB, Gültaşlar BK, Salduz A, Büyükkapu S, Olgaç NV, Kebudi R, Yazıcı H. High Expression of miR-218-5p in the Peripheral Blood Stream and Tumor Tissues of Pediatric Patients with Sarcomas. Biochem Genet 2024:10.1007/s10528-024-10873-8. [PMID: 38954213 DOI: 10.1007/s10528-024-10873-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 06/17/2024] [Indexed: 07/04/2024]
Abstract
Sarcomas are malignant tumors that may metastasize and the course of the disease is highly aggressive in children and young adults. Because of the rare incidence of sarcomas and the heterogeneity of tumors, there is a need for non-invasive diagnostic and prognostic biomarkers in sarcomas. The aim of the study was to investigate the level of miR-218-5p in peripheral blood and tumor tissue samples of Ewing's sarcoma, osteosarcoma, spindle cell sarcoma patients, and healthy controls, and assessed whether the corresponding molecule was a diagnostic and prognostic biomarker. The study was performed patients (n = 22) diagnosed and treated with Ewing's sarcoma and osteosarcoma and in a control group of 22 healthy children who were matched for age, gender, and ethnicity with the patient group. The expression level of miR-218-5p in RNA samples from peripheral blood and tissue samples were analyzed using the RT-PCR and the expression level of miR-218-5p was evaluated by comparison with the levels in patients and healthy controls. The expression level of miR-218-5p was found to be statistically higher (3.33-fold, p = 0.006) in pediatric patients with sarcomas and when the target genes of miR-218-5p were investigated using the bioinformatics tools, the miR-218-5p was found as an important miRNA in cancer. In this study, the miR-218-5p was shown for the first time to have been highly expressed in the peripheral blood and tumor tissue of sarcoma patients. The results suggest that miR-218-5p can be used as a diagnostic and prognostic biomarker in sarcomas and will be evaluated as an important therapeutic target.
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Affiliation(s)
- Fazilet Yıldız Özdenoğlu
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, 34093, Fatih, Istanbul, Türkiye
- Division of Cancer Genetics, Department of Basic Oncology, Health Sciences Institute, Istanbul University, 34093, Fatih, Istanbul, Türkiye
- Vocational School of Health Service, Medical LaboratortyTechniquies, İstanbul Okan University, Tuzla, Istanbul, Türkiye
| | - Demet Akdeniz Ödemiş
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, 34093, Fatih, Istanbul, Türkiye
- Turkey Cancer Institute, Health Institutes of Turkey, 34734, Kadıköy, Istanbul, Türkiye
| | - Seda Kılıç Erciyas
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, 34093, Fatih, Istanbul, Türkiye
| | - Şeref Buğra Tunçer
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, 34093, Fatih, Istanbul, Türkiye
| | - Büşra Kurt Gültaşlar
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, 34093, Fatih, Istanbul, Türkiye
| | - Ahmet Salduz
- Istanbul Faculty of Medicine, Department of Orthopedics and Traumatology, Istanbul University, Istanbul, Türkiye
| | - Sema Büyükkapu
- Division of Pediatric Hematology and Oncology, Department of Clinical Oncology, Oncology Institute, Istanbul University, 34093, Fatih, Istanbul, Türkiye
| | - Necat Vakur Olgaç
- Faculty of Dentistry, Department of Oral Pathology, Istanbul University, 34093, Fatih, Istanbul, Türkiye
| | - Rejin Kebudi
- Division of Pediatric Hematology and Oncology, Department of Clinical Oncology, Oncology Institute, Istanbul University, 34093, Fatih, Istanbul, Türkiye
| | - Hülya Yazıcı
- Division of Cancer Genetics, Department of Basic Oncology, Oncology Institute, Istanbul University, 34093, Fatih, Istanbul, Türkiye.
- Istanbul Arel Medical Faculty, Department of Medical Biology and Genetics, Istanbul Arel University, 34010, Zeytinburnu, Istanbul, Türkiye.
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Gündoğar Ö, Komut N, Bektaş S, Tetik F, Uçar N. Ewing sarcoma of the mandible: A rare case report and literature review. Diagn Cytopathol 2024; 52:E159-E163. [PMID: 38581426 DOI: 10.1002/dc.25316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 03/15/2024] [Accepted: 03/27/2024] [Indexed: 04/08/2024]
Abstract
Ewing sarcoma (ES) usually arises from long bones and affects the head and neck region in only 1%-4% of cases. We reported clinical, radiographic, cytomorphologic, and histomorphologic findings of the ES in the mandible, because of its rarity and radiologically misinterpreted as a parotid gland tumor. A 26-year-old male patient presented with a history of painfull cheek swelling. On magnetic resonance imaging, a mass measuring 50 × 48 × 45 mm was found eroding mandible and pushing back the parotid gland. Aspiration cytology was performed with suspicion of parotid gland tumor. Small, nucleated cells with nuclear indentation, inconspicuous nucleoli, and occasionally rosette-like arrangement were observed. Neuroendocrine immune markers were positive on cell block. It was diagnosed as small round cell neoplasm with neuroendocrine differentiation and biopsy was suggested. The differential diagnosis considered soft tissue and parotid gland tumors. The small round cell tumor morphology was seen on biopsy specimen and immunostaining was applied. The diagnosis for this case was ES of the mandible. ES of the mandible is unusual. Although the histogenesis is still unknown, various cells have been proposed as cells of origin namely, endothelial, hematopoietic, fibroblastic, mesenchymal stem cells or neural derived mesenchymal stem cells. Small cell morphology, CD99, CD56, neuron specific enolase, and synaptophysin expressions confirmed the diagnosis of ES. The differentiation of the ES from other small cell tumors may be difficult and requires awareness for histological and immunohistochemical features. It should be kept in mind that the diagnosis can be challenging due to uncommon locations and radiological misinterpreted.
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Affiliation(s)
- Özgecan Gündoğar
- Departmant of Pathology, University of Health Sciences Turkey, Gaziosmanpasa Training and Research Hospital, Istanbul, Turkey
| | - Neslihan Komut
- Departmant of Pathology, Tekirdağ İsmail Fehmi Cumalıoğlu City Hospital, Tekirdağ, Turkey
| | - Sibel Bektaş
- Departmant of Pathology, University of Health Sciences Turkey, Gaziosmanpasa Training and Research Hospital, Istanbul, Turkey
| | - Fatih Tetik
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Health Sciences Turkey, Gaziosmanpasa Training and Research Hospital, Istanbul, Turkey
| | - Neşe Uçar
- Department of Radiology, University of Health Sciences Turkey, Gaziosmanpasa Training and Research Hospital, Istanbul, Turkey
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Kewalramani Y, Parihar A, Reddy P, Mandlik R. Ewing's Sarcoma Presenting in the Paranasal Sinus - A Case Report. Ann Maxillofac Surg 2024; 14:228-231. [PMID: 39957884 PMCID: PMC11828065 DOI: 10.4103/ams.ams_49_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 05/21/2024] [Accepted: 07/02/2024] [Indexed: 02/18/2025] Open
Abstract
Rationale The aim of this study is to raise awareness among dentists regarding a potential outcome associated with the rapid growth of facial swellings. Patient Concerns We present a case of Ewing's sarcoma (ES) in a 23-year-old male who presented with a rapidly progressive swelling in the left maxillary region over six weeks. Diagnosis There was no significant intraoral dental finding other than a missing left upper first molar. Panoramic imaging initially suggested chronic sinusitis, but the swelling persisted despite treatment. A subsequent cone-beam computed tomography (CBCT) scan revealed a soft-tissue tumour affecting multiple sinuses, confirmed by an open biopsy as a small round cell tumour. Immunohistochemistry was used for precise diagnosis due to biopsy sample limitations and tumour variability. Treatment The patient's case was reviewed by our institution's tumour board. One month after diagnosis, chemotherapy began with alternating drugs for a total of 6 cycles. Outcomes A follow-up Positron Emission Tomography (PET)/Computed Tomography (CT) scan after two months of chemotherapy showed resolution of the hypermetabolic mass on the left side without evidence of metastatic disease. The patient is currently under regular follow-up. Take-Away Lessons Dentists should be vigilant for rapidly expanding oral or facial swellings. Early and accurate diagnosis can improve clinical management and survival rates for ES patients.
