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1

CD133 expression in chemo-resistant Ewing sarcoma cells  

Microsoft Academic Search

BACKGROUND: Some human cancers demonstrate cellular hierarchies in which tumor-initiating cancer stem cells generate progeny cells with reduced tumorigenic potential. This cancer stem cell population is proposed to be a source of therapy-resistant and recurrent disease. Ewing sarcoma family tumors (ESFT) are highly aggressive cancers in which drug-resistant, relapsed disease remains a significant clinical problem. Recently, the cell surface protein

Xiaohua Jiang; Ynnez Gwye; Darren Russell; Christine Cao; Dorothea Douglas; Long Hung; Heinrich Kovar; Timothy J Triche; Elizabeth R Lawlor

2010-01-01

2

Ewing’s sarcoma  

MedlinePLUS

Ewing's sarcoma is a malignant (cancerous) bone tumor that affects children. ... Ewing's sarcoma can occur any time during childhood and young adulthood, but usually develops during puberty, when bones ...

3

Chemotherapy in Ewing's sarcoma  

PubMed Central

Ewing’s sarcoma constitutes three per cent of all pediatric malignancies. Ewing’s sarcoma has generally been more responsive to chemotherapy than adult-type sarcomas, and chemotherapy is now recommended for all patients with this disease. It is essential to integrate local control measures in the form of surgery and/or radiotherapy at the appropriate time, along with chemotherapy to eradicate the disease. This approach has improved the survival substantially to the tune of 70% in localized disease, although outcome for metastatic disease remains dismal. Newer therapeutic approaches are required to improve outcome for metastatic and recurrent or refractory Ewing’s sarcoma in organized co-operative group trials.

Jain, Sandeep; Kapoor, Gauri

2010-01-01

4

[Ewing sarcoma. Diagnostic imaging].  

PubMed

Ewing's sarcoma is a highly malignant neoplasm of the bone whose origin is still uncertain. A strong relationship exists between Ewing's sarcoma and tumors of neural origin (Ewing family of tumors). Ewing's sarcoma must be distinguished from other round-cell tumors like lymphoma and neuroblastoma and also must be differentiated from osteogenic sarcomas. On plain radiographs, Ewing's sarcoma appears as a lytic or mixed lytic-sclerotic, rarely as predominantly sclerotic lesion with margins Lodwick grade III. It is located primarily in the diaphyseal and metadiaphyseal regions of the long bones of the lower extremities. A large soft tissue tumor is usually present. Magnetic resonance imaging is the imaging modality of choice to evaluate the extent of the primary lesion, to monitor the response to neoadjuvant chemotherapy and to follow up non-resected Ewing's sarcomas. Bone scintigraphy is necessary to detect skeletal metastasis, and 201thallium scanning has been shown to be sensitive in the monitoring of treatment response. Today, computed tomography is not longer used to image the tumor site; however, spiral CT of the lungs plays a central role as a staging and follow-up tool. PMID:9700772

Henk, C B; Grampp, S; Wiesbauer, P; Zoubek, A; Kainberger, F; Breitenseher, M; Mostbeck, G H; Imhof, H

1998-06-01

5

Targeted Therapies in Ewing's Sarcoma  

Microsoft Academic Search

Ewing's sarcoma, the second most common malignant bone tumor, is an extremely aggressive neoplasm, mainly occurring in children and adolescents. Ewing's sarcoma shows a low survival rate despite the adoption of multimodal treatments, including local control of the disease by surgery and\\/or radiotherapy and multidrug adjuvant chemotherapy. No new effective drugs have been recently described and proposed for sarcomas and,

KATIA SCOTLANDI

6

Promiscuous Partnerships in Ewing's Sarcoma  

PubMed Central

Ewing’s sarcoma is a highly aggressive bone and soft tissue tumor of children and young adults. At the molecular genetic level Ewing’s sarcoma is characterized by a balanced reciprocal translocation, t(11;22)(q24;q12), which encodes an oncogenic fusion protein and transcription factor EWS/FLI. This tumor-specific chimeric fusion retains the amino terminus of EWS, a member of the TET (TLS/EWS/TAF15) family of RNA-binding proteins, and the carboxy terminus of FLI, a member of the ETS family of transcription factors. In addition to EWS/FLI, variant translocation fusions belonging to the TET/ETS family have been identified in Ewing’s sarcoma. These studies solidified the importance of TET/ETS fusions in the pathogenesis of Ewing’s sarcoma and have since been used as diagnostic markers for the disease. EWS fusions with non-ETS transcription factor family members have been described in sarcomas that are clearly distinct from Ewing’s sarcoma. However, in recent years there have been reports of rare fusions in “Ewing’s-like tumors” that harbor the amino-terminus of EWS fused to the carboxy-terminal DNA or chromatin-interacting domains contributed by non-ETS proteins. This review aims to summarize the growing list of fusion oncogenes that characterize Ewing’s sarcoma and Ewing’s-like tumors and highlights important questions that need to be answered to further support the existing concept that Ewing’s sarcoma is strictly a “TET/ETS” fusion-driven malignancy. Understanding the molecular mechanisms of action of the various different fusion oncogenes will provide better insights into the biology underlying this rare but important solid tumor.

Sankar, Savita; Lessnick, Stephen L.

2011-01-01

7

[Cytodiagnosis of Ewing sarcoma].  

PubMed

Pelvic Ewing's sarcomas were studied by fine needle aspiration biopsy in two young male patients. Local pain, subfebrility, high ESR had occurred in both cases. X ray examination showed osteolytic lesions in both patients. The differential diagnostic question was, are the lesions osteomyelitis or malignant tumors? Fine needle aspiration biopsies and cytological examinations were performed in order to determine the nature of the lesions. The aspirates consisted of monotonous population of small undifferentiated tumor cells. The nuclei were monomorph with small nucleoli and finely granular chromatin. The tumor cells contained large amounts of PAS positive diastase-digestible granular cytoplasmic glycogen. The aspirated material was examined by immunocytochemistry and electronmicroscopy in one of the cases. Both of these methods had diagnostic value in our patients in the detection of Ewing's sarcoma. PMID:7936625

Járay, B; Balogh, Z

1994-09-25

8

Extraskeletal Neoplasm Resembling Ewing's Sarcoma.  

National Technical Information Service (NTIS)

This article reviews the pathologic features and the behavior of 39 small round, or oval cell sarcomas occurring in the soft tissues and considered histologically indistinguishable from Ewing's sarcoma of bone. The tumors affected chiefly young adults (me...

L. Angervall F. M. Enzinger

1974-01-01

9

Collecting and Storing Biological Samples From Patients With Ewing Sarcoma  

ClinicalTrials.gov

Askin Tumor; Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

2014-02-18

10

Genetics Home Reference: Ewing sarcoma  

MedlinePLUS

... bone cancer is called osteosarcoma). What are the genetic changes related to Ewing sarcoma? The most common ... Center . Where can I find general information about genetic conditions? The Handbook provides basic information about genetics ...

11

Primary Ewing's Sarcoma of the Lung  

PubMed Central

Most cases of Ewing's sarcoma are reported in the bone, and extraosseous Ewing's sarcoma is an extremely rare disease. Here, we report a rare case of primary pulmonary Ewing's sarcoma in a patient with hemoptysis. The patient underwent right upper lung lobe lobectomy with adjuvant chemotherapy and radiation therapy and has been free of recurrent disease for 4 years.

Hwang, Su Kyung; Park, Seung-Il; Kim, Yong-Hee; Kim, Hyeong Ryul

2014-01-01

12

Primary Ewing's Sarcoma of the Lung.  

PubMed

Most cases of Ewing's sarcoma are reported in the bone, and extraosseous Ewing's sarcoma is an extremely rare disease. Here, we report a rare case of primary pulmonary Ewing's sarcoma in a patient with hemoptysis. The patient underwent right upper lung lobe lobectomy with adjuvant chemotherapy and radiation therapy and has been free of recurrent disease for 4 years. PMID:24570867

Hwang, Su Kyung; Kim, Dong Kwan; Park, Seung-Il; Kim, Yong-Hee; Kim, Hyeong Ryul

2014-02-01

13

The biology of ewing sarcoma.  

PubMed

Objective. The goal of this study was to review the current literature on the biology of Ewing's sarcoma, including current treatments and the means by which an understanding of biological mechanisms could impact future treatments. Methods. A search of PubMed and The Cochrane Collaboration was performed. Both preclinical and clinical evidence was considered, but specific case reports were not. Primary research articles and reviews were analyzed with an emphasis on recent publications. Results. Ewing sarcoma is associated with specific chromosomal translocations and the resulting transcripts/proteins. Knowledge of the biology of Ewing sarcoma has been growing but has yet to significantly impact or produce new treatments. Localized cases have seen improvements in survival rates, but the same cannot be said of metastatic and recurrent cases. Standard surgical, radiation, and chemotherapy treatments are reaching their efficacy limits. Conclusion. Improving prognosis likely lies in advancing biomarkers and early diagnosis, determining a cell(s) of origin, and developing effective molecular therapeutics and antiangiogenic agents. Preclinical evidence suggests the utility of molecular therapies for Ewing sarcoma. Early clinical results also reveal potential for novel treatments but require further development and evaluation before widespread use can be advocated. PMID:23346417

Ross, Keir A; Smyth, Niall A; Murawski, Christopher D; Kennedy, John G

2013-01-01

14

Spinal Ewing sarcoma: Misleading appearances  

Microsoft Academic Search

The plain radiographic and computed tomographic (CT) findings in two unusual cases of spinal Ewing sarcoma are reported. Radiographic features resembling neuroblastoma in one case and aneurysmal bone cyst in the other were present. These findings may be misleading and distinguishing characteristics in each case are discussed.

James B. Weinstein; Marilyn J. Siegel; Rogers C. Griffith

1984-01-01

15

The Biology of Ewing Sarcoma  

PubMed Central

Objective. The goal of this study was to review the current literature on the biology of Ewing's sarcoma, including current treatments and the means by which an understanding of biological mechanisms could impact future treatments. Methods. A search of PubMed and The Cochrane Collaboration was performed. Both preclinical and clinical evidence was considered, but specific case reports were not. Primary research articles and reviews were analyzed with an emphasis on recent publications. Results. Ewing sarcoma is associated with specific chromosomal translocations and the resulting transcripts/proteins. Knowledge of the biology of Ewing sarcoma has been growing but has yet to significantly impact or produce new treatments. Localized cases have seen improvements in survival rates, but the same cannot be said of metastatic and recurrent cases. Standard surgical, radiation, and chemotherapy treatments are reaching their efficacy limits. Conclusion. Improving prognosis likely lies in advancing biomarkers and early diagnosis, determining a cell(s) of origin, and developing effective molecular therapeutics and antiangiogenic agents. Preclinical evidence suggests the utility of molecular therapies for Ewing sarcoma. Early clinical results also reveal potential for novel treatments but require further development and evaluation before widespread use can be advocated.

Ross, Keir A.; Smyth, Niall A.; Murawski, Christopher D.; Kennedy, John G.

2013-01-01

16

Imaging characteristics of primary cranial Ewing sarcoma  

Microsoft Academic Search

Background: Ewing sarcoma accounts for 10–15% of all childhood malignant bone tumours and is second in prevalence to osteosarcoma. The skull bones are an unusual site of origin of primary Ewing sarcoma in children. Previous reports concentrate on the neurosurgical aspects and relatively good outcome compared to other bone tumours of the calvarium. Reported cases mainly describe the imaging characteristics

Wai-Yung Li; Penelope Brock; Dawn E. Saunders

2005-01-01

17

Metastatic Ewing sarcoma masquerading as olfactory neuroblastoma  

Microsoft Academic Search

Ewing sarcoma is a malignant tumor of bone that rarely spreads to the head and neck. We describe an unusual case of metastatic Ewing sarcoma involving the calvarium mimicking olfactory neuroblastoma, an uncommon neuroectodermal tumor of the anterior skull base. Pertinent clinical, radiological, and pathologic features of these tumors are described, with particular attention to their imaging characteristics.

Ron C. Gaba; Joseph P. Cousins; Indu S. Basil; Hazar Shadid; Tibor Valyi-Nagy; Mahmood F. Mafee

2006-01-01

18

Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors  

ClinicalTrials.gov

Desmoplastic Small Round Cell Tumor; Ewing Sarcoma of Bone or Soft Tissue; Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

2014-06-09

19

Innovative therapies in Ewing Sarcoma.  

PubMed

Ewing Sarcoma is a developmental tumor characterized by balanced chromosomal translocations and formation of new fusion genes, which are the main hallmark of this rare entity. Despite the vast knowledge regarding the molecular aspects of this rare malignancy obtained in the last few years, including the discovery of new therapeutic targets, many questions still remain open. In this review we focus on the research on targeted therapies in this malignancy, and discussed some bottlenecks related to this such as the possible role of pathologists, the availability of samples, the lack of appropriate animal models, and the resources needed to carry out preclinical and clinical research. PMID:24316910

Amaral, Ana Teresa; Ordóñez, José Luis; Otero-Motta, Ana Pastora; García-Domínguez, Daniel J; Sevillano, María Victoria; de Álava, Enrique

2014-01-01

20

Targeted Therapy in Ewing Sarcoma  

PubMed Central

Despite marked improvement in the prognosis of patients with nonmetastatic Ewing sarcoma (ES), the outcome for patients with recurrent or metastatic disease remains poor. Insight into key biologic processes in ES could provide new therapeutic targets. The particular biologic feature of ES, the fusion of the EWS gene with a member of the ETS family of genes, is present in >95% of cases. The EWS-ETS chimeric protein leads to aberrant transcription that promotes tumor initiation and propagation via prosurvival and antiapoptotic pathways. Recent research has identified cooperating mutations important for ES tumorigenesis. This paper provides a summary of the latest research in ES and discusses potential novel targets for therapy.

Lissat, A.; Chao, M. M.; Kontny, U.

2012-01-01

21

Ewing's sarcoma of scapula: a rare entity  

PubMed Central

Ewing's sarcoma is the second most common malignant bone tumour of childhood and adolescence. It may affect any bone, but it is frequent in the femur, ilium and the tibia. Here the authors are reporting a case of Ewing's sarcoma involving scapula in a 14-year-old boy presenting with pain and swelling around the shoulder. Swelling was removed which on histopathological examination showed solid sheets closely packed, poorly differentiated small cells that have a high nuclear-cytoplasmic ratio, fine chromatin and small nucleoli. A tentative diagnosis of Ewing's sarcoma was made which was confirmed by immunohistochemistry.

Shahid, Mohammad; Varshney, Manoranjan; Maheshwari, Veena; Mubeen, Aysha; Siddiqui, Mohammed Azfar; Julfiqar, Julfiqar; Gaur, Kavita

2011-01-01

22

Diagnosis and Treatment of Ewing's Sarcoma  

Microsoft Academic Search

Ewing's sarcoma is a small round-cell tumor typically arising in the bones, rarely in soft tissues, of children and adolescents. Ewing's sarcoma has retained the most unfavorable prognosis of all primary musculoskeletal tumors. Prior to the use of multi-drug chemotherapy, long-term survival was less than 10%. The development of multi-disciplinary therapy with chemotherapy, irradiation, and surgery has increased current long-term

Yukihide Iwamoto

2007-01-01

23

Extraosseous Ewing sarcoma of the thyroid gland  

Microsoft Academic Search

Ewing sarcoma of the bone is a highly malignant round-cell tumor that typically presents between 10 to 20 years of age and\\u000a is more common in boys. It can have an extraosseous origin, although it is rare. We report a case of extraosseous Ewing sarcoma\\u000a in the thyroid gland in a 9-year-old girl.

Pavani Adapa; Tae-Woong Chung; Edwina J. Popek; Jill V. Hunter

2009-01-01

24

Treatment of Ewing's sarcoma in the cooperative Ewing's sarcoma study group  

Microsoft Academic Search

Multidisciplinary treatment approaches have greatly improved the prognosis of patients with Ewing's sarcoma. Four- or five-drug\\u000a combination chemotherapy regimens are combined with radiation and\\/or surgery for local control. Currently, in the Cooperative\\u000a Ewing's Sancoma Study (CESS) trials, approximately 60% of the protocol patients with Ewing's sarcoma show a relapse-free 10-year\\u000a survival. For improvement of local control, preoperative radiotherapy and\\/or brachytherapy

Toshifumi Ozaki; Winfried Winkelmann; Normann Willich; Herbert Jürgens

1997-01-01

25

WT1 regulates angiogenesis in Ewing Sarcoma  

PubMed Central

Angiogenesis is required for tumor growth. WT1, a protein that affects both mRNA transcription and splicing, has recently been shown to regulate expression of vascular endothelial growth factor (VEGF), one of the major mediators of angiogenesis. In the present study, we tested the hypothesis that WT1 is a key regulator of tumor angiogenesis in Ewing sarcoma. We expressed exogenous WT1 in the WT1-null Ewing sarcoma cell line, SK-ES-1, and we suppressed WT1 expression using shRNA in the WT1-positive Ewing sarcoma cell line, MHH-ES. Suppression of WT1 in MHH-ES cells impairs angiogenesis, while expression of WT1 in SK-ES-1 cells causes increased angiogenesis. Different WT1 isoforms result in vessels with distinct morphologies, and this correlates with preferential upregulation of particular VEGF isoforms. WT1-expressing tumors show increased expression of pro-angiogenic molecules such as VEGF, MMP9, Ang-1, and Tie-2, supporting the hypothesis that WT1 is a global regulator of angiogenesis. We also demonstrate that WT1 regulates the expression of a panel of pro-angiogenic molecules in Ewing sarcoma cell lines. Finally, we found that WT1 expression is correlated with VEGF expression, MMP9 expression, and microvessel density in samples of primary Ewing sarcoma. Thus, our results demonstrate that WT1 expression directly regulates tumor angiogenesis by controlling the expression of a panel of pro-angiogenic genes.

Katuri, Varalakshmi; Gerber, Stephanie; Qiu, Xiaofei; McCarty, Gregory; Goldstein, Seth D.; Hammers, Hans; Montgomery, Elizabeth; Chen, Allen R.; Loeb, David M.

2014-01-01

26

Radiographic appearance of Ewing sarcoma of the hands and feet: report from the Intergroup Ewing Sarcoma Study  

Microsoft Academic Search

Review of current data from the Intergroup Ewing Sarcoma Study (IESS) shows that Ewing sarcoma is rare in bones of the hands and feet. The 12 patients from the IESS protocols with hand or foot Ewing sarcoma are comparable to those already reported in the literature. With the exception of lesions in the calcaneus, the prognosis for disease-free survival is

W. R. Reinus; L. A. Gilula; S. K. Shirley; F. B. Askin; G. P. Siegal

1985-01-01

27

Treatment strategies for metastatic Ewing's sarcoma  

Microsoft Academic Search

Therapy in metastatic Ewing's sarcoma is reviewed using the methodology recommended by the guidelines project of the Federation of French Cancer Centres (FNCLCC) Standards, Options and Recommendation (SOR) Group. Twelve articles relating to conventional dose therapy and seven articles related to high-dose therapy were judged suitable for detailed appraisal. Rates of complete response (CR) at metastatic sites and local control

C. R. Pinkerton; A. Bataillard; S. Guillo; O. Oberlin; B. Fervers; T. Philip

2001-01-01

28

Novel Combination Chemotherapy for Localized Ewing Sarcoma  

Cancer.gov

In this clinical trial, researchers will test whether the addition of the drug combination vincristine, topotecan, and cyclophosphamide to a standard chemotherapy regimen improves overall survival and event-free survival in newly diagnosed patients with non-metastatic Ewing sarcoma of the bone or soft tissue (excluding the soft tissue of the skull).

29

EXTRA-OSSEOUS EWING SARCOMA  

Microsoft Academic Search

Background: Clinical data and data on outcome of extra-osseous Ewing tumors are scarce. Procedure: After a search for Ewing tumors in the database of a single institution over a period of 20 years, 16 out of 192 cases were found to have extra-osseous primary tumors. Results: Ages at initial diagnosis ranged from 2.5 to 17 years. Follow-up period ranged from

Hendrik van den Berg; Richard C. Heinen; Pal van der H. J; Johannes H. M. Merks

2009-01-01

30

Ewings Sarcoma of the Hand—A Case Report  

Microsoft Academic Search

Ewings sarcoma of the hand is relatively rare. Ewings sarcoma can present with minimal pain and swelling of the affected digit.\\u000a The Erythrocyte sedimentation rate and C-reactive protein may be high. Radiologically, Ewings sarcoma can present with a plethora\\u000a of features from permeative bone destruction to expansile lesions with or without periosteal reaction. Because of these features,\\u000a this can be

Srinivasan Rajappa; P. Gopinath Menon; Sandhya Sundaram

2010-01-01

31

Primary Ewing Sarcoma of the Stomach – A Newly Described Entity  

Microsoft Academic Search

The Ewing sarcoma family of tumors (ESFT) includes classic Ewing sarcoma of the bone, extraosseous or soft tissue Ewing sarcoma, Askin tumors of the chest wall, and peripheral primitive neuroectodermal tumors of the bone and soft tissues. They share a common neural histogenesis, tumor genetics and biology. The genetic hallmark of the ESFT is the presence of t(11;22)(q24;q12), which creates

S. Rafailidis; K. Ballas; K. Psarras; T. Pavlidis; N. Symeonidis; G. Marakis; A. Sakadamis

2009-01-01

32

Potential molecular targets for Ewing's sarcoma therapy  

PubMed Central

Ewing's sarcoma (ES) is a highly malignant tumor of children and young adults. Modern therapy for Ewing's sarcoma combines high-dose chemotherapy for systemic control of disease, with advanced surgical and/or radiation therapeutic approaches for local control. Despite optimal management, the cure rate for localized disease is only approximately 70%, whereas the cure rate for metastatic disease at presentation is less than 30%. Patients who experience long-term disease-free survival are at risk for significant side-effects of therapy, including infertility, limb dysfunction and an increased risk for second malignancies. The identification of new targets for innovative therapeutic approaches is, therefore, strongly needed for its treatment. Many new pharmaceutical agents have been tested in early phases of clinical trials in ES patients who have recurrent disease. While some agents led to partial response or stable disease, the percentages of drugs eliciting responses or causing an overall effect have been minimal. Furthermore, of the new pharmaceuticals being introduced to clinical practice, the most effective agents also have dose-limiting toxicities. Novel approaches are needed to minimize non-specific toxicity, both for patients with recurrence and at diagnosis. This report presents an overview of the potential molecular targets in ES and highlights the possibility that they may serve as therapeutic targets for the disease. Although additional investigations are required before most of these approaches can be assessed in the clinic, they provide a great deal of hope for patients with Ewing's sarcoma.

Jully, Babu; Rajkumar, Thangarajan

2012-01-01

33

Characteristics of human Ewing/PNET sarcoma models.  

PubMed

Ewing/PNET (peripheral neuroepithelioma) tumors are rare aggressive bone sarcomas occurring in young people. Rare-disease clinical trials can require global collaborations and many years. In vivo models that as accurately as possible reflect the clinical disease are helpful in selecting therapeutics with the most promise of positive clinical impact. Human Ewing/PNET sarcoma cell lines developed over the past 45 years are described. Several of these have undergone genetic analysis and have been confirmed to be those of Ewing/PNET sarcoma. The A673 Ewing sarcoma line has proven to be particularly useful in understanding the biology of this disease in the mouse. The chromosomal translocation producing the EWS/FLI1 fusion transcript characterizes clinical Ewing sarcoma. Cell lines that express this genetic profile are confirmed to be those of Ewing sarcoma. The A673 Ewing sarcoma line grows in culture and as a xenograft in immunodeficient mice. The A673 model has been used to study Ewing sarcoma angiogenesis and response to antiangiogenic agents. Many Ewing sarcoma clinical specimens express the cell surface protein endosialin. Several Ewing sarcoma cell lines, including the A673 line, also express cell surface endosialin when grown as subcutaneous tumor nodules and as disseminated disease; thus the A673 is a useful model for the study of endosialin biology and endosialin-directed therapies. With the advent of tools that allow characterization of clinical disease to facilitate optimal treatment, it becomes imperative, especially for rare tumors, to develop preclinical models reflecting disease subsets. Ewing PNET sarcomas are a rare disease where models are available. PMID:21422656

Teicher, Beverly A; Bagley, Rebecca G; Rouleau, Cecile; Kruger, Ariel; Ren, Yi; Kurtzberg, Leslie

2011-01-01

34

An Unusual Tumor of the Breast - Extraskeletal Ewing Sarcoma  

PubMed Central

Extraskeletal Ewing's Sarcoma/Primitive Neuroectodermal Tumor presenting as a breast mass is uncommon. It may pose a diagnostic challenge. In order to increase awareness and identify potential diagnostic pitfalls, we report a 24 year-old woman extraosseous Extraskeletal Ewing's Sarcoma/Primitive Neuroectodermal Tumor arising in the breast.

TASLI, FUNDA; OZKOK, GULIZ; AYKAS, AHMET; POSTACI, HAKAN; USLU, ADAM

2014-01-01

35

An unusual tumor of the breast - extraskeletal ewing sarcoma.  

PubMed

Extraskeletal Ewing's Sarcoma/Primitive Neuroectodermal Tumor presenting as a breast mass is uncommon. It may pose a diagnostic challenge. In order to increase awareness and identify potential diagnostic pitfalls, we report a 24 year-old woman extraosseous Extraskeletal Ewing's Sarcoma/Primitive Neuroectodermal Tumor arising in the breast. PMID:24791212

Ta?li, Funda; Ozkök, Güliz; Aykas, Ahmet; Postaci, Hakan; Uslu, Adam

2014-01-01

36

Plain radiographic predictors of survival in treated Ewing's sarcoma  

Microsoft Academic Search

We analyzed 16 radiographic features of primary Ewing's sarcoma in 342 patients from the IESS 7299 (Intergroup Ewing's Sarcoma Study) for prognostic significance. Of these, 3 features demonstrated a statistically significant relationship to survival:maximal tumor dimension, tumor location, and an appearance of honeycombing within the lesion. Those individuals with primary lesions centered in the pelvis, femur, or humerus had a

William R. Reinus; Edmund A. Gehan; Louis A. Gilula; Mark Nesbit

1992-01-01

37

Ewing's sarcoma of the ribs. A report from the Cooperative Ewing's Sarcoma Study  

Microsoft Academic Search

31 patients with primary Ewing's sarcoma of the ribs were treated according to the protocols of CESS 81, CESS 86P and CESS 86. The results of treatment were reviewed and analysed. 24 patients presented with localised disease and 7 with regional disease. 20 of 24 localised cases and 6 of 7 regional cases underwent tumour resection. All but 2 localised

T. Ozaki; N. Lindner; C. Hoffmann; A. Hillmann; R. Rödl; S. Blasius; T. Link; W. Winkelmann; H. Jürgens

1995-01-01

38

Combination Chemotherapy in Treating Patients With Non-Metastatic Extracranial Ewing Sarcoma  

ClinicalTrials.gov

Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Childhood Supratentorial Primitive Neuroectodermal Tumor; Ewing Sarcoma of Bone; Extraosseous Ewing Sarcoma; Extraosseous Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Peripheral Primitive Neuroectodermal Tumor of the Kidney; Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor

2014-02-05

39

Ewing's sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors  

PubMed Central

Ewing’s sarcoma is a highly malignant bone tumor found in children and adolescents, and the origin of this malignancy is not well understood. Here, we introduced a Ewing’s sarcoma–associated genetic fusion of the genes encoding the RNA-binding protein EWS and the transcription factor ETS (EWS-ETS) into a fraction of cells enriched for osteochondrogenic progenitors derived from the embryonic superficial zone (eSZ) of long bones collected from late gestational murine embryos. EWS-ETS fusions efficiently induced Ewing’s sarcoma–like small round cell sarcoma formation by these cells. Analysis of the eSZ revealed a fraction of a precursor cells that express growth/differentiation factor 5 (Gdf5), the transcription factor Erg, and parathyroid hormone-like hormone (Pthlh), and selection of the Pthlh-positive fraction alone further enhanced EWS-ETS–dependent tumor induction. Genes downstream of the EWS-ETS fusion protein were quite transcriptionally active in eSZ cells, especially in regions in which the chromatin structure of the ETS-responsive locus was open. Inhibition of ?-catenin, poly (ADP-ribose) polymerase 1 (PARP1), or enhancer of zeste homolog 2 (EZH2) suppressed cell growth in a murine model of Ewing’s sarcoma, suggesting the utility of the current system as a preclinical model. These results indicate that eSZ cells are highly enriched in precursors to Ewing’s sarcoma and provide clues to the histogenesis of Ewing’s sarcoma in bone.

Tanaka, Miwa; Yamazaki, Yukari; Kanno, Yohei; Igarashi, Katsuhide; Aisaki, Ken-ichi; Kanno, Jun; Nakamura, Takuro

2014-01-01

40

Mesenchymal Stem Cells and the Origin of Ewing's Sarcoma  

PubMed Central

The origin of Ewing's sarcoma is a subject of much debate. Once thought to be derived from primitive neuroectodermal cells, many now believe it to arise from a mesenchymal stem cell (MSC). Expression of the EWS-FLI1 fusion gene in MSCs changes cell morphology to resemble Ewing's sarcoma and induces expression of neuroectodermal markers. In murine cells, transformation to sarcomas can occur. In knockdown experiments, Ewing's sarcoma cells develop characteristics of MSCs and the ability to differentiate into mesodermal lineages. However, it cannot be concluded that MSCs are the cell of origin. The concept of an MSC still needs to be rigorously defined, and there may be different subpopulations of mesenchymal pluripotential cells. Furthermore, EWS-FLI1 by itself does not transform human cells, and cooperating mutations appear to be necessary. Therefore, while it is possible that Ewing's sarcoma may originate from a primitive mesenchymal cell, the idea needs to be refined further.

Lin, Patrick P.; Wang, Yongxing; Lozano, Guillermina

2011-01-01

41

[Ewing's sarcoma. New clinico-pathological aspects].  

PubMed

Ewing's sarcoma is a rare, but highly malignant bone tumor. During the years 1966-1983 we diagnosed and treated this tumor in 84 patients. Diagnosis of the tumor in an early stage is a prerequisite for successful therapy. Clinical and radiological findings contribute to the diagnosis, but histologic confirmation is indispensible. In addition to histomorphology we regard electron microscopy and the demonstration of glycogen as essential for the final diagnosis. The differential diagnosis includes haematogeneous osteomyelitis, malignant lymphoma, metastases from neuroblastomas, rhabdomyosarcoma and some benign bone tumors. New observations concerning the histogenesis of Ewing's sarcoma are discussed. The introduction of chemotherapy as part of a multimodality approach to treatment has substantially improved the prognosis in comparison to the previous results with surgery and radiation therapy. The role of surgery and radiation independently and in combination is discussed. We propose an approach to treatment based on our experience which involves surgical removal of the primary tumor after preoperative chemotherapy. The overall survival rate among our 84 patients was 40%. Among those who were diagnosed early and treated according to the recommended protocol 54% are alive. PMID:3788306

Matejovsky, Z; Povysil, C

1986-01-01

42

Cellular and humoral mechanisms of osteoclast formation in Ewing's sarcoma  

PubMed Central

Cellular mechanisms that account for tumour osteolysis associated with Ewing's sarcoma are uncertain. Osteoclasts are marrow-derived multinucleated cells (MNCs) that effect tumour osteolysis. Osteoclasts are known to form from macrophages by both receptor activator for nuclear factor-?B (RANK) ligand (RANKL)-dependent and -independent mechanisms. In this study, our aim has been to determine whether tumour-associated macrophages (TAMs) isolated from Ewing's sarcoma are capable of differentiating into osteoclasts and to characterise the cellular and humoral mechanisms whereby this occurs. Tumour-associated macrophages were isolated from two Ewing's sarcomas and cultured on both coverslips and dentine slices for up to 21 days with soluble RANKL and macrophage colony stimulating factor (M-CSF). Osteoclast formation from TAMs (CD14+) was evidenced by the formation of tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor (VNR)-positive MNCs, which were capable of carrying out lacunar resorption. This osteoclast formation was inhibited by the addition of bisphosphonates. Both Ewing's sarcoma-derived fibroblasts and some bone stromal cells expressed RANKL and supported osteoclast formation by a contact-dependent mechanism. We also found that osteoclast differentiation occurred when Ewing's TAMs were cultured with tumour necrosis factor (TNF)-? in the presence of M-CSF and that TC71 Ewing's sarcoma cells stimulated osteoclast formation through the release of a soluble factor, the action of which was abolished by an antibody to TNF-?. These results indicate that TAMs in Ewing's sarcoma are capable of osteoclast differentiation by both RANKL-dependent and TNF-?-dependent mechanisms and that Ewing's sarcoma cells produce osteoclastogenic factor(s). Our findings suggest that anti-resorptive and anti-osteoclastogenic therapies may be useful in inhibiting the osteolysis of Ewing's sarcoma.

Lau, Y S; Adamopoulos, I E; Sabokbar, A; Giele, H; Gibbons, C L M H; Athanasou, N A

2007-01-01

43

Ewing's sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors.  