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Affiliation(s)
- Yashika Kewalramani
- Department of Oral Medicine and Radiology, Government College of Dentistry, Indore, Madhya Pradesh, India
| | - Ajay Parihar
- Department of Oral Medicine and Radiology, Government College of Dentistry, Indore, Madhya Pradesh, India
| | - Prashanthi Reddy
- Department of Oral Medicine and Radiology, Government College of Dentistry, Indore, Madhya Pradesh, India
| | - Rashi Mandlik
- Department of Oral Medicine and Radiology, Government College of Dentistry, Indore, Madhya Pradesh, India
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Manatakis DK, Tsouknidas I, Mylonakis E, Tasis N, Antonopoulou MI, Acheimastos V, Mastoropoulou A, Korkolis DP. Primary adrenal Ewing sarcoma: A systematic review of the literature. World J Clin Cases 2023; 11:6782-6791. [PMID: 37900999 PMCID: PMC10600854 DOI: 10.12998/wjcc.v11.i28.6782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/18/2023] [Accepted: 09/12/2023] [Indexed: 09/25/2023] Open
Abstract
BACKGROUND Ewing sarcoma (ES) is a malignant neoplasm of neuroectodermal origin and is commonly observed in children and young adults. The musculoskeletal system is the main body system impacted and ES is rarely seen in the visceral organs particularly the adrenal gland. AIM To present a comprehensive review of primary adrenal ES, with emphasis on diagnosis, therapy and oncological outcomes. METHODS A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020. PubMed/ MEDLINE, EMBASE and Google Scholar bibliographic databases were searched to identify articles from 1989 to 2022 and included patients with ES/primitive neuroectodermal tumor (PNET) of the adrenal gland. PubMed, Google Scholar and EMBASE medical databases were searched, combining the terms "adrenal", "ES" and "PNET". Demographic, clinical, pathological and oncological data of patients were analyzed by SPSS version 29.0. RESULTS A total of 52 studies were included for review (47 case reports and 5 case series) with 66 patients reported to have primary adrenal ES. Mean age at diagnosis was 26.4 ± 15.4 years (37.9% males, 57.6% females, sex not reported in 3 cases). The most frequent complaint was abdominal/flank pain or discomfort (46.4%) followed by a palpable mass (25.0%), and the average duration of symptoms was 2.6 ± 3.1 mo. The imaging modality of choice was computed tomography scan (81.5%), followed by magnetic resonance imaging (20.4%). Preoperative staging revealed that 17 tumors (27.9%) were metastatic and 14 patients had inferior vena cava or renal vein neoplastic thrombus at initial diagnosis. Open adrenalectomy was performed in the majority of cases (80.0%), of which 27.9% required more extensive resection. Minimally invasive surgery was attempted in 8.2% of tumors. Complete surgical resection was achieved in 89.4% of the patients. Adjuvant therapy was administered to 32 patients, in the form of chemotherapy (62.5%), radiotherapy (3.1%) or combination (34.4%). Median overall survival was 15 mo and 24-mo overall survival was 40.5%. Median disease-free survival was 10 mo and 24-mo disease-free survival was 33.3%. CONCLUSION The significant progress in molecular biology and genetics of ES does not reflect on patient outcomes. ES remains an aggressive tumor with a poor prognosis and high mortality.
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Affiliation(s)
| | - Ioannis Tsouknidas
- General Surgery, Lankenau Medical Center, Main Line Health, Wynnewood, PA 19096, United States
| | - Emmanouil Mylonakis
- 2nd Department of Surgery, Athens Naval and Veterans Hospital, Athens 11521, Greece
| | - Nikolaos Tasis
- 2nd Department of Surgery, Athens Naval and Veterans Hospital, Athens 11521, Greece
- Department of Surgical Oncology, St Savvas Cancer Hospital, Athens 11522, Greece
| | | | | | | | - Dimitrios P Korkolis
- Department of Surgical Oncology, St Savvas Cancer Hospital, Athens 11522, Greece
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Almohaisen GA, Alhuwairini SF, Aljrayed MA, Alenezi MM, Alsaab F. Extraskeletal Ewing's sarcoma of the head and neck region in pediatric patients: A case report and literature review. Int J Surg Case Rep 2023; 106:108142. [PMID: 37141776 PMCID: PMC10176168 DOI: 10.1016/j.ijscr.2023.108142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/23/2023] [Accepted: 03/23/2023] [Indexed: 05/06/2023] Open
Abstract
INTRODUCTION AND IMPORTANCE Extraskeletal Ewing's sarcoma (EES) is a collection of malignant cells that appear small and round and occur mostly in pediatrics and adolescence. Head and neck EES tumors are considered rare and require multidisciplinary care to achieve ideal results in management. CASE PRESENTATION A 14-year-old boy who complained of a mass protruding from the back of his neck which gradually increased in size in the last few months prior to the diagnosis. He was referred to a pediatric otolaryngology clinic with a one-year history of chronic painless nape swelling. Ultrasound prior to the referral was done and the findings revealed a well-defined rounded hypoechoic lesion with internal vascularity. MRI was done and the impression was a large subcutaneous, well defined enhancing soft tissue lesion which raised the suspicion of sarcoma. The multidisciplinary team decision was to go for complete resection with a free margin followed by chemoradiation postoperatively. No evidence of recurrence was detected throughout the follow-up. CLINICAL DISCUSSION The literature review included ages of the pediatric group from 4 months up to 18-year-old. Clinical features are highly dependable on the size and site of the lesion. Complete resection of the tumor plays an important role in the local control and prognosis. CONCLUSION We present a rare case of extraskeletal Ewing's sarcoma of the nape. Computed tomography and magnetic resonance imaging are frequently used as imaging modalities in evaluating and diagnosing EES. Management commonly includes surgery with adjuvant chemotherapy to decrease recurrence and prolong the survival rate.
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Affiliation(s)
- Ghadi A Almohaisen
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
| | - Sara F Alhuwairini
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Maha A Aljrayed
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Mazyad M Alenezi
- Department of Otolaryngology Head and Neck Surgery, College of Medicine, Qassim University, Qassim, Saudi Arabia
| | - Fahad Alsaab
- Department of Pediatric Surgery, Ministry of the National Guard-Health Affairs, Riyadh, Saudi Arabia; Department of Pediatric Surgery, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; Department of Pediatric Surgery, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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Rooper LM, Gagan J, Bishop JA. A Low Grade Nasopharyngeal sarcoma With FUS::NACC1 Fusion and Immunohistochemical Evidence of Epithelial Differentiation: Expanding the Clinicopathologic Spectrum of an Emerging Entity. Head Neck Pathol 2023; 17:253-258. [PMID: 36169794 PMCID: PMC10063715 DOI: 10.1007/s12105-022-01488-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/09/2022] [Accepted: 08/11/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND RNA sequencing of unclassified soft tissue tumors has allowed for definition of multiple new entities. Antonescu et al. recently reported three case of low grade sarcoma with recurrent EWSR1/FUS::NACC1 fusion and distinctive storiform architecture that were suggestive of a novel tumor type. METHODS Here, we present a case of an additional sarcoma with FUS::NACC1 fusion that arose in the head and neck and showed immunohistochemical evidence of epithelial differentiation. RESULTS A 41 year old woman presented with throat and inner ear pain and was found to have a nasopharyngeal mass. Biopsy highlighted a spindle cell neoplasm composed of bland cells arranged in a tight storiform pattern. On immunohistochemistry, the tumor cells were focally positive for S100 in a fibrillary pattern but were also positive for high molecular weight cytokeratin, p40, and CD34. RNA sequencing demonstrated a FUS::NACC1 fusion. The patient remains free of disease 2 years after surgical resection. CONCLUSION These findings confirm the previously-reported recurrent storiform histology in sarcomas with EWSR1/FUS::NACC1 fusion while simultaneously expanding the immunohistochemical spectrum of this entity to include overt epithelial differentiation. With involvement of a head and neck mucosal site, these findings also expand the differential diagnosis to include multiple mesenchymal entities including spindle cell squamous cell carcinoma. Further recognition of this emerging entity via expanded RNA sequencing panels will be necessary to determine the prevalence of these unique features.
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Affiliation(s)
- Lisa M Rooper
- Department of Pathology, The Johns Hopkins University School of Medicine, 401 N. Broadway, 2242, 21231, Weinberg, Baltimore, MD, USA.
- Department of Oncology, The Johns Hopkins University School of Medicine, 401 N. Broadway, 2242, 21231, Weinberg, Baltimore, MD, USA.
| | - Jeffrey Gagan
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Justin A Bishop
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Abrahao-Machado LF, Pinto F, Antunes B, Volc S, Boldrini E, Camargo OPD, Reis RM. Clinical impact of brachyury expression in Ewing sarcoma patients. Adv Med Sci 2021; 66:321-325. [PMID: 34273746 DOI: 10.1016/j.advms.2021.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 05/21/2021] [Accepted: 06/25/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE The T-box transcription factor brachyury has been demonstrated as a prognostic factor in a variety of cancer types and considered a novel oncotarget in solid tumors. Brachyury acts as a regulator of the epithelial-mesenchymal transition (EMT) process, leading to more aggressive behavior and poorer prognosis. However, recent literature evidence suggests a tumor suppressor role in other neoplasms. In the present study, we aimed to study brachyury expression and its prognostic impact in Ewing sarcoma, an aggressive neoplasm of young individuals. METHODS We analyzed the expression of brachyury by immunohistochemistry in a series of 96 Ewing sarcomas in a tissue microarray and investigated the association of the protein expression with the clinical parameters and overall survival. RESULTS More than half of the cases (51%, n = 49) depicted positive nuclear brachyury expression, while a lack of expression was observed in 49% (n = 47) of cases. Nuclear brachyury staining was significantly associated with non-white ethnicity (p = 0.04) and axial localization (p = 0.025). Importantly, lack of brachyury expression was significantly associated with lower overall survival in multivariate analyses (hazard ratio - HR: 2.227, p = 0.008). CONCLUSIONS Our findings indicate, that brachyury is an independent prognostic biomarker in Ewing sarcoma, which might suggest a tumor suppressor role and which yet to be fully elucidated.
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Aging and Cancer: The Waning of Community Bonds. Cells 2021; 10:cells10092269. [PMID: 34571918 PMCID: PMC8468626 DOI: 10.3390/cells10092269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer often arises in the context of an altered tissue landscape. We argue that a major contribution of aging towards increasing the risk of neoplastic disease is conveyed through effects on the microenvironment. It is now firmly established that aged tissues are prone to develop clones of altered cells, most of which are compatible with a normal histological appearance. Such increased clonogenic potential results in part from a generalized decrease in proliferative fitness, favoring the emergence of more competitive variant clones. However, specific cellular genotypes can emerge with reduced cooperative and integrative capacity, leading to disruption of tissue architecture and paving the way towards progression to overt neoplastic phenotypes.
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Sevim H, Çelik H, Düşünceli L, Ceyhan CS, Molotkova A, Nakazawa K, Graham GT, Petro JR, Toretsky JA, Üren A. Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells. PLoS One 2021; 16:e0253170. [PMID: 34133426 PMCID: PMC8208565 DOI: 10.1371/journal.pone.0253170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 05/29/2021] [Indexed: 01/17/2023] Open
Abstract
Clofarabine, an FDA approved purine analog, is used in the treatment of relapsed or refractory acute lymphoblastic leukemia. Clofarabine acts by inhibiting DNA synthesis. We demonstrated that clofarabine may have a novel function though inhibiting CD99, a transmembrane protein highly expressed on Ewing Sarcoma (ES) cells. CD99 is a validated target in ES whose inhibition may lead to a high therapeutic index for patients. Here we present additional data to support the hypothesis that clofarabine acts on CD99 and regulates key signaling pathways in ES. Cellular thermal shift assay indicated a direct interaction between clofarabine and CD99 in ES cell lysates. Clofarabine induced ES cell death does not require clofarabine's conversion to its active form by deoxycytidine kinase. A phosphokinase array screen with clofarabine and a CD99 blocking antibody identified alterations in signaling pathways. CD99 inhibition with clofarabine in ES cells caused rapid and sustained phosphorylation of ERK, MSK, and CREB. However, activation of this pathway did not correlate with clofarabine induced ES cell death. In summary, we demonstrated that clofarabine may activate ERK, MSK, and CREB phosphorylation through CD99 within minutes, however this paradoxical activation and subsequent ES cell death requires additional investigation.
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Affiliation(s)
- Handan Sevim
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Haydar Çelik
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Levent Düşünceli
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Ceyda S. Ceyhan
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Anna Molotkova
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Kay Nakazawa
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Garrett T. Graham
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Jeffrey R. Petro
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Jeffrey A. Toretsky
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Aykut Üren
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
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12
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Shadhu K, Ramlagun-Mungur D, Ping XC. Ewing sarcoma of the jejunum: A case report and literature review. World J Gastrointest Surg 2021; 13:507-515. [PMID: 34122739 PMCID: PMC8167841 DOI: 10.4240/wjgs.v13.i5.507] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 04/22/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ewing sarcomas (ESs) are highly aggressive malignancy and are predominant in the long bones of extremities of children and young adults with a slight male predilection and rarely presents at extra skeletal locations.
CASE SUMMARY A 55-year-old woman came to our hospital after finding elevated tumor biomarkers during her physical examination. Her enhanced computed tomography scan showed a jejunal mass. The patient underwent laparoscopic enterectomy. The mass was later diagnosed as ES, evidenced by fluorescence in situ hybridization whereby the GLP ES breakpoint region 1 probe was used, showing that more than 10% of the cells showed a red-green-yellow signal proving the breakpoint rearrangement of the ES breakpoint region 1 gene in chromosome 22.
CONCLUSION We describe a case of localized ES at the jejunum in China based on the literature.
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Affiliation(s)
- Kamleshsingh Shadhu
- Department of General Surgery, Gastrointestinal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Pre-registration House Officer, Medical Council of Mauritius, Floreal 0000, Plaine Whilhems, Mauritius
| | - Dadhija Ramlagun-Mungur
- Department of General Surgery, Gastrointestinal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Pre-registration House Officer, Medical Council of Mauritius, Floreal 0000, Plaine Whilhems, Mauritius
| | - Xiao-Chun Ping
- Department of General Surgery, Gastrointestinal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
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13
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da Silva Ferreira V, Eugenio MFC, Del Nery Dos Santos E, de Souza W, Sant'Anna C. Cellular toxicology and mechanism of the response to silver-based nanoparticle exposure in Ewing's sarcoma cells. NANOTECHNOLOGY 2021; 32:115101. [PMID: 33254155 DOI: 10.1088/1361-6528/abcef3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Ewing's sarcoma is the most aggressive connective tissue tumor, mainly affecting children and adolescents; the 5 year survival rate is only 50%. Current treatments have poor effectiveness, and more efficient treatments are being sought. Silver-based nanoparticles, such as silver chloride nanoparticles (AgCl-NPs) and silver/silver chloride (Ag/AgCl-NPs) nanoparticles, can be biologically produced and can release Ag+ ions into solution; however, their antitumor activity has been minimally investigated. The aim of this study was to evaluate the antitumor potential of AgCl-NPs and Ag/AgCl-NPs against Ewing's sarcoma cells. A673 cells (Ewing's sarcoma) were treated for 72 h with 0-12.5 μg ml-1 of Ag/AgCl-NPs or 0-40 μg ml-1 of AgCl-NPs. Human cells from the RPE-1 cell line (pigmented retinal epithelium) were used as a model of nontumor cells. The RPE-1 cells were less affected by the administration of AgCl-NPs or Ag/AgCl-NPs, with small reductions in the number of cells and viability and a small increase in apoptosis rates, while lysosomal damage, changes in reactive oxygen species (ROS) production, loss of mitochondrial membrane potential and alterations in microfilaments or cell areas were not observed. A673 tumor cells had significantly reduced number and viability levels when treated with AgCl-NPs, with reductions of 65.05% and 99.17%, respectively, whereas with Ag/AgCl-NP treatment, reductions of 65.53% and 92.51% were observed, respectively. When treated with silver-based nanoparticles, A673 cells also showed a significant increase in ROS production and loss of mitochondrial membrane potential, which culminated in an increase in the percentage of apoptosis among the population. Lysosomal damage was also observed when A673 cells were treated with the highest concentration of AgCl-NPs. In conclusion, the results showed that both AgCl-NPs and Ag/AgCl-NPs had some antitumor activity with minimal effects against healthy cells, which demonstrated the possibility of their use in cancer therapy.