PubMed

Ewing's sarcoma is a highly malignant bone tumor found in children and adolescents, and the origin of this malignancy is not well understood. Here, we introduced a Ewing's sarcoma-associated genetic fusion of the genes encoding the RNA-binding protein EWS and the transcription factor ETS (EWS-ETS) into a fraction of cells enriched for osteochondrogenic progenitors derived from the embryonic superficial zone (eSZ) of long bones collected from late gestational murine embryos. EWS-ETS fusions efficiently induced Ewing's sarcoma-like small round cell sarcoma formation by these cells. Analysis of the eSZ revealed a fraction of a precursor cells that express growth/differentiation factor 5 (Gdf5), the transcription factor Erg, and parathyroid hormone-like hormone (Pthlh), and selection of the Pthlh-positive fraction alone further enhanced EWS-ETS-dependent tumor induction. Genes downstream of the EWS-ETS fusion protein were quite transcriptionally active in eSZ cells, especially in regions in which the chromatin structure of the ETS-responsive locus was open. Inhibition of ?-catenin, poly (ADP-ribose) polymerase 1 (PARP1), or enhancer of zeste homolog 2 (EZH2) suppressed cell growth in a murine model of Ewing's sarcoma, suggesting the utility of the current system as a preclinical model. These results indicate that eSZ cells are highly enriched in precursors to Ewing's sarcoma and provide clues to the histogenesis of Ewing's sarcoma in bone. PMID:24911143

Tanaka, Miwa; Yamazaki, Yukari; Kanno, Yohei; Igarashi, Katsuhide; Aisaki, Ken-Ichi; Kanno, Jun; Nakamura, Takuro

2014-07-01

44

Cellular and humoral mechanisms of osteoclast formation in Ewing's sarcoma  

Microsoft Academic Search

Cellular mechanisms that account for tumour osteolysis associated with Ewing's sarcoma are uncertain. Osteoclasts are marrow-derived multinucleated cells (MNCs) that effect tumour osteolysis. Osteoclasts are known to form from macrophages by both receptor activator for nuclear factor-?B (RANK) ligand (RANKL)-dependent and -independent mechanisms. In this study, our aim has been to determine whether tumour-associated macrophages (TAMs) isolated from Ewing's sarcoma

Y S Lau; I E Adamopoulos; A Sabokbar; H Giele; C L M H Gibbons; N A Athanasou

2007-01-01

45

Localized Ewing sarcoma of the tibia  

PubMed Central

Ewing sarcoma (ES) is a high-grade malignant primary round cell tumour of bone in which there is commonly extension into extraosseous soft tissues at the time of diagnosis. This report details the clinical, radiological and pathological features of a case of ES of the tibia in which there was extensive osseous involvement but no infiltration beyond the periosteum into surrounding soft tissue. We also record the findings of one other ES case that exhibited similar behaviour. Both cases were male, involved the tibia and had the characteristic t (11;22) (q24;q12) translocation. No recurrence of tumour or metastasis has been seen in these two cases, both of which have had 6?years follow-up. Our findings indicate that there is heterogeneity in the behaviour of ES and show that localized ES is associated with a good prognosis.

2013-01-01

46

Primary extraosseous Ewing sarcoma of the orbit.  

PubMed

A 40-year-old man presented with painless, progressive vision loss and mild proptosis of the OD. CT revealed a right intraconal mass with slight penetration of the optic canal not contiguous with any bony structure. Incisional biopsy through a transfrontal orbitotomy revealed a diffuse growth of homogeneous, small, round cells. Immunohistochemical stains were positive for vimentin and MIC2 (CD99), and the translocation at EWS gene (22q12) was detected. Metastatic workup and a full-body bone scan were negative, confirming primary orbital extraosseous Ewing sarcoma. The patient received neoadjuvant chemotherapy and an orbital exenteration with preservation of eyelids and conjunctiva. He also received adjuvant chemotherapy and local radiotherapy, and he has remained disease-free for almost 3 years. PMID:23247035

Alio, Jorge L; Sales-Sanz, Marco; Vaz, Maria A; Barrancos, Constanza; Reguero, Maria E; Diamantopoulus, Jorge; Poveda, Pedro

2013-01-01

47

Immunohistological characterization of a Ewing's sarcoma case.  

PubMed

The histogenesis of Ewing's sarcoma (ES) remains uncertain. Mesenchymal and neuroectodermal origins were the most recent hypotheses. In an attempt to test these two hypotheses, frozen sections of an ES with the chromosomal translocation t(11;22) have been studied using a panel of antibodies directed against monocytes/macrophages cell surface antigens (Leu M1, Leu M2, Leu M3, and MO1), and against neural components (NSE, S-100, T4, and HNK-1). None of these antigens were detected. Positive reactions were obtained with antibodies recognizing HLA II antigen and B2-microglobulin. From a panel of various intermediate filaments only vimentin was shown to be present. None of the two hypotheses could be supported by the results obtained from the immunohistological analysis of the tumor studied. In the absence of a specific immunological pattern, the chromosomal t(11;22)(q24;q12) marker remains the only diagnostic criterion of ES. PMID:3180134

Lizard-Nacol, S; Mugneret, F; Turc-Carel, C; Justrabo, E

1988-01-01

48

Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma  

PubMed Central

Purpose of review In 2012, two publications revealed a particular sensitivity of Ewing sarcoma cells to the inhibition of poly(ADP-ribose) polymerase (PARP). This review updates the reader on PARP function, the development of PARP inhibitors (PARPi) and the evidence for targeting PARP in Ewing sarcoma. It concludes with a description of ongoing/emerging PARPi clinical trials in patients with Ewing sarcoma. Recent findings PARP has a major role in DNA repair, and is a transcription regulator. The oncoprotein in Ewing sarcoma, EWS-FLI1, is proposed to interact with PARP-1, driving PARP-1 expression, which further promotes transcriptional activation by EWS-FLI1. Thus, there are two rationales for PARPi in the treatment of Ewing sarcoma: to disrupt the interaction between EWS-FLI1 and PARP, and for chemo-potentiation or radio-potentiation. The first clinical trial with a single agent PARPi failed to show significant responses, but preclinical evidence for combinations of PARPi with chemotherapy or radiotherapy is very promising. Summary Despite initial excitement for the potential of PARPi as single agent therapy in Ewing sarcoma, the emerging preclinical data now strongly support testing PARPi in combination with chemo/radiotherapy clinically.

Vormoor, Britta; Curtin, Nicola J.

2014-01-01

49

Ewing's sarcoma cancer stem cell targeted therapy.  

PubMed

Ewing`s sarcoma (ES) family of tumors (ESFTs) are round cell tumors of bone and soft tissues, afflicting children and young adults. This review summarizes the present findings about ES cancer stem cell (CSC) targeted therapy: prognostic factors, chromosomal translocations, initiation, epigenetic mechanisms, candidate cell of ES origin (Mesenchymal stem cells (MSCs) and Neural crest stem cells (NCSCs)). The ES CSC model, histopathogenesis, histogenesis, pathogenesis, ES mediated Hematopoietic stem progenitor cells (HSPCs) senescence are also discussed. ESFTs therapy is reviewed concerning CSCs, radiotherapy, risk of subsequent neoplasms, stem cell (SC) support, promising therapeutic targets for ES CSCs (CSC markers, immune targeting, RNAi phenotyping screens, proposed new drugs), candidate EWS-FLI1 target genes and further directions (including human embryonic stem cells (hESCs)). Bone marrow-derived human MSCs are permissive for EWS-FLI1 expression with transition to ESFT-like cellular phenotype. ESFTs are genetically related to NCSC, permissive for EWS-FLI1 expression and susceptible to oncogene-induced immortalization. Primitive neuroectodermal features and MSC origin of ESFTs provide a basis of immune targeting. The microRNAs profile of ES CSCs is shared by ESCs and CSCs from divergent tumor types. Successful reprogramming of differentiated human somatic cells into a pluripotent state allows creation of patient- and disease-specific SCs. The functional role of endogenous EWS at stem cell level on both senescence and tumorigenesis is a link between cancer and aging. The regulatory mechanisms of oncogenic activity of EWS fusions could provide new prognostic biomarkers, therapeutic opportunities and tumor-specific anticancer agents against ESFTs. PMID:24294922

Todorova, Roumiana

2014-01-01

50

Radiographic Appearance of Ewing Sarcoma of the Hands and Feet: Report from the  

Microsoft Academic Search

Review of current data from the Intergroup Ewing Sarcoma Study (lESS) shows that Ewing sarcoma is rare in bones of the hands and feet. The 12 patients from the lESS protocols with hand or foot Ewing sarcoma are comparable to those already reported in the literature. With the exception of lesions in the calcaneus, the prognosis for disease- free survival

William A. Remus; Louis A. GiIul; Sandra K. Shirley; Frederic B. Askin; Gene P. Siegal

51

A single institution experience of combined modality management of extra skeletal Ewings sarcoma  

Microsoft Academic Search

BACKGROUND: Extraskeletal Ewings sarcoma are rare tumors for which there is no consensus on optimal management. METHODS: A retrospective review of the clinical features, treatment and outcome of patients with extraskeletal Ewings sarcoma who reported to a single institution between January 1992 – December 2003 is reported. RESULTS: A total of 19 patients with extraskeletal Ewings sarcoma were identified. Of

Ramachandran Venkitaraman; Mathew K George; S Ganapathy Ramanan; TG Sagar

2007-01-01

52

Germline PTPRD mutations in Ewing sarcoma: biologic and clinical implications.  

PubMed

Ewing sarcoma occurs in children, adolescents and young adults. High STAT3 levels have been reported in approximately 50% of patients with Ewing sarcoma, and may be important in tumorigenesis. Protein tyrosine phosphatase delta (PTPRD) is a tumor suppressor that inhibits STAT3 activation. To date, while somatic mutations in PTPRD have been reported in diverse tumors, germline mutations of PTPRD have not been investigated in Ewing sarcoma or other cancers. We identified a novel germline mutation in the PTPRD gene in three of eight patients (37.5%) with metastatic Ewing sarcoma. Although the functional impact in two of the patients is unclear, in one of them the aberration was annotated as a W775stop germline mutation, and would be expected to lead to gene truncation and, hence, loss of the STAT3 dephosphorylation function of PTPRD. Since STAT3 is phosphorylated after being recruited to the insulin growth factor receptor (IGF-1R), suppression of IGF-1R could attenuate the enhanced STAT3 activation expected in the presence of PTPRD mutations. Of interest, two of three patients with germline PTPRD mutations achieved durable complete responses following treatment with IGF-1R monoclonal antibody-based therapies. Our pilot data suggest that PTPRD germline mutations may play a role in the development of Ewing sarcoma, a disease of young people, and their presence may have implications for therapy. PMID:23800680

Jiang, Yunyun; Janku, Filip; Subbiah, Vivek; Angelo, Laura S; Naing, Aung; Anderson, Peter M; Herzog, Cynthia E; Fu, Siqing; Benjamin, Robert S; Kurzrock, Razelle

2013-06-01

53

Germline PTPRD Mutations in Ewing Sarcoma: Biologic and Clinical Implications  

PubMed Central

Ewing sarcoma occurs in children, adolescents and young adults. High STAT3 levels have been reported in approximately 50% of patients with Ewing sarcoma, and may be important in tumorigenesis. Protein tyrosine phosphatase delta (PTPRD) is a tumor suppressor that inhibits STAT3 activation. To date, while somatic mutations in PTPRD have been reported in diverse tumors, germline mutations of PTPRD have not been investigated in Ewing sarcoma or other cancers. We identified a novel germline mutation in the PTPRD gene in three of eight patients (37.5%) with metastatic Ewing sarcoma. Although the functional impact in two of the patients is unclear, in one of them the aberration was annotated as a W775stop germline mutation, and would be expected to lead to gene truncation and, hence, loss of the STAT3 dephosphorylation function of PTPRD. Since STAT3 is phosphorylated after being recruited to the insulin growth factor receptor (IGF-1R), suppression of IGF-1R could attenuate the enhanced STAT3 activation expected in the presence of PTPRD mutations. Of interest, two of three patients with germline PTPRD mutations achieved durable complete responses following treatment with IGF-1R monoclonal antibody-based therapies. Our pilot data suggest that PTPRD germline mutations may play a role in the development of Ewing sarcoma, a disease of young people, and their presence may have implications for therapy.

Subbiah, Vivek; Angelo, Laura S.; Naing, Aung; Anderson, Peter M.; Herzog, Cynthia E.; Fu, Siqing; Benjamin, Robert S.; Kurzrock, Razelle

2013-01-01

54

Round cell sarcomas beyond Ewing: emerging entities.  

PubMed

Primitive small blue round cell tumours (SBRCT) of childhood and young adults have been problematic to diagnose and classify. Diagnosis is also complicated in cases with atypical morphology, aberrant immunoprofiles and unusual clinical presentations. Even with the increased use of ancillary techniques in archival material, such as immunohistochemistry and molecular/genetic methods, a proportion of these tumours cannot be subclassified into specific histological types. A subset of tumours resembling microscopically the Ewing sarcoma family of tumours (EFT), being composed of primitive small round cells and occurring in paediatric or young adult age groups, remain unclassified, being negative for EWSR1, SS18(SYT), DDIT3(CHOP) and FOXO1(FKHR) gene rearrangements by FISH/RT-PCR. A small number of cases sharing the undifferentiated EFT appearance have been characterized recently carrying BCOR-CCNB3 or CIC-DUX4 fusions. However, based on the somewhat limited number of cases, it remains unclear if these newly defined genetic entities belong to any of the pre-existing clinicopathological disorders or represent altogether novel conditions. This review presents the latest molecular findings related to these SBRCTs, beyond the common EWSR1-ETS fusions. Specific attention has been paid to morphological features not associated typically with classic EFT, and the value of ancillary tests that can be applied when dealing with EWSR1-negative SBRCTs is discussed. PMID:24215322

Antonescu, Cristina

2014-01-01

55

Adult Intramedullary Ewing Sarcoma of the Proximal Hip  

PubMed Central

Ewing sarcoma of bone is classically a permeative lesion in the diaphysis of long bones in children. While they occur primarily in children and adolescents, they can be seen in young adults in their 20s, but these are typically seen in flat bones. The permeative nature of the lesion can elicit new bone formation creating a partially sclerotic appearance, cortical expansion presenting as a “Codman triangle,” or have an “onion-skin” type of aggressive periosteal reaction/periostitis. Ewing sarcoma is rarely seen without an associated soft-tissue mass and is even rarer to just have benign-appearing periostitis (e.g., thick, uniform, or wavy cortex). We present such a case of Ewing sarcoma in a young adult confined to just the medullary metadiaphysis without cortical erosion or soft-tissue mass. To the best of our knowledge, this is the first case to be reported in the radiology literature.

Jasti, Siva; Rafferty, William; Lackman, Richard

2014-01-01

56

Primary Adult Renal Ewing's Sarcoma: A Rare Entity  

PubMed Central

Background. Ewing's sarcoma of extraskeletal origin is uncommon and that is of primary renal origin in adults are rare. There is no consensus on the optimal management of Ewing's tumors of renal origin. Methods. A retrospective review of the clinical features, treatment, and outcome of adult patients with primary renal extra-skeletal Ewing's sarcoma who were treated at the Royal Marsden hospital from January 1993–December 2007 is reported. Results. Seven adult patients with primary renal Ewing's sarcoma were identified. All four patients with nonmetastatic disease had radical nephrectomy and received adjuvant chemotherapy +/? radiotherapy. Two developed metastatic disease while on adjuvant chemotherapy, and one patient relapsed after 55 months. The three patients with metastatic disease at presentation did not have nephrectomy and were treated with chemotherapy. All three patients had disease progression with a dismal outcome. Only one patient in the whole group is alive and disease free. The median overall survival was 62.8 months, and the median disease-free survival in patients with nonmetastatic disease after combined modality treatment was 30.3 months. Conclusion. Primary adult renal Ewing's sarcoma is an aggressive tumor with a propensity for early metastasis. Radical nephrectomy with adjuvant combination chemotherapy produced the best results but the outlook remained poor with only one patient experiencing long disease-free survival.

Mukkunda, Ravindra; Venkitaraman, Ramachandran; Thway, Khin; Min, Toon; Fisher, Cyril; Horwich, Alan; Judson, Ian

2009-01-01

57

Hematometrocolpos in an adolescent female treated for pelvic Ewing sarcoma.  

PubMed

Radiation therapy is often used to achieve local control of pelvic Ewing sarcoma in children. The effects of radiation on the female reproductive tract have been well documented in adults with gynecological malignancies, but the long-term consequences of pelvic radiation in pre-pubertal or adolescent girls are not as well described. We report a case of hematometrocolpos developing in an adolescent previously treated with chemotherapy and radiation therapy for pelvic Ewing sarcoma. We describe the clinical presentation, radiographic features, gross pathology, treatment strategies, outcome, as well as putative predisposing factors and preventative interventions. PMID:16550535

Gaillard, Pamela; Krasin, Matthew J; Laningham, Fred H; Hoffer, Fredric A; Davidoff, Andrew M; Spunt, Sheri L; Smiley, Linda; Skapek, Stephen X

2008-01-01

58

Ewing sarcoma of the kidney: a rare entity.  

PubMed

Ewing sarcoma and primitive peripheral neuroectodermal tumor (PNET) are high-grade malignant tumors typically found in children and adolescents. These tumors belong to the family of small round cell tumors and are of neuroectodermal origin. Primary Ewing sarcoma of the kidney is rare and because of that is an infrequent differential diagnosis in urologic malignancies. Renal PNET mostly presents with nonspecific symptoms such as hematuria and abdominal pain. The imaging findings are uncharacteristic. The diagnosis is based on the histology, immunohistochemistry, and molecular pathologic findings. Once PNET has been diagnosed, multimodal treatment is indicated. Despite all treatment options, the prognosis of those with metastatic disease is poor. PMID:24523977

Almeida, Maria Fernanda Arruda; Patnana, Madhavi; Korivi, Brinda Rao; Kalhor, Neda; Marcal, Leonardo

2014-01-01

59

Preclinical and clinical significance of heparanase in Ewing's sarcoma  

PubMed Central

Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains of heparan sulfate proteoglycans, activity that is strongly implicated in cell migration and invasion associated with tumor metastasis, angiogenesis, and inflammation. Heparanase up-regulation was documented in an increasing number of human carcinomas, correlating with reduced postoperative survival rate and enhanced tumor angiogenesis. Expression and significance of heparanase in human sarcomas has not been so far reported. Here, we applied the Ewing's sarcoma cell line TC71 and demonstrated a potent inhibition of cell invasion in vitro and tumor xenograft growth in vivo upon treatment with a specific inhibitor of heparanase enzymatic activity (compound SST0001, non-anticoagulant N-acetylated, glycol split heparin). Next, we examined heparanase expression and cellular localization by immunostaining of a cohort of 69 patients diagnosed with Ewing's sarcoma. Heparanase staining was noted in all patients. Notably, heparanase staining intensity correlated with increased tumor size (p=0.04) and with patients' age (p=0.03), two prognostic factors associated with a worse outcome. Our study indicates that heparanase expression is induced in Ewing's sarcoma and associates with poor prognosis. Moreover, it encourages the inclusion of heparanase inhibitors (i.e., SST0001) in newly developed therapeutic modalities directed against Ewing's sarcoma and likely other malignancies.

Shafat, Itay; Ben-Arush, Myriam Weyl; Issakov, Josephine; Meller, Isaac; Naroditsky, Inna; Tortoteto, Monica; Cassinelli, Giuliana; Lanzi, Cinzia; Pisano, Claudio; Ilan, Neta; Vlodavsky, Israel; Zunino, Franco

2010-01-01

60

Ewing Sarcoma: Molecular Characterization and Potential Molecular Therapeutic Targets  

Microsoft Academic Search

\\u000a Ewing sarcoma (ES) is the second most common sarcoma affecting children and young adults. Emerging evidence indicates that\\u000a ES is likely the result of spontaneous genetic translocation and the fusion gene EWS-FLI-1 drives ES pathogenesis. ES can\\u000a be reliably diagnosed on tissue by cytology, histology, and immunohistochemistry. However, molecular confirmation and characterization\\u000a are important. Tumor stage is still the most

Marilyn M. Bui; Paul J. Zhang

61

Primary Disseminated Multifocal Ewing Sarcoma: Results of the Euro-EWING 99 Trial  

Microsoft Academic Search

Purpose To improve the poor prognosis of patients with primary disseminated multifocal Ewing sarcomas (PDMES) with a dose-intense treatment concept. Patients and Methods From 1999 to 2005, 281 patients with PDMES were enrolled onto the Euro-EWING 99 R3 study. Median age was 16.2 years (range, 0.4 to 49 years). Recommended treatment consisted of six cycles of vincristine, ifosfamide, doxorubicin, and

R. Ladenstein; U. Pötschger; Deley Le M. C; J. Whelan; M. Paulussen; O. Oberlin; H. van den Berg; U. Dirksen; L. Hjorth; J. Michon; I. Lewis; A. Craft; H. Jürgens

2010-01-01

62

Neuroectoderm-associated antigens on Ewing's sarcoma cell lines.  

PubMed

The histogenesis of Ewing's sarcoma, the second most frequent primary bone tumor in humans, remains controversial. Ten Ewing cell lines were analyzed by immunological methods. Surface antigens recognized on Ewing cells were found to be related to the neuroectoderm lineage. They included ganglioside GD2, a marker of neuroectodermal tissues and tumors, and an acidic glycolipid detected by monoclonal antibody HNK-1 in the nervous system. The P61 rat monoclonal antibody that reacts with a peptide moiety of neural cell adhesion molecule (N-CAM) and a rabbit antiserum raised to purified mouse N-CAM also stained Ewing cells. Flow cytometry analysis performed using these reagents allowed the definition of four distinct Ewing phenotypes: all reagents equally stained group 1 lines; group 2 lines were strongly reactive with anti-N-CAM reagents, by contrast with a fainter staining with HNK-1 and anti-GD2 antibodies; all reagents but P61 were strongly reactive with group 3 lines; in group 4, Ewing lines were stained by P61 but only poorly by the anti-N-CAM antiserum. Several antibodies to melanoma and neuroblastoma associated antigens including two monoclonal antibodies to the nerve growth factor receptor were also found to react with Ewing cells. By contrast, all antibodies detecting antigens specifically expressed in hematopoietic cell lineages were totally unreactive. HLA class II antigens were never detected while the level of expression of class I antigens varied to a large extent. Ewing cells are characterized by a specific t(11;22)(q23-24;q12) translocation also observed in neuroepithelioma, a neuroectodermal tumor. Thus, Ewing's sarcoma cells share antigenic and karyotypic features with derivatives of the neuroectoderm possibly indicating a related histogenesis. PMID:3024814

Lipinski, M; Braham, K; Philip, I; Wiels, J; Philip, T; Goridis, C; Lenoir, G M; Tursz, T

1987-01-01

63

Ewing sarcoma superimposed on a previous osteochondroma in multiple osteochondromatosis.  

PubMed

It has been reported that patients with hereditary multiple exostoses (called multiple osteochondromatosis by the World Health Organization) are at increased risk for malignant transformation of osteochondromas to secondary chondrosarcomas. A review of the literature found 14 cases showing transformation of osteochondromas into osteosarcomas; however, Ewing sarcoma has never been reported superimposed on an osteochondroma. This article presents the case of a boy who underwent biopsy of a previously existent osteochondroma for which the pathology report showed cytologic and immunohistochemical properties consistent with Ewing sarcoma. A 13-year-old boy with hereditary multiple exostoses (multiple osteochondromatosis) presented to an orthopedic clinic because of waxing and waning pain superficial to a previous osteochondroma on the lateral aspect of the right leg, below the knee, of 1 month's duration. On examination, inflammation was noted over a bony mass associated with tenderness to palpation of the affected area. There was no evidence of penetrating injury or trauma, and the patient reported no constitutional symptoms, including fever. Radiographs showed marked osteolysis and signs of periosteal reaction. Magnetic resonance imaging showed evidence of cortical bone erosion and extension of the mass into soft tissue. Malignant transformation was suspected, and the patient underwent biopsy. The pathology findings were consistent with Ewing sarcoma. The highly uncommon presentation of this malignancy must serve as a red flag to other physicians who treat patients with hereditary multiple exostoses. Ewing sarcoma tends to be of higher grade and have a worse prognosis than other malignancies that are more commonly seen in these patients. PMID:24762849

Marrero Barrera, Pablo A; Marrero Ortiz, Pablo V

2014-04-01

64

Survival of Patients with Ewing's Sarcoma in Yazd-Iran.  

PubMed

Background: The Ewing's sarcoma family is a group of small round cell tumors which accounts for 10-15% of all primary bone neoplasms. The aim of this study was to evaluate the survival of Ewing's sarcoma patients in our province and to determine of influencing factors. Materials and Methods: All patients with documented Ewing's sarcoma/ primitive neuroectodermal tumor(PNET) family pathology were enrolled in this study during a period of eight years. For all of them local and systemic therapy were carried out. Overall and event free survival and prognostic factors were evaluated. Results: Thirty two patients were enrolled in the study. The median age was 17.5 years. Twenty (65.2%) were male and 9 (28.1%) were aged 14 years or less. Mean disease free survival was 26.8 (95%CI; 13.8-39.9) months and five year disease free survival was 26%. Mean overall survival was 38.7 months (95%CI; 25.9-50.6) and median overall survival was 24 months. Five year overall survival was 25%. From the variables evaluated , only presence of metastatic disease at presentation (p value=0. 028) and complete response (p value =0. 006) had significant relations to overall survival. Conclusions: Survival of Ewing's sarcoma in our province is disappointing. It seems to be mostly due to less effective treatment. Administration of adequate chemotherapy dosage, resection of tumor with negative margins and precise assessment of irradiation volume may prove helpful. PMID:24998554

Akhavan, Ali; Binesh, Fariba; Shamshiri, Hadi; Ghanadi, Fazllolah

2014-01-01

65

Ewing's sarcoma in mandibular similar to dental abscess.  

PubMed

Ewing's sarcoma is a rare malignant neoplasm that comprises approximately 4-6% of primary bone tumors. In most cases, femur and pelvis are affected, and less commonly the head and neck areas (in the jaws, usually the mandible). These tumors have been reported more frequently in males, mostly aged 5-20 years old. Systemic symptoms and signs such as fever, weight loss, anemia, leukocytosis, and elevated erythrocyte sedimentation rate (ESR) may be the first signs in oral Ewing's sarcoma. Such signs and symptoms are also seen in odontogenic infections and abscess. In one case, the patient went to a dentist with pain, swelling, and abscess similar to odontogenic infection and patient's tooth was pulled due to misdiagnosis. This tumor has an aggressive clinical behavior and is identified with rapid growth and high probability of metastasis at diagnosis. Thus, it is necessary to differentiate it from a dental abscess. As for the treatment of Ewing's sarcoma, first the tumor must undergo chemotherapy to reduce its size and, eventually, it undergoes extensive surgery. This case report deals with a 16-year-old patient wrongly diagnosed with odontogenic infection and abscess, and hospitalized. As the symptoms did not remit, biopsy was carried out and the patient was operated on with Ewing's sarcoma diagnosis. PMID:24627870

Keshani, Forouz; Jahanshahi, Gholamreza; Attar, Bijan Movahedian; Kalantari, Mahsa; Razavi, Seyed Mohammad; Hashemzade, Zahra; Tavakoli, Payam

2014-01-01

66

Prognostic Impact of Ink4a Deletion in Ewing Sarcoma  

Microsoft Academic Search

BACKGROUND. The primary genetic alteration in > 95% of Ewing sarcomas (ES) is a specific fusion of EWS with FLIT or ERG. Secondary genetic alterations possibly involved in progression of ES are not well understood. A recent study found loss of the negative cell cycle regulator gene INK4A in 8 of 27 ES samples (30%). To confirm these findings and

Guo Wei; Cristina R. Antonescu; Enrique de Alava; Denis H Y Leung; Andrew G. Huvos; Paul A. Meyers; John H. Healey; Marc Ladanyi

2000-01-01

67

Ewing sarcoma of the mandibular condyle: Multidisciplinary management optimizes outcome  

Microsoft Academic Search

Background. Ewing sarcoma (ES) is a rare, pri- mary malignancy of bone that occurs in childhood and early adolescence. Improved methods of diagnosis and treatment have dramatically increased survival over the last 20 years. Treatment mainstays are chemotherapy and surgical tumor resection. ES usually occurs in long bones of the axial skeleton; however, it may rarely arise in facial structures,

Lynn W. Solomon; Jennifer L. Frustino; Thom R. Loree; Martin L. Brecher; Ronald A. Alberico; Maureen Sullivan

2008-01-01

68

Recurrence of Ewing sarcomas of the chest wall  

Microsoft Academic Search

BACKGROUND: Ewing sarcomas (ES) of the chest wall are rare. Local recurrences occur in approximately 20% of these patients; however literature on this topic is scarce. Our aim was to analyze the influence of the extent of surgical resection on outcome, and to find positive prognostic factors for survival. PROCEDURE: A retrospective analysis of all patients who were under 18

Karlijn M. E. Meys; Richard C. Heinen; Henk van den Berg; Daniel C. Aronson

2008-01-01

69

Spinal Epidural Extraskeletal Ewing Sarcoma: MR Findings in Two Cases  

Microsoft Academic Search

Summary: We report the CT myelography and MR find- ings of two cases of extraskeletal Ewing sarcoma involving the spinal epidural and paravertebral spaces in a middle- aged man (case 1) and a young woman (case 2). In both cases CT myelography showed epidural and paravertebral masses on one side, with widening of the ipsilateral neural foramina at the C5-C6

Ji Hoon Shin; Ho Kyu Lee; Seung Chul Rhim; Kyung-Ja Cho; Choong Gon Choi; Dae Chul Suh

70

Factors Affecting EWS-FLI1 Activity in Ewing's Sarcoma  

PubMed Central

Ewing's sarcoma family tumors (ESFT) are characterized by specific chromosomal translocations, which give rise to EWS-ETS chimeric proteins. These aberrant transcription factors are the main pathogenic drivers of ESFT. Elucidation of the factors influencing EWS-ETS expression and/or activity will guide the development of novel therapeutic agents against this fatal disease.

Herrero-Martin, David; Fourtouna, Argyro; Niedan, Stephan; Riedmann, Lucia T.; Schwentner, Raphaela; Aryee, Dave N. T.

2011-01-01

71

Targeting the p53 Pathway in Ewing Sarcoma.  

PubMed

The p53 tumour suppressor plays a pivotal role in the prevention of oncogenic transformation. Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of the TP53 gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins. Interestingly, genetic lesions in the TP53 gene are only observed in 10% of Ewing Sarcomas, with the majority of these sarcomas expressing a functional wild-type p53. In addition, the p53 downstream signaling pathways and DNA-damage cell cycle checkpoints remain functionally intact in these sarcomas. This paper summarizes recent insights into the functional capabilities and regulation of p53 in Ewing Sarcoma, with a particular focus on the cross-talk between p53 and the EWS-FLI1 gene rearrangement frequently associated with this disease. The development of several activators of p53 is discussed, with recent evidence demonstrating the potential of small molecule p53 activators as a promising systemic therapeutic approach for the treatment of Ewing Sarcomas with wild-type p53. PMID:21197471

Neilsen, Paul M; Pishas, Kathleen I; Callen, David F; Thomas, David M

2011-01-01

72

Role of radiation therapy in the management of nonmetastatic Ewing's sarcoma of bone. Report of the intergroup Ewing's sarcoma study  

Microsoft Academic Search

The role of radiation therapy in local tumor control and decreased incidence of pulmonary metastasis is reported in 271 patients who were entered into the Intergroup Ewing's Sarcoma Study with more than one year follow-up and on whom all radiotherapy records were reviewed. The majority of the patients were irradiated to the primary tumor with doses of 4500 to 6500

Carlos A. Perez; Melvin Tefft; Mark Nesbit; E. Omer Burgert Jr.; Teresa Vietti; John Kissane; Douglas J. Pritchard; Edmund A. Gehan

1981-01-01

73

Radiation therapy in the multimodal management of Ewing's sarcoma of bone: report of the Intergroup Ewing's Sarcoma Study  

Microsoft Academic Search

This paper is a progress report on the role of radiation therapy (RT) in local tumor control and the decreased incidence of pulmonary metastasis in 251 patients entered in the Intergroup Ewing's Sarcoma Study. All were followed for more that 1 year, and their RT records were reviewed. Doses to the primary tumor in the range of 4,500--6,500 rad were

C. A. Perez; M. Tefft; M. E. Jr. Nesbit; E. O. Jr. Burgert; T. J. Vietti; J. Kissane; D. J. Pritchard; E. A. Gehan

1981-01-01

74

Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma.  

PubMed

As a result of overlapping morphologic and immunohistochemical features, it can be difficult to distinguish synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma/primitive neuroectodermal tumor in core biopsies. To analyze and compare immunohistochemical profiles, we stained tissue microarrays of 23 synovial sarcomas, 23 malignant peripheral nerve sheath tumors, and 27 Ewing sarcomas with 22 antibodies potentially useful in the differential diagnosis, and analyzed the data with cluster analysis. Stain intensity was scored as none, weak, or strong. For CD99, tumors with membranous accentuation were independently categorized. Cluster analysis sorted five groups, with like tumors clustering together. Synovial sarcoma clustered into two groups: one cytokeratin and EMA positive (n = 11), the other mostly cytokeratin negative, EMA positive, bcl-2 positive and mostly CD56 positive (n = 9). Malignant peripheral nerve sheath tumor clustered into two groups: one S100 positive, with nestin and NGFR positivity in most (n = 10), the other mostly S100 negative, and variably but mostly weakly positive for nestin and NGFR (n = 11). Ewing sarcomas clustered into a single group driven by membranous CD99 staining. Thirteen cases failed to cluster (outliers), while three Ewing sarcomas clustered into groups of other tumor types. Paired antibodies for each tumor type determined by visual assessment of cluster analysis data and statistical calculations of specificity, sensitivity, and predictive values showed that EMA/CK7 for synovial sarcoma, nestin/S100 for malignant peripheral nerve sheath tumor, and membranous CD99/Fli-1 for Ewing sarcoma yielded high specificity and positive predictive values. Cluster analysis also highlighted aberrant staining reactions and diagnostic pitfalls in these tumors. Hierarchical cluster analysis is an effective method for analyzing high-volume immunohistochemical data. PMID:16528378

Olsen, Stephen H; Thomas, Dafydd G; Lucas, David R

2006-05-01

75

FOXM1 Is an Oncogenic Mediator in Ewing Sarcoma  

PubMed Central

Ewing Family Tumors (Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor) are common bone and soft tissue malignancies of childhood, adolescence and young adulthood. Chromosomal translocation in these tumors produces fusion oncogenes of the EWS/ETS class, with EWS/FLI1 being by far the most common. EWS/ETS chimera are the only well established driver mutations in these tumors and they function as aberrant transcription factors. Understanding the downstream genes whose expression is modified has been a central approach to the study of these tumors. FOXM1 is a proliferation associated transcription factor which has increasingly been found to play a role in the pathogenesis of a wide range of human cancers. Here we demonstrate that FOXM1 is expressed in Ewing primary tumors and cell lines. Reduction in FOXM1 expression in Ewing cell lines results in diminished potential for anchorage independent growth. FOXM1 expression is enhanced by EWS/FLI1, though, unlike other tumor systems, it is not driven by expression of the EWS/FLI1 target GLI1. Thiostrepton is a compound known to inhibit FOXM1 by direct binding. We show that Thiostrepton diminishes FOXM1 expression in Ewing cell lines and this reduction reduces cell viability through an apoptotic mechanism. FOXM1 is involved in Ewing tumor pathogenesis and may prove to be a useful therapeutic target in Ewing tumors.

Christensen, Laura; Joo, Jay; Lee, Sean; Wai, Daniel; Triche, Timothy J.; May, William A.

2013-01-01

76

FOXM1 is an oncogenic mediator in Ewing Sarcoma.  