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Affiliation(s)
- Veronica da Silva Ferreira
- Laboratory of Microscopy Applied to Life Science-Lamav, National Institute of Metrology, Quality and Technology-Inmetro, Duque de Caxias, RJ, 25250-020, Brazil
- Post-graduation Program on Translational Biomedicine-Biotrans, Duque de Caxias, RJ, 25071-202, Brazil
| | - Mateus Ferreira Conz Eugenio
- Laboratory of Microscopy Applied to Life Science-Lamav, National Institute of Metrology, Quality and Technology-Inmetro, Duque de Caxias, RJ, 25250-020, Brazil
- Post-graduation Program on Translational Biomedicine-Biotrans, Duque de Caxias, RJ, 25071-202, Brazil
| | - Elaine Del Nery Dos Santos
- Plateforme BioPhenics, Département de Recherche Translationnelle, Centre de Recherche-Institut Curie, Paris, F-75005, France
| | - Wanderley de Souza
- Post-graduation Program on Translational Biomedicine-Biotrans, Duque de Caxias, RJ, 25071-202, Brazil
- National Institute of Science and Technology for Structural Biology and Bioimaging, Rio de Janeiro, RJ, 21949-900, Brazil
- Laboratory of Cellular Ultrastructure Hertha Meyer, Federal University of Rio de Janeiro-UFRJ, Rio de Janeiro, RJ, 21949-900, Brazil
| | - Celso Sant'Anna
- Laboratory of Microscopy Applied to Life Science-Lamav, National Institute of Metrology, Quality and Technology-Inmetro, Duque de Caxias, RJ, 25250-020, Brazil
- Post-graduation Program on Translational Biomedicine-Biotrans, Duque de Caxias, RJ, 25071-202, Brazil
- National Institute of Science and Technology for Structural Biology and Bioimaging, Rio de Janeiro, RJ, 21949-900, Brazil
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14
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Xu L, Xie X, Shi X, Zhang P, Liu A, Wang J, Zhang B. Potential application of genomic profiling for the diagnosis and treatment of patients with sarcoma. Oncol Lett 2021; 21:353. [PMID: 33747210 PMCID: PMC7967939 DOI: 10.3892/ol.2021.12614] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 12/14/2020] [Indexed: 01/13/2023] Open
Abstract
Sarcomas represent a heterogeneous group of mesenchymal malignancies arising at various locations in the soft tissue and bone. Though a rare disease, sarcoma affects ~200,000 patients worldwide every year. The prognosis of patients with sarcoma is poor, and targeted therapy options are limited; therefore, accurate diagnosis and classification are essential for effective treatment. Sarcoma samples were acquired from 199 patients, in which TP53 (39.70%, 79/199), CDKN2A (19.10%, 38/199), CDKN2B (15.08%, 30/199), KIT (14.07%, 28/199), ATRX (10.05%, 20/199) and RB1 (10.05%, 20/199) were identified as the most commonly mutated genes (>10% incidence). Among 64 soft-tissue sarcomas that were unclassified by immunohistochemistry, 15 (23.44%, 15/64) were subsequently classified using next-generation sequencing (NGS). For the most part, the sarcoma subtypes were evenly distributed between male and female patients, while a significant association with sex was detected in leiomyosarcomas. Statistical analysis showed that osteosarcoma, Ewing's sarcoma, gastrointestinal stromal tumors and liposarcoma were all significantly associated with the patient age, and that angiosarcoma was significantly associated with high tumor mutational burden. Furthermore, serially mutated genes associated with myxofibrosarcoma, gastrointestinal stromal tumor, osteosarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma and Ewing's sarcoma were identified, as well as neurotrophic tropomyosin-related kinase (NTRK) fusions of IRF2BP2-NTRK1, MEF2A-NTRK3 and ITFG1-NTRK3. Collectively, the results of the present study suggest that NGS-targeting provides potential new biomarkers for sarcoma diagnosis, and may guide more precise therapeutic strategies for patients with bone and soft-tissue sarcomas.
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Affiliation(s)
- Libin Xu
- Department of Orthopedic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Xianbiao Xie
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat Sen University, Guangzhou, Guangdong 510080, P.R. China
| | | | - Peng Zhang
- OrigiMed Co. Ltd., Shanghai 201114, P.R. China
| | - Angen Liu
- OrigiMed Co. Ltd., Shanghai 201114, P.R. China
| | - Jian Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Bo Zhang
- Department of Pathology, Peking University Third Hospital, Beijing 100191, P.R. China
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15
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Infantile intraorbital Ewing's sarcoma: case report and review of the literature. Childs Nerv Syst 2021; 37:299-304. [PMID: 32314023 DOI: 10.1007/s00381-020-04606-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 04/02/2020] [Indexed: 10/24/2022]
Abstract
We reported a 7-month-old female with intraorbital Ewing's sarcoma. Infantile Ewing's sarcoma is rare and its prognosis is poor. Ewing's sarcoma of orbital origin is even rare. There has been only 1 case of infantile intraorbital Ewing's sarcoma reported, and only 5 infantile primary orbital ESFTs (Ewing's sarcoma family of tumors) have been reported. Among these 5 cases, 2 infants who did not receive multimodal therapy died, whereas 3 who received multimodal therapy demonstrated long-term survival. The present case was also treated with multimodal therapy consisting of surgery, chemotherapy, and proton beam radiotherapy. There is no recurrence at 15 months follow-up. No specific treatment strategies have been established yet, and accumulation of cases is necessary. Ewing's sarcoma should be included in the differential diagnosis of infantile intraorbital tumors.
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16
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Bissonnette C, Shilo K, Liebner D, Rogers A, Pollock RE, Iwenofu OH. An EWSR1-CREB3L1 Fusion Gene in Extraskeletal Undifferentiated Round Cell Sarcoma Expands the Spectrum of Genetic Landscape in the "Ewing-Like" Undifferentiated Round Cell Sarcomas. Int J Surg Pathol 2020; 29:109-116. [PMID: 32506986 DOI: 10.1177/1066896920929081] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The molecular findings in Ewing sarcoma have greatly expanded in recent years. Furthermore, this is particularly true for the subset termed "Ewing-like" undifferentiated round cell sarcomas in which new translocations have been reported since the fourth edition of the WHO Classification of Tumours of Soft Tissue and Bone. Amid this expanding genetic landscape, we report a case of extraskeletal undifferentiated round cell "Ewing-like" sarcoma in a 27-year-old female. The patient presented with a large lung mass accompanied on staging imaging by deposits suspicious for metastatic disease in the humerus, calvarium, and lymph nodes of the neck and chest. Biopsy of the lung mass revealed a densely packed monotonous proliferation of round, uniform neoplastic cells with scant cytoplasm. By immunohistochemistry, the tumor cells were diffusely positive for CD99, synaptophysin, TLE1, EMA, and MUC4 and negative for FLI1, PAX7, AE1/3, S100, SOX10, WT1, p63, desmin, and HMB45. Fluorescence in situ hybridization demonstrated rearrangement of the EWSR1 gene. Next-generation sequencing based assay revealed an EWSR1-CREB3L1 fusion. Taken together, the histomorphologic and molecular findings were considered consistent with an undifferentiated round cell sarcoma with an EWSR1-CREB3L1 fusion. Although described in entities such as sclerosing epithelioid fibrosarcoma, low-grade fibromyxoid sarcoma, and small cell osteosarcoma, this has not been previously described in undifferentiated round cell ("Ewing-like") sarcoma. This finding adds to the growing list of undifferentiated round cell sarcomas with Ewing-like morphologic phenotype-associated fusion genes and may contribute to further defining and characterizing the different subset of tumors in the Ewing family of tumors.
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Affiliation(s)
- Caroline Bissonnette
- Division of Oral and Maxillofacial Pathology and Radiology, The Ohio State University College of Dentistry, Columbus, OH, USA
| | - Konstantin Shilo
- Department of Pathology & Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - David Liebner
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, United States.,Division of Computational Biology and Bioinformatics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA
| | - Alan Rogers
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Raphael E Pollock
- The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - O Hans Iwenofu
- Department of Pathology & Laboratory Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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17
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Ruan X, Zheng J, Liu X, Liu Y, Liu L, Ma J, He Q, Yang C, Wang D, Cai H, Li Z, Liu J, Xue Y. lncRNA LINC00665 Stabilized by TAF15 Impeded the Malignant Biological Behaviors of Glioma Cells via STAU1-Mediated mRNA Degradation. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 20:823-840. [PMID: 32464546 PMCID: PMC7256440 DOI: 10.1016/j.omtn.2020.05.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/23/2020] [Accepted: 05/01/2020] [Indexed: 12/11/2022]
Abstract
Glioma is a brain cancer characterized by strong invasiveness with limited treatment options and poor prognosis. Recently, dysregulation of long non-coding RNAs (lncRNAs) has emerged as an important component in cellular processes and tumorigenesis. In this study, we demonstrated that TATA-box binding protein associated factor 15 (TAF15) and long intergenic non-protein coding RNA 665 (LINC00665) were both downregulated in glioma tissues and cells. TAF15 overexpression enhanced the stability of LINC00665, inhibiting malignant biological behaviors of glioma cells. Both metal regulatory transcription factor 1 (MTF1) and YY2 transcription factor (YY2) showed high expression levels in glioma tissues and cells, and their knockdown inhibited malignant progression. Mechanistically, overexpression of LINC00665 was confirmed to destabilize MTF1 and YY2 mRNA by interacting with STAU1, and knockdown of STAU1 could rescue the MTF1 and YY2 mRNA degradation caused by LINC00665 overexpression. G2 and S-phase expressed 1 (GTSE1) was identified as an oncogene in glioma, and knockdown of MTF1 or YY2 decreased the mRNA and protein expression levels of GTSE1 through direct binding to the GTSE1 promoter region. Our study highlights a key role of the TAF15/LINC00665/MTF1(YY2)/GTSE1 axis in modulating the malignant biological behaviors of glioma cells, suggesting novel mechanisms by which lncRNAs affect STAU1-mediated mRNA stability, which can inform new molecular therapies for glioma.