PubMed

Ewing Family Tumors (Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor) are common bone and soft tissue malignancies of childhood, adolescence and young adulthood. Chromosomal translocation in these tumors produces fusion oncogenes of the EWS/ETS class, with EWS/FLI1 being by far the most common. EWS/ETS chimera are the only well established driver mutations in these tumors and they function as aberrant transcription factors. Understanding the downstream genes whose expression is modified has been a central approach to the study of these tumors. FOXM1 is a proliferation associated transcription factor which has increasingly been found to play a role in the pathogenesis of a wide range of human cancers. Here we demonstrate that FOXM1 is expressed in Ewing primary tumors and cell lines. Reduction in FOXM1 expression in Ewing cell lines results in diminished potential for anchorage independent growth. FOXM1 expression is enhanced by EWS/FLI1, though, unlike other tumor systems, it is not driven by expression of the EWS/FLI1 target GLI1. Thiostrepton is a compound known to inhibit FOXM1 by direct binding. We show that Thiostrepton diminishes FOXM1 expression in Ewing cell lines and this reduction reduces cell viability through an apoptotic mechanism. FOXM1 is involved in Ewing tumor pathogenesis and may prove to be a useful therapeutic target in Ewing tumors. PMID:23365673

Christensen, Laura; Joo, Jay; Lee, Sean; Wai, Daniel; Triche, Timothy J; May, William A

2013-01-01

77

Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewing's sarcoma  

PubMed Central

Summary The most prevalent forms of bone cancer are osteosarcoma, chondrosarcoma, and Ewing’s sarcoma. Although chemotherapy and radiotherapy have replaced traditional surgical treatments, survival rates have undergone only marginal improvements. Current knowledge of the molecular pathways involved in each type of cancer has led to better approaches in cancer treatment. A number of cell signaling molecules are involved in tumorigenesis, and specific targets have been identified based on these signal transducers. This review highlights some of the important cellular pathways and potential therapeutic targets, tumor site-specific irradiation techniques, and novel drug delivery systems used to administer these drugs.

Dai, Xing; Ma, Wei; He, Xijing; Jha, Rajiv Kumar

2011-01-01

78

Gastropleural Fistula: A Rare Complication of Ewing Sarcoma  

PubMed Central

Gastropleural fistula (GPF) is a rare condition that can occur as a consequence of prior pulmonary surgery, trauma, or malignancy. Conservative management usually fails, and gastrectomy and even thoracotomy is often required, especially in debilitated patients. We present a patient with GPF who had a history of Ewing's sarcoma. Diagnosis of GPF was confirmed by upper gastrointestinal system endoscopy and radiographic contrast examination, and the patient underwent a laparoscopic wedge resection of the fistula. To our knowledge, this is the first report of a GPF, in the formation of which recurrence of Ewing's sarcoma had played a role and in the treatment of which wedge resection of the fistula was performed. Laparoscopic treatment of GPF may be associated with less morbidity and should be considered as the initial procedure of choice.

Kones, Osman; Basoglu, Irfan; Al?s, Halil

2013-01-01

79

Neglected primary Ewing's sarcoma of ethmoid presenting as surgical emergency  

PubMed Central

We present a male child with primary Ewing's sarcoma arising from ethmoid sinuses with intradural and extracranial extension (bilateral nasal cavities, orbits, and maxillary sinuses). This is a rare condition. He presented with recurrent episodes of epistaxis for 2 years, sudden onset rapidly progressive bilateral proptosis, with painful restriction of extraocular movements, and decreased visual acuity for 4 days. Sudden complete loss of vision following admission demanded emergency tumor decompression.

Shukla, Dinesh; Rao, Vinjamuri Srinivas; Rajesh, Alugolu; Purohit, Aniruddh Kumar

2013-01-01

80

Prognostic Impact of P53 Status in Ewing Sarcoma  

Microsoft Academic Search

BACKGROUND: Disease stage at the time of diagnosis and response to therapy are the main prognostic factors for patients with Ewing sarcoma or peripheral neuroectodermal tumor (ES\\/PNET). The primary genetic alteration in ES\\/PNET, the fusion of the EWS gene with FLI1 or ERG, is diagnostically highly specific for these tumors, and molecular variation in the structure of the EWS-FLI1 fusion

Enrique de Alava; Cristina R. Antonescu; Angel Panizo; Denis H Y Leung; Paul A. Meyers; Andrew G. Huvos; F. J. Pardo-Mindan; John H. Healey; Marc Ladanyi

2000-01-01

81

Expression of Therapeutic Targets in Ewing Sarcoma Family Tumors  

Microsoft Academic Search

Ewing sarcoma family tumor is an aggressive malignant tumor of bone and soft tissue in children and adolescents. Despite advances in modern therapy, metastasis occurs in 20-25% of cases and results in mortality in 80% of patients. Intracellular molecules mTOR, Akt, VEGF, NF-kappa B and BRAF are important kinases and transcription factors that regulate the proliferation of tumor cells. We

Atif A. Ahmed; Ashley K. Sherman; Bruce R. Pawel

82

Dumbbell-shaped Ewing’s sarcoma family of tumor of thoracic spine in a child  

Microsoft Academic Search

An 8-year-old boy was referred due to difficulty in walking. T1-weighted MRI detected a well-marginated lesion expanding from\\u000a the epidural region in the spinal canal to the paravertebral area through the Th9 and Th10 intervertebral foramen. The patient\\u000a underwent a biopsy under video-assisted thoracoscopy and the tumor was diagnosed as Ewing’s sarcoma family of tumor (ESFT).\\u000a Imaging confirmed that the

Shuichiro Uehara; Takaharu Oue; Akihiro Yoneda; Yoshiko Hashii; Hideaki Ohta; Masahiro Fukuzawa

2008-01-01

83

Phenotypic characterization of Ewing sarcoma cell lines with monoclonal antibodies.  

PubMed

The histogenesis of Ewing sarcoma, the second most frequent bone tumor in humans, remains controversial. Four Ewing cell lines were analyzed by immunological methods. A panel of antibodies directed to T, B, and myelomonocytic markers gave negative results. Surface antigens recognized on Ewing cells were found to be related to the neuroectoderm lineage. Ganglioside GD2, a marker of neuroectodermal tissues and tumors, was present on all lines. These were also stained by the mouse monoclonal antibody HNK-1, which detects a carbohydrate epitope present on several glycoconjugates of the nervous system, including two glycoproteins, the myelin-associated glycoprotein and the neural cell-adhesion molecule (N-CAM), and an acidic glycolipid of the peripheral nervous system. The P61 monoclonal antibody, which reacts with a peptide moiety of N-CAM, and a rabbit antiserum, raised to purified mouse N-CAM and not recognizing the HNK-1-defined epitope, were also reactive. By contrast, all antibodies specific for hematopoietic cell surface antigens were totally negative. Besides these antigenic features, Ewing sarcoma cells are characterized by a specific t(11;22)(q24;q12) translocation also observed in neuroepithelioma, a neuroectodermal tumor, suggesting a possible evolutionary related origin. The recent finding that the human N-CAM gene is located at the vicinity of the breakpoint on chromosome 11 indicates that it might be involved in genetic rearrangements occurring in this region. PMID:3760036

Lipinski, M; Braham, K; Philip, I; Wiels, J; Philip, T; Dellagi, K; Goridis, C; Lenoir, G M; Tursz, T

1986-01-01

84

Amyloid precursor-like protein 2 suppresses irradiation-induced apoptosis in Ewing sarcoma cells and is elevated in immune-evasive Ewing sarcoma cells.  

PubMed

Despite surgery, chemotherapy, and radiotherapy treatments, the children, adolescents, and young adults who are diagnosed with metastasized Ewing sarcoma face a dismal prognosis. Amyloid precursor-like protein 2 (APLP2) has recently been implicated in the survival of cancer cells and in our current study, APLP2's contribution to the survival of Ewing sarcoma cells was examined. APLP2 was readily detected in all Ewing sarcoma cell lines analyzed by western blotting, with the TC71 Ewing sarcoma cells expressing the lowest level of APLP2 among the lines. While irradiation induces apoptosis in TC71 Ewing sarcoma cells (as we determined by quantifying the proportion of cells in the sub-G 1 population), transfection of additional APLP2 into TC71 decreased irradiation-induced apoptosis. Consistent with these findings, in parallel studies, we noted that isolates of the TC71 cell line that survived co-culture with lymphokine-activated killer (LAK) cells (which kill by inducing apoptosis in target cells) displayed increased expression of APLP2, in addition to smaller sub-G 1 cell populations after irradiation. Together, these findings suggest that APLP2 lowers the sensitivity of Ewing sarcoma cells to radiotherapy-induced apoptosis and that APLP2 expression is increased in Ewing sarcoma cells able to survive exposure to cytotoxic immune cells. PMID:23792571

Peters, Haley L; Yan, Ying; Nordgren, Tara M; Cutucache, Christine E; Joshi, Shantaram S; Solheim, Joyce C

2013-08-01

85

Hypoxia and hypoglycaemia in Ewing's sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor  

Microsoft Academic Search

BACKGROUND: Hypoxia regulates gene expression via the transcription factor HIF (Hypoxia-Inducible Factor). Little is known regarding HIF expression and function in primary bone sarcomas. We describe HIF expression and phenotypic effects of hypoxia, hypoglycaemia and HIF in Ewing's sarcoma and osteosarcoma. METHODS: HIF-1? and HIF-2? immunohistochemistry was performed on a Ewing's tumour tissue array. Ewing's sarcoma and osteosarcoma cell lines

Helen J Knowles; Karl-Ludwig Schaefer; Uta Dirksen; Nicholas A Athanasou

2010-01-01

86

A rare case of congenital Ewing sarcoma/PNET of the scapula.  

PubMed

Ewing sarcoma (ES)/primitive neuroectodermal tumors (PNET) are known to occur at both central and peripheral locations, as well as at skeletal and extraskeletal sites. They most commonly occur in the first 2 decades of life. We report a rare case of congenital Ewing sarcoma/primitive neuroectodermal tumor arising from the scapula. PMID:24072238

Jinkala, Sree Rekha; Basu, Debdatta; Mathath, Dinesan; Dubashi, Biswajit; Bhaumik, Arpita

2014-03-01

87

Prognostic significance of tumor volume in localized Ewing's sarcoma of bone in children and adolescents  

Microsoft Academic Search

A total of 60 consecutive patients with localized Ewing's sarcoma of bone who were entered into the Cooperative Ewing's Sarcoma Study of the German Society of Pediatric Oncology from January 1981 until April 1985 were evaluable for tumor volume at diagnosis. The tumor volume was calculated from plain X-rays and CT scans as ellipsoidal or cylindrical depending on the tumor

V. Göbel; H. Jiirgens; G. Etspiiler; H. Kemperdick; R. M. Jungblut; U. Stienen; U. Göbel

1987-01-01

88

Tumor Cell Plasticity in Ewing Sarcoma, an Alternative Circulatory System Stimulated by Hypoxia  

Microsoft Academic Search

A striking feature of Ewing sarcoma is the presence of blood lakes lined by tumor cells. The significance of these structures, if any, is unknown. Here, we report that the extent of blood lakes correlates with poor clinical outcomes, whereas varia- bles of angiogenesis do not. We also show that Ewing sarcoma cells form vessel-like tubes in vitro and express

Femke Hillen; Patrick Pauwels; Karolien Castermans; Maxine G. B. Tran; Rafael Sciot; Esther Hauben; Pancras C. W. Hogendoorn; Olivier Delattre; Patrick H. Maxwell; Mary J. C. Hendrix; Arjan W. Griffioen

89

Angiogenesis and Ewing sarcoma—relationship to pulmonary metastasis and survival  

Microsoft Academic Search

Background\\/PurposeIntratumoral angiogenesis quantified by microvessel density (MVD) has been shown to be a strong prognostic indicator in a number of malignant tumors. Its association with prognosis in Ewing sarcoma has not been previously studied. The aim of our study was to investigate the relationship between angiogenesis and clinical outcome in Ewing sarcoma.

Danko Mikuli?; Ivana Ili?; Mladen ?epuli?; Jasminka Stepan Giljevi?; Dubravko Orli?; Boidar ?upan?i?; Ivan Fattorini; Sven Seiwerth

2006-01-01

90

Clinical and biological significance of hepatoma-derived growth factor in Ewing's sarcoma.  

PubMed

We sought to investigate the clinicopathological significance and biological function of hepatoma-derived growth factor (HDGF) in Ewing's sarcoma. Our results showed that HDGF expression is up-regulated in Ewing's sarcoma. Nuclear HDGF expression is significantly associated with tumour volume (p < 0.001), metastases at diagnosis (p < 0.001), low overall survival rate (p < 0.001) and low disease-free survival rate (p < 0.001). HDGF knock-down results in significant reduction of Ewing's sarcoma cell growth, proliferation and enhances tumourigenesis, both in vitro and in vivo. Meanwhile, HDGF knock-down causes cell cycle arrest and enhanced sensitization to serum starvation-induced apoptosis. Furthermore, recombinant HDGF promotes proliferation and colony formation of Ewing's sarcoma cells. Ninety-eight candidate HDGF downstream genes were identified in Ewing's sarcoma cells using cDNA microarray analysis. In addition, we found that HDGF knock-down inhibited FLI1 expression in Ewing's sarcoma cells at the mRNA and protein levels. Our findings suggest that HDGF exhibits oncogenic properties and may be a novel prognostic factor in Ewing's sarcoma. Targeting HDGF might be a potential therapeutic strategy for Ewing's sarcoma. PMID:23878072

Yang, Yang; Li, Hui; Zhang, Fenfen; Shi, Huijuan; Zhen, Tiantian; Dai, Sujuan; Kang, Lili; Liang, Yingjie; Wang, Jin; Han, Anjia

2013-11-01

91

RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing's sarcoma  

Microsoft Academic Search

BACKGROUND: Ewing's sarcomas are aggressive musculoskeletal tumors occurring most frequently in the long and flat bones as a solitary lesion mostly during the teen-age years of life. With current treatments, significant number of patients relapse and survival is poor for those with metastatic disease. As part of novel target discovery in Ewing's sarcoma, we applied RNAi mediated phenotypic profiling to

Shilpi Arora; Irma M Gonzales; R. Tanner Hagelstrom; Christian Beaudry; Ashish Choudhary; Chao Sima; Raoul Tibes; Spyro Mousses; David O Azorsa

2010-01-01

92

Periosteal Ewing's Sarcoma: Report of Two New Cases and Review of the Literature  

PubMed Central

Background. The origin of Ewing's sarcoma in a periosteal location is rare and not clearly documented. Other malignant bone tumors appear to have a somewhat better prognosis when confined between periosteum and bone. Is it the same for periosteal Ewing's sarcoma? Methods. We describe two new cases and comprehensively review the literature consisting of 18 documented cases since the condition was first described in 1986 (S.M. Bator.Cancer 58:1781– 4). Results. Periosteal Ewing's sarcoma differs from the other forms of Ewing's sarcoma in terms of sex predominance, location of tumor, surgical stage at presentation and typical imaging studies. Eighteen out of the 20 patients were reported to be alive with no evidence of disease. Conclusions. It seems that the prognosis of this rare variant of Ewing's sarcoma family of tumors might be better but the small number of cases precludes such a firm conclusion.

Kollender, Yehuda; Shabat, Shay; Nirkin, Alexander; Issakov, Josephine; Flusser, Gideon; Merimsky, Ofer

1999-01-01

93

Whole-Body Radiation Therapy, Systemic Chemotherapy, and High-Dose Chemotherapy Followed By Stem Cell Rescue in Treating Patients With Poor-Risk Ewing Sarcoma  

ClinicalTrials.gov

Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Ewing Sarcoma of Bone; Extraosseous Ewing Sarcoma; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor

2014-02-11

94

Modeling Ewing sarcoma tumors in vitro with 3D scaffolds  

PubMed Central

The pronounced biological influence of the tumor microenvironment on cancer progression and metastasis has gained increased recognition over the past decade, yet most preclinical antineoplastic drug testing is still reliant on conventional 2D cell culture systems. Although monolayer cultures recapitulate some of the phenotypic traits observed clinically, they are limited in their ability to model the full range of microenvironmental cues, such as ones elicited by 3D cell–cell and cell–extracellular matrix interactions. To address these shortcomings, we established an ex vivo 3D Ewing sarcoma model that closely mimics the morphology, growth kinetics, and protein expression profile of human tumors. We observed that Ewing sarcoma cells cultured in porous 3D electrospun poly(?-caprolactone) scaffolds not only were more resistant to traditional cytotoxic drugs than were cells in 2D monolayer culture but also exhibited remarkable differences in the expression pattern of the insulin-like growth factor-1 receptor/mammalian target of rapamycin pathway. This 3D model of the bone microenvironment may have broad applicability for mechanistic studies of bone sarcomas and exhibits the potential to augment preclinical evaluation of antineoplastic drug candidates for these malignancies.

Fong, Eliza Li Shan; Lamhamedi-Cherradi, Salah-Eddine; Burdett, Emily; Ramamoorthy, Vandhana; Lazar, Alexander J.; Kasper, F. Kurtis; Farach-Carson, Mary C.; Vishwamitra, Deeksha; Demicco, Elizabeth G.; Menegaz, Brian A.; Amin, Hesham M.; Mikos, Antonios G.; Ludwig, Joseph A.

2013-01-01

95

Proton Radiotherapy for Pediatric Ewing's Sarcoma: Initial Clinical Outcomes  

SciTech Connect

Purpose: Proton radiotherapy (PT) has been prescribed similarly to photon radiotherapy to achieve comparable disease control rates at comparable doses. The chief advantage of protons in this setting is to reduce acute and late toxicities by decreasing the amount of normal tissue irradiated. We report the preliminary clinical outcomes including late effects on our pediatric Ewing's sarcoma patients treated with PT at the Francis H. Burr Proton Therapy Center at Massachusetts General Hospital (Boston, MA). Methods and Materials: This was a retrospective review of the medical records of 30 children with Ewing's sarcoma who were treated with PT between April 2003 and April 2009. Results: A total of 14 male and 16 female patients with tumors in several anatomic sites were treated with PT at a median age of 10 years. The median dose was 54 Gy (relative biological effectiveness) with a median follow-up of 38.4 months. The 3-year actuarial rates of event-free survival, local control, and overall survival were 60%, 86%, and 89%, respectively. PT was acutely well tolerated, with mostly mild-to-moderate skin reactions. At the time of writing, the only serious late effects have been four hematologic malignancies, which are known risks of topoisomerase and anthracyline exposure. Conclusions: Proton radiotherapy was well tolerated, with few adverse events. Longer follow-up is needed to more fully assess tumor control and late effects, but the preliminary results are encouraging.

Rombi, Barbara [ATreP (Provincial Agency for Proton Therapy), Trento (Italy); DeLaney, Thomas F.; MacDonald, Shannon M. [Department of Radiation Oncology, Massachusetts General Hospital-Harvard Medical School, Boston, MA (United States); Huang, Mary S.; Ebb, David H. [Department of Pediatric Hematology and Oncology, Massachusetts General Hospital-Harvard Medical School, Boston, MA (United States); Liebsch, Norbert J. [Department of Radiation Oncology, Massachusetts General Hospital-Harvard Medical School, Boston, MA (United States); Raskin, Kevin A. [Department of Orthopaedic Surgery, Massachusetts General Hospital-Harvard Medical School, Boston, MA (United States); Yeap, Beow Y. [Department of Medicine, Massachusetts General Hospital-Harvard Medical School, Boston, MA (United States); Marcus, Karen J. [Division of Radiation Oncology, Children's Hospital Boston, MA (United States); Tarbell, Nancy J. [Department of Radiation Oncology, Massachusetts General Hospital-Harvard Medical School, Boston, MA (United States); Yock, Torunn I., E-mail: tyock@partners.org [Department of Radiation Oncology, Massachusetts General Hospital-Harvard Medical School, Boston, MA (United States)

2012-03-01

96

Combining PARP-1 inhibition and radiation in ewing sarcoma results in lethal DNA damage.  

PubMed

Ewing sarcomas (ES) harbor a chromosomal translocation that fuses the EWS gene to an ETS transcription factor, most commonly Friend leukemia integration 1 (FLI1). The EWS-FLI1 fusion protein acts in a positive feedback loop to maintain the expression of PARP-1, which is involved in repair of DNA damage. Here, we examine the effects of PARP-1 inhibition and radiation therapy on Ewing sarcomas. In proliferation assays, the Ewing sarcoma cell lines RD-ES and SK-N-MC were much more sensitive than non-Ewing sarcoma cell lines to the PARP-1 inhibitor olaparib (Ola; IC50 0.5-1 ?mol/L vs. >5 ?mol/L) and to radiation (IC50 2-4 Gy vs. >6 Gy). PARP-1 inhibition with short hairpin RNA (shRNA) or Ola sensitized Ewing sarcoma cells, but not non-Ewing sarcoma cells, to radiation therapy in both proliferation and colony formation assays. Using the Comet assay, radiation of Ewing sarcoma cells with Ola, compared to without Ola, resulted in more DNA damage at 1 hour (mean tail moment 36-54 vs. 26-28) and sustained DNA damage at 24 hours (24-29 vs. 6-8). This DNA damage led to a 2.9- to 4.0-fold increase in apoptosis and a 1.6- to 2.4-fold increase in cell death. The effect of PARP-1 inhibition and radiation therapy on Ewing sarcoma cells was lost when EWS-FLI1 was silenced by shRNA. A small dose of radiation therapy (4 Gy), when combined with PARP-1 inhibition, stopped the growth of SK-N-MC flank tumors xenografts. In conclusion, PARP-1 inhibition in Ewing sarcomas amplifies the level and duration of DNA damage caused by radiation therapy, leading to synergistic increases in apoptosis and cell death in a EWS-FLI1-dependent manner. PMID:23966622

Lee, Hae-June; Yoon, Changhwan; Schmidt, Benjamin; Park, Do Joong; Zhang, Alexia Y; Erkizan, Hayriye V; Toretsky, Jeffrey A; Kirsch, David G; Yoon, Sam S

2013-11-01

97

Primary Ewing's Sarcoma of the Kidney in a 73-Year-Old Man.  

PubMed

Objective. Ewing's sarcoma of the kidney is rare and is usually found in young adults. We present here a single case study of Ewing's sarcoma found in an elderly man. Material and methods. A 73-year-old man underwent routine surgery for hydrocoele of the testis. He developed urinary obstruction symptoms, and radiological examinations revealed a tumour in the right kidney. Results. Microscopical, immunohistochemical, and molecular pathological analysis of the tumour was consistent with Ewing's sarcoma. FISH showed rearrangement of chromosomes 22q12 (EWSR1). The patient subsequently underwent nephrectomy followed by 6 adjuvant chemotherapy cycles. Follow-up after 7 months shows no recurrence. Conclusion. This case report presents not only the rare finding of Ewing's sarcoma in the kidney, but also the occurrence of this tumour entity in an elderly patient. Treatment options for the different types of renal tumours are vastly different and the need for a correct diagnosis is, therefore, vital. PMID:21776194

Wedde, T B; Lobmaier, I V K; Brennhovd, B; Lohne, F; Hall, K S

2011-01-01

98

Primary Ewing's Sarcoma of the Kidney in a 73-Year-Old Man  

PubMed Central

Objective. Ewing's sarcoma of the kidney is rare and is usually found in young adults. We present here a single case study of Ewing's sarcoma found in an elderly man. Material and methods. A 73-year-old man underwent routine surgery for hydrocoele of the testis. He developed urinary obstruction symptoms, and radiological examinations revealed a tumour in the right kidney. Results. Microscopical, immunohistochemical, and molecular pathological analysis of the tumour was consistent with Ewing's sarcoma. FISH showed rearrangement of chromosomes 22q12 (EWSR1). The patient subsequently underwent nephrectomy followed by 6 adjuvant chemotherapy cycles. Follow-up after 7 months shows no recurrence. Conclusion. This case report presents not only the rare finding of Ewing's sarcoma in the kidney, but also the occurrence of this tumour entity in an elderly patient. Treatment options for the different types of renal tumours are vastly different and the need for a correct diagnosis is, therefore, vital.

Wedde, T. B.; Lobmaier, I. V. K.; Brennhovd, B.; Lohne, F.; Hall, K. S.

2011-01-01

99

A Novel Role for Keratin 17 in Coordinating Oncogenic Transformation and Cellular Adhesion in Ewing Sarcoma  

PubMed Central

Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma.

Sankar, Savita; Tanner, Jason M.; Bell, Russell; Chaturvedi, Aashi; Randall, R. Lor; Beckerle, Mary C.

2013-01-01

100

Clinical Correlations of Genetic Changes by Comparative Genomic Hybridization in Ewing Sarcoma and Related Tumors  

Microsoft Academic Search

Our previous comparative genomic hybridization (CGH) study of Ewing sarcoma and related tumors showed that DNA sequence copy number increases of 1q21?q22 and of chromosomes 8 and 12 were associated with trends toward poor survival (Armengol et al., Br J Cancer 1997, 75, 1403–1409). These trends were not statistically significant. In the present study, we analyzed 28 primary Ewing sarcomas

M Tarkkanen; S Kiuru-Kuhlefelt; C Blomqvist; G Armengol; T Böhling; T Ekfors; M Virolainen; P Lindholm; O Monge; P Picci; S Knuutila; I Elomaa

1999-01-01

101

A long-term review of the treatment of patients with Ewing's sarcoma in one institution  

Microsoft Academic Search

Aims: The treatment of patients suffering from Ewing's sarcoma has changed over the last three decades. We report the analyses, significant prognostic factors, interdisciplinary approach and development of therapy in one institution in Austria. Methods: One hundred and forty-two patients treated for Ewing's sarcoma between 1949 and 1994 were reviewed. Median follow-up was 8.5 years. Fifty-six patients were treated between

M. Sluga; R. Windhager; S. Lang; H. Heinzl; P. Krepler; F. Mittermayer; M. Dominkus; A. Zoubek; R. Kotz

2001-01-01

102

2Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production  

Microsoft Academic Search

The Ewing sarcoma is the second most common bone tumor in children and young adults. Despite the advances in therapy, the 5-year survival rate for patients with metastatic disease is poor, indicating the need for alternative treatments. Here, we report that 2-methoxy-estradiol (2-Me), a natural estrogen metabolite, induced a caspase-dependent apoptosis of Ewing sarcoma-derived cells independently of their p53 status.

Mojgan Djavaheri-Mergny; Juana Wietzerbin; Françoise Besançon

2003-01-01

103

Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours  

PubMed Central

Background Ewing sarcoma/PNET is managed with treatment paradigms involving combinations of chemotherapy, surgery, and sometimes radiation. Although the 5-year survival rate of non-metastatic disease approaches 70%, those cases that are metastatic and those that recur have 5-year survival rates of less than 20%. Molecularly targeted treatments offer the potential to further improve treatment outcomes. Methods A PUBMED search was performed from 1997 to 2011. Published literature that included the topic of the Ewing sarcoma/PNET was also referenced. Results Insulin-like growth factor-1 receptor (IGF-1R) antagonists have demonstrated modest single agent efficacy in phase I/II clinical trials in Ewing sarcoma/PNET, but have a strong preclinical rationale. Based on in vitro and animal data, treatment using antisense RNA and cDNA oligonucleotides directed at silencing the EWS-FLI chimera that occurs in most Ewing sarcoma/PNET may have potential therapeutic importance. However drug delivery and degradation problems may limit this therapeutic approach. Protein-protein interactions can be targeted by inhibition of RNA helicase A, which binds to EWS/FLI as part of the transcriptional complex. Tumour necrosis factor related apoptosis inducing ligand induction using interferon has been used in preclinical models. Interferons may be incorporated into future chemotherapeutic treatment paradigms. Histone deacetylase inhibitors can restore TGF-? receptor II allowing TFF-? signalling, which appears to inhibit growth of Ewing sarcoma/PNET cell lines in vitro. Immunotherapy using allogeneic natural killer cells has activity in Ewing sarcoma/PNET cell lines and xenograft models. Finally, cyclin dependent kinase inhibitors such as flavopiridol may be clinically efficacious in relapsed Ewing sarcoma/PNET. Conclusion Preclinical evidence exists that targeted therapeutics may be efficacious in the ESFT. IGF-1R antagonists have demonstrated efficacy in phase I/II clinical trials, although predicting responses remains a challenge. The future treatment of Ewing sarcoma/PNET is likely to be improved by these scientific advances.

2012-01-01

104

Latent adrenal Ewing sarcoma family of tumors: A case report.  

PubMed

Ewing sarcoma family of tumors (ESFT) is derived from the neural crest, which originates from basal embryo cells in the primitive neural tube. ESFT often arises at the bone, chest wall, and soft tissues of the thoracic region. However, ESFT that arises from the adrenal gland is much rarer and it is usually revealed by clinical symptoms. We report an autopsy case of suicidal hanging, in which adrenal ESFT was incidentally revealed. To our knowledge, this is the first case of latent ESFT arising from the adrenal gland. Autopsy can sometimes reveal latent disease. Some of these latent diseases are very rare and we would not be able to detect them without a complete autopsy. As forensic pathologists, we should attempt to perform a complete autopsy and report new discoveries for the development of medicine. PMID:22981088

Yamamoto, Takuma; Takasu, Kosho; Emoto, Yuko; Umehara, Takahiro; Ikematsu, Kazuya; Shikata, Nobuaki; Iino, Morio; Matoba, Ryoji

2013-03-01

105

Ewing sarcoma: prognostic criteria, outcomes and future treatment.  

PubMed

Ewing sarcoma (EWS) is a bone tumor occurring primarily in adolescence and young adulthood. Multi-institutional clinical trials have improved the outcome for patients with nonmetastatic EWS, but not with metastatic EWS. Furthermore, although 30% of EWS recur, multi-institutional studies have not been completed for this high-risk group. Planning such studies has been hampered by both the lack of novel therapies and the inability to incorporate the biology of EWS. While the importance and detail of the EWS-FLI-1 translocation between chromosomes 11 and 22 are described, these have not yet led to new drug development for this orphan tumor. However, recent evidence supporting novel cytotoxic therapy, antiangiogenic therapy, and receptor-targeted therapy provides reason for optimism for patients with high-risk disease. PMID:18402528

Leavey, Patrick J; Collier, Anderson B

2008-04-01

106

Ethnicity and age disparities in Ewing sarcoma outcome.  

PubMed

This institutional retrospective review studied Ewing sarcomas from 1987-2011. Among 135 patients, 127 (19 Hispanic and 108 white/non-Hispanic) were analyzed (excluding small sample sized groups) finding 15% Hispanic, 85% non-Hispanic, 27% <18 years, 21% >40 years and 1-272 months follow-up (median 41). Age was significantly associated with overall survival (OS) (p = 0.01), whereby <18 years had a higher probability of 5-year survival (OS 61%) than >40 years (OS 37.6%). Ethnicity was marginally statistically significant (OS, p = 0.065); whereby median survival was clinically significant (white non-Hispanic 63 months and Hispanic 23 months). Hispanic ethnicity and older age are independent poor prognostic factors. PMID:23043418

Koohbanani, Bianca; Han, Gang; Reed, Damon; Zhao, Qing; Yi, Ding; Henderson-Jackson, Evita; Bui, Marilyn M

2013-07-01

107

Outcome of Ewing sarcoma in a multidisciplinary setting in Lebanon.  

PubMed

Treatment of Ewing sarcoma (ES) necessitates coordinated multi-disciplinary care. We analyzed outcome for 39 patients treated at a single institution in Lebanon, a developing country with available multidisciplinary treatment modalities, where financial barriers to care are overcome by a fundraising system. Median follow-up was 58 months. Five-year overall and event-free survival were 76% and 58%, respectively, for localized disease, and 40% and 38%, respectively, for metastatic disease. We conclude that, in a country with emerging economy, by following international protocols and ensuring availability of needed resources, outcome of patients with ES is similar to that in developed countries. Pediatr Blood Cancer 2014; 61:1472-1475. © 2014 Wiley Periodicals, Inc. PMID:24395458

Abou Ali, Bilal; Nader, Ralph; Tamim, Hani; Eid, Toufic; Boulos, Fouad; Khoury, Nabil; Akel, Samir; Haidar, Rachid; Saghieh, Said; Abboud, Miguel; Muwakkit, Samar; El-Solh, Hassan; Saab, Raya

2014-08-01

108

Ewing's sarcoma arising from the adrenal gland in a young male: a case report  

PubMed Central

Background Ewing’s sarcoma uncommonly arises from extraosseous soft tissue or parenchymal organs. Primary adrenal Ewing’s Sarcoma, although very rare, is extremely aggressive and commonly fatal. Case presentation A 17 year old Pakistani male was referred to the outpatient oncology clinic at our center with a three month history of concomitant pain, swelling and dragging sensation in the right hypochondrium. Abdominal examination revealed a large, firm mass in the right hypochondrium extending into the right lumbar region and epigastrium. His genital exam was unremarkable and there were no stigmata of hepatic or adrenal disease. Computed tomography scans revealed a large peripherally enhancing mass in the hepatorenal area, biopsy of which showed a neoplastic lesion composed of small round blue cells which exhibited abundance of glycogen and stained diffusely positive for CD99 (MIC2 antigen). Fluorescence in situ hybridization demonstrated gene rearrangement at chromosome 22q12 which confirmed the diagnosis of Ewing’s sarcoma. Staging scans revealed pulmonary metastasis and hence he was commenced on systemic chemotherapy. Conclusion This case report highlights the importance of keeping Ewing’s sarcoma in mind when a young patient presents with a large non-functional adrenal mass.

2013-01-01

109

Neuroectodermal differentiation in Ewing's sarcoma family of tumors does not predict tumor behavior  

Microsoft Academic Search

The observation that neuroectodermal differentiation imparts a worse prognosis to the Ewing family of tumors has been suggested by some studies and refuted by others. To assess whether the diagnosis of Ewing's sarcoma versus peripheral primitive neuroectodermal tumor (PNET) affects prognosis, we analyzed tumors from 63 analogously treated pediatric and young adult patients from the National Cancer Institute and St

David M Parham; Yasmine Hijazi; Seth M Steinberg; William H Meyer; Marc Horowitz; Chin-Yuan Tzen; Leonard H Wexler; Maria Tsokos

1999-01-01

110

ARTICLES Potential Use of Imatinib in Ewing's Sarcoma: Evidence for In Vitro and In Vivo Activity  

Microsoft Academic Search

Background: Ewing's sarcoma cells express c-kit, a receptor tyrosine kinase, and its ligand, stem cell factor (SCF), cre- ating a potential autocrine loop that may promote tumor survival. We thus examined whether the specific tyrosine kinase inhibitor imatinib mesylate (hereafter imatinib; for- merly STI571) could inhibit the proliferation of Ewing's sar- coma cells in vitro and in vivo. Methods: The

Melinda S. Merchant; Chan-Wook Woo; Crystal L. Mackall; Carol J. Thiele

2002-01-01

111

Rare presentation of Ewing's sarcoma: a case report and literature review.  