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Affiliation(s)
- Xuelei Ruan
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Jian Zheng
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Xiaobai Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Yunhui Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Libo Liu
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Jun Ma
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Qianru He
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Chunqing Yang
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Di Wang
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Heng Cai
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Zhen Li
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Jing Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Yixue Xue
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China.
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18
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Pisconti S, Della Vittoria Scarpati G, Buonerba C, Messinese S, Carella R, Di Marzo M, Di Lorenzo G, Lazzari G, Perri F, Solla R. Management of Ewing Sarcoma Family of Tumors: A Short Description of a Rare Primitive Uterine pPNET and Literature Review. Onco Targets Ther 2020; 13:1179-1184. [PMID: 32110037 PMCID: PMC7034293 DOI: 10.2147/ott.s213233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 12/12/2019] [Indexed: 11/25/2022] Open
Abstract
Purpose To describe the outcome of a patient with a rare primitive uterine pPNET and to perform a review of the available data in literature, leading the clinicians to better face this rare disease. Methods We have rescued data regarding the multidisciplinary treatment of pPNET from the PUBMED database, highlighting also issues regarding the pathogenesis and the genetic landscape of the ESFTs (Ewing Sarcoma Family of Tumors). Results Ewing sarcoma and primitive neuroectodermal tumors (PNETs) are small round cell tumors presenting with different degrees of neuroectodermal differentiation. PNETs are further divided into central PNET and peripheral PNET (pPNET). Since pPNETs share the same genetic background of Ewing Sarcomas, they are considered to belong to the Ewing Sarcoma Family of Tumors (ESFTs). Multimodality treatment currently represents the best choice to offer to the affected patients. Conclusion Although pPNETs are generally diagnosed in children and young adults, an elderly woman aged 85 years came to our attention after a diagnosis of uterine pPNET. Her medical history is presented here, along with a literature review of the subject, highlighting the main biological, pathological and clinical features, with a hypothesis about the possible future therapeutic approaches for these rare malignancies.
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Affiliation(s)
| | | | - Carlo Buonerba
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Naples, Italy
| | | | | | - Massimiliano Di Marzo
- Department of Abdominal Surgery, National Tumor Institute of Naples IRCCS G. Pascale, Naples, Italy
| | - Giuseppe Di Lorenzo
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Naples, Italy
| | - Grazia Lazzari
- Department of Radiation Oncology, POC, SS Annunziata, Taranto, Italy
| | - Francesco Perri
- Head and Neck Medical Oncology Unit, National Tumor Institute of Naples IRCCS G. Pascale, Naples, Italy
| | - Raffaele Solla
- Department of Radiation Oncology, University of Naples Federico II, Naples, Italy.,Italian National Research Council, Institute of Biostructure & Bioimaging, Naples, Italy
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19
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Montoya C, Rey L, Rodríguez J, Fernández MJ, Troncoso D, Cañas A, Moreno O, Henríquez B, Rojas A. Epigenetic control of the EWS‑FLI1 promoter in Ewing's sarcoma. Oncol Rep 2020; 43:1199-1207. [PMID: 32323788 PMCID: PMC7057940 DOI: 10.3892/or.2020.7489] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 10/04/2019] [Indexed: 11/09/2022] Open
Abstract
Ewing sarcoma (ES) is a primary bone marrow tumor that very rarely develops in extra-osseous tissues, such as lung. The hallmark of ES tumors is a translocation between chromosomes 11 and 22, resulting in a fusion protein, commonly referred to as EWS-FLI1. The epigenetic profile (histone acetylation and methylation enrichment of the promoter region) that may regulate the expression of the aberrant transcription factor EWS-FLI1, remains poorly studied and understood. Knowledge of epigenetic patterns associated with covalent histone modification and expression of enzymes associated with this process, can contribute to the understanding of the molecular basis of the disease, as well as to the identification of possible molecular targets involved in expression of the EWS-FLI1 gene, so that therapeutic strategies may be improved in the future. In the present study, the transcriptional activation and repression of the EWS-FLI1 fusion gene in ES was accompanied by selective deposition of histone markers on its promoter. The EWS-FLI1 fusion gene was evaluated in two patients with ES using conventional cytogenetic, fluorescence in situ hybridization and nested PCR assays, which revealed that the aberrant expression of the EWS-FLI1 gene is accompanied by enrichment of H3K4Me3, H3K9ac and H3K27ac at the promoter region.
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Affiliation(s)
- C Montoya
- Institute of Human Genetics, Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá 110231, Colombia, Chile
| | - L Rey
- Institute of Human Genetics, Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá 110231, Colombia, Chile
| | - J Rodríguez
- Department of Pathology, Hospital Universitario San Ignacio, Bogotá 110231, Colombia, Chile
| | - M J Fernández
- Department of Physiological Sciences, Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá 110231, Colombia, Chile
| | - D Troncoso
- Institute of Human Genetics, Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá 110231, Colombia, Chile
| | - A Cañas
- Department of Internal Medicine, Hospital Universitario San Ignacio, Bogotá 110231, Colombia, Chile
| | - O Moreno
- Institute of Human Genetics, Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá 110231, Colombia
| | - B Henríquez
- Faculty of Medicine and Science, Universidad San Sebastián, Santiago 7510157, Chile
| | - A Rojas
- Institute of Human Genetics, Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá 110231, Colombia
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20
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Brčić I, Brodowicz T, Cerroni L, Kashofer K, Serbanescu GL, Kasseroler MT, Amann G, Scheipl S, Szkandera J, Leithner A, Liegl-Atzwanger B. Undifferentiated round cell sarcomas with CIC-DUX4 gene fusion: expanding the clinical spectrum. Pathology 2020; 52:236-242. [PMID: 31870501 DOI: 10.1016/j.pathol.2019.09.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 09/13/2019] [Accepted: 09/18/2019] [Indexed: 12/22/2022]
Abstract
Round cell sarcomas are a heterogeneous group of mesenchymal neoplasms with overlapping morphology and immunohistochemical profile. Ewing sarcoma is the most well-known tumour in this group characterised by EWSR1/FUS rearrangements with members of the ETS family of transcription factors. Undifferentiated round cell sarcomas lacking these rearrangements, known as 'Ewing-like' sarcomas, usually show atypical clinical presentation and focal CD99 positivity. This group of tumours can be subdivided into: capicua transcriptional repressor (CIC)-rearranged sarcomas, Bcl6 corepressor (BCOR)-rearranged sarcomas, sarcomas with EWSR1 fusion to non-ETS family members and unclassified round cell sarcomas. We describe seven new cases of CIC-DUX4 rearranged sarcomas with their clinicopathological features, two of which presented in unusual locations (skin and lymph node). Patient age ranged between 23 and 54 years, three of whom were female. In five cases, aggressive behaviour was observed with rapid disease progression and lethal outcome within 15 months. One patient achieved a complete response after chemotherapy. The last patient whose tumour was located purely in the dermis demonstrated no residual tumour in the re-resection specimen, was not given any further treatment and showed no sign of disease after 24 months. Immunohistochemically, tumour cells in all cases showed focal membranous CD99 positivity, while WT1 N-/C-terminus were positive in all 5/5 cases (nuclear and/or cytoplasmic). NGS analysis revealed a CIC-DUX4 fusion in all cases. This study expands the spectrum of anatomical locations of CIC-DUX4 rearranged sarcomas, highlighting the inclusion of this rare entity in the differential diagnosis of undifferentiated tumours in various anatomical locations outside of soft tissues.
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Affiliation(s)
- Iva Brčić
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Thomas Brodowicz
- Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Centre, Medical University Vienna, Vienna, Austria
| | - Lorenzo Cerroni
- Department of Dermatology, Medical University of Graz, Graz, Austria
| | - Karl Kashofer
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | | | | | - Gabriele Amann
- Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria
| | - Susanne Scheipl
- Department of Orthopedics and Trauma, Medical University of Graz, Graz, Austria
| | - Joanna Szkandera
- Clinical Division of Medical Oncology, Department of Medicine, Comprehensive Cancer Centre Graz, Medical University of Graz, Graz, Austria
| | - Andreas Leithner
- Department of Orthopedics and Trauma, Medical University of Graz, Graz, Austria
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21
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He S, Huang Q, Hu J, Li L, Xiao Y, Yu H, Han Z, Wang T, Zhou W, Wei H, Xiao J. EWS-FLI1-mediated tenascin-C expression promotes tumour progression by targeting MALAT1 through integrin α5β1-mediated YAP activation in Ewing sarcoma. Br J Cancer 2019; 121:922-933. [PMID: 31649319 PMCID: PMC6889507 DOI: 10.1038/s41416-019-0608-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 09/23/2019] [Accepted: 10/01/2019] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The extracellular matrix has been critically associated with the tumorigenesis and progression of Ewing sarcoma (ES). However, the regulatory and prognostic roles of tenascin-C (TNC) in ES remain unclear. METHODS TNC expression was examined in specimens by immunohistochemistry, and the association of TNC expression with ES patient survival was also analysed. TNC-knockout cell lines were constructed using CRISPR/Cas9 methods. In vitro experiments and in vivo bioluminescent imaging using BALB/c nude mice were conducted to evaluate the effect of TNC on ES tumour progression. RNA sequencing was performed, and the underlying mechanism of TNC was further explored. RESULTS TNC was overexpressed in ES tissue and cell lines, and TNC overexpression was associated with poor survival in ES patients. TNC enhanced cell proliferation, migration and angiogenesis in vitro and promoted ES metastasis in vivo. The oncoprotein EWS-FLI1 profoundly increased TNC expression by directly binding to the TNC promoter region. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) upregulation induced by Yes-associated protein (YAP) activation was responsible for TNC-regulated ES tumour progression. Activated integrin α5β1 signalling might be correlated with YAP dephosphorylation and nuclear translocation. CONCLUSIONS TNC may promote ES tumour progression by targeting MALAT1 through integrin α5β1-mediated YAP activation.
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Affiliation(s)
- Shaohui He
- Spinal Tumor Center, Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, P. R. China
| | - Quan Huang
- Spinal Tumor Center, Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, P. R. China
| | - Jinbo Hu
- Spinal Tumor Center, Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, P. R. China
| | - Lei Li
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, P. R. China
| | - Yanbin Xiao
- Department of Orthopaedics, Musculoskeletal Tumor Center of Yunnan Province, the Third Affiliated Hospital of Kunming Medical University, Kunming Medical University, Kunming, 650106, Yunnan, P. R. China
| | - Hongyu Yu
- Department of Pathology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, P. R. China
| | - Zhitao Han
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, P. R. China
| | - Ting Wang
- Spinal Tumor Center, Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, P. R. China
| | - Wang Zhou
- Spinal Tumor Center, Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, P. R. China. .,School of Medicine, Tsinghua University, Beijing, 100084, P. R. China.
| | - Haifeng Wei
- Spinal Tumor Center, Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, P. R. China.
| | - Jianru Xiao
- Spinal Tumor Center, Department of Orthopaedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, P. R. China.
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22
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Xiao GQ, Sherrod AE, Hurth KM. ZBTB16: A new biomarker for primitive neuroectodermal tumor element / Ewing sarcoma. Pathol Res Pract 2019; 215:152536. [PMID: 31326195 DOI: 10.1016/j.prp.2019.152536] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 06/19/2019] [Accepted: 07/12/2019] [Indexed: 10/26/2022]
Abstract
Primitive neuroectodermal tumor (PNET) traditionally encompasses two different classes of tumors with similar morphology - PNET of the peripheral nervous system (pPNET) and PNET of the central nervous system (cPNET). The latter also includes germ cell tumor-derived PNET (gPNET). There are currently no specific markers for gPNET. This study seeks to investigate the expression of ZBTB16 in PNET and other small round blue cell tumors as well as its potential diagnostic utility. Immunohistochemical expression of the ZBTB16 was studied in a total of 27 PNETs (12 pPNETs, 8 cPNETs, 3 primary testicular gPNETs, and 4 metastatic gPNETs) and 38 small round blue cell tumors. Positive expression for ZBTB16 was seen diffusely in 9/12 (75%), moderately in 2/12 (17%) and focally in 1/12 (8%) of pPNETs, diffusely in 3/7 (43%) and moderately in 4/7 (57%) of gPNETs, and diffusely in 2/8 (25%), moderately in 2/8 (25%) and focally in 4/8 (50%) of cPNETs. Whereas, all of the 38 non-PNET small round blue cell tumors were nonreactive. The results suggest that ZBTB16 is a highly sensitive and specific biomarker for both pPNET and gPNET/cPNET. ZBTB16 effectively differentiates PNETs from other small round blue cell tumor mimics, including the two most common germ cell tumor-derived somatic malignancies - rhabdomyosarcoma and nephroblastoma. Of note, compared to the expression of ZBTB16 in pPNET/Ewing sarcoma and gPNET, the expression of ZBTB16 in cPNET was more variable, which appears consistent with the heterogeneity of cPNET. The close proximity of ZBTB16 and FLI-1 genes on chromosome 11q may explain the overexpression of ZBTB16 in PNET, especially in pPNET with t(1122) translocation.
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Affiliation(s)
- Guang-Qian Xiao
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, United States.
| | - Andy E Sherrod
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, United States
| | - Kyle M Hurth
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, United States
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23
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Kong W, Hayashi T, Fiches G, Xu Q, Li MZ, Que J, Liu S, Zhang W, Qi J, Santoso N, Elledge SJ, Zhu J. Diversified Application of Barcoded PLATO (PLATO-BC) Platform for Identification of Protein Interactions. GENOMICS, PROTEOMICS & BIOINFORMATICS 2019; 17:319-331. [PMID: 31494268 PMCID: PMC6818353 DOI: 10.1016/j.gpb.2018.12.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 10/24/2018] [Accepted: 12/21/2018] [Indexed: 11/29/2022]
Abstract
Proteins usually associate with other molecules physically to execute their functions. Identifying these interactions is important for the functional analysis of proteins. Previously, we reported the parallel analysis of translated ORFs (PLATO) to couple ribosome display of full-length ORFs with affinity enrichment of mRNA/protein/ribosome complexes for the "bait" molecules, followed by the deep sequencing analysis of mRNA. However, the sample processing, from extraction of precipitated mRNA to generation of DNA libraries, includes numerous steps, which is tedious and may cause the loss of materials. Barcoded PLATO (PLATO-BC), an improved platform was further developed to test its application for protein interaction discovery. In this report, we tested the antisera-antigen interaction using serum samples from patients with inclusion body myositis (IBM). Tripartite motif containing 21 (TRIM21) was identified as a potentially new IBM autoantigen. We also expanded the application of PLATO-BC to identify protein interactions for JQ1, single ubiquitin peptide, and NS5 protein of Zika virus. From PLATO-BC analyses, we identified new protein interactions for these "bait" molecules. We demonstrate that Ewing sarcoma breakpoint region 1 (EWSR1) binds to JQ1 and their interactions may interrupt the EWSR1 association with acetylated histone H4. RIO kinase 3 (RIOK3), a newly identified ubiquitin-binding protein, is preferentially associated with K63-ubiquitin chain. We also find that Zika NS5 protein interacts with two previously unreported host proteins, par-3 family cell polarity regulator (PARD3) and chromosome 19 open reading frame 53 (C19orf53), whose attenuated expression benefits the replication of Zika virus. These results further demonstrate that PLATO-BC is capable of identifying novel protein interactions for various types of "bait" molecules.