PubMed

Ewing's sarcoma rarely occurs in the bones of the hand and feet. The clinical presentations represent a degree of overlap among various benign and infective etiologies. The diagnosis was confirmed by gold standard biopsy. We present a case of Ewing's tumor in a 13-year-old girl and discuss its rare presentation, and also offer a literature review. PMID:19471180

Jerome, J Terrence Jose; Sankaran, Balu; Varghese, Mathew; Thomas, Simon; Thirumagal, S K

2008-09-01

112

From the radiologic pathology archives: ewing sarcoma family of tumors: radiologic-pathologic correlation.  

PubMed

The Ewing sarcoma family of tumors includes osseous Ewing sarcoma, extraskeletal Ewing sarcoma, primitive neuroectodermal tumor, and Askin tumor. They share a karyotype abnormality with translocation involving chromosomes 11 and 22. Histologically, these lesions demonstrate crowded sheets of small round blue cells. Imaging features of osseous Ewing sarcoma often suggest the diagnosis, with aggressive long-bone destruction in the metadiaphysis of an adolescent or young adult and an associated soft-tissue mass. Focal areas of cortical destruction are frequent, allowing continuity between the intraosseous and extraosseous components. This continuity is also commonly seen as subtle channels extending through the cortex at computed tomography or magnetic resonance (MR) imaging, a finding that reflects the underlying pathologic appearance. Extraskeletal Ewing sarcoma commonly demonstrates a nonspecific radiologic appearance of a large soft-tissue mass affecting the paraspinal region or lower extremity. Askin tumor represents extraskeletal Ewing sarcoma involving the chest wall. Imaging typically reveals a large pleural-based mass and associated pleural effusion. Treatment of these tumors is usually a combination of neoadjuvant chemotherapy followed by surgical resection, which may be supplemented with radiation therapy. Imaging, particularly MR, is also vital to evaluate response to neoadjuvant therapy, direct surgical resection, and detect local recurrence or metastatic disease. PMID:23674776

Murphey, Mark D; Senchak, Lien T; Mambalam, Pramod K; Logie, Chika I; Klassen-Fischer, Mary K; Kransdorf, Mark J

2013-05-01

113

Ewing sarcoma of the rib with normal blood flow and blood pool imagings on a 3-phase bone scan.  

PubMed

Ewing sarcoma is the second most common pediatric malignant bone tumor. It usually presents as a hot spot on a 3-phase bone scan as a result of increased vascularity of the tumor and new bone formation. However, aggressive Ewing sarcoma can also appear as a cold lesion. We present the features of a Ewing sarcoma of the rib on a 3-phase bone scan in a child who was being investigated for rib fracture after trauma. PMID:16100480

Alfeeli, Mahmoud A; Naddaf, Sleiman Y; Syed, Ghulam M S

2005-09-01

114

Expression profiling of EWS\\/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma  

Microsoft Academic Search

Summary Our understanding of Ewing's sarcoma development mediated by the EWS\\/FLI fusion protein has been limited by a lack of knowledge regarding the tumor cell of origin. To circumvent this, we analyzed the function of EWS\\/FLI in Ewing's sarcoma itself.Bycombiningretroviral-mediatedRNAinterferencewithreexpressionstudies,weshowthatongoingEWS\\/FLIexpres- sion is required for the tumorigenic phenotype of Ewing's sarcoma. We used this system to define the full complement of

Richard Smith; Leah A. Owen; Deborah J. Trem; Jenny S. Wong; Jennifer S. Whangbo; Todd R. Golub; Stephen L. Lessnick

2006-01-01

115

A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis  

PubMed Central

SUMMARY Ewing’s sarcoma, a malignant bone tumor of children and young adults, is a member of the small-round-blue-cell tumor family. Ewing’s sarcoma family tumors (ESFTs), which include peripheral primitive neuroectodermal tumors (PNETs), are characterized by chromosomal translocations that generate fusions between the EWS gene and ETS-family transcription factors, most commonly FLI1. The EWS-FLI1 fusion oncoprotein represents an attractive therapeutic target for treatment of Ewing’s sarcoma. The cell of origin of ESFT and the molecular mechanisms by which EWS-FLI1 mediates tumorigenesis remain unknown, and few animal models of Ewing’s sarcoma exist. Here, we report the use of zebrafish as a vertebrate model of EWS-FLI1 function and tumorigenesis. Mosaic expression of the human EWS-FLI1 fusion protein in zebrafish caused the development of tumors with histology strongly resembling that of human Ewing’s sarcoma. The incidence of tumors increased in a p53 mutant background, suggesting that the p53 pathway suppresses EWS-FLI1-driven tumorigenesis. Gene expression profiling of the zebrafish tumors defined a set of genes that might be regulated by EWS-FLI1, including the zebrafish ortholog of a crucial EWS-FLI1 target gene in humans. Stable zebrafish transgenic lines expressing EWS-FLI1 under the control of the heat-shock promoter exhibit altered embryonic development and defective convergence and extension, suggesting that EWS-FLI1 interacts with conserved developmental pathways. These results indicate that functional targets of EWS-FLI1 that mediate tumorigenesis are conserved from zebrafish to human and provide a novel context in which to study the function of this fusion oncogene.

Leacock, Stefanie W.; Basse, Audrey N.; Chandler, Garvin L.; Kirk, Anne M.; Rakheja, Dinesh; Amatruda, James F.

2012-01-01

116

Role of radiation therapy in the management of nonmetastatic Ewing's sarcoma of bone. Report of the intergroup Ewing's sarcoma study  

SciTech Connect

The role of radiation therapy in local tumor control and decreased incidence of pulmonary metastasis is reported in 271 patients who were entered into the Intergroup Ewing's Sarcoma Study with more than one year follow-up and on whom all radiotherapy records were reviewed. The majority of the patients were irradiated to the primary tumor with doses of 4500 to 6500 rad in five to six weeks in combination with systemic administration of three drugs (vincristine, actinomycin-D and cyclophosphamide) or four drugs (vincristine, actinomycin-D, cyclophosphamide and adriamycin). One of the groups of patients was treated with three drugs and bilateral pulmonary irradiation (1500 rad, uncorrected dose, in two weeks). Preliminary analysis shows an overall local primary tumor control of 89%. Patients with lesions in the pelvis had a local failure rate of 17% (9 of 52) and in the humerus 23% (7 of 31). Factors affecting local recurrences are analyzed in detail. Distant metastases have been noted in 40% of all patients; the highest proportion was noted in the pelvis (49%). There was a significant difference in the appearance of pulmonary metastases in the patients who were treated with four drugs (9.7%) and in the group who received three drugs and pulmonary irradiation (23.5%) when compared with the patients treated with three drugs only (37%). Intensive chemotherapy and radiotherapy significantly improve local tumor control and survival of patients with localized Ewing's sarcoma. However, the high incidence of metastasis suggests the need for more effective systemic chemotherapy to further improve treatment results. It is very important to determine the optimal dose of irradiation and minimal volume to be treated in order to achieve optimal survival and primary tumor control with the least sequela.

Perez, C.A. (Washington Univ. School of Medicine, St. Louis, MO); Tefft, M.; Nesbit, M.; Burgert, E.O. Jr.; Vietti, T.; Kissane, J.; Pritchard, D.J.; Gehan, E.A.

1981-02-01

117

Radiation therapy in the multimodal management of Ewing's sarcoma of bone: report of the Intergroup Ewing's Sarcoma Study  

SciTech Connect

This paper is a progress report on the role of radiation therapy (RT) in local tumor control and the decreased incidence of pulmonary metastasis in 251 patients entered in the Intergroup Ewing's Sarcoma Study. All were followed for more that 1 year, and their RT records were reviewed. Doses to the primary tumor in the range of 4,500--6,500 rad were administered over approximately 5 to 6 weeks in combination with 4 drugs, i.e., vincristine (VCR), dactinomycin (DAC), cyclophosphamide (CY), and adriamycin, or only the first 3. One group of patients received the 3 drugs and bilateral pulmonary irradiation (approximately 1,500 rad in 2 wk). Preliminary analysis showed a local primary tumor control of approximately 90%. Patients with lesions in the pelvis and humerus had local failure rates of 13% (7 of 54) and 21.4% (6 of 28), respectively. The treatment groups differed significantly in the incidence of pulmonary metastasis. Patients treated with the 4 drugs (regimen 1) had a 14% incidence, whereas 42% of those treated with only 3 drugs (regimen 2) developed pulmonary metastases. Of all patients treated with 3 drugs and pulmonary irradiation (regimen 3), 18% showed lung metastases. The study indicated that intensive chemotherapy and RT significantly improved the local control and survival of patients with localized Ewing's sarcoma. However, the high incidence of metastasis indicated the need for more effective systemic chemotherapy for further improvement of treatment results. More studies are needed so we can define the volume to be treated and the optimal dose of irradiation to determine a therapeutic strategy that will yield optimal survival and tumor control with the fewest sequelae.

Perez, C.A.; Tefft, M.; Nesbit, M.E. Jr.; Burgert, E.O. Jr.; Vietti, T.J.; Kissane, J.; Pritchard, D.J.; Gehan, E.A.

1981-04-01

118

Disseminated Intracranial Ewing's Sarcoma in an Adult: A Rare and Difficult Diagnosis  

PubMed Central

The Ewing sarcoma family of tumors comprises a rare class of cancers of mesenchymal origin. Cases of Ewing's sarcoma in the central nervous system – specifically, intracranial Ewing's – are extremely rare. Almost all reported cases have occurred in children. However, this rare presentation can also occur in the adult population. It is important to distinguish these tumors from primitive neuroectodermal tumors at the time of diagnosis. Testing for EWSR1(22q12) gene rearrangement using fluorescence in situ hybridization is a useful tool for making the distinction between these 2 similar but distinct entities. We present here the case of a middle-aged male patient with intracranial Ewing's sarcoma, and discuss diagnostic challenges and potential new treatment approaches for this rare disease.

Lou, Emil; Sumrall, Ashley L.; Cummings, Thomas J.; Korones, David N.; Weaver, Susan A.; Peters, Katherine B.

2012-01-01

119

Primary Ewing sarcoma of the kidney: a symptomatic presentation and review of the literature  

PubMed Central

The objective of this review is to discuss the unique nature of primary renal Ewing sarcoma, including incidence, presentation and management. We also report on a common pattern of presentation, consisting of acute flank pain mimicking a renal stone colic, with or without hydronephrosis, and a renal mass discovered during imaging studies of renal Ewing sarcoma. We present our case of renal Ewing sarcoma along with imaging and pathological analysis. We also performed a retrospective review of all cases of renal Ewing sarcoma using PubMed. A total of 48 cases of renal EWS sarcoma have been reported and analyzed in this review. A mean age of 30.4 years was found along with a 61% male predominance. The mean survival was 26.14 months with a lower median survival in patients with advanced metastatic disease. Primary Ewing sarcoma of the kidney is rare. The diagnosis of primary renal EWS can be difficult and is based on a combination of electron microscopy, immunohistochemistry, chromosomal analysis, fluorescence in situ hybridization (FISH) and light microscopy.

Hakky, Tariq S.; Gonzalvo, Americo A.; Lockhart, Jorge L.

2013-01-01

120

Primary Ewing sarcoma of the kidney: a symptomatic presentation and review of the literature.  

PubMed

The objective of this review is to discuss the unique nature of primary renal Ewing sarcoma, including incidence, presentation and management. We also report on a common pattern of presentation, consisting of acute flank pain mimicking a renal stone colic, with or without hydronephrosis, and a renal mass discovered during imaging studies of renal Ewing sarcoma. We present our case of renal Ewing sarcoma along with imaging and pathological analysis. We also performed a retrospective review of all cases of renal Ewing sarcoma using PubMed. A total of 48 cases of renal EWS sarcoma have been reported and analyzed in this review. A mean age of 30.4 years was found along with a 61% male predominance. The mean survival was 26.14 months with a lower median survival in patients with advanced metastatic disease. Primary Ewing sarcoma of the kidney is rare. The diagnosis of primary renal EWS can be difficult and is based on a combination of electron microscopy, immunohistochemistry, chromosomal analysis, fluorescence in situ hybridization (FISH) and light microscopy. PMID:23730330

Hakky, Tariq S; Gonzalvo, Americo A; Lockhart, Jorge L; Rodriguez, Alejandro R

2013-06-01

121

Ewing Sarcoma Protein Ewsr1 Maintains Mitotic Integrity and Proneural Cell Survival in the Zebrafish Embryo  

Microsoft Academic Search

BackgroundThe Ewing sarcoma breakpoint region 1 gene (EWSR1), also known as EWS, is fused to a number of different partner genes as a result of chromosomal translocation in diverse sarcomas. Despite the involvement of EWSR1 in these diverse sarcomas, the in vivo function of wild type EWSR1 remains unclear.Principal FindingsWe identified two zebrafish EWSR1 orthologues, ewsr1a and ewsr1b, and demonstrate

Mizuki Azuma; Lisa J. Embree; Hatem Sabaawy; Dennis D. Hickstein; Carl-Philipp Heisenberg

2007-01-01

122

Salient features of mesenchymal stem cells--implications for Ewing sarcoma modeling  

PubMed Central

Despite a heightened appreciation of the many defining molecular aberrations in Ewing sarcoma, the cooperative genetic environment and permissive cell of origin essential for EWS/ETS-mediated oncogenesis remain elusive. Consequently, inducible animal and in vitro models of Ewing sarcoma from a native cellular context are unable to fully recapitulate malignant transformation. Despite these shortcomings, human, and murine mesenchymal stem cells (MSCs) are the closest working in vitro systems available. MSCs are tolerant of ectopic EWS/FLI expression, which is accompanied by a molecular signature most similar to Ewing sarcoma. Whether MSCs are the elusive cell of origin or simply a tolerant platform of the EWS/FLI transcriptome, these cells have become an excellent molecular tool to investigate and manipulate oncogenesis in Ewing sarcoma. Our understanding of the biological complexity and heterogeneity of human MSCs (hMSCs) has increased substantially over time and as such, appreciation and utilization of these salient complexities may greatly enhance the efficient use of these cells as surrogate models for Ewing sarcoma tumorigenesis.

Monument, Michael J.; Bernthal, Nicholas M.; Randall, R. Lor

2013-01-01

123

Addition of Ifosfamide and Etoposide to Standard Chemotherapy for Ewing's Sarcoma and Primitive Neuroectodermal Tumor of Bone  

Microsoft Academic Search

background Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, high- ly malignant tumors of children, adolescents, and young adults. A new drug combina- tion, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition

Holcombe E. Grier; Mark D. Krailo; Nancy J. Tarbell; Michael P. Link; Christopher J. H. Fryer; Douglas J. Pritchard; Mark C. Gebhardt; Paul S. Dickman; Elizabeth J. Perlman; Paul A. Meyers; Sarah S. Donaldson; Sheila Moore; Aaron R. Rausen; Teresa J. Vietti; James S. Miser

2010-01-01

124

Ewing sarcoma of the ribResults of an intergroup study with analysis of outcome by timing of resection  

Microsoft Academic Search

Objective: We sought to establish the outcome and optimal therapeutic sequence for patients with nonmetastatic Ewing sarcoma\\/primitive neuroectodermal tumor of the chest wall. Methods: Patients 30 years of age or younger with nonmetastatic Ewing sarcoma\\/primitive neuroectodermal tumor of the bone were randomly assigned to receive vincristine, doxorubicin, cyclophosphamide, and dactinomycin or those drugs alternating with ifosfamide and etoposide. Local control

Robert C. Shamberger; Michael P. LaQuaglia; Mark D. Krailo; James S. Miser; Douglas J. Pritchard; Mark C. Gebhardt; John H. Healey; Nancy J. Tarbell; Christopher J. H. Fryer; Paul A. Meyers; Holcombe E. Grier

2000-01-01

125

The ganglioside antigen GD2 is surface-expressed in Ewing sarcoma and allows for MHC-independent immune targeting  

PubMed Central

Background: Novel treatment strategies are needed to cure disseminated Ewing sarcoma. Primitive neuroectodermal features and a mesenchymal stem cell origin are both compatible with aberrant expression of the ganglioside antigen GD2 and led us to explore GD2 immune targeting in this cancer. Methods: We investigated GD2 expression in Ewing sarcoma by immunofluorescence staining. We then assessed the antitumour activity of T cells expressing a chimeric antigen receptor specific for GD2 against Ewing sarcoma in vitro and in vivo. Results: Surface GD2 was detected in 10 out of 10 Ewing sarcoma cell lines and 3 out of 3 primary cell cultures. Moreover, diagnostic biopsies from 12 of 14 patients had uniform GD2 expression. T cells specifically modified to express the GD2-specific chimeric receptor 14. G2a-28? efficiently interacted with Ewing sarcoma cells, resulting in antigen-specific secretion of cytokines. Moreover, chimeric receptor gene-modified T cells from healthy donors and from a patient exerted potent, GD2-specific cytolytic responses to allogeneic and autologous Ewing sarcoma, including tumour cells grown as multicellular, anchorage-independent spheres. GD2-specific T cells further had activity against Ewing sarcoma xenografts. Conclusion: GD2 surface expression is a characteristic of Ewing sarcomas and provides a suitable target antigen for immunotherapeutic strategies to eradicate micrometastatic cells and prevent relapse in high-risk disease.

Kailayangiri, S; Altvater, B; Meltzer, J; Pscherer, S; Luecke, A; Dierkes, C; Titze, U; Leuchte, K; Landmeier, S; Hotfilder, M; Dirksen, U; Hardes, J; Gosheger, G; Juergens, H; Rossig, C

2012-01-01

126

Oncostatin M is a growth factor for Ewing sarcoma.  

PubMed

Primary bone tumors, osteosarcomas and chondrosarcomas, derive from mesenchymal stem cells committed into osteoblasts and chondrocytes; in Ewing sarcomas (ESs), the oncogenic fusion protein EWS-FLI1 prevents mesenchymal differentiation and induces neuroectodermic features. Oncostatin M (OSM) is a cytokine from the IL-6 family that modulates proliferation and differentiation in numerous cells. The basis for inhibition versus induction of proliferation by this cytokine is obscure, although MYC was described as a potent molecular switch in OSM signaling. We show herein that, in contrast to osteosarcomas and chondrosarcomas, for which OSM was cytostatic, OSM induced proliferation of ES cell lines. Knockdown experiments demonstrated that growth induction by OSM depends on both types I [leukemia inhibitory factor receptor (LIFR)] and II [OSM receptor (OSMR)] receptors, high STAT3 activation, and induction of MYC to a high expression level. Indeed, ES cell lines, mice xenografts, and patient biopsy specimens poorly expressed LIF, precluding LIFR lysosomal degradation and OSMR transcriptional induction, thus leading to a high LIFR/OSMR ratio. Because other neuroectodermic tumors (ie, glioma, medulloblastoma, and neuroblastoma) had a similar expression profile, the main role of EWS-FLI1 could be through maintenance of stemness and neuroectodermic features, characterized by a low LIF, a high LIFR/OSMR ratio, and high MYC expression. Thus, this study on rare bone malignancies gives valuable insights on more common cancer regulatory mechanisms and could provide new therapeutic opportunities. PMID:22982441

David, Emmanuelle; Tirode, Franck; Baud'huin, Marc; Guihard, Pierre; Laud, Karine; Delattre, Olivier; Heymann, Marie F; Heymann, Dominique; Redini, Françoise; Blanchard, Frédéric

2012-11-01

127

ERBB4 confers metastatic capacity in Ewing sarcoma  

PubMed Central

Metastatic spread is the single-most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment-induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K-Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4-mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease-free survival, and increased expression is observed in metastatic compared to primary patient-matched ES biopsies. Our findings identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES.

Mendoza-Naranjo, Ariadna; El-Naggar, Amal; Wai, Daniel H; Mistry, Priti; Lazic, Nikola; Ayala, Fernanda Rocha Rojas; da Cunha, Isabela Werneck; Rodriguez-Viciana, Pablo; Cheng, Hongwei; Tavares Guerreiro Fregnani, Jose H; Reynolds, Patrick; Arceci, Robert J; Nicholson, Andrew; Triche, Timothy J; Soares, Fernando A; Flanagan, Adrienne M; Wang, Yuzhuo Z; Strauss, Sandra J; Sorensen, Poul H

2013-01-01

128

Functional epigenetic approach identifies frequently methylated genes in Ewing sarcoma.  

PubMed

Using a candidate gene approach we recently identified frequent methylation of the RASSF2 gene associated with poor overall survival in Ewing sarcoma (ES). To identify effective biomarkers in ES on a genome-wide scale, we used a functionally proven epigenetic approach, in which gene expression was induced in ES cell lines by treatment with a demethylating agent followed by hybridization onto high density gene expression microarrays. After following a strict selection criterion, 34 genes were selected for expression and methylation analysis in ES cell lines and primary ES. Eight genes (CTHRC1, DNAJA4, ECHDC2, NEFH, NPTX2, PHF11, RARRES2, TSGA14) showed methylation frequencies of>20% in ES tumors (range 24-71%), these genes were expressed in human bone marrow derived mesenchymal stem cells (hBMSC) and hypermethylation was associated with transcriptional silencing. Methylation of NPTX2 or PHF11 was associated with poorer prognosis in ES. In addition, six of the above genes also showed methylation frequency of>20% (range 36-50%) in osteosarcomas. Identification of these genes may provide insights into bone cancer tumorigenesis and development of epigenetic biomarkers for prognosis and detection of these rare tumor types. PMID:24005033

Alholle, Abdullah; Brini, Anna T; Gharanei, Seley; Vaiyapuri, Sumathi; Arrigoni, Elena; Dallol, Ashraf; Gentle, Dean; Kishida, Takeshi; Hiruma, Toru; Avigad, Smadar; Grimer, Robert; Maher, Eamonn R; Latif, Farida

2013-11-01

129

ERBB4 confers metastatic capacity in Ewing sarcoma.  

PubMed

Metastatic spread is the single-most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment-induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K-Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4-mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease-free survival, and increased expression is observed in metastatic compared to primary patient-matched ES biopsies. Our findings identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES. PMID:23681745

Mendoza-Naranjo, Ariadna; El-Naggar, Amal; Wai, Daniel H; Mistry, Priti; Lazic, Nikola; Ayala, Fernanda Rocha Rojas; da Cunha, Isabela Werneck; Rodriguez-Viciana, Pablo; Cheng, Hongwei; Tavares Guerreiro Fregnani, Jose H; Reynolds, Patrick; Arceci, Robert J; Nicholson, Andrew; Triche, Timothy J; Soares, Fernando A; Flanagan, Adrienne M; Wang, Yuzhuo Z; Strauss, Sandra J; Sorensen, Poul H

2013-07-01

130

Gastric Ewing sarcoma/primitive neuroectodermal tumor: A case report  

PubMed Central

Ewing sarcoma/primitive neuroectodermal tumors (ES/PNETs) may arise in bone or soft tissue; however, these tumors rarely originate in the stomach. To the best of our knowledge, only four cases have previously been reported in the English-language literature. A 41-year-old Japanese woman was admitted with abdominal pain and underwent gastrectomy to remove the primary tumor. Immunohistochemistry, chromosomal karyotype and molecular analysis using reverse transcription-polymerase chain reaction were performed in the tumor specimens obtained. Tumor cells showed positive immunoreactivity for CD99, vimentin, CD117 (c-kit), S100, chromogranin A and synaptophysin. The tumor was a gastric ES/PNET with the EWS-FLI1 fusion gene translocation t(11;22)(q24;q12). Multiple repeat metastasectomies, as well as multi-agent chemotherapy and radiotherapy were performed for recurrent disease. Despite treatment, the patient succumbed due to progressive disease 110 months after the initial surgery for gastric ES/PNET. A review of the reported cases suggests that patients with gastric ES/PNETs have an unfavorable prognosis following resection due to the high propensity of these tumors to metastasize. Thus, multimodal treatment approaches including surgery, as well as multi-agent chemotherapy and radiotherapy may provide a survival benefit for patients with gastric ES/PNETs.

INOUE, MAKOTO; WAKAI, TOSHIFUMI; KORITA, PAVEL V.; SAKATA, JUN; KUROSAKI, RYO; OGOSE, AKIRA; KAWASHIMA, HIROYUKI; SHIRAI, YOSHIO; AJIOKA, YOICHI; HATAKEYAMA, KATSUYOSHI

2011-01-01

131

Primary metastasized extraskeletal Ewing sarcoma of the vulva: report of a case and review of the literature  

Microsoft Academic Search

Purpose  Ewing’s sarcoma (ES) and primitive neuroectodermal tumor (PNET) are closely related malignant neoplasms, usually affecting\\u000a the skeletal system. Extraosseous ES\\/PNETs are uncommon, with occasional reports of tumors affecting the genitourinary tract.\\u000a Only few cases of primary vulvar Ewing’s sarcoma\\/PNET have previously been reported.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  We present a patient with primary vulvar Ewing's sarcoma with pulmonary metastasis who presented at the Department

Katharina Kelling; Frank Noack; Christopher Altgassen; Peter Kujath; Michael K. Bohlmann; Friederike Hoellen

132

Five-year results in Ewing's sarcoma. The Scandinavian Sarcoma Group experience with the SSG IX protocol  

Microsoft Academic Search

The first Scandinavian protocol for Ewing's sarcoma, SSG IV, resulted in a local control rate of 74% and 5-year metastasis-free survival (MFS) of 43%. The second protocol, SSG IX, was started in order to improve upon these results. It featured four chemotherapy cycles, each consisting of two courses of VAI (vincristine, doxorubicin, ifosfamide) alternating with one course of PAI (cisplatin,

I. Elomaa; C. P. Blomqvist; G. Saeter; M. Åkerman; E. Stenwig; T. Wiebe; O. Björk; T. A. Alvegård

2000-01-01

133

Targeting the EWSR1-FLI1 oncogene-induced protein kinase PKC-? abolishes ewing sarcoma growth.  

PubMed

Ewing sarcoma is a rare but aggressive disease most common in young adults. This cancer is driven by a unique chimeric fusion oncogene but targeted strategies have been elusive. Here we report the identification of the protein kinase PKC-ß (PRKCB) as a disease-specific druggable target for treatment of Ewing sarcoma. We found that transcriptional activation of PRKCB was directly regulated by the chimeric fusion oncogene EWSR1-FLI1 that drives this cancer. PRKCB phosphorylated histone H3T6 to permit global maintenance of H3K4 trimethylation at a variety of gene promoters. PRKCB loss induced apoptosis in vitro and prevented tumor growth in vivo. Gene expression profiling revealed a strong overlap between genes modulated by EWSR1-FLI1 and PRKCB in regulating crucial signaling pathways. Taken together, our findings offer a preclinical proof-of-concept for PRKCB as a promising therapeutic target in Ewing sarcoma. PMID:22930730

Surdez, Didier; Benetkiewicz, Magdalena; Perrin, Virginie; Han, Zhi-Yan; Pierron, Gaëlle; Ballet, Stelly; Lamoureux, François; Rédini, Françoise; Decouvelaere, Anne-Valérie; Daudigeos-Dubus, Estelle; Geoerger, Birgit; de Pinieux, Gonzague; Delattre, Olivier; Tirode, Franck

2012-09-01

134

Huntsman Cancer Institute researchers discover possible new treatment for Ewing sarcoma  

Cancer.gov

Discovery of a new drug with high potential to treat Ewing sarcoma, an often deadly cancer of children and young adults, and the previously unknown mechanism behind it, come hand-in-hand in a new study by researchers from Huntsman Cancer Institute (HCI) at the University of Utah. In the lab, researchers found that an enzyme, called lysine specific demethylase (LSD-1), interacts with EWS/FLI to turn off gene expression in Ewing sarcoma. By turning off specific genes, the EWS/FLI-LSD1 complex causes Ewing sarcoma development. The team is now working to further test LSD inhibitors in animal models as they work toward approval of a first-in-man clinical trial.

135

Extraskeletal Ewing's Sarcoma of the Head and Neck Presenting as Blindness  

PubMed Central

Extraskeletal Ewing's sarcoma is rarely found in the head and neck regions. We report an unusual case of extraskeletal Ewing's Sarcoma of the parapharynx region in a 49-year-old man who presented with blindness. MRI examination showed marked enhancement of tumor thrombosis involving the superior sagittal sinus, straight sinus, transverse sinus, sigmoid sinus, and internal jugular vein. The final diagnosis was extraskeletal Ewing's sarcoma after biopsy of the internal jugular vein thrombosis by histopathological evaluation and immunohistochemical assay. In addition, the patient was diagnosed as having adenocarcinoma of the rectum by biopsy of the rectal mass. The patient was treated with systemic chemotherapy and showed improved response with durable remission. The patient's visual acuity, however, did not improve.

Cho, Sung In; Park, Yeon Hee; Cho, Jang Hyun; Yang, Sung Hyun; Youn, Sang Min; Ko, Jae Soo

2007-01-01

136

The Value of Local Treatment in Patients With Primary, Disseminated, Multifocal Ewing Sarcoma (PDMES)  

Microsoft Academic Search

BACKGROUND: The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES) was investigated. METHODS: We analyzed 120 patients registered into the European Ewing Tumor Working Initiative of National Groups (EURO-E.W.I.N.G. 99) trial at the trial center of Muenster from 1998 to 2006. Median age was 16.2 years. Local treatment of the primary tumor was surgery in

Julia Haeusler; Andreas Ranft; Tobias Boelling; Georg Gosheger; Gabriele Braun-Munzinger; Volker Vieth; Stefan Burdach; Henk van den Berg; Heribert Juergens; Uta Dirksen

2010-01-01

137

Development of Ewing's Sarcoma from Primary Bone Marrow Derived Mesenchymal Progenitor Cells  

Microsoft Academic Search

Ewing's sarcoma is a member of Ewing's family tumors (EFTs) and the second most common solid bone and soft tissue malignancy of children and young adults. It is associated in 85% of cases with the t(11;22)(q24:q12) chromosomal trans- location that generates fusion of the 5V segment of the EWS gene with the 3V segment of the ETS family gene FLI-1.

Luisa Cironi; Paolo Provero; Konstantinos Kaloulis; Carlos Garcia-Echeverria; Francesco Hoffmann; Andreas Trumpp; Ivan Stamenkovic

2005-01-01

138

The EWS/FLI Oncogene Drives Changes in Cellular Morphology, Adhesion, and Migration in Ewing Sarcoma  

PubMed Central

Ewing sarcoma is a tumor of the bone and soft tissue caused by the expression of a translocation-derived oncogenic transcription factor, EWS/FLI. Overt metastases are associated with a poor prognosis in Ewing sarcoma, but patients without overt metastases frequently harbor micrometastatic disease at presentation. This suggests that the metastatic potential of Ewing sarcoma exists at an early stage during tumor development. We have therefore explored whether the inciting oncogenic event in Ewing sarcoma, EWS/FLI, directly modulates tumor cell features that support metastasis, such as cell adhesion, cell migration, and cytoarchitecture. We used an RNAi-based approach in patient-derived Ewing sarcoma cell lines. Although we hypothesized that EWS/FLI might induce classic metastatic features, such as increased cell adhesion, migration, and invasion (similar to the phenotypes observed when epithelial malignancies undergo an epithelial-to-mesenchymal transition during the process of metastasis), surprisingly, we found the opposite. Thus, EWS/FLI expression inhibited the adhesion of isolated cells in culture and prevented adhesion in an in vivo mouse lung assay. Cell migration was similarly inhibited by EWS/FLI expression. Furthermore, EWS/FLI expression caused a striking loss of organized actin stress fibers and focal adhesions and a concomitant loss of cell spreading, suggesting that EWS/FLI disrupts the mesenchymal phenotype of a putative tumor cell-of-origin. These data suggest a new paradigm for the dissemination and metastasis of mesenchymally derived tumors: these tumors may disseminate via a “passive/stochastic” model rather than via an “active” epithelial-to-mesenchymal type transition. In the case of Ewing sarcoma, it appears that the loss of cell adhesion needed to promote tumor cell dissemination might be induced by the EWS/FLI oncogene itself rather than via an accumulation of stepwise mutations.

Chaturvedi, Aashi; Hoffman, Laura M.; Welm, Alana L.; Lessnick, Stephen L.

2012-01-01

139

Growth-Promoting Role of the miR-106a~363 Cluster in Ewing Sarcoma  

PubMed Central

MicroRNAs (miRs) have been identified as potent regulators of both normal development and the hallmarks of cancer. Targeting of microRNAs has been shown to have preclinical promise, and select miR-based therapies are now in clinical trials. Ewing Sarcoma is a biologically aggressive pediatric cancer with little change in clinical outcomes despite improved chemotherapeutic regimens. There is a substantial need for new therapies to improve Ewing Sarcoma outcomes and to prevent chemotherapy-related secondary sequelae. Most Ewing Sarcoma tumors are driven by the EWS/Fli-1 fusion oncoprotein, acting as a gain-of-function transcription factor causing dysregulation of a variety of targets, including microRNAs. Our previous studies, and those of others, have identified upregulation of miRs belonging to the related miR-17?92a, miR-106b?25, and miR-106a?363 clusters in Ewing Sarcoma. However, the functional consequences of this have not been characterized, nor has miR blockade been explored as an anti-cancer strategy in Ewing Sarcoma. To simulate a potential therapeutic approach, we examined the effects of blockade of these clusters, and their component miRs. Using colony formation as a read-out, we find that blockade of selected individual cluster component miRs, using specific inhibitors, has little or no effect. Combinatorial inhibition using miR “sponge” methodology, on the other hand, is inhibitory to colony formation, with blockade of whole clusters generally more effective than blockade of miR families. We show that a miR-blocking sponge directed against the poorly characterized miR-106a?363 cluster is a particularly potent inhibitor of clonogenic growth in a subset of Ewing Sarcoma cell lines. We further identify upregulation of miR-15a as a downstream mechanism contributing to the miR-106a?363 sponge growth-inhibitory effect. Taken together, our studies provide support for a pro-oncogenic role of the miR-106a?363 cluster in Ewing Sarcoma, and identify miR-106a?363 blockade, as well as miR-15a replacement, as possible strategies for inhibition of Ewing Sarcoma growth.

Dylla, Layne; Jedlicka, Paul

2013-01-01

140

Ewing's Sarcoma of the Lesser Sac Masquerading as a Pancreatic Tumor  

PubMed Central

Extraosseous Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is an uncommon, aggressive, and malignant tumor with a poor patient outcome. Its occurrence in the lesser sac is a rare event and to the best of our knowledge, has not been previously described. The present case was clinically and radiologically misdiagnosed as a pancreatic tumor/gastrointestinal stromal tumor. Histopathology revealed a tumor with "small round cells" that were positive for CD99, confirming the diagnosis of ES/PNET. This report highlights the importance of considering Ewing's sarcoma in the differential diagnosis of intraabdominal, extraintestinal masses.

Rao, Lakshmi; Rodrigues, Gabriel; Suresh, B P

2012-01-01

141

A very rare cause of neck pain: primary Ewing sarcoma of the axis.  

PubMed

We report the case of a 7-year-old boy who presented with a 1-month history of neck pain, left-sided torticollis, and no neurological deficit. Computed tomography and magnetic resonance imaging revealed an expansile lesion in the axis, with epidural and prevertebral soft tissue components. Histopathologic examination of the biopsy specimen revealed primary vertebral Ewing sarcoma. This is the first case of primary vertebral Ewing sarcoma that has presented with torticollis. It is essential for physicians to be familiar with this condition and the associated imaging findings because early diagnosis of such cases is the key to better prognosis. PMID:24196088

Aydin, Ramazan; Bilgici, Meltem Ceyhan; Dagcinar, Adnan

2013-11-01

142

ZEB2 Represses the Epithelial Phenotype and Facilitates Metastasis in Ewing Sarcoma.  

PubMed

The vast majority of cancer-related deaths are attributable to metastasis. Effective treatment of metastatic disease will be improved by a better understanding of the molecular mechanisms contributing to this phenomenon. Much of the work in this field has focused on metastasis of carcinomas, tumors of epithelial origin, while metastasis of sarcomas, tumors of mesenchymal origin, remains poorly understood. Experimental evidence from studies in carcinomas, coupled with clinical observations, highlights the importance of both epithelial and mesenchymal characteristics in these cancer cells that make them competent for metastasis. We set out to test if similar cellular plasticity contributes to sarcoma metastasis. We found that the transcription factor, ZEB2, repressed epithelial gene expression in Ewing sarcoma cells, and this, in turn, repressed the epithelial phenotype. When ZEB2 was experimentally reduced in these cells, epithelial characteristics including decreased migratory ability and cytoskeleton rearrangements were observed. Furthermore, ZEB2 reduction in Ewing sarcoma cells resulted in a decreased metastatic potential using a mouse metastasis model. Our data show that Ewing sarcoma cells may have more epithelial plasticity than previously appreciated. This coupled with previous data demonstrating Ewing sarcoma cells also have mesenchymal features primes these cells to successfully metastasize. This is clinically relevant for 2 important reasons. First, this may offer a therapeutic opportunity to induce characteristics of one cell type or the other depending on the stage of the disease. Second, and more broadly, this raises questions about the cell of origin in Ewing sarcoma and may inform future animal models of the disease. PMID:24386509

Wiles, Elizabeth T; Bell, Russell; Thomas, Dafydd; Beckerle, Mary; Lessnick, Stephen L

2013-11-01

143

Ewing Sarcoma: influence of TP53 Arg72Pro and MDM2 T309G SNPs.  

PubMed

The Ewing Sarcoma is an important tumor of bone and soft tissue. The SNPs Arg72Pro of TP53 and T309G of MDM2 have been associated with many cancer types and have been differently distributed among populations worldwide. Based on a case-control design, this study aimed to assess the role of these SNPs in 24 Ewing Sarcoma patients, compared to 91 control individuals. DNA samples were extracted from blood and genotyped for both SNPs by PCR-RFLP and confirmed by DNA sequencing. The results showed an association between the G allele of the T309G and Ewing Sarcoma (P=0.02). Comparing to the TT carriers, the risk of G allele carriers was 3.35 (95% CI=1.22-9.21) with P=0.02. At the genotypic level, an association of the TT genotype with the control group (P=0.03) was found. Comparing to the TT genotype, the risk of TG and GG was 2.97 (95% CI=1.03-8.58) with P=0.04 and 5.00 (95% CI=1.23-20.34) with P=0.02, respectively. No associations regarding the Arg72Pro SNP were found. Considering that the T309G has been associated with several types of cancer, including sarcomas, our results indicate that this SNP may also be important to Ewing Sarcoma predisposition. PMID:23661019

Thurow, Helena S; Hartwig, Fernando P; Alho, Clarice S; Silva, Deborah S B S; Roesler, Rafael; Abujamra, Ana Lucia; de Farias, Caroline Brunetto; Brunetto, Algemir Lunardi; Horta, Bernardo L; Dellagostin, Odir A; Collares, Tiago; Seixas, Fabiana K

2013-08-01

144

CXCL16 and CXCR6 in Ewing sarcoma family tumor.  

PubMed

Chemokines are a family of peptide mediators that play an essential role in cellular migration and intracellular communication in tumor cells as well as immune cells. We hypothesized that the CXCL16-CXCR6 ligand-receptor system plays an important role in Ewing sarcoma (ES) family tumor (ESFT) progression. Using real-time quantitative reverse transcription-polymerase chain reaction, we investigated the mRNA expression of CXCL16, CXCR6, and ADAM 10 in various cell lines. We also investigated the expression of CXCL16, CXCR6, ADAM 10, and ADAM 17 in tissue samples from 61 ESFT patients using immunohistochemistry. The mRNA expression levels of CXCL16 and CXCR6 in the ES cell line were higher than those in the other cell lines. Immunohistochemical staining revealed that CXCL16 and CXCR6 were highly expressed in tumor cells of ESFT and showed a positive correlation between them. The expression of CXCL16 and CXCR6 was associated with the occurrence of lung metastasis. Univariate analysis revealed that CXCL16 or CXCR6 expression was associated with worse prognosis of ESFT patients. In addition, CXCL16 and CXCR6 expression was associated with shorter overall survival irrespective of other prognostic factors. Our results suggest that the CXCL16/CXCR6 axis appears to be important in the progression of ESFT, resulting in more aggressive clinical behavior. Furthermore, there may be a decrease in the overall survival in ESFT patients who have tumors that stain strongly for CXCL16 and CXCR6. PMID:24507753

Na, Ki Yong; Kim, Hyun-Sook; Jung, Woon-Won; Sung, Ji-Youn; Kalil, Ricardo Karam; Kim, Youn Wha; Park, Yong-Koo

2014-04-01

145

Multiplex RT-PCR assay for the differential diagnosis of alveolar rhabdomyosarcoma and Ewing's sarcoma.  

PubMed Central

Cytogenetic analysis has defined specific translocations associated with two of the most common small round cell tumors of childhood, t(11;22) in Ewing's sarcoma and t(2;13) in alveolar rhabdomyosarcoma. We and others have previously demonstrated the diagnostic utility of a reverse transcriptase polymerase chain reaction (RT-PCR) assay for the detection of the t(11;22) encoded EWS/FLI-1 chimeric message in Ewing's sarcoma. More recently, we have cloned the t(2;13)(q35;q14) translocation and have shown that it results in the fusion of the PAX3 gene on chromosome 2 to FKHR, a novel member of the fork-head family of transcription factors on chromosome 13. To define the morphological spectrum of childhood sarcomas that express the t(2;13) encoded PAX3/FKHR chimeric message, we have performed RT-PCR analysis on samples from 44 primary pediatric sarcomas and 8 sarcoma cell lines. PAX3/FKHR chimeric messages were detected in 24 of 27 alveolar, 2 of 12 embryonal, and 0 of 1 pleomorphic rhabdomyosarcoma and in 1 of 2 ectomesenchymomas. In contrast, none of 8 Ewing's sarcomas or 2 undifferentiated sarcomas expressed this message. Chimeric transcripts were detected in all cases with cytogenetic evidence of the (2;13) translocation, and in each case the chimeric PAX3/FKHR message had the identical junction sequence, suggesting that genomic chromosome breaks were clustered in a single intron in both genes. By combining the PAX3/FKHR RT-PCR assay with primers for detection of the Ewing's sarcoma t(11;22) encoded EWS/FLI-1 chimeric transcript, we have developed a multiplex RT-PCR reaction that allows the rapid and accurate identification of either translocation in a biopsy sample. Images Figure 1 Figure 2 Figure 3 Figure 4

Downing, J. R.; Khandekar, A.; Shurtleff, S. A.; Head, D. R.; Parham, D. M.; Webber, B. L.; Pappo, A. S.; Hulshof, M. G.; Conn, W. P.; Shapiro, D. N.

1995-01-01

146

High-throughput tyrosine kinase activity profiling identifies FAK as a candidate therapeutic target in Ewing sarcoma.  

PubMed

Limited progress has been made in the treatment of advanced-stage pediatric solid tumors despite the accelerated pace of cancer discovery over the last decade. Tyrosine kinase inhibition is one tractable therapeutic modality for treating human malignancy. However, little is known about the kinases critical to the development or maintenance of many pediatric solid tumors such as Ewing sarcoma. Using a fluorescent, bead-based technology to profile activated tyrosine kinases, we identified focal adhesion kinase (FAK, PTK2) as a candidate target in Ewing sarcoma. FAK is a tyrosine kinase critical for cellular adhesion, growth, and survival. As such, it is a compelling target for cancer-based therapy. In this study, we have shown that FAK is highly phosphorylated in primary Ewing sarcoma tumor samples and that downregulation of FAK by short hairpin RNA and treatment with a FAK-selective kinase inhibitor, PF-562271, impaired growth and colony formation in Ewing sarcoma cell lines. Moreover, treatment of Ewing sarcoma cell lines with PF-562271 induced apoptosis and led to downregulation of AKT/mTOR and CAS activity. Finally, we showed that small-molecule inhibition of FAK attenuated Ewing sarcoma tumor growth in vivo. With FAK inhibitors currently in early-phase clinical trials for adult malignancies, these findings may bear immediate relevance to patients with Ewing sarcoma. PMID:23536552

Crompton, Brian D; Carlton, Anne L; Thorner, Aaron R; Christie, Amanda L; Du, Jinyan; Calicchio, Monica L; Rivera, Miguel N; Fleming, Mark D; Kohl, Nancy E; Kung, Andrew L; Stegmaier, Kimberly

2013-05-01

147

Ezrin mediates growth and survival in Ewing's sarcoma through the AKT/mTOR, but not the MAPK, signaling pathway.  

PubMed

Recent reports on the role of the membrane-cytoskeleton linker protein ezrin in sarcomas showed an effect on the formation of metastases, dependent on the level of ezrin expression. In this study, we explore the role of ezrin in Ewing's sarcoma, a frequently fatal mesenchymal neoplasm of children and young adults. Through both immunohistochemistry and Western immunoblot studies we find ubiquitous, high-level expression of ezrin in Ewing's sarcoma. In contrast to the observations in osteosarcoma and rhabdomyosarcoma, we demonstrate that inhibition of ezrin-mediated signal transduction, through the expression of a non-phosphorylatable T567A mutant, slows primary growth of Ewing's sarcoma cells in vitro. This reduction in growth is a result of increased apoptosis in the mutant expressing cells. We further show that expression of this mutant reduces the ability of Ewing's sarcoma cells to form experimental metastases in vivo. Molecular examination reveals that the action of ezrin in Ewing's sarcoma is dependent on the AKT/mTOR signal transduction cascade, but not MAP Kinase. These results, therefore, demonstrate that, in Ewing's sarcoma, the biology of ezrin is distinct from that described in other sarcomas. This study further validates ezrin as a potential therapeutic target. PMID:17028919

Krishnan, Kartik; Bruce, Ben; Hewitt, Stephen; Thomas, Dafydd; Khanna, Chand; Helman, Lee J

2006-01-01

148

Low Levels of Common Enzyme Key to Resistance in Ewing's Sarcoma  

Cancer.gov

A study from scientists at the University of Freiburg, Germany, and their collaborators at the NCI, has pinpointed a potential mechanism for resistance of Ewing's sarcoma, a type of bone cancer, to a protein that may be useful in fighting cancer -- and a possible method for overcoming this resistance.

149

Ewing sarcoma of the first metacarpal with a 9-year follow-up: case report.  

PubMed

Ewing sarcoma is a primary bone tumor that rarely occurs in the hand. We present a case involving the thumb metacarpal with long-term follow-up. Carpometacarpal and metacarpophalangeal arthrodeses with autograft are relatively simple procedures that stabilized the thumb and preserved satisfactory function. PMID:23809471

Ramos-Pascua, Luis R; Fernández-Hernández, Oscar; Sánchez Herráez, Sergio; Santos Sánchez, José Ángel; Flores Corral, Teresa

2013-08-01

150

IVC tumor thrombus: an advanced case of rare extraosseous Ewing sarcoma of the adrenal gland.  

PubMed

Extraosseous Ewing sarcoma (ES) of the adrenal gland is a rare, aggressive tumor of young adults, with <10 cases reported. We present the radiological findings of an unusual case of adrenal and renal vein tumor thrombosis extending into the inferior vena cava, secondary to ES of the adrenal gland in a 26-year-old female. PMID:22656426

Saboo, Sachin S; Krajewski, Katherine M; Jagannathan, Jyothi P; Ramaiya, Nikhil

2012-06-01

151

Use of MR Imaging to Assess Results of Chemotherapy for Ewing Sarcoma  

Microsoft Academic Search

MR imaging was used to monitor the results of initial chemotherapy of primary Ewing sarcoma of bone. The signal intensities of the soft-tissue and marrow components of the tumor were evaluated on T2-weighted images obtained in 10 patients (nine with responsive tumors) at presentation and during and immediately after completion of two cycles of chemotherapy. MR evidence of marrow and

Michael A. Lemmi; Neyssa M. Marina; Whitney Slade; David M. Parham; Jesse J. Jenkins; William H. Meyer

152

The role of magnetic resonance imaging in the evaluation of Ewing sarcoma  

Microsoft Academic Search

The experience with magnetic resonance imaging (MRI) in 27 patients with Ewing sarcoma is reported and compared with computed tomography (CT) and plain films. Plain radiography proved to be the best imaging method to asses probable histological diagnosis in all cases (n=6). For the evaluation of chemotherapeutic response (n=4), CT and MRI gave the same information about the variation in

Christophe Frouge; Daniel Vanel; Christine Coffre; Dominique Couanet; Genevieve Contesso; Danielle Sarrazin

1988-01-01

153

Long-term results in 144 localized Ewing's sarcoma patients treated with combined therapy  

Microsoft Academic Search

The results of 144 previously untreated cases of primary Ewing's sarcoma of bone are reported with a minimum follow-up of 5 years. This series was treated between 1972 and 1982 at Istituto Ortopedico Rizzoli with a combined therapy. The local control of the disease consisted of amputation (ten cases), resection followed by radiation therapy (35-45 Gy) (48 cases) and radiation

Gaetano Bacci; Aldo Toni; Maddalena Avella; Marco Manfrini; Alessandra Sudanese; Daniela Ciaroni; Stefano Boriani; Ermanno Emiliani; Mario Campanacci

1989-01-01

154

Prognostic factors for local and distant control in Ewing sarcoma family of tumors  

Microsoft Academic Search

Background: Advances in the treatment of Ewing sarcoma family of tumors (ESFT) are the result of improvements in systemic and local therapies. The individual contributions of each treatment component cannot be analyzed separately; improvements in local and systemic control can influence each other. Patients and methods: We reviewed the records of 220 patients treated on institutional protocols from 1979 to

C. Rodrõ ´ guez-Galindo; F. Navid; T. Liu; C. A. Billups; B. N. Rao; M. J. Krasin

2008-01-01

155

Ewing Sarcoma Family of Tumors Express Adenovirus Receptors and Are Susceptible to Adenovirus-Mediated Oncolysis  

Microsoft Academic Search

Purpose: Attenuated viruses derived from adenoviruses (Ad) that kill tumor cells (oncolysis) are currently in clinical trials for se- lected cancers. Some cancers have proven resistant to Ad infection due to low expression of viral receptors. The authors sought to determine whether members of the Ewing sarcoma family of tu- mors (ESFTs) express Ad receptors and are sensitive to Ad-

Anna M. Rice; Mark A. Currier; Lisa C. Adams; Neeti S. Bharatan; Margaret H. Collins; Jean D. Snyder; JAVED KHAN; Timothy P. Cripe

2002-01-01

156

Chest Wall Ewing Sarcoma Family of Tumors: Long-Term Outcomes  

Microsoft Academic Search

Purpose: To review the 40-year University of Florida experience treating Ewing sarcoma family of tumors of the chest wall. Methods and Materials: Thirty-nine patients were treated from 1966 to 2006. Of the patients, 22 were treated with radiotherapy (RT) alone, and 17 patients were treated with surgery with or without RT. Of 9 patients with metastatic disease, 8 were treated

Daniel J. Indelicato; Sameer R. Keole; Joanne P. Lagmay; Christopher G. Morris; C. Parker Gibbs Jr.; Mark T. Scarborough; Saleem Islam; Robert B. Marcus Jr.

2011-01-01

157

BMI1 Promotes Ewing Sarcoma Tumorigenicity Independent of CDKN2A Repression  

Microsoft Academic Search

Deregulation of the polycomb group gene BMI-1 is implicated in the pathogenesis of many human cancers. In this study, we have investigated if the Ewing sarcoma family of tumors (ESFT) expresses BMI-1 and whether it functions as an oncogene in this highly aggressive group of bone and soft tissue tumors. Our data show that BMI-1 is highly expressed by ESFT

Dorothea Douglas; Jessie Hao-Ru Hsu; Aaron Cooper; Diana Abdueva; John van Doorninck; Hiro Shimada; Timothy J. Triche; Elizabeth R. Lawlor

2008-01-01

158

Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma  

Microsoft Academic Search

The aim of this study was to identify risk factors associated with PFS in patients with Ewing sarcoma undergoing ASCT; 116 patients underwent ASCT in 1989–2000 and reported to the Center for International Blood and Marrow Transplant Research. Eighty patients (69%) received ASCT as first-line therapy and 36 (31%), for recurrent disease. Risk factors affecting ASCT were analyzed with use

S L Gardner; J Carreras; C Boudreau; B M Camitta; R H Adams; A R Chen; S M Davies; J R Edwards; A C Grovas; G A Hale; H M Lazarus; M Arora; P J Stiff; M Eapen

2008-01-01

159

Classification of histopathologic changes following chemotherapy in Ewing's sarcoma of bone  

Microsoft Academic Search

A uniform classification of response to chemotherapy is essential to allow comparison of local effect and ultimate prognosis between different therapy schedules. We define a histological grading system for assessment of the response to chemotherapy in Ewing's sarcoma, based on the amount and architectural pattern of residual histologically viable-appearing tumour, the preferential sites of minimal residual tumour and the amount

H. J. Woude; J. L. Bloem; A. H. M. Taminiau; M. A. Nooy; P. C. W. Hogendoorn

1994-01-01

160

Protein expression of KIT and gene mutation of c-kit and PDGFRs in Ewing sarcomas  

Microsoft Academic Search

Ewing sarcoma is a highly malignant tumor of bone preferentially arising in children and young adults. Its 5-year survival rate is only 50% despite the use of multimodal therapeutic approaches, requiring a search for new therapeutic targets and the development of novel therapeutic modalities. KIT and PDGFRs are type III receptor tyrosine kinases, and activating mutations in c-kit (which encodes

Eduard Santini Araujo; Ricardo K. Kalil; Patrizia Bacchini; Franco Bertoni; K. Krishnan Unni; Yong-Koo Park

2007-01-01

161

The role of surgery in children with head and neck rhabdomyosarcoma and Ewing's sarcoma  

Microsoft Academic Search

Rhabdomyosarcoma and Ewing's sarcoma are relatively common malignant tumours in paediatric population. In the past, surgery was the mainstay of treatment and survival rates were poor. Afterwards, the development of multi-agent chemotherapy protocols during the past four decades resulted in a dramatic improvement in long-term survival. As a consequence, the significance of surgery has been the subject of critical discussion

P. Gradoni; D. Giordano; G. Oretti; M. Fantoni; T. Ferri

2010-01-01

162

Resection of pulmonary metastases in pediatric patients with Ewing sarcoma improves survival  

Microsoft Academic Search

BackgroundEwing sarcoma (ES) is the second most common bone tumor in children, and survival of those with metastatic ES has not improved. Previous studies have shown a survival benefit to whole lung irradiation in patients with pulmonary metastases and may be given either before, after, or instead of surgical pulmonary metastasectomy (PM). The contribution of surgery compared with irradiation in

Phillip A. Letourneau; Brett Shackett; Lianchun Xiao; Jonathan Trent; Kuo Jen Tsao; Kevin Lally; Andrea Hayes-Jordan

2011-01-01

163

Tumour volume as a predictor of necrosis after chemotherapy in Ewing's sarcoma  

Microsoft Academic Search

e studied the CT and MR scans, and the histology of 50 patients with primary Ewing's sarcoma of bone to determine the association between the change in tumour volume and necrosis after chemotherapy, and to ascertain their influence on prognosis. The mean age of the patients was 17 years. The limbs were involved in 40 and the axial bones in

A. Abudu; A. M. Davies; P. B. Pynsent; D. C. Mangham; R. M. Tillman; S. R. Carter; R. J. Grimer

1999-01-01

164

Mechanism and relevance of EWS/FLI-mediated transcriptional repression in Ewing sarcoma  

PubMed Central

Ewing sarcoma provides an important model for transcription-factor mediated oncogenic transformation because of its reliance on the ETS-type fusion oncoprotein EWS/FLI. EWS/FLI functions as a transcriptional activator and transcriptional activation is required for its oncogenic activity. Here we demonstrate that a previously less-well characterized transcriptional repressive function of the EWS/FLI fusion is also required for the transformed phenotype of Ewing sarcoma. Through comparison of EWS/FLI transcriptional profiling and genome-wide localization data, we define the complement of EWS/FLI direct downregulated target genes. We demonstrate that LOX is a previously undescribed EWS/FLI-repressed target that inhibits the transformed phenotype of Ewing sarcoma cells. Mechanistic studies demonstrate that the NuRD co-repressor complex interacts with EWS/FLI, and that its associated histone deacetylase and LSD1 activities contribute to the repressive function. Taken together, these data reveal a previously unknown molecular function for EWS/FLI, demonstrate a more highly coordinated oncogenic transcriptional hierarchy mediated by EWS/FLI than previously suspected, and implicate a new paradigm for therapeutic intervention aimed at controlling NuRD activity in Ewing sarcoma tumors.

Sankar, Savita; Bell, Russell; Stephens, Bret; Zhuo, Rupeng; Sharma, Sunil; Bearss, David J.; Lessnick, Stephen L.

2014-01-01

165

MD Anderson-led study finds two targeted therapies act against Ewing's sarcoma tumors  

Cancer.gov

A pair of targeted therapies shrank tumors in some patients with treatment-resistant Ewing's sarcoma or desmoplastic small-round-cell tumors, according to research led by investigators from The University of Texas MD Anderson Cancer Center reported at the American Association for Cancer Research Annual Meeting 2012.

166

Metastatic Ewing's sarcoma/PNET of kidney in 40 year old patient  

PubMed Central

Introduction Primary renal Ewing sarcoma/PNET is an uncommon and very aggressive tumor. Presentation of case : We report the case of a young woman who underwent nephrectomy for a renal mass from unknown etiology. Histologic analysis found small tumoral cells in rosette formation, and immunohistochemical staining was positive for CD99, and focally positive for vimentin and Protein S-100. A post operative abdominal computed tomography (CT) scan revealed a residual renal processus with hepatic wounds and abdominal metastatic nodes. After 6 cycles of chemotherapy including Vincristine, Doxorubicin, Cyclophosphamide, the response was considered as good. Discussion Ewing's sarcoma/PNET of kidney is a member of the family of small round cell tumors and it should be differentiated from Wilms tumor, neuroblastoma, rhabdomyosarcoma and lymphoblastic lymphoma. The principle management of its treatment have been extrapolated from the treatment of osseous Ewing sarcoma of bone. Conclusion Despite aggressive treatment, primary renal Ewing sarcoma/PNET has a poor prognosis. It requires a multidisciplinary approach including oncologists, urologists and radiation oncologists.

Kairouani, Mouna; Mokrim, Maha; Mellas, Nawfel; Khennoussi, Basma; M'rabti, Hind El; Boutayeb, Saber; Errihani, Hassan

2012-01-01

167

Very Late Local Relapse of Ewing's Sarcoma of the Head and Neck treated with Aggressive Multimodal Therapy  

PubMed Central

Ewing's sarcoma's relapse rarely occurs more than two years after the initial diagnosis. We report the case of a 26-year-old man with a history of Ewing's sarcoma of the left maxillary sinus at the age of 10 who presented with a very late local relapse, 16 years after the first occurrence of disease. Ultimate control was achieved after multimodal therapy including surgery, high-dose chemotherapy, and radiotherapy. This report indicates that local relapses of Ewing's sarcoma can be treated with curative intent in selected cases.

Thariat, J.; Italiano, A.; Peyrade, F.; Birtwisle-Peyrottes, I.; Gastaud, L.; Dassonville, O.; Thyss, A.

2008-01-01

168

Clinical Features and Outcomes in Patients with Ewing Sarcoma and Regional Lymph Node Involvement  

PubMed Central

Background A minority of patients with Ewing sarcoma present with regional lymph node involvement. We investigated if patient characteristics and outcomes differ between patients with Ewing sarcoma with and without regional node involvement. Procedure Patients < 40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) reported to the SEER database from 1973 to 2008 were evaluated based on the presence (n=91) or absence (n=1361) of regional node involvement. Patient characteristics were analyzed using Fisher exact tests. Overall survival was estimated by Kaplan-Meier methods and evaluated using log-rank tests and Cox models. Results Patients with regional node involvement were more likely to have extraskeletal primary tumors (65.9% vs. 31.2%; p < 0.001) and axial tumors (71.1% vs. 59.6%; p = 0.03) compared to patients without regional node involvement. The incidence of regional node involvement was 12.4% for patients with extraskeletal primary tumors compared to 3.2% for patients with skeletal tumors. Five-year overall survival from diagnosis was inferior for patients with regional node involvement compared to those without regional node involvement (45.9% vs. 60.3%; p < 0.001). On multivariate analysis, regional node involvement was predictive of inferior overall survival independent of age, metastatic status, tumor site, and soft tissue origin (hazard ratio 1.59; 95% CI 1.16–2.19). Conclusions Patients with extraskeletal Ewing sarcoma should undergo evaluation for regional node involvement. If validated, our findings indicate that regional node involvement may be an independent adverse prognostic factor in Ewing sarcoma, and potentially useful in risk-stratifying patients with otherwise localized disease.

Applebaum, Mark A.; Goldsby, Robert; Neuhaus, John; DuBois, Steven G.

2011-01-01

169

Differentially Expressed miRNAs in Ewing Sarcoma Compared to Mesenchymal Stem Cells: Low miR-31 Expression with Effects on Proliferation and Invasion  

PubMed Central

Ewing sarcoma, the second most common bone tumor in children and young adults, is an aggressive malignancy with a strong potential to metastasize. Ewing sarcoma is characterised by translocations encoding fusion transcription factors with an EWSR1 transactivation domain fused to an ETS family DNA binding domain. microRNAs are post-transcriptional regulators of gene expression and aberrantly expressed microRNAs have been identified as tumor suppressors or oncogenes in most cancer types. To identify potential oncogenic and tumor suppressor microRNAs in Ewing sarcoma, we determined and compared the expression of 377 microRNAs in 40 Ewing sarcoma biopsies, 6 Ewing sarcoma cell lines and mesenchymal stem cells, the putative cellular origin of Ewing sarcoma, from 6 healthy donors. Of the 35 differentially expressed microRNAs identified (fold change >4 and q<0.05), 19 were higher and 16 lower expressed in Ewing sarcoma. In comparisons between Ewing sarcoma samples with EWS-FLI or EWS-ERG translocations, with differing dissemination characteristics and of primary samples and metastases no significantly differential expressed microRNAs were detected using various stringency criteria. For miR-31, the microRNA with lowest expression in comparison to mesenchymal stem cells, functional analyses were performed to determine its potential as a tumor suppressor in Ewing sarcoma. Two of four miR-31 transfected Ewing sarcoma cell lines showed a significantly reduced proliferation (19% and 33% reduction) due to increased apoptosis in one and increased length of G1-phase in the other cell line. All three tested miR-31 transfected Ewing sarcoma cell lines showed significantly reduced invasiveness (56% to 71% reduction). In summary, we identified 35 microRNAs differentially expressed in Ewing sarcoma and demonstrate that miR-31 affects proliferation and invasion of Ewing sarcoma cell lines in ex vivo assays.

Karnuth, Bianca; Dedy, Nicolas; Spieker, Tilmann; Lawlor, Elizabeth R.; Gattenlohner, Stefan; Ranft, Andreas; Dirksen, Uta; Jurgens, Heribert; Brauninger, Andreas

2014-01-01

170

Differentially expressed miRNAs in Ewing sarcoma compared to mesenchymal stem cells: low miR-31 expression with effects on proliferation and invasion.  

PubMed

Ewing sarcoma, the second most common bone tumor in children and young adults, is an aggressive malignancy with a strong potential to metastasize. Ewing sarcoma is characterised by translocations encoding fusion transcription factors with an EWSR1 transactivation domain fused to an ETS family DNA binding domain. microRNAs are post-transcriptional regulators of gene expression and aberrantly expressed microRNAs have been identified as tumor suppressors or oncogenes in most cancer types. To identify potential oncogenic and tumor suppressor microRNAs in Ewing sarcoma, we determined and compared the expression of 377 microRNAs in 40 Ewing sarcoma biopsies, 6 Ewing sarcoma cell lines and mesenchymal stem cells, the putative cellular origin of Ewing sarcoma, from 6 healthy donors. Of the 35 differentially expressed microRNAs identified (fold change >4 and q<0.05), 19 were higher and 16 lower expressed in Ewing sarcoma. In comparisons between Ewing sarcoma samples with EWS-FLI or EWS-ERG translocations, with differing dissemination characteristics and of primary samples and metastases no significantly differential expressed microRNAs were detected using various stringency criteria. For miR-31, the microRNA with lowest expression in comparison to mesenchymal stem cells, functional analyses were performed to determine its potential as a tumor suppressor in Ewing sarcoma. Two of four miR-31 transfected Ewing sarcoma cell lines showed a significantly reduced proliferation (19% and 33% reduction) due to increased apoptosis in one and increased length of G1-phase in the other cell line. All three tested miR-31 transfected Ewing sarcoma cell lines showed significantly reduced invasiveness (56% to 71% reduction). In summary, we identified 35 microRNAs differentially expressed in Ewing sarcoma and demonstrate that miR-31 affects proliferation and invasion of Ewing sarcoma cell lines in ex vivo assays. PMID:24667836

Karnuth, Bianca; Dedy, Nicolas; Spieker, Tilmann; Lawlor, Elizabeth R; Gattenlöhner, Stefan; Ranft, Andreas; Dirksen, Uta; Jürgens, Heribert; Bräuninger, Andreas

2014-01-01

171

Ewing Sarcoma, an enigmatic malignancy of likely progenitor cell origin, driven by transcription factor oncogenic fusions.  

PubMed

Since its first description by James Ewing in 1921, Ewing Sarcoma has been a cryptic malignancy. A poorly differentiated tumor of uncertain histogenesis and aggressive biologic behavior, it is the second most common malignancy of bone and soft tissue affecting adolescents and young adults. Some two decades ago, the understanding of Ewing Sarcoma biology took a leap forward with the identification of recurrent EWS/Ets fusions, which drive onco-genesis in this disease. A further leap forward occurred over the last half decade with the application of gene silencing, global expression profiling and primary cell culture technologies to the study of this disease. Resulting work has revealed EWS/Ets fusions to be surprisingly versatile regulators of gene expression, and has narrowed the search for the elusive cell of origin. Improved understanding of EWS/Ets biology and relevant oncogenic pathways has in turn led to the development of targeted therapies, including, recently, small molecules targeting key complexes involving the oncogenic fusion itself. In many respects still remaining an enigma, Ewing Sarcoma is an important model for cancers originating in progenitor-type cells or manifesting progenitor-type cell features, and cancers containing recurrent oncogenic fusions, the latter a surprisingly expanding number. PMID:20490326

Jedlicka, Paul

2010-01-01

172

Left atrial extension of metastatic lung tumor via pulmonary vein: report on the first case of Ewing sarcoma  

PubMed Central

Extension of metastatic lung tumors into the left atrium via pulmonary veins is rare. Here, we report the first case of Ewing sarcoma exhibiting such extension. A 31-year-old man with pulmonary metastasis from Ewing sarcoma presented with a mass in the left lung, extending to the left atrium through the left inferior pulmonary vein. As the patient was considered to be at risk of tumor embolism, the mass was excised surgically.