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Affiliation(s)
- Weili Kong
- Department of Microbiology and Immunology, Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Tsuyoshi Hayashi
- Department of Microbiology and Immunology, Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Guillaume Fiches
- Department of Microbiology and Immunology, Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Qikai Xu
- Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Mamie Z Li
- Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Shuai Liu
- Department of Chemistry, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA 02125, USA
| | - Wei Zhang
- Department of Chemistry, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA 02125, USA
| | - Jun Qi
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Netty Santoso
- Department of Microbiology and Immunology, Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Stephen J Elledge
- Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Jian Zhu
- Department of Pathology, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
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24
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Masaoutis C, Korkolopoulou P, Theocharis S. Exosomes in sarcomas: Tiny messengers with broad implications in diagnosis, surveillance, prognosis and treatment. Cancer Lett 2019; 449:172-177. [PMID: 30779943 DOI: 10.1016/j.canlet.2019.02.025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 02/08/2019] [Accepted: 02/12/2019] [Indexed: 12/13/2022]
Abstract
Exosomes are cell-secreted extracellular vesicles, which contain an array of biomolecules, such as proteins, mRNAs, microRNAs, and lipids, take part in intercellular communication and mediate tumor-host interactions. They are increasingly considered as a source of biomarkers for liquid biopsies as well as potential drug vectors. Sarcomas are rare malignant mesenchymal tumours and due to their relative rarity exosomes have not been investigated in as extensively as in epithelial malignancies. Nonetheless, valuable information has been gathered over the last years on the roles of exosomes in sarcomas. In the present review we summarize all relevant data obtained so far from cell lines, animal models and patients with emphasis on their potential clinical utility.
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Affiliation(s)
- Christos Masaoutis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Penelope Korkolopoulou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece.
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25
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Yau DTW, Chan JKC, Bao S, Zheng Z, Lau GTC, Chan ACL. Bone Sarcoma WithEWSR1-NFATC2Fusion: Sarcoma With Varied Morphology and Amplification of Fusion Gene Distinct From Ewing Sarcoma. Int J Surg Pathol 2019; 27:561-567. [PMID: 30714449 DOI: 10.1177/1066896919827093] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Ewing sarcomas are typified by EWSR1 fusion to ETS gene family members. Tumors with fusion partners other than ETS family members and atypical histologic features pose significant diagnostic challenges and controversies as to their classification. In this article, we report a tumor with EWSR1-NFATC2 fusion in the left femur of a 43-year-old man and with unusual morphologic features that resemble undifferentiated high-grade sarcoma. Analysis together with reported cases in the literature shows that tumors with EWSR1-NFATC2 exhibit distinctive clinicopathologic features, including predilection for young male adults, highly variable histology that varies from round cell tumors frequently associated with nuclear irregularity, short spindle cells with nuclear pleomorphism, to myoepithelial tumor-like with or without myxohyaline matrix. They show variable positivity to CD99, frequent expression of cytokeratins, and consistent high-level amplification of EWSR1-NFATC2 fusion gene with distinctive gene expression profile. These tumors thus deserve classification separate from Ewing sarcoma.
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Affiliation(s)
| | | | - Siyu Bao
- City University of Hong Kong, Hong Kong, SAR China
| | - Zongli Zheng
- City University of Hong Kong, Hong Kong, SAR China
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26
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Louati S, Senhaji N, Chbani L, Bennis S. EWSR1 Rearrangement and CD99 Expression as Diagnostic Biomarkers for Ewing/PNET Sarcomas in a Moroccan Population. DISEASE MARKERS 2018; 2018:7971019. [PMID: 30319719 PMCID: PMC6167566 DOI: 10.1155/2018/7971019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 08/16/2018] [Accepted: 08/18/2018] [Indexed: 11/23/2022]
Abstract
Ewing sarcoma/primitive neuroectodermal tumor (Ewing/PNET sarcomas or EPS) are a group of round cell tumors. Malignant round cell tumors form a large and diverse group that includes rhabdomyosarcoma, synovial sarcoma, non-Hodgkin's lymphoma, neuroblastoma, hepatoblastoma, Wilm's tumor, desmoplastic small round cell tumor, and other morphologically similar entities. Differential diagnosis of Ewing sarcoma/primitive neuroectodermal tumor (Ewing/PNET sarcomas or EPS) is difficult. In addition to morphology and immunohistochemistry (IHC), differential diagnosis of these tumors is based on molecular analysis of the EWSR1 gene rearrangement using fluorescent in situ hybridization (FISH) technique. We investigated the diagnostic value of combined CD99 immunostaining and EWSR1 t(22q12) alteration using a dual-color, break-apart rearrangement probe in forty-one formalin-fixed paraffin-embedded (FFPE) tissue samples from pediatric and adult patients diagnosed with EPS. IHC was performed in all cases using the CD99 antibody and showed a positivity of 92.7% in the enrolled cases (38/41) followed by FISH analysis where 48.8% of the cases (20/41) were rearranged. Sensitivity and specificity for IHC assays were 88% and 58%, respectively. Notably, FISH had a sensitivity of 100% and a specificity of 87%. In addition, CD99 positivity was found to correlate with EWSR1 rearrangement (p < 0.05). This report shows that FISH has better sensitivity and specificity than IHC in the Moroccan population, and supports its combination with CD99 immunostaining as diagnostic biomarkers for this rare malignant entity."
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Affiliation(s)
- Sara Louati
- Bioactive Molecules, Structure and Functions Laboratory, Faculty of Sciences and Techniques, Sidi Mohamed ben Abdellah University of Fez, Morocco
- Pathological Anatomy and Molecular Pathology Department, Hassan II University Hospital of Fez, Morocco
| | - Nadia Senhaji
- Bioactive Molecules, Structure and Functions Laboratory, Faculty of Sciences and Techniques, Sidi Mohamed ben Abdellah University of Fez, Morocco
| | - Laila Chbani
- Pathological Anatomy and Molecular Pathology Department, Hassan II University Hospital of Fez, Morocco
- Biomedical and Translational Research Laboratory, Faculty of Medicine and Pharmacy, Sidi Mohamed ben Abdellah University of Fez, Morocco
| | - Sanae Bennis
- Pathological Anatomy and Molecular Pathology Department, Hassan II University Hospital of Fez, Morocco
- Biomedical and Translational Research Laboratory, Faculty of Medicine and Pharmacy, Sidi Mohamed ben Abdellah University of Fez, Morocco
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27
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Fry EA, Mallakin A, Inoue K. Translocations involving ETS family proteins in human cancer. INTEGRATIVE CANCER SCIENCE AND THERAPEUTICS 2018; 5:10.15761/ICST.1000281. [PMID: 30542624 PMCID: PMC6287620 DOI: 10.15761/icst.1000281] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The ETS transcription factors regulate expression of genes involved in normal cell development, proliferation, differentiation, angiogenesis, and apoptosis, consisting of 28 family members in humans. Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating certain gene transcriptions. ETS1 and ETS2 are the founding members of the ETS family and regulate transcription by binding to ETS sequences. Three chimeric genes involving ETS genes have been identified in human cancers, which are EWS-FLI1 in Ewing's sarcoma, TMPRSS2-ERG in prostate cancer, and ETV6-RUNX1 in acute lymphocytic leukemia. Although these fusion transcripts definitely contribute to the pathogenesis of the disease, the impact of these fusion transcripts on patients' prognosis is highly controversial. In the present review, the roles of ETS protein translocations in human carcinogenesis are discussed.
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Affiliation(s)
- Elizabeth A. Fry
- Dept. of Pathology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157 USA
| | | | - Kazushi Inoue
- Dept. of Pathology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157 USA
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28
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Lin CY, Shukla A, Grady JP, Fink JL, Dray E, Duijf PHG. Translocation Breakpoints Preferentially Occur in Euchromatin and Acrocentric Chromosomes. Cancers (Basel) 2018; 10:cancers10010013. [PMID: 29316705 PMCID: PMC5789363 DOI: 10.3390/cancers10010013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 12/11/2017] [Accepted: 01/05/2018] [Indexed: 12/12/2022] Open
Abstract
Chromosomal translocations drive the development of many hematological and some solid cancers. Several factors have been identified to explain the non-random occurrence of translocation breakpoints in the genome. These include chromatin density, gene density and CCCTC-binding factor (CTCF)/cohesin binding site density. However, such factors are at least partially interdependent. Using 13,844 and 1563 karyotypes from human blood and solid cancers, respectively, our multiple regression analysis only identified chromatin density as the primary statistically significant predictor. Specifically, translocation breakpoints preferentially occur in open chromatin. Also, blood and solid tumors show markedly distinct translocation signatures. Strikingly, translocation breakpoints occur significantly more frequently in acrocentric chromosomes than in non-acrocentric chromosomes. Thus, translocations are probably often generated around nucleoli in the inner nucleoplasm, away from the nuclear envelope. Importantly, our findings remain true both in multivariate analyses and after removal of highly recurrent translocations. Finally, we applied pairwise probabilistic co-occurrence modeling. In addition to well-known highly prevalent translocations, such as those resulting in BCR-ABL1 (BCR-ABL) and RUNX1-RUNX1T1 (AML1-ETO) fusion genes, we identified significantly underrepresented translocations with putative fusion genes, which are probably subject to strong negative selection during tumor evolution. Taken together, our findings provide novel insights into the generation and selection of translocations during cancer development.