Funakoshi, Yohei; Mukohara, Toru; Kataoka, Tomoko; Tomioka, Hideo; Chayahara, Naoko; Fujiwara, Yutaka; Kiyota, Naomi; Shirasaka, Tomonori; Oka, Takanori; Okada, Kenji; Okita, Yutaka; Hara, Shigeo; Itoh, Tomoo; Fumita, Soichi; Nakagawa, Kazuhiko; Minami, Hironobu

2010-01-01

173

The Ewing's sarcoma oncoprotein EWS\\/FLI induces a p53-dependent growth arrest in primary human fibroblasts  

Microsoft Academic Search

Ewing's sarcoma is associated with a fusion between the EWS and FLI1 genes, forming an EWS\\/FLI fusion protein. We developed a system for the identification of cooperative mutations in this tumor through expression of EWS\\/FLI in primary human fibroblasts. Gene expression profiling demonstrated that this system recapitulates many features of Ewing's sarcoma. EWS\\/FLI-expressing cells underwent growth arrest, suggesting that growth

Stephen L. Lessnick; Caroline S. Dacwag; Todd R. Golub

2002-01-01

174

Differential Transactivation by Alternative EWS-FLI1 Fusion Proteins Correlates with Clinical Heterogeneity in Ewing's Sarcoma 1  

Microsoft Academic Search

The t(11;22)(q24;q12) translocation is present in up to 95% of cases of Ewing's sarcoma and results in the formation of an EWS-FLI1 fusion gene which encodes a chimeric transcription factor. The proximate role of EWS-FLI1 in the pathogenesis of Ewing's sarcoma is thought to involve the activation of as yet largely unknown target genes. Many alternative forms of EWS-FLI1 exist

Patrick P. Lin; Rachel I. Brody; Aimee C. Hamelin; James E. Bradner; John H. Healey; Marc Ladanyi

175

Junction region of EWS-FLI1 fusion protein has a dominant negative effect in Ewing's Sarcoma in vitro  

PubMed Central

Background Ewing’s sarcoma is a malignancy characterized by a specific 11:22 chromosomal translocation which generates a novel EWS-FLI1 fusion protein functioning as an aberrant transcription factor. In the present study, we have further characterized the junction region of the EWS-FLI1 fusion protein. Methods In-silico model of EWS-FLI1 fusion protein was analysed for ligand binding sites, and a putative region (amino acid (aa) 251–343 of the type 1 fusion protein) in the vicinity of the fusion junction was cloned and expressed using bacterial expression. The recombinant protein was characterized by Circular Dichroism (CD). We then expressed aa 251–280 ectopically in Ewing’s sarcoma cell-line and its effect on cell proliferation, tumorigenicity and expression of EWS-FLI1 target genes were analysed. Results Our modelling analysis indicated that Junction region (aa 251–343) encompasses potential ligand biding sites in the EWS-FLI1 protein and when expressed in bacteria was present as soluble form. Ectopically expressing this region in Ewing’s sarcoma cells inhibited tumorigenicity, and EWS-FLI1 target genes indicating a dominant negative biological effect. Conclusions Junction region can be exploited further as target for drug development in future to specifically target EWS-FLI1 in Ewing’s Sarcoma.

2012-01-01

176

Analysis of the p16INK4, p14ARF, p15, TP53, and MDM2 Genes and Their Prognostic Implications in Osteosarcoma and Ewing Sarcoma  

Microsoft Academic Search

We examined alterations of the p16INK4, p14ARF, p15, TP53, and MDM2 genes in 30 osteosarcomas and 24 Ewing sarcomas. Among 21 osteosarcomas and 24 Ewing sarcomas, p16INK4, p14ARF, and p15 abnormalities were found in 4 (19%), 2 (9%), and 3 (14%) osteosarcomas, respectively, and in 4 (17%), 3 (13%), and 4 (17%) Ewing sarcomas, respectively. The alterations of p16INK4, p14ARF,

Takashi Tsuchiya; Ki-ichi Sekine; Shin-ichi Hinohara; Takeshi Namiki; Tsutomu Nobori; Yasuhiko Kaneko

2000-01-01

177

MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future Directions  

PubMed Central

The introduction of cytotoxic chemotherapeutic drugs in the 1970's improved the survival rate of patients with bone sarcomas and allowed limb salvage surgeries. However, since the turn of the century, survival data has plateaued for a subset of metastatic, nonresponding osteo, and/or Ewing sarcomas. In addition, most high-grade chondrosarcoma does not respond to current chemotherapy. With an increased understanding of molecular pathways governing oncogenesis, modern targeted therapy regimens may enhance the efficacy of current therapeutic modalities. Mitogen-Activated Protein Kinases (MAPK)/Extracellular-Signal-Regulated Kinases (ERK) are key regulators of oncogenic phenotypes such as proliferation, invasion, angiogenesis, and inflammatory responses; which are the hallmarks of cancer. Consequently, MAPK/ERK inhibitors have emerged as promising therapeutic targets for certain types of cancers, but there have been sparse reports in bone sarcomas. Scattered papers suggest that MAPK targeting inhibits proliferation, local invasiveness, metastasis, and drug resistance in bone sarcomas. A recent clinical trial showed some clinical benefits in patients with unresectable or metastatic osteosarcomas following MAPK/ERK targeting therapy. Despite in vitro proof of therapeutic concept, there are no sufficient in vivo or clinical data available for Ewing sarcomas or chondrosarcomas. Further experimental and clinical trials are awaited in order to bring MAPK targeting into a clinical arena.

Chandhanayingyong, Chandhanarat; Kim, Yuhree; Staples, J. Robert; Hahn, Cody; Lee, Francis Youngin

2012-01-01

178

Granulocyte colony stimulating factor permits dose intensification by interval compression in the treatment of Ewing's sarcomas and soft tissue sarcomas in children  

Microsoft Academic Search

71 children with sarcomas were treated in a prospective pilot study to determine whether granulocyte colony stimulating factor (G-CSF) permits compression of the interval between chemotherapy cycles. Patients had Ewing's sarcoma\\/primitive neuroectodermal tumour (PNET), rhabdomyosarcoma, non-rhabdo soft tissue sarcomas or other advanced soft tissue tumours. The chemotherapy alternated vincristine–doxorubicin–cyclophosphamide and ifosfamide–etoposide, with G-CSF between courses. Therapy had two phases: induction

R. B Womer; R. T Daller; J. Gallagher Fenton; J. S Miser

2000-01-01

179

Massive venous thrombosis of inferior vena cava as primary manifestation of renal Ewing's sarcoma.  

PubMed

We report an extraordinarily rare case of a 17-year-old male with an extraskeletal Ewing's sarcoma (ESS) of the kidney and a massive thrombosis involving the inferior vena cava (IVC), from the iliac axis to the right atrium. This onset resembled renal cell carcinoma (RCC), although histological examination revealed it was an extraskeletal Ewing's sarcoma/peripheral neuro-ectodermal tumor (EES/PNET). EES/PNET should benefit from neoadjuvant chemotherapy to reduce the risk of metastasis and of recurrent disease due to delay in suitable treatment. Therefore, in the presence of a renal mass with tumor extension of IVC, it is reasonable to bear in mind that other tumors, apart from RCC, could occur. In such cases, a US or CT-scan guided biopsy could be useful. PMID:21612762

Rizzo, D; Barone, G; Ruggiero, A; Maurizi, P; Furfaro, I F; Castagneto, M; Riccardi, R

2011-06-01

180

Extraosseous Ewing's sarcoma / primitive neuroectodermal tumor of the sacral nerve plexus.  

PubMed

We report an unusual case of Ewing's sarcoma / primitive neuroectodermal tumor (PNET) of the sacral nerve plexus in a 9-year-old boy who presented with a soft tissue swelling and severe piercing pain in the lower back region. MRI of the lumbosacral spine showed a lobulated soft tissue mass with clubbed finger-like projections along the path of the sacral nerves, which had caused widening of the spinal canal and the sacral foramina (S2-S4 level). There was presacral extension and posterior scalloping of the sacral vertebrae. Histopathology of the lesion confirmed Ewing's sarcoma / PNET of the sacral spinal nerve plexus. The patient responded favorably to chemotherapy and radiotherapy, showing clinical and radiological improvement. PMID:19881073

Narula, M K; Gupta, Nishant; Anand, Rama; Kapoor, Sudhir

2009-01-01

181

Outcome of flat bone sarcomas (other than Ewing's) in children and adolescents: a study of 25 cases  

Microsoft Academic Search

We analysed the clinical features and outcome of young patients with non-Ewing's flat bone sarcoma treated during the era of contemporary chemotherapy. The characteristics and outcome of 25 patients (15 males and 10 females) with primary or radiation-related flat bone sarcoma treated in the Pediatrics Department at the Institut Gustave Roussy from 1981 to 1999 were reviewed. In all, 20

V Minard-Colin; C Kalifa; J-M Guinebretiere; L Brugieres; J Dubousset; J-L Habrand; G Vassal; O Hartmann

2004-01-01

182

Ewing's sarcoma of mandible: A case report and review of Indian literature  

PubMed Central

Ewing's sarcoma (ES) is a rare malignancy primarily affecting skeletal system and it is commonly diagnosed in children and young adults. It seldom occurs in the head and neck region. ES has poor prognosis because of uncontrolled metastatic potential making early diagnosis and intervention critical for survival of the patient. This paper reports a rare case of ES involving mandible in an 8-year-old girl with clinical, radiological, histopathological and immunohistochemical features.

Mukherjee, Arnab; Ray, Jay Gopal; Bhattacharya, Sourav; Deb, Tushar

2012-01-01

183

Preclinical tests shows agent stops 'slippery' proteins from binding, causing Ewing sarcoma  

Cancer.gov

Continuous infusion of a novel agent not only halted the progression of Ewing sarcoma in rats, while some tumors also regressed to the point that cancer cells could not be detected microscopically, say researchers at Georgetown Lombardi Comprehensive Cancer Center. Their study, which will be presented at the 2013 annual meeting of the American Society of Clinical Oncology, provides pre-clinical evidence necessary to initiate a clinical trial.

184

A Decade in Banking Ewing Sarcoma: A Report from the Children's Oncology Group  

PubMed Central

Outcomes for patients with metastatic and recurrent Ewing sarcoma remain poor and a better understanding of the biology of this malignancy is critical to the development of prognostic biomarkers and novel therapies. Therefore, the Children’s Oncology Group (COG) has created tissue banking protocols designed to collect high quality, clinically annotated, tumor specimens that can be distributed to researchers to perform basic science and correlative investigation. Data from the COG Ewing sarcoma tissue banking protocols AEWS02B1 and its successor study AEWS07B1 were reviewed in this study. Six-hundred and thirty five patients were enrolled on AEWS02B1 and 396 patients have had tissue submitted to AEWS07B1. The average age of participation was 13.2?years. About 86% were less than 19?years old and only 6% were greater than 21?years of age at diagnosis. When compared to SEER data, approximately 18% of all cases and only 8% of all patients >20?years old diagnosed with Ewing sarcoma annually in the United States have had tumor banked. The majority of participants submitted formalin fixed, paraffin embedded, primary tumor and blood samples. In total, fresh frozen tissue was submitted for only 29% of cases. Only seven metastatic tumor samples have been collected. Although the COG has been successful in collecting tumor samples from patients newly diagnosed with Ewing sarcoma, fresh frozen tumor specimens from primary and metastatic disease are critically needed, especially from young adult patients, in order to conduct high quality basic science and translational research investigation with a goal of developing better treatments.

Borinstein, Scott C.; Beeler, Natalie; Block, John J.; Gorlick, Richard; Grohar, Patrick; Jedlicka, Paul; Krailo, Mark; Morris, Carol; Phillips, Sharon; Siegal, Gene P.; Lawlor, Elizabeth R.; Lessnick, Stephen L.

2013-01-01

185

EWS\\/FLI1 Regulates Tumor Angiogenesis in Ewing's Sarcoma via Suppression of Thrombospondins  

Microsoft Academic Search

Suppression of the expression of antiangiogenic factors has been closely associated with multiple malignancies. Throm- bospondins 1 and 2 are members of a family of angiogenic inhibitors that are regulated by several oncogenes. In this study, we investigate the role of thrombospondins in Ewing's sarcoma and their regulation by EWS\\/ETS fusion oncopro- teins. We show that the EWS\\/FLI1 fusion suppresses

Gary Potikyan; Rupert O. V. Savene; Julie M. Gaulden; Zhichao Zhou; Eugenie S. Kleinerman; Stephen L. Lessnick; Christopher T. Denny

2007-01-01

186

Ipsilateral pedicled fibular flap for tibial reconstruction after Ewing sarcoma resection  

Microsoft Academic Search

Ewing sarcoma is a rare and lethal malignant bone tumor, mostly affecting young male patients, and has a predilection for\\u000a the femur, tibia, pelvis, and humerus. Based on the use of improved staging systems, chemotherapy, radiation, and resective\\u000a surgery, actually most patients live and retain function of their limbs. The concept of limb-sparing surgery has evolved over\\u000a the last three

Ricardo Horta Oliveira; José Manuel Amarante; Jorge Cruz Reis; António Costa-Ferreira; Marco Rebelo; Ricardo São Simão; André Pinho; Gilberto Costa; Pedro Silva; Rita Filipe

2011-01-01

187

Primary intradural extraosseous Ewing's sarcoma of the lumbar spine presenting with acute bleeding.  

PubMed

We report the case of a 28-year-old female with primary extraosseous Ewing's sarcoma who presented initially with a low back pain and a right S1 radicular pain. Before scheduled surgical removal, she suddenly developed an unusual complication of an acute hemorrhage and an acute cauda equina syndrome. Emergency surgery was done which demonstrated an acute bleeding. Treatment was followed by the chemotherapy and the adjuvant radiotherapy. Follow-up has been done for 6 years after presentation. PMID:23472623

Khalatbari, M R; Jalaeikhoo, H; Moharamzad, Y

2013-12-01

188

Mutations of the p53 Gene Are Involved in Ewing's Sarcomas but not in Neuroblastomas1  

Microsoft Academic Search

We have investigated the frequency of p53 gene mutations in Ewing's sarcoma (ES) and neuroblastoma (NB) by using polymerase chain reac tion-single strand conformation polymorphism analysis for genomic DNA or complementary DNA generated from total RNA. Mutations of the p53 gene were found in six of seven ES cell lines: a missense mutation of TGC (Cys)-»TAC (Try) at codon 141

Hiruaki Komuro; Yasuhide Hayashi; Machiko Kawamura; Kenshi Hayashi; Yasuhiko Kaneko; Shigehiko Kamoshita; Ryoji Hanada; Keiko Vaniamolo; Teruaki Hongo; Masao Yantada; Yoshiaki Tsuchida

189

BMI1 suppresses contact inhibition and stabilizes YAP in Ewing sarcoma  

Microsoft Academic Search

The polycomb group family protein BMI-1 is overexpressed by and functions as an oncogene in many different human cancers. We have previously shown that BMI-1 promotes the tumorigenicity of Ewing sarcoma family tumors (ESFTs) and that this is mediated independently of CDKN2A repression. In this study, we have discovered that high levels of BMI-1 confer resistance to contact inhibition in

J H Hsu; E R Lawlor

2011-01-01

190

Is neuro-ectodermal differentiation of Ewing's sarcoma of bone associated with an unfavourable prognosis?  

Microsoft Academic Search

Among Ewing's sarcoma (ES) of bone and related entities are tumours with neuro-ectodermal features that could represent a biologically distinct type. In order to assess the prognostic significance of the various forms of ES, a retrospective joint study involving three cancer centres in Europe and the U.S.A. was initiated. The material from 315 primary ES was reviewed by a panel

Ph. Terrier; M. Henry-Amar; T. J. Triche; M. E. Horowitz; M.-J. Terrier-Lacombe; J. S. Miser; T. J. Kinsella; G. Contesso; A. Llombart-Bosch

1995-01-01

191

Regulation of FAS Exon Definition and Apoptosis by the Ewing Sarcoma Protein.  

PubMed

The Ewing sarcoma protein EWS is an RNA and DNA binding protein implicated in transcription, pre-mRNA splicing, and DNA damage response. Using CLIP-seq, we identified EWS RNA binding sites in exonic regions near 5' splice sites. A prominent target was exon 6 of the FAS/CD95 receptor, which is alternatively spliced to generate isoforms with opposing activities in programmed cell death. Depletion and overexpression experiments showed that EWS promotes exon 6 inclusion and consequently the synthesis of the proapoptotic FAS/CD95 isoform, whereas an EWS-FLI1 fusion protein characteristic of Ewing sarcomas shows decreased activity. Biochemical analyses revealed that EWS binding promotes the recruitment of U1snRNP and U2AF65 to the splice sites flanking exon 6 and therefore exon definition. Consistent with a role for EWS in the regulation of programmed cell death, cells depleted of EWS show decreased sensitivity to FAS-induced apoptosis, and elevated EWS expression enhances apoptosis in EWS-haploinsufficient Ewing sarcoma cells. PMID:24813895

Paronetto, Maria Paola; Bernardis, Isabella; Volpe, Elisabetta; Bechara, Elias; Sebestyén, Endre; Eyras, Eduardo; Valcárcel, Juan

2014-05-22

192

RASSF2 methylation is a strong prognostic marker in younger age patients with Ewing sarcoma.  

PubMed

Ras-association domain family of genes consist of 10 members (RASSF1-RASSF10), all containing a Ras-association (RA) domain in either the C- or the N-terminus. Several members of this gene family are frequently methylated in common sporadic cancers; however, the role of the RASSF gene family in rare types of cancers, such as bone cancer, has remained largely uninvestigated. In this report, we investigated the methylation status of RASSF1A and RASSF2 in Ewing sarcoma (ES). Quantitative real-time methylation analysis (MethyLight) demonstrated that both genes were frequently methylated in Ewing sarcoma tumors (52.5% and 42.5%, respectively) as well as in ES cell lines and gene expression was upregulated in methylated cell lines after treatment with 5-aza-2'-deoxcytidine. Overexpression of either RASSF1A or RASSF2 reduced colony formation ability of ES cells. RASSF2 methylation correlated with poor overall survival (p = 0.028) and this association was more pronounced in patients under the age of 18 y (p = 0.002). These results suggest that both RASSF1A and RASSF2 are novel epigenetically inactivated tumor suppressor genes in Ewing sarcoma and RASSF2 methylation may have prognostic implications for ES patients. PMID:23887284

Gharanei, Seley; Brini, Anna T; Vaiyapuri, Sumathi; Alholle, Abdullah; Dallol, Ashraf; Arrigoni, Elena; Kishida, Takeshi; Hiruma, Toru; Avigad, Smadar; Grimer, Robert; Maher, Eamonn R; Latif, Farida

2013-09-01

193

Ewing Sarcoma Cells Secrete EWS/Fli-1 Fusion mRNA via Microvesicles  

PubMed Central

Tumours defined as Ewing sarcoma (ES) constitute a group of highly malignant neoplasms that most often affect children and young adults in the first 2 decades of life. The EWS/Fli-1 fusion gene, a product of the translocation t(11;22) (q24; 12), is detected in 95% of ES patients. Recently, it was validated that cells emit a heterogeneous mixture of vesicular, organelle-like structures (microvesicles, MVs) into their surroundings including blood and body fluids, and that these MVs contain a selected set of tumor-related proteins and high levels of mRNAs and miRNAs. In this present study, we detected the Ewing sarcoma-specific EWS/Fli-1 mRNA in MVs from the culture medium of ES cell lines carrying t(11;22) (q24; 12). Also, we detected this fusion gene in approximately 40% of the blood samples from mice inoculated with xenografts of TC135 or A673 cells. These findings indicate the EWS/Fli-1 mRNA in MVs might be a new non-invasive diagnostic marker for specific cases of Ewing sarcoma.

Tsugita, Masanori; Yamada, Nami; Noguchi, Shunsuke; Yamada, Kazunari; Moritake, Hiroshi; Shimizu, Katsuji; Akao, Yukihiro; Ohno, Takatoshi

2013-01-01

194

Clinical Outcomes of Adult Patients With Relapsed Ewing Sarcoma: A 30-Year Single-Institution Experience.  

PubMed

OBJECTIVES:: We aimed to determine the prognostic factors that influence the outcome of adult patients who have disease relapse after treatment for localized Ewing sarcoma. METHODS:: We retrospectively searched for the records of patients aged 18 years and older with localized Ewing sarcoma at Mayo Clinic, Rochester, Minnesota, from 1977 to 2007, who had disease relapse after initial treatment. Patient records were reviewed to analyze factors affecting survival. RESULTS:: A total of 49 patients were identified. The 5-year postrelapse survival rate was 30%. Significant factors affecting the 5-year postrelapse survival rate included site of initial relapse (local vs. distant, 55% vs. 22%, P=0.045); time to relapse (<2 vs. ?2 y from original diagnosis, 12% vs. 50%, P=0.003); and second remission with complete surgical resection versus definitive radiotherapy to the recurrent disease (48% vs. 13%, P<0.001). None of these factors were significant on multivariate modeling. CONCLUSIONS:: Adult patients with Ewing sarcoma who have disease relapse after primary treatment of localized disease will continue to have recurrences regardless of the modality of salvage therapy. Those that have relapse locally or >2 years after the initial diagnosis and are able to achieve a second remission with definitive surgical or radiation therapy have better survival than those who have disease relapse distantly or before the 2-year time point. PMID:23466580

Robinson, Steven I; Ahmed, Safia K; Okuno, Scott H; Arndt, Carola A S; Rose, Peter S; Laack, Nadia N

2013-03-01

195

Massive pleural effusion in an 18-year-old girl with Ewing sarcoma.  

PubMed

Ewing sarcoma is a bone tumour that commonly appears between ages five and 10 in the diaphysis of the long bones and predominantly presents with pain and swelling. The case of an 18-year-old girl who presented with back pain, cough, dyspnea, weakness and fever is described. Chest radiograph showed a homogenous density in the middle and inferior zones of the right hemithorax. Thoracic computed tomography revealed a diffuse pleural effusion and a 6.99 cm x 4.45 cm solid mass composed of lobulated, small cystic lesions and calcifications in the right hemithorax. Biochemical analysis of pleural fluid showed hemorrhagic effusion and exudate. A pleural needle biopsy demonstrated solid uniform tumour cells with narrowed cytoplasm, round nuclei and uncertain nucleoli. All of the tumour cell cytoplasms stained with CD99. The pathological examination supported Ewing sarcoma. Three-phase Tc-99m methylene diphosphonate scintigraphy of the whole body showed pathological tracer uptake in a broad area of the eighth costal bone and in smaller areas of the ninth and 10th costal bones. This case is reported because Ewing sarcoma is a rare cause of pleural effusion in clinical practice among younger adults. PMID:15332140

Ozge, Cengiz; Calikoglu, Mukadder; Cinel, Leyla; Apaydin, F Demir; Ozgür, Eylem S

2004-01-01

196

Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma.  

PubMed

Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2. PMID:22327514

Postel-Vinay, Sophie; Véron, Amélie S; Tirode, Franck; Pierron, Gaelle; Reynaud, Stéphanie; Kovar, Heinrich; Oberlin, Odile; Lapouble, Eve; Ballet, Stelly; Lucchesi, Carlo; Kontny, Udo; González-Neira, Anna; Picci, Piero; Alonso, Javier; Patino-Garcia, Ana; de Paillerets, Brigitte Bressac; Laud, Karine; Dina, Christian; Froguel, Philippe; Clavel-Chapelon, Françoise; Doz, Francois; Michon, Jean; Chanock, Stephen J; Thomas, Gilles; Cox, David G; Delattre, Olivier

2012-03-01

197

GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing's sarcoma oncogenesis and therapeutic resistance.  

PubMed

Ewing's sarcoma is a malignant bone-associated tumor of children and young adults. Most cases of Ewing's sarcoma express the EWS/FLI fusion protein. EWS/FLI functions as an aberrant ETS-type transcription factor and serves as the master regulator of Ewing's sarcoma-transformed phenotype. We recently showed that EWS/FLI regulates one of its key targets, NR0B1, through a GGAA-microsatellite in its promoter. Whether other critical EWS/FLI targets are also regulated by GGAA-microsatellites was unknown. In this study, we combined transcriptional analysis, whole genome localization data, and RNA interference knockdown to identify glutathione S-transferase M4 (GSTM4) as a critical EWS/FLI target gene in Ewing's sarcoma. We found that EWS/FLI directly binds the GSTM4 promoter, and regulates GSTM4 expression through a GGAA-microsatellite in its promoter. Reduction of GSTM4 levels caused a loss of oncogenic transformation. Furthermore, reduction of GSTM4 resulted in an increased sensitivity of Ewing's sarcoma cells to chemotherapeutic agents, suggesting a role for this protein in drug resistance. Consistent with this hypothesis, patients with Ewing's sarcoma whose tumors had higher levels of GSTM4 expression had worse outcomes than those with lower expression levels. These data show that GSTM4 contributes to the cancerous behavior of Ewing's sarcoma and define a wider role for GGAA-microsatellites in EWS/FLI function than previously appreciated. These data also suggest a novel therapeutic resistance mechanism, in which the central oncogenic abnormality directly regulates a resistance gene. PMID:19718047

Luo, W; Gangwal, K; Sankar, S; Boucher, K M; Thomas, D; Lessnick, S L

2009-11-19

198

EWS and RE1-Silencing Transcription Factor Inhibit Neuronal Phenotype Development and Oncogenic Transformation in Ewing Sarcoma  

PubMed Central

The gene encoding EWS (EWSR1) is involved in various chromosomal translocations that cause the production of oncoproteins responsible for multiple cancers including Ewing sarcoma, myxoid liposarcoma, soft tissue clear cell sarcoma, and desmoplastic small round cell sarcoma. It is well known that EWS fuses to FLI to create EWS/FLI, which is the abnormal transcription factor that drives tumor development in Ewing sarcoma. However, the role of wild-type EWS in Ewing sarcoma pathogenesis remains unclear. In the current study, we identified EWS-regulated genes and cellular processes through RNA interference combined with RNA sequencing and functional annotation analyses. Interestingly, we found that EWS and EWS/FLI co-regulate a significant cluster of genes, indicating an interplay between the 2 proteins in regulating cellular functions. We found that among the EWS–down-regulated genes are a subset of neuronal genes that contain binding sites for the RE1-silencing transcription factor (REST or neuron-restrictive silencer factor [NRSF]), neuron-restrictive silencer element (NRSE), suggesting a cooperative interaction between REST and EWS in gene regulation. Co-immunoprecipitation analysis demonstrated that EWS interacts directly with REST. Genome-wide binding analysis showed that EWS binds chromatin at or near NRSE. Furthermore, functional studies revealed that both EWS and REST inhibit neuronal phenotype development and oncogenic transformation in Ewing sarcoma cells. Our data implicate an important role of EWS in the development of Ewing sarcoma phenotype and highlight a potential value in modulating EWS function in the treatment of Ewing sarcoma and other EWS translocation–based cancers.

Sankar, Savita; Gomez, Nicholas C.; Bell, Russell; Patel, Mukund; Davis, Ian J.; Lessnick, Stephen L.

2013-01-01

199

Case report: Reconstruction of an intercalary defect with bone transport after resection of Ewing's sarcoma.  

PubMed

We report a 13-year-old girl with Ewing's sarcoma of the tibia who was treated with multiagent chemotherapy, followed by local control tumor surgery consisting of wide resection of the tumor and bone transport with distraction osteogenesis for reconstruction. The bone defect created by resection was 13 cm long and was replaced by bone transport using a monolateral external fixator. Evaluation of the resected specimen revealed wide tumor-free margins with 100% chemonecrosis. A planned Harmon-type autogenous bone grafting between the middle and proximal segments of the tibia (docking site) was done primarily after docking occurred, and a solid union was obtained by 23 months after resection. The bone healing index (treatment index) was 54 days/1 cm distraction, which is indicative of slow healing. Clinical evaluation of the affected extremity using the Musculoskeletal Tumor Society rating system revealed 80% normal functional capability. Indications for bone transport in reconstruction of bone defects created by wide resection of bone sarcomas are discussed. In retrospect, we have concerns regarding the suitability of this technique in the setting of diaphyseal sarcoma reconstruction in patients with Ewing's sarcoma who require aggressive and intense multiagent chemotherapy. PMID:15864062

Dormans, John P; Ofluoglu, Onder; Erol, Bulent; Moroz, Leslie; Davidson, Richard S

2005-05-01

200

Primary vaginal Ewing's sarcoma or primitive neuroectodermal tumor in a 17-year-old woman: a case report  

PubMed Central

Introduction Primary Ewing's sarcoma or primitive neuroectodermal tumor of the genital tract of women is uncommon. Rarer still is its occurrence in the vagina, with only five cases described so far. Out of these, only one case was confirmed using molecular analysis. Case presentation We present an extremely rare case of Ewing's sarcoma or primitive neuroectodermal tumor in a 17-year-old Indian girl. She presented with a vaginal mass that was initially diagnosed as a malignant round cell tumor. Immunohistochemistry showed diffuse positivity for vimentin, membranous positivity for MIC2, and positivity for BCL2 and FLI-1. On the other hand, she was negative for cytokeratin, epithelial membrane antigen, desmin, Myo D-1, myogenin and smooth muscle actin. A diagnosis of primitive neuroectodermal tumor was thus offered. Furthermore, a molecular analysis of our patient using reverse transcription-polymerase chain reaction technique showed positivity for t(11; 22) (q24; q12) (EWSR1-FLI1), thus confirming the diagnosis of a Ewing's sarcoma/primitive neuroectodermal tumor. Our patient was offered chemotherapy on Institutional protocol EFT 2001. Conclusion This is a rare case of primary vaginal Ewing's sarcoma or primitive neuroectodermal tumor, which was confirmed with molecular analysis, in the youngest patient known so far. This study reinforces the value of integrating morphological features with membranous MIC2 positivity, along with application of molecular techniques in objective identification of an Ewing's sarcoma or primitive neuroectodermal tumor at uncommon sites.

2010-01-01

201

Anchorage-independent growth of Ewing sarcoma cells under serum-free conditions is not associated with stem-cell like phenotype and function.  

PubMed

Novel treatment strategies for Ewing sarcoma aim to eliminate residual tumor cells that have maintained the capacity to reinitiate tumor growth after intensive conventional therapy. Preclinical models that more closely mimic in vivo tumor growth than standard monolayer cultures are needed. Sphere formation under anchorage-independent, serum-free conditions has been proposed to enrich for cells with tumor-initiating, stem cell-like properties in various solid cancers. In the present study, we assessed the phenotype and functional stem cell characteristics of Ewing sarcoma spheres. Spheres were generated under serum-free culture conditions from four Ewing sarcoma cell lines and four relapse tumor biopsies. Standard monolayer cultures were established as controls. Median levels of surface expression of the Ewing sarcoma marker CD99 as well as the supposed stem cell marker CD133 and the neural crest marker CD57 were comparable between spheres and monolayers. Ewing sarcoma spheres from individual tumors failed to continuously self-renew by secondary sphere formation. They contained variable proportions of side populations (SPs). Sphere culture did not enhance the in vivo tumorigenicity of Ewing sarcoma cells in a murine xenograft model. We conclude that sphere formation under serum-free conditions is not a reliable tool to enrich for cells with stem cell characteristics in Ewing sarcoma. By mimicking the anchorage-independent, multicellular growth of Ewing sarcoma micrometastases, in vitro sphere growth may still add value as a preclinical tool to evaluate the efficacy of novel therapeutics. PMID:24927333

Leuchte, Katharina; Altvater, Bianca; Hoffschlag, Simeon; Potratz, Jenny; Meltzer, Jutta; Clemens, Dagmar; Luecke, Andrea; Hardes, Jendrik; Dirksen, Uta; Juergens, Heribert; Kailayangiri, Sareetha; Rossig, Claudia

2014-08-01

202

Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS\\/ets protein in Ewing sarcoma  

Microsoft Academic Search

The chromosomal translocation specifically linked to the Ewing sarcoma family results in the generation of fusion proteins comprising the amino terminal portion of EWS and the DNA-binding domain of ets transcription factors. The EWS\\/ets chimeric proteins act as aberrant transcription factors leading to tumorigenic processes. We searched for genes specifically activated in Ewing sarcoma cells but not in other tumor

Mariko Fukuma; Hajime Okita; Jun-ichi Hata; Akihiro Umezawa

2003-01-01

203

The Genomic Landscape of the Ewing Sarcoma Family of Tumors Reveals Recurrent STAG2 Mutation  

PubMed Central

The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p?=?0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p?=?0.15) and a modest decrease in overall survival (p?=?0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.

Brohl, Andrew S.; Solomon, David A.; Chang, Wendy; Wang, Jianjun; Song, Young; Sindiri, Sivasish; Patidar, Rajesh; Hurd, Laura; Chen, Li; Shern, Jack F.; Liao, Hongling; Wen, Xinyu; Gerard, Julia; Kim, Jung-Sik; Lopez Guerrero, Jose Antonio; Machado, Isidro; Wai, Daniel H.; Picci, Piero; Triche, Timothy; Horvai, Andrew E.; Miettinen, Markku; Wei, Jun S.; Catchpool, Daniel; Llombart-Bosch, Antonio; Waldman, Todd; Khan, Javed

2014-01-01

204

Fine-Needle Aspiration Cytology of Ewing's Sarcoma of Thoracic Spine with Extension into the Intradural Space  

PubMed Central

Ewing's sarcoma/peripheral primitive neuroectodermal tumor is a small, round, and blue cell malignancy that occurs most often in bone and soft tissues of children and young adults. The intraspinal manifestation of the disease is rare, and when present, this is often misdiagnosed with other varieties of primary spinal tumors. Fine-needle aspiration cytology (FNAC) plays important role in the early diagnosis of these cases. We report such a case of Ewing's sarcoma of thoracic spine with extension into the intradural space, which was initially suspected to be a case of metastatic lesion in an 18-year-old boy.

Bordia, Sandhya; Meena, Sweta; Meena, Bijendar Kumar; Rajak, Vijay

2014-01-01

205

18 F-FDG PET response to neoadjuvant chemotherapy for Ewing sarcoma and osteosarcoma are different  

Microsoft Academic Search

Objective  Ewing sarcoma (ES) and osteosarcoma (OS) have different biological characteristics and respond differently to chemotherapy.\\u000a We reviewed 18F-FDG PET imaging characteristics of ES and OS patients at baseline and following treatment to determine whether this biological\\u000a variation is reflected in their imaging phenotype.\\u000a \\u000a \\u000a \\u000a \\u000a Materials and methods  A retrospective review of ES and OS patients treated with neoadjuvant chemotherapy and surgery was

Louie L. Gaston; Claudia Di Bella; John Slavin; Rodney J. Hicks; Peter F. M. Choong

2011-01-01

206

CT and MR findings in a neuroforaminal extraskeletal Ewing sarcoma mimicking benign nerve sheath tumor  

Microsoft Academic Search

Introduction  We report the CT and MR findings in a 30-year-old man with extraskeletal Ewing sarcoma (EES) involving the left neural foramen\\u000a at L5–S1 level.\\u000a \\u000a \\u000a \\u000a \\u000a Materials and methods  The patient was evaluated with preoperative lumbosacral CT and MR imaging and postoperative lumbosacral MR imaging.\\u000a \\u000a \\u000a \\u000a Results   The lesion was hyperdense on CT, isointense on T1- and T2-weighted MR images, and enhanced homogeneously after

S. Avcu; H. N. Özcan; M. ?zmirli; M. Lemmerling

207

Imaging of primary Ewing sarcoma with /sup 13/N-L-glutamate  

SciTech Connect

Eleven patients with untreated primary Ewing sarcoma were studied with intravenously administered /sup 13/N-labeled L-glutamate. Seven were repeatedly scanned during chemotherapy using this agent and /sup 99m/Tc-methylene diphosphonate (/sup 99m/Tc-MDP). The untreated primary tumor was distinctly visualized with /sup 13/N-L-glutamate in all cases; the distribution of /sup 13/N label in the tumor sometimes differed from that of /sup 99m/Tc. A kinetic study showed rapid uptake of /sup 13/N by tumor tissue. Repeat scans following therapy indicated that /sup 13/N-L-glutamate and /sup 99m/Tc-MDP uptake showed changes consistent with histological findings following subsequent surgery. /sup 13/N uptake often decreased more markedly than /sup 99m/Tc uptake during chemotherapy, but metastatic lesions were not visualized with /sup 13/N-L-glutamate. Tumor imaging with this labeled amino acid may be of value in assessing the response of primary Ewing sarcoma to chemotherapy.

Reiman, R.E.; Rosen, G.; Gelbard, A.A.; Benua, R.S.; Laughlin, J.S.

1982-02-01

208

Proliferation of Ewing sarcoma cell lines is suppressed by the receptor tyrosine kinase inhibitors gefitinib and vandetanib  

Microsoft Academic Search

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have gained much attention in recent years as targeted agents for the treatment of a wide range of human cancers. We have investigated the effect of the TKIs gefitinib and vandetanib on tumor cell lines derived from Ewing sarcoma, a highly malignant tumor affecting bone and soft tissue in children and young adults. Gefitinib is

Mattias K Andersson; Pierre Åman

2008-01-01

209

Ewing sarcoma/peripheral primitive neuroectodermal tumor: adult abdominal tumors with an Ewing sarcoma gene rearrangement demonstrated by fluorescence in situ hybridization in paraffin sections.  

PubMed

The differential diagnosis of small round cell tumors is exhaustive and requires ancillary studies. Relatively recently, fluorescence in situ hybridization (FISH) using probes for specific gene rearrangements has gained wide acceptance. This technique is particularly useful in the differential diagnosis of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) and desmoplastic small round-cell tumor (DSRCT). In ES/PNET, the EWS gene is juxtaposed to the FLI-1 gene in 85% of cases and to the ERG gene in another 7% of cases; the EWS gene is juxtaposed to the WTI gene in DSRCT. Documentation of the EWS gene rearrangements in EWS/PNET has previously been demonstrated in frozen tissue. We report 2 unusual cases of EWS/PNET diagnosed in abdominal tumors in adults. Although the immunohistochemical results supported a diagnosis of ES/PNET, 1 case morphologically resembled DSRCT. The diagnosis in these 2 cases was confirmed by the FISH demonstration of EWS/FLI-1 gene fusion in paraffin-embedded tissue. Thus, the usefulness of FISH demonstration of an EWS gene rearrangement with these specific probes in such unusual cases is supported and is demonstrated in paraffin-embedded tissue. PMID:15354743

Gardner, Laura J; Ayala, Alberto G; Monforte, Hector L; Dunphy, Cherie H

2004-06-01

210

EWS/FLI1 regulates EYA3 in Ewing's sarcoma via modulation of microRNA-708, resulting in increased cell survival and chemoresistance  

PubMed Central

Ewing's sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histological response to initial chemotherapy have a poor overall prognosis. Therefore, it is important to identify molecules involved in resistance to chemotherapy. Herein, we demonstrate that the DNA-repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing's sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell of origin of Ewing's sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor. We further demonstrate that EWS/FLI1 mediates upregulation of EYA3 via repression of miR-708, a microRNA that targets the EYA3 3?UTR, rather than by binding the EYA3 promoter directly. Importantly, we demonstrate that high levels of EYA3 significantly correlate with low levels of miR-708 in Ewing's sarcoma samples, suggesting that this miR-mediated mechanism of EYA3 regulation holds true in human cancers. Because EYA proteins are important for cell survival during development, we examine, and demonstrate, that loss of EYA3 decreases survival of Ewing's sarcoma cells. Most importantly, knockdown of EYA3 in Ewing's sarcoma cells leads to sensitization to DNA-damaging chemotherapeutics used in the treatment of Ewing's sarcoma, and as expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA damage less effectively than their control counterparts. These studies identify EYA3 as a novel mediator of chemoresistance in Ewing's sarcoma and define the molecular mechanisms of both EYA3 overexpression and of EYA3-mediated chemoresistance.

Robin, Tyler P; Smith, Anna; McKinsey, Erin; Reaves, Lisa; Jedlicka, Paul; Ford, Heide L.

2012-01-01

211

A second nonrandom translocation, der(16)t(1;16)(q21;q13), in Ewing sarcoma and peripheral neuroectodermal tumor  

Microsoft Academic Search

The majority of Ewing sarcomas and peripheral neuroectodermal tumors (PNET) that have been karyotyped contain a specific translocation, t(11;22)(q23;q11). We report here a second nonrandom translocation, der( 16)t(1; 16)(q21;q13), in 2 of 20 cases of Ewing sarcoma (seven previously unreported) and 2 of 7 cases of PNET (all previously unreported). All cases with this translocation also contained the t(l 1;22).

E. C. Douglass; S. T. Rowe; M. Valentine; D. Parham; W. H. Meyer; E. I. Thompson

1990-01-01

212

Atypical growth on MRI in a case of Ewing's sarcoma despite lower SUV on PET.  

PubMed

Ewing's sarcoma is a rare primary bone malignancy of small round blue cells. Treatment typically consists of neoadjuvant chemotherapy, surgical resection, and adjuvant chemotherapy. The disease response to chemotherapy can be followed with fluorodeoxyglucose (FDG) positron emission tomography (PET), which measures the metabolic activity of the tumor, and by magnetic resonance imaging (MRI), which measures tumor size. We present a unique case in which the tumor grew in size following neoadjuvant chemotherapy but decreased in metabolic activity, making it difficult to judge efficacy of the chemotherapy. An atypical response to chemotherapy in this case caused tumor growth due to a fibrotic reaction while viable tumor cells were eradicated. This case highlights the ability of FDG-PET scan to identify the uncommon situation in which a tumor that increased in size may have had a favorable response to chemotherapy. This possibility should be considered in similar cases in which FDG-PET scan shows diminishing metabolic activity despite tumor growth. PMID:24352763

Sanford, Zachary; Israelsen, Stanford; Sehgal, Rajesh; Cheung, Felix H

2014-06-01

213

Ewing sarcoma/primitive neuroectodermal tumor of the kidney in a child.  

PubMed

A 6-year-old female was admitted with abdominal pain and a mass in the right abdomen. Her lactose dehydrogenase level was 1,200 IU/L, and neuron specific enolase was 120 ng/ml. Computed tomography scan confirmed a large right renal mass with necrosis. A right radical nephrectomy was performed. The tumor was completely encapsulated. Based on small round cell histology, strong MIC-2 (CD99) positive tumor cells, and EWS-FLI-1 fusion transcript, Ewing sarcoma/primitive neuroectodermal tumor of the kidney was diagnosed. Induction and follow-up with seven cycles of chemotherapy were given after surgery. She has had no evidence of recurrence 90 months from diagnosis. PMID:16544300

Maeda, Miho; Tsuda, Akio; Yamanishi, Shingo; Uchikoba, Yoko; Fukunaga, Yoshitaka; Okita, Hajime; Hata, Jun-Ichi

2008-01-01

214

Ewing sarcoma with 7;22 translocation: three new cases and clinicopathological characterization.  

PubMed

Ewing sarcoma (ES) is the second most common primary bone malignancy in children and is typically characterized by a translocation involving the EWS gene on chromosome 22 and a member of the ETS family of genes: FLI1 (90%), ERG1 (5%), ETV1 (1%), ETV4 (1%), and FEV (1%). We identified three new cases of t(7;22) (p22;q12) (EWS-ETV1) ES and a literature search revealed an additional six cases. In comparison to conventional ES with t(11;22) (q24;q12) (EWS-FLI1), the t(7;22) ES variant has a higher propensity for females and children in a younger age group and it occurs more commonly in extraosseous locations. PMID:22432475

Shulman, Sarah Catherine; Katzenstein, Howard; Bridge, Julia; Bannister, Lucas L; Qayed, Muna; Oskouei, Shervin; Shehata, Bahig M

2012-12-01

215

Dramatic response to Cisplatin window therapy in a boy with advanced metastatic ewing sarcoma.  

PubMed

Ewing sarcoma (ES) is the second most common type of primary bone malignancy, and retains a high propensity to metastasize; the prognosis of patients with disseminated disease is very poor, with an event-free survival rate of <20%. Current multimodality treatment for ES consists of combined chemotherapy before and concurrent with surgery and local radiotherapy for the involved bone. Cisplatin is one of the most widely used drugs for the treatment of bone tumors in children, but is not currently used in ES. We describe a child with multifocal ES, treated with a phase II trial including a single-drug window therapy, which displayed a dramatic response to 2 courses of cisplatin and had a favorable outcome. PMID:23892353

Trizzino, Antonino; Ziino, Ottavio; Parafioriti, Antonina; Podda, Marta; Tropia, Serena; Luksch, Roberto; D'Angelo, Paolo

2013-08-01

216

Long-term results in 144 localized Ewing's sarcoma patients treated with combined therapy  

SciTech Connect

The results of 144 previously untreated cases of primary Ewing's sarcoma of bone are reported with a minimum follow-up of 5 years. This series was treated between 1972 and 1982 at Istituto Ortopedico Rizzoli with a combined therapy. The local control of the disease consisted of amputation (ten cases), resection followed by radiation therapy (35-45 Gy) (48 cases) and radiation therapy alone (40-60 Gy) (86 cases). Adjuvant chemotherapy, rigorously standardized, was performed according two different protocols: the first (85 cases treated in the period 1972-1978) consisted of vincristine (VCR) Adriamycin (doxorubicin) (ADM), and cyclophosphamide (EDX); the second (59 cases treated in the period 1979-1982) of VCR, ADM, EDX and dactinomycin (DACT). At a follow-up of 5 to 16 years (median, 9), 59 patients (41%) are continuously disease-free (CDF), 81 (56%) developed metastatic disease and/or local recurrence, and four (3%) had a second malignancy. Three factors seem to be correlated to prognosis: the site of the initial lesion (only 23% of the pelvic lesions are represented in the CDF group versus 46% of the other locations); the chemotherapy protocol (32% of the cases in the first protocol are CDF versus 54% in the second); the type of local treatment (60% of the patients treated with amputation or resection plus radiotherapy versus 28% of those treated with radiation therapy alone are CDF). A local recurrence was observed in 24% of the patients (8% in the group locally treated with surgery or surgery plus radiation therapy versus 36% in the group treated with radiation therapy alone). These data suggest that even though adjuvant chemotherapy can improve the long-term results in localized Ewing's sarcoma patients, this disease still represents, in a high percentage of cases, a lethal process whose final prognosis widely depends on the local control of the lesion.

Bacci, G.; Toni, A.; Avella, M.; Manfrini, M.; Sudanese, A.; Ciaroni, D.; Boriani, S.; Emiliani, E.; Campanacci, M.

1989-04-15

217

Sarcomas (other than Ewing's) of flat bones in children and adolescents. A clinicopathologic study.  

PubMed

The clinicopathologic features and response to therapy of 28 patients with non-Ewing's flat bone sarcoma treated at St. Jude Children's Research Hospital, Memphis, Tennessee, over a 25-year period were reviewed. Twenty-two patients had osteosarcoma, four malignant fibrous histiocytoma, one chondrosarcoma, and one fibrosarcoma. Ages at diagnosis ranged from 3 to 24 years (median, 15 years). Primary sites were craniofacial bones in ten patients, pelvis eight, scapula four, ribs two, metatarsal bones two, clavicle one, and vertebra one. All primary tumors were associated with soft tissue extension; none of the patients had metastatic disease at presentation. Six cases represented second malignancies that arose 5 to 16 years after irradiation for an unrelated tumor. Complete excision was possible in ten patients, eight of whom received postoperative chemotherapy. Five of these patients remain free of disease 1.8+ to 13+ years (median, 8.1 years) from diagnosis. Prolonged remissions after adjuvant chemotherapy were achieved in only two of 18 patients after incomplete surgical resection or biopsy. The median survival time in this group was 1 year (range, 0.2-7.7+ years). The remaining 16 patients had progressive local disease, but only two developed concurrent metastases. Thus, complete surgical resection appears to maximize disease-free survival in patients with non-Ewing's flat bone sarcoma. For the large percentage of patients in whom total resection is not possible, because of soft tissue extension and local invasion of bulky tumors, preoperative chemotherapy may increase the likelihood of complete excision and improve long-term survival. PMID:2297650

Kellie, S J; Pratt, C B; Parham, D M; Fleming, I D; Meyer, W H; Rao, B N

1990-02-15

218

A case of primary mediastinal Ewing's sarcoma / primitive neuroectodermal tumor presenting with initial compression of superior vena cava  

PubMed Central

Ewing's sarcomas and peripheral primitive neuroectodermal tumors (ES/PNETs) are high grade malignant neoplasms. These malignancies are characterized by a chromosome 22 rearrangement, arise from bone or soft tissue, predominantly affect children and young adults, and are grouped in the Ewing family of tumors. Multimodality treatment programs are the treatment of choice. Primary localization of ES/PNET in the mediastinum is extremely rare. We describe a case of ES/PNET presenting as a mediastinal mass with tracheal compression and initial signs of superior vena cava in a 66-year-old woman.

Reali, Alessia; Mortellaro, Gianluca; Allis, Simona; Trevisiol, Edoardo; Anglesio, Silvia Maria; Bartoncini, Sara; Redda, Maria Grazia Ruo

2013-01-01

219

Epithelial marker expression does not rule out a diagnosis of Ewing's sarcoma family of tumours.  

PubMed

Epithelial marker expression has been reported in Ewing's sarcoma family of tumors (ESFT). However, cytokeratin (CK), epithelial membrane antigen (EMA), and carcino embryonic antigen (CEA) prevalence has not been assessed thoroughly in a large series of genetically confirmed ESFT. The aim of the present study is to confirm the presence of epithelial markers in a large group of ESFT tested genetically for any of their specific gene fusions and the differential diagnosis with other small round cell tumors. To establish the prevalence of epithelial markers, we then performed immunohistochemical studies with antibodies CK (AE1/AE3), CK8/18, CK34?12, EMA, E-cadherin, and CEA on 415 genetically confirmed ESFT. Immunoreactivity to cytokeratin, EMA, and CEA was present in 19.2%, 6.6%, and 20.8% of cases, respectively. There was no significant association between epithelial markers and histological subtypes, but the atypical variant of ESFT expressed these markers in a high proportion compared with the peripheral neuroectodermal tumors and the conventional variant. The present findings confirm that epithelial marker expression in ESFT, including EMA and CEA, does not rule out a diagnosis of ESFT, and the integration of clinical, radiological, histopathological, immunohistochemical, and molecular genetic findings should form the basis for the diagnosis of bone and soft tissue sarcomas, especially in tumors with atypical or unusual phenotype. PMID:21887539

Machado, Isidro; Navarro, Samuel; López-Guerrero, Jose A; Alberghini, Marco; Picci, Piero; Llombart-Bosch, Antonio

2011-10-01

220

Van Nes rotationplasty as a treatment method for Ewing's sarcoma in a 14-month-old?  

PubMed Central

INTRODUCTION In recent years, the rotationplasty procedure has become popular amongst tumour surgeons as an alternative to endoprosthetic replacement or amputation. There are very few documented cases of this technique in young patients with malignancy. PRESENTATION OF CASE We describe an extremely rare case of Ewing's sarcoma in a 14-month-old boy that involved the entire length of the left femur. At initial presentation, pulmonary metastatic spread had occurred and there was no neurovascular involvement. Complete response to neo-adjuvant chemotherapy was achieved prior to performing the definitive surgical procedure. DISCUSSION This case highlights the many reconstructive options and difficulties encountered in managing such extremely young patients with aggressive malignant disease. In this case, a complete femoral excision was necessary and various treatment options were explored. These included irradiation and re-implantation, endoprosthetic replacement and manufacturing a custom growing prosthesis. Taking future functional, psychological and social implications into consideration, we performed a total femoral excision and Van Nes rotationplasty of the tibia at our institute. Histological analysis of the tumour resection showed clear tumour margins and at 1 year clinical review, the patient demonstrates good functional outcome with no evidence of disease recurrence. CONCLUSION Van Nes rotationplasty is a viable reconstructive option in young patients with sarcoma of the femur. We believe this to be the youngest reported case of rotationplasty in current literature.

Bhamra, Jagmeet S.; Abdul-Jabar, Hani B.; McKenna, David; Ng Man Sun, Stephen; Gillott, Elizabeth; Pollock, Robin

2013-01-01

221

Primitive neuroectodermal tumor\\/Ewing’s sarcoma of the urinary bladder: a case report and its molecular diagnosis  

Microsoft Academic Search

We report a rare case of primitive neuroectodermal tumor\\/Ewing’s sarcoma (PNET\\/ES) arising from the urinary bladder. A 65-year-old\\u000a man presented with hematuria and dysuria. Computed tomography revealed an enlarged invasive tumor at the base of the bladder.\\u000a No additional abnormal findings were disclosed by other diagnostic imaging methods. The surgical specimens showed small round\\u000a cell tumor with positive staining for

Yohei Okada; Shigeyoshi Kamata; Takumi Akashi; Morihito Kurata; Takuro Nakamura; Kazunori Kihara

222

Transformation induced by Ewing's sarcoma associated EWS\\/FLI-1 is suppressed by KRAB\\/FLI-1  

Microsoft Academic Search

Ewing's sarcoma is a childhood bone tumour with poor prognosis, most commonly associated with a t(11;22)(q24;q12) reciprocal translocation that fuses the EWS and FLI-1 genes, resulting in the production of an aberrant chimeric transcription factor EWS\\/FLI-1. To elucidate the mechanisms by which EWS\\/FLI-1 mediates transformation in mouse models, we have generated a murine Ews\\/Fli-1 fusion protein. We demonstrate that this

D Chan; T J Wilson; D Xu; H E Cowdery; E Sanij; P J Hertzog; I Kola

2003-01-01

223

Cytogenetic Confirmation of a Gastrointestinal Stromal Tumor and Ewing Sarcoma\\/Primitive Neuroectodermal Tumor in a Single Patient  

Microsoft Academic Search

We report a rare case in which two tumor entities, a gastrointestinal stromal tumor (GIST) and Ewing sarcoma\\/primitive neuroectodermal tumor (ES\\/PNET), with distinct cytogenetic features occurred in a single patient. The patient was a 72-year-old woman. The first tumor was a sub- mucosal gastric tumor and was diagnosed as a low-risk group GIST based on morphological characteristics and the results

Shunsuke Kondo; Umio Yamaguchi; Shinji Sakurai; Yoshisuke Ikezawa; Hirokazu Chuman; Ukihide Tateishi; Koh Furuta; Tadashi Hasegawa

224

Oncogenic Serine-Threonine Kinase Receptor-Associated Protein Modulates the Function of Ewing Sarcoma Protein through a Novel Mechanism  

Microsoft Academic Search

Although much is known about the oncogenic functions of chimeric Ewing sarcoma (EWS) fusion proteins that result from chromosomal translocations, the cellular role of the normal EWS protein is not well characterized. We have previously identified a WDdomain-containing protein, serine-threonine kinase receptor-associated protein (STRAP), which inhibits transforming growth factor B (TGF-B) signaling through interaction with receptors and Smad7 and promotes

Govindaraj Anumanthan; Sunil K. Halder; David B. Friedman; Pran K. Datta

2006-01-01

225

Interferon ? and tumour necrosis factor ? induce a synergistic antiproliferative response in human Ewing's sarcoma cells in vitro  

Microsoft Academic Search

Three human cell lines derived from Ewing's sarcoma (RM-82, VH-64, and WE-68) were investigated to establish the influence of recombinant human interferon ? (rhIFN?) and tumour necrosis factor ? (rhTNF?) on cell proliferation and survival and to characterize IFN? and TNF? receptor expression. Incorporation of [3H]thymidine into cells was inhibited by rhIFN? after 24 h of incubation. Half-maximal inhibition was

F. van Valen; W. Winkelmann; S. Burdach; U. Göbel; H. Jürgens

1993-01-01

226

Tumor volume or dynamic contrast-enhanced MRI for prediction of clinical outcome of Ewing sarcoma family of tumors  

Microsoft Academic Search

Background. The identification of risk factors that predict poor clinical outcome at the time of diagnosis could lead to intensified\\u000a early therapy and improved outcome for pediatric patients with Ewing sarcoma family of tumors (ESFT). Objective. To compare the effectiveness of static magnetic resonance (MR) imaging measurements of tumor volume with variables obtained\\u000a by dynamic contrast-enhanced MR imaging (DEMRI) in

Shannon L. Miller; F. A. Hoffer; Wilburn E. Reddick; Shengjie Wu; John O. Glass; Suzanne A. Gronemeyer; Mithat Haliloglu; Alexander Y. Nikanorov; Xiaoping Xiong; Alberto S. Pappo

2001-01-01

227

1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma  

Microsoft Academic Search

Despite extensive characterization of the role of the EWS-ETS fusions, little is known about secondary genetic alterations and their clinical contribution to Ewing sarcoma (ES). It has been demonstrated that the molecular structure of EWS-ETS lacks prognostic value. Moreover, CDKN2A deletion and TP53 mutation, despite carrying a poor prognosis, are infrequent. In this scenario identifying secondary genetic alterations with a

C Mackintosh; J L Ordóñez; D J García-Domínguez; V Sevillano; A Llombart-Bosch; K Szuhai; K Scotlandi; M Alberghini; R Sciot; F Sinnaeve; P C W Hogendoorn; P Picci; S Knuutila; U Dirksen; M Debiec-Rychter; K-L Schaefer; E de Álava

2012-01-01

228

Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWS\\/FLI Modulator in Ewing Sarcoma  

Microsoft Academic Search

Background The presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although

Kimberly Stegmaier; Jenny S. Wong; Kenneth N. Ross; Kwan T. Chow; David Peck; Renee D. Wright; Stephen L. Lessnick; Andrew L. Kung; Todd R. Golub

2007-01-01

229

EWS-FLI1 inhibits TNF?-induced NF?B-dependent transcription in Ewing sarcoma cells  

Microsoft Academic Search

Ewing sarcoma is primarily caused by a t(11;22) chromosomal translocation encoding the EWS-FLI1 fusion protein. To exert its oncogenic function, EWS-FLI1 acts as an aberrant transcription factor, broadly altering the gene expression profile of tumor cells. Nuclear factor-kappaB (NF?B) is a tightly regulated transcription factor controlling cell survival, proliferation and differentiation, as well as tumorigenesis. NF?B activity is very low

Julie Lagirand-Cantaloube; Karine Laud; Alain Lilienbaum; Franck Tirode; Olivier Delattre; Christian Auclair; Marie-Hélène Kryszke

2010-01-01

230

High ALDH Activity Identifies Chemotherapy-Resistant Ewing's Sarcoma Stem Cells That Retain Sensitivity to EWS-FLI1 Inhibition  

Microsoft Academic Search

BackgroundCancer stem cells are a chemotherapy-resistant population capable of self-renewal and of regenerating the bulk tumor, thereby causing relapse and patient death. Ewing's sarcoma, the second most common form of bone tumor in adolescents and young adults, follows a clinical pattern consistent with the Cancer Stem Cell model – remission is easily achieved, even for patients with metastatic disease, but

Ola Awad; Jason T. Yustein; Preeti Shah; Naheed Gul; Varalakshmi Katuri; Alison O'Neill; Yali Kong; Milton L. Brown; Jeffrey A. Toretsky; David M. Loeb; Terence Lee

2010-01-01

231

Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWS\\/FLI Modulator in Ewing Sarcoma  

Microsoft Academic Search

BackgroundThe presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although the

Kimberly Stegmaier; Jenny S Wong; Kenneth N Ross; Kwan T Chow; David Peck; Renee D Wright; Stephen L Lessnick; Andrew L Kung; Todd R Golub

2007-01-01

232

Extraskeletal Ewing's sarcoma/primitive neuroectodermal tumor of the posterior mediastinum with t(11;22)(q24;q12).  

PubMed

Ewing's sarcoma/primitive neuroectodermal tumor family of tumors is part of a rare group of malignant neoplasms with small round-cell morphology. We describe a 24-year-old woman who presented with non-specific back pain. A chest radiograph and magnetic resonance imaging demonstrated an extraosseous, dumbbell-shaped mass of the posterior mediastinum with extension into the spinal canal. The patient underwent a left posterolateral thoracotomy and a T3-5 laminectomy with subsequent multi-agent chemotherapy. Histopathologic examination of the tumor demonstrated sheets of primitive small round malignant cells that showed no visible differentiation. Neoplastic cells were strongly immunoreactive for CD99 and vimentin and were negative for chromogranin, synaptophysin, CD31, CD34, calcitonin, desmin, low-molecular weight cytokeratins, wide-spectrum cytokeratins, leukocyte common antigen, S-100 protein, and thyroid transcription factor-1. The neoplasm was diagnosed as a Ewing's sarcoma/primitive neuroectodermal tumor, and cytogenetic studies confirmed a t(11;22)(q24;q12) chromosomal translocation and an associated trisomy of chromosome 2, supporting the histologic diagnosis. Extraskeletal Ewing's sarcoma/primitive neuroectodermal tumors are rare neoplasms that should be distinguished from other small round-cell tumors by morphology and ancillary laboratory techniques. Although rare, they need to be considered in the differential diagnosis of primary mediastinal tumors. PMID:19267114

Manduch, Marosh; Dexter, David F; Ellis, Peter M; Reid, Kenneth; Isotalo, Phillip A

2008-01-01

233

Genomic EWS-FLI1 Fusion Sequences in Ewing Sarcoma Resemble Breakpoint Characteristics of Immature Lymphoid Malignancies  

PubMed Central

Chromosomal translocations between the EWS gene and members of the ETS gene family are characteristic molecular features of the Ewing sarcoma. The most common translocation t(11;22)(q24;q12) fuses the EWS gene to FLI1, and is present in 85–90% of Ewing sarcomas. In the present study, a specifically designed multiplex long-range PCR assay was applied to amplify genomic EWS-FLI1 fusion sites from as little as 100 ng template DNA. Characterization of the EWS-FLI1 fusion sites of 42 pediatric and young adult Ewing sarcoma patients and seven cell lines revealed a clustering in the 5? region of the EWS-breakpoint cluster region (BCR), in contrast to random distribution of breakpoints in the FLI1-BCR. No association of breakpoints with various recombination-inducing sequence motifs was identified. The occurrence of small deletions and duplications at the genomic junction is characteristic of involvement of the non-homologous end-joining (NHEJ) repair system, similar to findings at chromosomal breakpoints in pediatric leukemia and lymphoma.

Berger, Manfred; Dirksen, Uta; Braeuninger, Andreas; Koehler, Gabriele; Juergens, Heribert

2013-01-01

234

Chest Wall Ewing Sarcoma Family of Tumors: Long-Term Outcomes  

SciTech Connect

Purpose: To review the 40-year University of Florida experience treating Ewing sarcoma family of tumors of the chest wall. Methods and Materials: Thirty-nine patients were treated from 1966 to 2006. Of the patients, 22 were treated with radiotherapy (RT) alone, and 17 patients were treated with surgery with or without RT. Of 9 patients with metastatic disease, 8 were treated with RT alone. The risk profiles of each group were otherwise similar. The median age was 16.6 years, and the most frequent primary site was the rib (n = 17). The median potential follow-up was 19.2 years. Results: The 5-year actuarial overall survival (OS), cause-specific survival (CSS), and local control (LC) rates were 34%, 34%, and 72%, respectively. For the nonmetastatic subset (n = 30), the 5-year OS, CSS, and LC rates were 44%, 44%, and 79%, respectively. LC was not statistically significantly different between patients treated with RT alone (61%) vs. surgery + RT (75%). None of the 4 patients treated with surgery alone experienced local failure. No patient or treatment variable was significantly associated with local failure. Of the patients, 26% experienced Common Toxicity Criteria (CTC) Grade 3+ toxicity, including 2 pulmonary deaths. Modern intensive systemic therapy helped increase the 5-year CSS from 7% to 49% in patients treated after 1984 (p = 0.03). Conclusions: This is the largest single-institution series describing the treatment of chest wall Ewing tumors. Despite improvements in survival, obtaining local control is challenging and often accompanied by morbidity. Effort should be focused on identifying tumors amenable to combined-modality local therapy and to improving RT techniques.

Indelicato, Daniel J., E-mail: dindelicato@floridaproton.org [Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL, and University of Florida Proton Therapy Institute, Jacksonville, FL (United States); Keole, Sameer R. [Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL, and University of Florida Proton Therapy Institute, Jacksonville, FL (United States); Lagmay, Joanne P. [Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL (United States); Morris, Christopher G. [Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL, and the University of Florida Proton Therapy Institute, Jacksonville, FL (United States); Gibbs, C. Parker; Scarborough, Mark T. [Department of Orthopedic Surgery, University of Florida College of Medicine, Gainesville, FL (United States); Islam, Saleem [Department of Surgery at the University of Florida College of Medicine, Gainesville, FL (United States); Marcus, Robert B. [Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL, and the University of Florida Proton Therapy Institute, Jacksonville, FL (United States)

2011-09-01

235

EWS/FLI and its Downstream Target NR0B1 Interact Directly to Modulate Transcription and Oncogenesis in Ewing's Sarcoma  

PubMed Central

Most Ewing's sarcomas harbor chromosomal translocations that encode fusions between EWS and ETS family members. The most common fusion, EWS/FLI, consists of an EWSR1-derived strong transcriptional activation domain fused, in frame, to the DNA binding domain-containing portion of FLI1. EWS/FLI functions as an aberrant transcription factor to regulate genes that mediate the oncogenic phenotype of Ewing's sarcoma. One of these regulated genes, NR0B1, encodes a co-repressor protein, and likely plays a transcriptional role in tumorigenesis. However, the genes that NR0B1 regulates and the transcription factors it interacts with in Ewing's sarcoma are largely unknown. We used transcriptional profiling and chromatin immunoprecipitation to identify genes that are regulated by NR0B1, and compared these data to similar data for EWS/FLI. While the transcriptional profile overlapped as expected, we also found that the genome-wide localization of NR0B1and EWS/FLI overlapped as well, suggesting that they regulate some genes coordinately. Further analysis revealed that NR0B1 and EWS/FLI physically interact. This protein-protein interaction is likely to be relevant for Ewing's sarcoma development because mutations in NR0B1 that disrupt the interaction have transcriptional consequences and also abrogate oncogenic transformation. Taken together, these data suggest that EWS/FLI and NR0B1 physically interact, coordinately modulate gene expression, and mediate the transformed phenotype of Ewing's sarcoma.

Kinsey, Michelle; Smith, Richard; Iyer, Anita K.; McCabe, Edward R.B.; Lessnick, Stephen L.

2009-01-01

236

Arsenic trioxide concentration determines the fate of Ewing's sarcoma family tumors and neuroblastoma cells in vitro.  

PubMed

Arsenic trioxide (As(2)O(3)) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner. We assessed the effects of As(2)O(3) in CADO-ES Ewing's sarcoma (ES), JK-GMS peripheral primitive neuroectodermal tumor (PNET), and SH-SY5Y neuroblastoma cells, as they share common histogenetic backgrounds. As(2)O(3) at low concentrations (0.1-1 microM) induced SH-SY5Y differentiation, and whereas PNET cells acquired a slightly differentiated phenotype, change was minimal in ES cells. Extracellular signal-regulated kinase 2 (ERK2) was activated at low As(2)O(3) concentrations, and PD98059, an inhibitor of MEK-1, blocked SH-SY5Y cell differentiation by As(2)O(3). High concentrations (2-10 microM) of As(2)O(3) induced the apoptosis in all three cell lines, and this was accompanied by the activation of c-jun N-terminal kinase. The generation of H(2)O(2) and activation of caspase 3 were identified as critical components of As(2)O(3)-induced apoptosis in all of the above cell lines. Fibroblast growth factor 2 enhanced As(2)O(3)-induced apoptosis in JK-GMS cells. The overall effects of As(2)O(3) strongly suggest that it has therapeutic potential for the treatment of ES/PNET. PMID:16930595

Jung, Hyun Sook; Kim, Han-Seong; Lee, Min-Jae; Shin, Hee Young; Ahn, Hyo Seop; Ryu, Kyung-Ha; Seoh, Ju-Young; Kim, Chong Jai; Jang, Ja June

2006-09-01

237

Chest wall resection for Ewing's sarcoma of the rib: an unnecessary procedure. 1988. Updated in 1995.  

PubMed

Approximately 10% of all cases of Ewing's sarcoma arise from a rib. Conventional management has included chest wall resection (3 or more ribs) and radiation therapy. These forms of therapy have led to complications such as scoliosis and local deformity. The addition of radiation therapy can result in damage to the lung and adjacent viscera and also potentiate pulmonary restrictive disease. Between 1971 and 1978, 9 patients were treated with surgery, radiation therapy, and combination chemotherapy (three- or four-drug regimen). Only 2 patients (22%) survive. Since 1979, 14 patients were entered into a new protocol consisting of sequential induction chemotherapy, followed by delayed surgical resection whenever feasible. Three patients had complete resection of their primary lesion at onset. Initially, 7 patients had either biopsy (N = 4) or incomplete chest wall resection N = 3). All 4 patients with biopsy only at diagnosis had excellent responses to induction chemotherapy, allowing delayed resection of the involved rib without chest wall resection. Overall, 12 of 14 patients (86%) treated since 1979 survive, with only 2 receiving radiation therapy for residual disease in the primary rib site. PMID:8526658

Rao, B N; Hayes, F A; Thompson, E I; Kumar, A P; Fleming, I D; Green, A A; Austin, B A; Pate, J W; Hustu, H O

1995-11-01

238

Ewing's sarcoma. Radiographic pattern of healing and bony complications in patients with long-term survival  

SciTech Connect

The radiographic appearance of Ewing's sarcoma was studied retrospectively in 22 patients who survived 5 years or longer after diagnosis and treatment. Expected changes from treatment, including regression of the extraosseous soft tissue mass, periostitis, and reconstitution of the cortex, occurred in all patients. Local recurrence occurred in one patient 10 years after complete remission whereas secondary osteosarcoma occurred more than 5 years after complete remission in two other cases. Both recurrent and secondary tumors presented as new lytic foci at the site of the original primary lesion. Lytic changes from radiation (radiation osteitis) may develop more than 2 years after treatment and in this sample; such findings were widely distributed in the radiation port. The authors conclude that bone remodeling and postradiation changes occur slowly over 2 years after treatment, and that any localized lysis at the primary site is suspicious for recurrence or secondary neoplasm. Knowledge of the expected changes and patterns of local recurrence and secondary neoplasms helps one to detect any significant change in its early phase.