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Affiliation(s)
- Cheng-Yu Lin
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia.
| | - Ankit Shukla
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia.
| | - John P Grady
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia.
| | - J Lynn Fink
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia.
| | - Eloise Dray
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia.
- Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia.
| | - Pascal H G Duijf
- University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia.
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29
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Abrahao-Machado LF, Antunes B, Filippi RZ, Volc S, Boldrini E, Menezes WP, Reis RM, de Camargo OP. Loss of MTAP expression is a negative prognostic marker in Ewing sarcoma family of tumors. Biomark Med 2018; 12:35-44. [DOI: 10.2217/bmm-2017-0152] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: The Ewing sarcoma family of tumors (ESFT) is a group of malignant small round cell neoplasms of bones and soft tissues closely histogenetically related. Methylthioadenosine phosphorylase (MTAP) deficiency has been recently associated with increased tumor aggressiveness and poor outcomes in different types of neoplasms. However, the expression of this biomarker and its biological role in ESFT remain largely unknown. Methods: Immunohistochemical expression of MTAP was accessed in 112 patients with ESFT in a tissue microarray platform and associated with clinicopathological parameters and overall survival (OS). Results: Loss of MTAP expression was significantly associated with lower OS in both univariate and multivariate analyses. Conclusion: Loss of MTAP expression is an independent negative prognostic biomarker in ESFT.
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Affiliation(s)
| | - Bruno Antunes
- Department of Othopedics Surgery, Barretos Cancer Hospital, Barretos, SP, Brazil
| | - Renee Zon Filippi
- Institute of Orthopedics & Traumatology, Faculty of Medicine, University of São Paulo (FMUSP), São Paulo, SP, Brazil
| | - Sahlua Volc
- Oncology Department, Barretos Cancer Hospital, Barretos, SP, Brazil
| | - Erica Boldrini
- Pediatrics Department, Barretos Cancer Hospital, Barretos, SP, Brazil
| | - Weder P Menezes
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
| | - Rui M Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Life & Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Olavo Pires de Camargo
- Institute of Orthopedics & Traumatology, Faculty of Medicine, University of São Paulo (FMUSP), São Paulo, SP, Brazil
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30
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NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma. Hum Pathol 2017; 65:225-230. [DOI: 10.1016/j.humpath.2017.01.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 12/19/2016] [Accepted: 01/17/2017] [Indexed: 11/24/2022]
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Li T, Zhang F, Cao Y, Ning S, Bi Y, Xue W, Ren L. Primary Ewing's sarcoma/primitive neuroectodermal tumor of the ileum: case report of a 16-year-old Chinese female and literature review. Diagn Pathol 2017; 12:37. [PMID: 28472972 PMCID: PMC5418692 DOI: 10.1186/s13000-017-0626-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 04/17/2017] [Indexed: 12/21/2022] Open
Abstract
Background Ewing’s sarcoma (ES) and primitive neuroectodermal tumors (PNET) are closely related tumors. Although soft tissue ES/PNET are common in clinical practice, they are rare in the small intestine. Because of the absence of characteristic clinical symptoms, they are easily misdiagnosed as other benign or malignant diseases. Case presentation Here, we present the case of a 16-year-old female who complained of anemia and interval hematochezia. Her serum test results showed only a slight elevation of CA-125 and a low level of hemoglobin. Computer tomography and magnetic resonance imaging revealed a cystic and solid mass in the lower abdominal quadrant and pelvic region, which prompted suspicion of a malignant gastrointestinal stromal tumor of the small intestine. After resection, the tumor’s histology and immunohistochemistry (positive for CD99, vimentin and synaptophysin) results suggested ES/PNET. Fluorescent in situ hybridization tests proved the breakpoint rearrangement of the EWSR1 gene in chr 22.Ultrastructural analysis revealed neurosecretory and glycogen granules in the tumor cell cytoplasm. Conclusions Together, these data supported the diagnosis of a rare case of localized ES/PNET in the small intestine without adjuvant chemo- or radiotherapy. To our knowledge, this is the first report from China of a primary small bowel ES/PNET in the English-language literature. In addition, on the basis of findings from previous publications and the current case, the optimal treatment for localized gastrointestinal ES/PNET is discussed.
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Affiliation(s)
- Teng Li
- Department of Pathology, The General Hospital of Air force, PLA, Fucheng Road 30th, Beijing, China
| | - Fang Zhang
- Department of Pathology, The General Hospital of Air force, PLA, Fucheng Road 30th, Beijing, China
| | - Yarui Cao
- Department of Pathology, The General Hospital of Air force, PLA, Fucheng Road 30th, Beijing, China
| | - Shoubin Ning
- Department of Gastroenterology, The General Hospital of Air force, PLA, Fucheng Road 30th, Beijing, China
| | - Yongmin Bi
- Department of Radio and Imaging, The General Hospital of Air force, PLA, Fucheng Road 30th, Beijing, China
| | - Weicheng Xue
- Department of Pathology, Beijing Cancer Hospital, Fucheng Road 52nd, Beijing, China
| | - Li Ren
- Department of Pathology, The General Hospital of Air force, PLA, Fucheng Road 30th, Beijing, China.
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Tudor-Green B, Fonseca FP, Gomez RS, Brennan PA. Current update on the diagnosis and management of head and neck hard tissue sarcomas. J Oral Pathol Med 2017; 46:667-673. [DOI: 10.1111/jop.12573] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2017] [Indexed: 12/29/2022]
Affiliation(s)
- Ben Tudor-Green
- Department of Plastic and Reconstructive Surgery; Royal Devon & Exeter Hospital; Exeter UK
- Department of Oral and Maxillofacial Surgery; Queen Alexandra Hospital; Portsmouth UK
| | - Felipe Paiva Fonseca
- Department of Oral Surgery and Pathology; School of Dentistry; Universidade Federal de Minas Gerais; Belo Horizonte Brazil
| | - Ricardo S. Gomez
- Department of Oral Surgery and Pathology; School of Dentistry; Universidade Federal de Minas Gerais; Belo Horizonte Brazil
| | - Peter A. Brennan
- Department of Oral and Maxillofacial Surgery; Queen Alexandra Hospital; Portsmouth UK
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Grohar PJ, Janeway KA, Mase LD, Schiffman JD. Advances in the Treatment of Pediatric Bone Sarcomas. Am Soc Clin Oncol Educ Book 2017; 37:725-735. [PMID: 28561686 PMCID: PMC6066791 DOI: 10.1200/edbk_175378] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
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.
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Affiliation(s)
- Patrick J Grohar
- From the Van Andel Research Institute/Helen DeVos Children's Hospital, Grand Rapids, MI; Harvard Medical School, Boston, MA; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA; Department of Pediatrics and Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Katherine A Janeway
- From the Van Andel Research Institute/Helen DeVos Children's Hospital, Grand Rapids, MI; Harvard Medical School, Boston, MA; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA; Department of Pediatrics and Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Luke D Mase
- From the Van Andel Research Institute/Helen DeVos Children's Hospital, Grand Rapids, MI; Harvard Medical School, Boston, MA; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA; Department of Pediatrics and Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Joshua D Schiffman
- From the Van Andel Research Institute/Helen DeVos Children's Hospital, Grand Rapids, MI; Harvard Medical School, Boston, MA; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA; Department of Pediatrics and Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
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35
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Flores M, Caram A, Derrick E, Reith JD, Bancroft L, Scherer K. Ewing Sarcoma of the Pelvis with an Atypical Radiographic Appearance: A Mimicker of Non-malignant Etiologies. Cureus 2016; 8:e787. [PMID: 27774356 PMCID: PMC5071172 DOI: 10.7759/cureus.787] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Ewing sarcoma (ES) is a primary malignant bone tumor which most commonly arises in children and young adults. The common clinical presentation with ES includes nighttime pain or pain related to activity, though patients may also present with a combination of localized swelling, a palpable mass, pathologic fracture, and constitutional symptoms. Clinical diagnosis may be delayed when a patient presents with clinical or imaging findings that overlap with non-malignant etiologies, such as fibrous dysplasia (FD) or osteomyelitis. Furthermore, multimodality imaging, including computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine may prove inconclusive in particular cases. Suspicion for malignancy should not be overlooked. A biopsy must be considered, unless the diagnosis is evident, such as a clinical response to antibiotics in the setting of osteomyelitis.
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