Ehara, S.; Kattapuram, S.V.; Egglin, T.K. (Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston (United States))

1991-10-01

239

Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer.  

PubMed

Deregulated E2F transcription factor activity occurs in the vast majority of human tumors and has been solidly implicated in disturbances of cell cycle control, proliferation, and apoptosis. Aberrant E2F regulatory activity is often caused by impairment of control through pRB function, but little is known about the interplay of other oncoproteins with E2F. Here we show that ETS transcription factor fusions resulting from disease driving rearrangements in Ewing sarcoma (ES) and prostate cancer (PC) are one such class of oncoproteins. We performed an integrative study of genome-wide DNA-binding and transcription data in EWSR1/FLI1 expressing ES and TMPRSS2/ERG containing PC cells. Supported by promoter activity and mutation analyses, we demonstrate that a large fraction of E2F3 target genes are synergistically coregulated by these aberrant ETS proteins. We propose that the oncogenic effect of ETS fusion oncoproteins is in part mediated by the disruptive effect of the E2F-ETS interaction on cell cycle control. Additionally, a detailed analysis of the regulatory targets of the characteristic EWSR1/FLI1 fusion in ES identifies two functionally distinct gene sets. While synergistic regulation in concert with E2F in the promoter of target genes has a generally activating effect, EWSR1/FLI1 binding independent of E2F3 is predominantly associated with repressed differentiation genes. Thus, EWSR1/FLI1 appears to promote oncogenesis by simultaneously promoting cell proliferation and perturbing differentiation. PMID:23940108

Bilke, Sven; Schwentner, Raphaela; Yang, Fan; Kauer, Maximilian; Jug, Gunhild; Walker, Robert L; Davis, Sean; Zhu, Yuelin J; Pineda, Marbin; Meltzer, Paul S; Kovar, Heinrich

2013-11-01

240

A rare case of translocation (12;22) (p13;Q) in Ewing's sarcoma  

PubMed Central

Cytogenetic or immunohistochemical studies are often required to differentiate Ewing's sarcoma (ES) from other small round cell tumors. Herein we report a case of 13-year-old boy who presented with a large presacral lesion. Hemogram and biochemical parameters were normal except lactate dehydrogenase showing value of 96.40/IU/L, magnetic resonance imaging of the spine showed a large mass in presacral lesion (8 cm × 7 cm × 9 cm), with destruction of the sacrum (S2 S3 and S4) with interspinal extension. Bone scan showed multiple pelvic bone lesions, radiograph of chest, ultrasound of abdomen, pelvis and electrocardiogram were within normal limits. Bone marrow was not involved. Cells from the fine needle aspirate were cultured for short term using RPMI medium and karyotype obtained showed a t(12;22)(p12;q12) instead of the classic t(11;22). Diagnosis of ES was also confirmed by studies using immunohistochemistry for MIC2 which was positive, synaptophysin was inconclusive and leukocyte common antigen, desmin negative. This case provides evidence of the importance of chromosome 22, in the etiology of the disease.

Jahan, S. K. Kousar; Mayanna, Mangala Gowri; Kavitha, B. L.; Patil, Akkamahadevi; Kumari, Prasanna

2014-01-01

241

Axial Skeletal Location Predicts Poor Outcome in Ewing's Sarcoma: A Single Institution Experience  

PubMed Central

Introduction. Ewing's sarcomas (EWSs) of bone and soft tissue are neuroectodermal tumors that affect both axial and appendicular locations. We hypothesized that axial location predicted poor outcome in EWS patients. Materials and Methods. Sixty-seven patients (57 with bone EWS and 10 with soft tissue EWS) were identified from our database. Thirty-four (51%) had axial EWS and 33 (49%) had appendicular EWS. Statistical analyses identified predictors of poor outcome. Results and Discussion. Axial location, large size, metastases at presentation, lack of definitive treatment, and positive surgical margins all correlated with poor outcome in univariate analysis. In multivariate analysis, axial location still predicted poor outcome when adjusted for pretreatment variables. Axial location was not statistically predictive of poor outcome when adjusted for treatment variables. Conclusions. Anatomic location has a negative effect on outcome in EWS that cannot be completely explained by pretreatment or treatment factors. Additional studies are required to determine if there is a biologic difference between axial and appendicular EWS.

Weiss, Kurt R.; Biau, David J.; Bhumbra, Rej; Griffin, Anthony M.; Blackstein, Martin E.; Chung, Peter; Catton, Charles; O'Sullivan, Brian; Ferguson, Peter C.; Wunder, Jay S.

2011-01-01

242

Molecular Inversion Probe analysis detects novel copy number alterations in Ewing Sarcoma  

PubMed Central

Ewing sarcoma (ES) is the second most common bone tumor in children and young adults, with dismal outcomes for metastatic and relapsed disease. To better understand the molecular pathogenesis of ES and to identify new prognostic markers, we used molecular inversion probes (MIPs) to evaluate copy number alterations (CNAs) and loss of heterozygosity (LOH) in formalin-fixed paraffin-embedded (FFPE) samples which included 40 ES primary tumors and 12 ES metastatic lesions. CNAs were correlated with clinical features and outcome, and validated by immunohistochemistry (IHC). We identified previously reported CNAs, in addition to SMARCB1 (INI1/SNF5) homozygous loss and copy neutral LOH. IHC confirmed SMARCB1 protein loss in 7–10% of clinically-diagnosed ES tumors in three separate cohorts (University of Utah [N=40], Children’s Oncology Group [N=31], and University of Michigan [N=55]). A multifactor copy number (MCN)-index was highly predictive of overall survival (39% vs. 100%, P<0.001). We also identified RELN gene deletions unique to 25% of ES metastatic samples. In summary, we identified both known and novel CNAs using MIP technology for the first time in FFPE samples from patients with ES. CNAs detected by microarray correlate with outcome and may be useful for risk-stratification in future clinical trials.

Jahromi, Mona S.; Putnam, Angelica R.; Druzgal, Colleen; Wright, Jennifer; Spraker, Holly; Kinsey, Michelle; Zhou, Holly; Boucher, Ken; Randall, R. Lor; Jones, Kevin B.; Lucas, David; Rosenberg, Andrew; Thomas, Dafydd; Lessnick, Stephen L.; Schiffman, Joshua D.

2013-01-01

243

Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer  

PubMed Central

Deregulated E2F transcription factor activity occurs in the vast majority of human tumors and has been solidly implicated in disturbances of cell cycle control, proliferation, and apoptosis. Aberrant E2F regulatory activity is often caused by impairment of control through pRB function, but little is known about the interplay of other oncoproteins with E2F. Here we show that ETS transcription factor fusions resulting from disease driving rearrangements in Ewing sarcoma (ES) and prostate cancer (PC) are one such class of oncoproteins. We performed an integrative study of genome-wide DNA-binding and transcription data in EWSR1/FLI1 expressing ES and TMPRSS2/ERG containing PC cells. Supported by promoter activity and mutation analyses, we demonstrate that a large fraction of E2F3 target genes are synergistically coregulated by these aberrant ETS proteins. We propose that the oncogenic effect of ETS fusion oncoproteins is in part mediated by the disruptive effect of the E2F–ETS interaction on cell cycle control. Additionally, a detailed analysis of the regulatory targets of the characteristic EWSR1/FLI1 fusion in ES identifies two functionally distinct gene sets. While synergistic regulation in concert with E2F in the promoter of target genes has a generally activating effect, EWSR1/FLI1 binding independent of E2F3 is predominantly associated with repressed differentiation genes. Thus, EWSR1/FLI1 appears to promote oncogenesis by simultaneously promoting cell proliferation and perturbing differentiation.

Bilke, Sven; Schwentner, Raphaela; Yang, Fan; Kauer, Maximilian; Jug, Gunhild; Walker, Robert L.; Davis, Sean; Zhu, Yuelin J.; Pineda, Marbin; Meltzer, Paul S.; Kovar, Heinrich

2013-01-01

244

IGF1 Is a Common Target Gene of Ewing's Sarcoma Fusion Proteins in Mesenchymal Progenitor Cells  

PubMed Central

Background The EWS-FLI-1 fusion protein is associated with 85–90% of Ewing's sarcoma family tumors (ESFT), the remaining 10–15% of cases expressing chimeric genes encoding EWS or FUS fused to one of several ets transcription factor family members, including ERG-1, FEV, ETV1 and ETV6. ESFT are dependent on insulin-like growth factor-1 (IGF-1) for growth and survival and recent evidence suggests that mesenchymal progenitor/stem cells constitute a candidate ESFT origin. Methodology/Principal Findings To address the functional relatedness between ESFT-associated fusion proteins, we compared mouse progenitor cell (MPC) permissiveness for EWS-FLI-1, EWS-ERG and FUS-ERG expression and assessed the corresponding expression profile changes. Whereas all MPC isolates tested could stably express EWS-FLI-1, only some sustained stable EWS-ERG expression and none could express FUS-ERG for more than 3–5 days. Only 14% and 4% of the total number of genes that were respectively induced and repressed in MPCs by the three fusion proteins were shared. However, all three fusion proteins, but neither FLI-1 nor ERG-1 alone, activated the IGF1 promoter and induced IGF1 expression. Conclusion/Significance Whereas expression of different ESFT-associated fusion proteins may require distinct cellular microenvironments and induce transcriptome changes of limited similarity, IGF1 induction may provide one common mechanism for their implication in ESFT pathogenesis.

Cironi, Luisa; Riggi, Nicolo; Provero, Paolo; Wolf, Natalie; Suva, Mario-Luca; Suva, Domizio; Kindler, Vincent; Stamenkovic, Ivan

2008-01-01

245

Adult ewing sarcoma: survival and local control outcomes in 102 patients with localized disease.  

PubMed

Objectives. To assess the clinical features and local control (LC) outcomes in adult patients with localized Ewing Sarcoma (ES). Methods. The records of 102 ES patients with localized disease ?18?years of age seen from 1977 to 2007 were reviewed. Factors relevant to prognosis, survival, and LC were analyzed. Results. The 5-year overall survival (OS) and event-free survival (EFS) were 60% and 52%, respectively, for the entire cohort. Treatment era (1977-1992 versus 1993-2007) remained an independent prognostic factor for OS on multivariate analysis, with improved outcomes observed in the 1993-2007 era (P = 0.02). The 5-year OS and EFS for the 1993-2007 era were 73% and 60%, respectively. Ifosfamide and etoposide based chemotherapy and surgery were more routinely used in the 1993-2007 era (P < 0.01). The 5-year local failure rate (LFR) was 14%, with a 5-year LFR of 18% for surgery, 33% for radiation, and 0% for combined surgery and radiation in the 1993-2007 era (P = 0.17). Conclusion. Modern survival outcomes for adults with localized ES are similar to multi-institutional results in children. This improvement over time is associated with treatment intensification with chemotherapy and increased use of surgery. Aggressive LC (combined surgery and radiation) may improve outcomes in poor prognosis patients. PMID:23840168

Ahmed, Safia K; Robinson, Steven I; Okuno, Scott H; Rose, Peter S; Laack, Nadia N Issa

2013-01-01

246

Localizing potentially active post-transcriptional regulations in the Ewing's sarcoma gene regulatory network  

PubMed Central

Background A wide range of techniques is now available for analyzing regulatory networks. Nonetheless, most of these techniques fail to interpret large-scale transcriptional data at the post-translational level. Results We address the question of using large-scale transcriptomic observation of a system perturbation to analyze a regulatory network which contained several types of interactions - transcriptional and post-translational. Our method consisted of post-processing the outputs of an open-source tool named BioQuali - an automatic constraint-based analysis mimicking biologist's local reasoning on a large scale. The post-processing relied on differences in the behavior of the transcriptional and post-translational levels in the network. As a case study, we analyzed a network representation of the genes and proteins controlled by an oncogene in the context of Ewing's sarcoma. The analysis allowed us to pinpoint active interactions specific to this cancer. We also identified the parts of the network which were incomplete and should be submitted for further investigation. Conclusions The proposed approach is effective for the qualitative analysis of cancer networks. It allows the integrative use of experimental data of various types in order to identify the specific information that should be considered a priority in the initial - and possibly very large - experimental dataset. Iteratively, new dataset can be introduced into the analysis to improve the network representation and make it more specific.

2010-01-01

247

Identification of a tripartite import signal in the Ewing Sarcoma protein (EWS)  

SciTech Connect

The Ewing Sarcoma (EWS) protein is a ubiquitously expressed RNA processing factor that localises predominantly to the nucleus. However, the mechanism through which EWS enters the nucleus remains unclear, with differing reports identifying three separate import signals within the EWS protein. Here we have utilized a panel of truncated EWS proteins to clarify the reported nuclear localisation signals. We describe three C-terminal domains that are important for efficient EWS nuclear localization: (1) the third RGG-motif; (2) the last 10 amino acids (known as the PY-import motif); and (3) the zinc-finger motif. Although these three domains are involved in nuclear import, they are not independently capable of driving the efficient import of a GFP-moiety. However, collectively they form a complex tripartite signal that efficiently drives GFP-import into the nucleus. This study helps clarify the EWS import signal, and the identification of the involvement of both the RGG- and zinc-finger motifs has wide reaching implications.

Shaw, Debra J.; Morse, Robert; Todd, Adrian G. [Clinical Neurobiology, IBCS, Peninsula College of Medicine and Dentistry, Exeter EX1 2LU (United Kingdom)] [Clinical Neurobiology, IBCS, Peninsula College of Medicine and Dentistry, Exeter EX1 2LU (United Kingdom); Eggleton, Paul [Inflammation and Musculoskeletal Disease, IBCS, Peninsula College of Medicine and Dentistry, Exeter EX1 2LU (United Kingdom) [Inflammation and Musculoskeletal Disease, IBCS, Peninsula College of Medicine and Dentistry, Exeter EX1 2LU (United Kingdom); MRC Immunochemistry Unit, University of Oxford, Oxford OX1 3QU (United Kingdom); Lorson, Christian L. [Department of Veterinary Pathobiology, Bond Life Sciences Center, 1201 Rollins Road, University of Missouri, Columbia, MO 65211 (United States)] [Department of Veterinary Pathobiology, Bond Life Sciences Center, 1201 Rollins Road, University of Missouri, Columbia, MO 65211 (United States); Young, Philip J., E-mail: philip.young@pms.ac.uk [Clinical Neurobiology, IBCS, Peninsula College of Medicine and Dentistry, Exeter EX1 2LU (United Kingdom)

2009-12-25

248

Autologous stem cell transplantation for high-risk Ewing's sarcoma and other pediatric solid tumors.  

PubMed

The prognosis for many pediatric and young adult patients with solid tumors that have metastasized at the time of diagnosis or have relapsed after therapy remains very poor. The steep dose-response curve of many of these tumors to alkylating agents makes myeloablative chemotherapy followed by autologous stem cell transplantation (ASCT) an attractive potential therapy. The role of ASCT for these high-risk patients is yet to be conclusively determined. We have transplanted 36 patients on two consecutive protocols with a variety of histological diagnoses. Overall survival (OS) was 63% (95% CI: 47-79%) at 1 year and 33% (95% CI: 16-50%) at 3 years. Patients with a diagnosis of Ewing's sarcoma (ES) or desmoplastic small round cell tumor (DSRCT) had significantly better survival than those with other diagnoses with estimated 3-year OS of 54% (95% CI: 29-79%) for this group of patients (P = 0.03). There were two transplant-related deaths both attributable to hepatic veno-occlusive disease. Median follow-up among survivors is 3.5 years (range: 0.6-7.9 years). These data justify continued investigation of ASCT as a consolidation therapy in patients with metastatic or relapsed ES and DSRCT. PMID:16273111

Fraser, C J; Weigel, B J; Perentesis, J P; Dusenbery, K E; DeFor, T E; Baker, K S; Verneris, M R

2006-01-01

249

Targeting receptor tyrosine kinases in osteosarcoma and Ewing sarcoma: current hurdles and future perspectives.  

PubMed

Osteosarcoma (OS) and Ewing sarcoma (ES) are the two most common types of primary bone cancer, which mainly affect children and young adults. Despite intensive multi-modal treatment, the survival of both OS and ES has not improved much during the last decades and new therapeutic options are awaited. One promising approach is the specific targeting of transmembrane receptor tyrosine kinases (RTKs) implicated in these types of bone cancer. However, despite encouraging in vitro and in vivo results, apart from intriguing results of Insulin-like Growth Factor-1 Receptor (IGF-1R) antibodies in ES, clinical studies are limited or disappointing. Primary resistance to RTK inhibitors is frequently observed in OS and ES patients, and even patients that initially respond well eventually develop acquired resistance. There are, however, a few remarks to make concerning the current set-up of clinical trials and about strategies to improve RTK-based treatments in OS and ES. This review provides an overview concerning current RTK-mediated therapies in OS and ES and discusses the problems observed in the clinic. More importantly, we describe several strategies to overcome resistance to RTK inhibitors which may significantly improve outcome of OS and ES patients. PMID:24582852

Fleuren, Emmy D G; Versleijen-Jonkers, Yvonne M H; Boerman, Otto C; van der Graaf, Winette T A

2014-04-01

250

Molecular inversion probe analysis detects novel copy number alterations in Ewing sarcoma.  

PubMed

Ewing sarcoma (ES) is the second most common bone tumor in children and young adults, with dismal outcomes for metastatic and relapsed disease. To better understand the molecular pathogenesis of ES and to identify new prognostic markers, we used molecular inversion probes (MIPs) to evaluate copy number alterations (CNAs) and loss of heterozygosity (LOH) in formalin-fixed paraffin-embedded (FFPE) samples, which included 40 ES primary tumors and 12 ES metastatic lesions. CNAs were correlated with clinical features and outcome, and validated by immunohistochemistry (IHC). We identified previously reported CNAs, in addition to SMARCB1 (INI1/SNF5) homozygous loss and copy neutral LOH. IHC confirmed SMARCB1 protein loss in 7-10% of clinically diagnosed ES tumors in three separate cohorts (University of Utah [N = 40], Children's Oncology Group [N = 31], and University of Michigan [N = 55]). A multifactor copy number (MCN)-index was highly predictive of overall survival (39% vs. 100%, P < 0.001). We also identified RELN gene deletions unique to 25% of ES metastatic samples. In summary, we identified both known and novel CNAs using MIP technology for the first time in FFPE samples from patients with ES. CNAs detected by microarray correlate with outcome and may be useful for risk stratification in future clinical trials. PMID:22868000

Jahromi, Mona S; Putnam, Angelica R; Druzgal, Colleen; Wright, Jennifer; Spraker-Perlman, Holly; Kinsey, Michelle; Zhou, Holly; Boucher, Kenneth M; Randall, R Lor; Jones, Kevin B; Lucas, David; Rosenberg, Andrew; Thomas, Dafydd; Lessnick, Stephen L; Schiffman, Joshua D

2012-01-01

251

Systems biology of Ewing sarcoma: a network model of EWS-FLI1 effect on proliferation and apoptosis  

PubMed Central

Ewing sarcoma is the second most frequent pediatric bone tumor. In most of the patients, a chromosomal translocation leads to the expression of the EWS-FLI1 chimeric transcription factor that is the major oncogene in this pathology. Relative genetic simplicity of Ewing sarcoma makes it particularly attractive for studying cancer in a systemic manner. Silencing EWS-FLI1 induces cell cycle alteration and ultimately leads to apoptosis, but the exact molecular mechanisms underlying this phenotype are unclear. In this study, a network linking EWS-FLI1 to cell cycle and apoptosis phenotypes was constructed through an original method of network reconstruction. Transcriptome time-series after EWS-FLI1 silencing were used to identify core modulated genes by an original scoring method based on fitting expression profile dynamics curves. Literature data mining was then used to connect these modulated genes into a network. The validity of a subpart of this network was assessed by siRNA/RT-QPCR experiments on four additional Ewing cell lines and confirmed most of the links. Based on the network and the transcriptome data, CUL1 was identified as a new potential target of EWS-FLI1. Altogether, using an original methodology of data integration, we provide the first version of EWS-FLI1 network model of cell cycle and apoptosis regulation.

Stoll, Gautier; Surdez, Didier; Tirode, Franck; Laud, Karine; Barillot, Emmanuel; Zinovyev, Andrei; Delattre, Olivier

2013-01-01

252

Development of a preclinical orthotopic xenograft model of ewing sarcoma and other human malignant bone disease using advanced in vivo imaging.  

PubMed

Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG) and Rag2(-/-/)?c(-/-) mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000-5000) injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised "malignant" bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which resemble the human disease. We have shown the utility of small animal bioimaging for tracking disease progression, making this model a useful assay for preclinical drug testing. PMID:24409320

Vormoor, Britta; Knizia, Henrike K; Batey, Michael A; Almeida, Gilberto S; Wilson, Ian; Dildey, Petra; Sharma, Abhishek; Blair, Helen; Hide, I Geoff; Heidenreich, Olaf; Vormoor, Josef; Maxwell, Ross J; Bacon, Chris M

2014-01-01

253

Association of EWS-FLI1 Type 1 Fusion with Lower Proliferative Rate in Ewing's Sarcoma  

PubMed Central

The Ewing’s sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the EWS gene with a member of the ETS family of transcription factors, either FLI1 (90–95%) or ERG (5–10%). A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type of EWS-FLI1 fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with tumor cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with defined EWS-ETS fusions (45 EWS-FLI1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in tumors with EWS-FLI1 type 1 than those with non-type 1 EWS-FLI1, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing EWS-FLI1 to EWS-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher’s exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of EWS-FLI1 are paralleled by differences in proliferative rate, possibly mediated by differential regulation of the IGF-1R pathway.

de Alava, Enrique; Panizo, Angel; Antonescu, Cristina R.; Huvos, Andrew G.; Pardo-Mindan, F. Javier; Barr, Frederic G.; Ladanyi, Marc

2000-01-01

254

Radiation therapy for Ewing's sarcoma: Results from Memorial Sloan-Kettering in the modern era  

SciTech Connect

Purpose: To evaluate the outcomes of patients with Ewing's sarcoma family of tumors (ESFT) treated with modern radiotherapy techniques with MRI along with optimal chemotherapy. Methods and Materials: The records of all 60 patients with ESFT who received radiation to the primary site between 1990 and 2004 were reviewed. All patients received chemotherapy, including vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Radiation was used as the sole modality for local control in 31 patients and was given either before (n = 3) or after surgical resection (n = 26) in the remainder. All patients had MRI and CT scan-based treatment planning, and 43% received intensity-modulated radiation therapy. Radiation doses ranged from 30 Gy to 60 Gy (median, 51 Gy), and 35% received hyperfractionated radiotherapy. Results: Median age was 16 years (range, 2-40 years). Because of selection bias for radiotherapy, the majority of primary tumors were centrally located (72%): spine (n = 18), pelvis (n = 15), extremities (n 12), chest wall (n = 5), head and neck (n = 5), and other (n = 5). Thirty-eight percent of patients presented with metastatic disease, and 52% of primary tumors were {>=}8 cm. Actuarial 3-year local control was 77%. The presence of metastases at diagnosis was an adverse prognostic factor for local control (84% vs. 61%, p = 0.036). No other predictive factors for local failure were identified. In patients without metastatic disease, 3-year disease-free and overall survival rates were 70% and 86%, respectively, whereas in patients with metastases they were both 21%. Follow-up of surviving patients was 6-178 months (median, 41 months). Conclusion: In this unfavorable cohort of ESFT patients, radiation therapy was an effective modality for local control, especially for patients without metastases. The presence of metastases at diagnosis is a predictive factor not only for death but also for local failure.

La, Trang H. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Meyers, Paul A. [Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Wexler, Leonard H. [Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Alektiar, Kaled M. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Healey, John H. [Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Laquaglia, Michael P. [Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Boland, Patrick J. [Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Wolden, Suzanne L. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY (United States)]. E-mail: woldens@mskcc.org

2006-02-01

255

Ewing Sarcoma of the Bone in Children under 6 Years of Age  

PubMed Central

Background Ewing Sarcoma Family Tumours (ESFT) are rare in early childhood. The aim of this study was to report the clinical characteristics and outcome of children under 6 years of age affected by ESFT of the bone in Italy. Methods The records of all the children diagnosed with osseous ESFT in centres members of the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) from 1990 to 2008 were reviewed. The Kaplan–Meier method was used for estimating overall and progression-free survival (OS, PFS) curves; multivariate analyses were performed using Cox proportional hazards regression model. Results This study includes 62 patients. An axial primary localization was present in 66% of patients, with the primary site in the chest wall in 34%. Fourteen (23%) patients presented metastatic disease. The 5-year OS and PFS were 73% (95% confidence interval, CI, 58–83%) and 72% (95% CI 57–83%) for patients with localized disease and 38% (95% CI 17–60%) and 21% (95% CI 5–45%) for patients with metastatic disease. Metastatic spread, skull/pelvis/spine primary localization, progression during treatment and no surgery predicted worse survival (P<0.01), while patients treated in the last decade had better survival (P ?=?0.002). In fact, the 5-year OS and PFS for patients diagnosed in the period 2000–2008 were 89% (95% CI 71–96%) and 86% (95% CI 66–94%), respectively. Conclusion The axial localization is the most common site of ESFT in pre-scholar children. Patients treated in the most recent period have an excellent outcome.

De Ioris, Maria Antonietta; Prete, Arcangelo; Cozza, Raffaele; Podda, Marta; Manzitti, Carla; Pession, Andrea; Schiavello, Elisabetta; Contoli, Benedetta; Balter, Rita; Fagioli, Franca; Bisogno, Gianni; Amoroso, Loredana

2013-01-01

256

Let-7a Is a Direct EWS-FLI-1 Target Implicated in Ewing's Sarcoma Development  

PubMed Central

Ewing's sarcoma family tumors (ESFT) are the second most common bone malignancy in children and young adults, characterized by unique chromosomal translocations that in 85% of cases lead to expression of the EWS-FLI-1 fusion protein. EWS-FLI-1 functions as an aberrant transcription factor that can both induce and suppress members of its target gene repertoire. We have recently demonstrated that EWS-FLI-1 can alter microRNA (miRNA) expression and that miRNA145 is a direct EWS-FLI-1 target whose suppression is implicated in ESFT development. Here, we use miRNA arrays to compare the global miRNA expression profile of human mesenchymal stem cells (MSC) and ESFT cell lines, and show that ESFT display a distinct miRNA signature that includes induction of the oncogenic miRNA 17–92 cluster and repression of the tumor suppressor let-7 family. We demonstrate that direct repression of let-7a by EWS-FLI-1 participates in the tumorigenic potential of ESFT cells in vivo. The mechanism whereby let-7a expression regulates ESFT growth is shown to be mediated by its target gene HMGA2, as let-7a overexpression and HMGA2 repression both block ESFT cell tumorigenicity. Consistent with these observations, systemic delivery of synthetic let-7a into ESFT-bearing mice restored its expression in tumor cells, decreased HMGA2 expression levels and resulted in ESFT growth inhibition in vivo. Our observations provide evidence that deregulation of let-7a target gene expression participates in ESFT development and identify let-7a as promising new therapeutic target for one of the most aggressive pediatric malignancies.

Suva, Mario-Luca; Janiszewska, Michalina; Horlbeck, Janine; Baumer, Karine; Provero, Paolo; Stamenkovic, Ivan

2011-01-01

257

Pharmacokinetic modeling optimizes inhibition of the 'undruggable' EWS-FLI1 transcription factor in Ewing Sarcoma.  

PubMed

Transcription factors have long been deemed 'undruggable' targets for therapeutics. Enhanced recognition of protein biochemistry as well as the need to have more targeted approaches to treat cancer has rendered transcription factors approachable for therapeutic development. Since transcription factors lack enzymatic domains, the specific targeting of these proteins has unique challenges. One challenge is the hydrophobic microenvironment that affects small molecules gaining access to block protein interactions. The most attractive transcription factors to target are those formed from tumor specific chromosomal translocations that are validated oncogenic driver proteins. EWS-FLI1 is a fusion protein that results from the pathognomonic translocation of Ewing sarcoma (ES). Our past work created the small molecule YK-4-279 that blocks EWS-FLI1 from interacting with RNA Helicase A (RHA). To fulfill long-standing promise in the field by creating a clinically useful drug, steps are required to allow for in vivo administration. These investigations identify the need for continuous presence of the small molecule protein-protein inhibitor for a period of days. We describe the pharmacokinetics of YK-4-279 and its individual enantiomers. In vivo studies confirm prior in vitro experiments showing (S)-YK-4-279 as the EWS-FLI1 specific enantiomer demonstrating both induction of apoptosis and reduction of EWS-FLI1 regulated caveolin-1 protein. We have created the first rat xenograft model of ES, treated with (S)-YK-4-279 dosing based upon PK modeling leading to a sustained complete response in 2 of 6 ES tumors. Combining laboratory studies, pharmacokinetic measurements, and modeling has allowed us to create a paradigm that can be optimized for in vivo systems using both in vitro data and pharmacokinetic simulations. Thus, (S)-YK-4-279 as a small molecule drug is ready for continued development towards a first-in-human, first-in-class, clinical trial. PMID:24481407

Hong, Sung-Hyeok; Youbi, Sarah E; Hong, S Peter; Kallakury, Bhaskar; Monroe, Phillip; Erkizan, Hayriye V; Barber-Rotenberg, Julie S; Houghton, Peter; Üren, Aykut; Toretsky, Jeffrey A

2014-01-30

258

Characterization and Drug Resistance Patterns of Ewing's Sarcoma Family Tumor Cell Lines  

PubMed Central

Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.

May, William A.; Grigoryan, Rita S.; Keshelava, Nino; Cabral, Daniel J.; Christensen, Laura L.; Jenabi, Jasmine; Ji, Lingyun; Triche, Timothy J.; Lawlor, Elizabeth R.; Reynolds, C. Patrick

2013-01-01

259

Gene expression profiling of peripheral blood cells: new insights into Ewing sarcoma biology and clinical applications.  

PubMed

Ewing sarcoma (ES) is a group of highly aggressive small round cell tumors of bone or soft tissue with high metastatic potential and low cure rate. ES tumors are associated with a rapid osteolysis and necrosis. The currently accepted clinical prognostic parameters do not accurately predict survival of high-risk patients. Moreover, neither the subtype of EWS-FLI1/ERG in the tumor, nor the detection of fusion transcripts in the peripheral blood (PB) samples, has prognostic value in ES patients. We evaluated the prevalence of circulating tumor cells (CTCs) in 34 adult ES patients. Since CTCs were confirmed in only small subset of patients, we further explored the expression profiles of PB leukocytes using a panel of genes associated with immune system status and increased tumor invasiveness. Moreover, we analyzed the alterations of the routine blood tests in the examined cohort of patients and correlated our findings with the clinical outcome. A uniform decrease in ZAP70 expression in PB cells among all ES patients, as compared to healthy individuals, was observed. Monocytosis and the abnormal expression of CDH2 and CDT2 genes in the PB cells significantly correlated with poor prognosis in ES patients. Our study supports the previously proposed hypothesis of systemic nature of ES. Based on the PB cell expression profiles, we propose a mechanism by which immune system may be involved in intensification of osteoclastogenesis and disease progression in ES patients. Moreover, we demonstrate the prognostic value of molecular PB testing at the time of routine histopathological diagnosis. PMID:25008066

Przybyl, Joanna; Kozak, Katarzyna; Kosela, Hanna; Falkowski, Slawomir; Switaj, Tomasz; Lugowska, Iwona; Szumera-Cieckiewicz, Anna; Ptaszynski, Konrad; Grygalewicz, Beata; Chechlinska, Magdalena; Pienkowska-Grela, Barbara; Debiec-Rychter, Maria; Siedlecki, Janusz A; Rutkowski, Piotr

2014-08-01

260

V-ATPase is a candidate therapeutic target for Ewing sarcoma.  

PubMed

Suppression of oxidative phosphorylation combined with enhanced aerobic glycolysis and the resulting increased generation of protons are common features of several types of cancer. An efficient mechanism to escape cell death resulting from intracellular acidification is proton pump activation. In Ewing sarcoma (ES), although the tumor-associated chimeric gene EWS-FLI1 is known to induce the accumulation of hypoxia-induced transcription factor HIF-1?, derangements in metabolic pathways have been neglected so far as candidate pathogenetic mechanisms. In this paper, we observed that ES cells simultaneously activate mitochondrial respiration and high levels of glycolysis. Moreover, although the most effective detoxification mechanism of proton intracellular storage is lysosomal compartmentalization, ES cells show a poorly represented lysosomal compartment, but a high sensitivity to the anti-lysosomal agent bafilomycin A1, targeting the V-ATPase proton pump. We therefore investigated the role of V-ATPase in the acidification activity of ES cells. ES cells with the highest GAPDH and V-ATPase expression also showed the highest acidification rate. Moreover, the localization of V-ATPase was both on the vacuolar and the plasma membrane of all ES cell lines. The acidic extracellular pH that we reproduced in vitro promoted high invasion ability and clonogenic efficiency. Finally, targeting V-ATPase with siRNA and omeprazole treatments, we obtained a significant selective reduction of tumor cell number. In summary, glycolytic activity and activation of V-ATPase are crucial mechanisms of survival of ES cells and can be considered as promising selective targets for the treatment of this tumor. PMID:23579072

Avnet, Sofia; Di Pompo, Gemma; Lemma, Silvia; Salerno, Manuela; Perut, Francesca; Bonuccelli, Gloria; Granchi, Donatella; Zini, Nicoletta; Baldini, Nicola

2013-08-01

261

Adult Ewing Sarcoma: Survival and Local Control Outcomes in 36 Patients With Metastatic Disease.  

PubMed

OBJECTIVES:: To assess the clinical features and outcomes in adult patients with metastatic Ewing sarcoma (ES). METHODS:: The records of 36 ES patients with metastatic disease ?18 years seen from 1977 to 2007 at the Mayo Clinic were studied retrospectively. Factors relevant to prognosis, survival, and local control (LC) were analyzed. RESULTS:: The 4-year overall survival (OS) and event-free survival (EFS) rates were 20% and 11%, respectively. Patients treated from 1993 to 2007 had significantly improved outcomes compared with those treated from 1977 to 1992: 4-year OS and EFS of 31% and 16%, respectively, versus 0% (P=0.01). Primary tumor (P=0.005 and 0.04) and metastatic sites (P=0.05) were independent EFS prognostic factors. Four patients (11%) received surgery, 18 (50%) radiation therapy (RT), 4 (11%) surgery+radiation therapy (S+RT), and 10 (28%) received no LC. The 4-year EFS rates were 0% for surgery, 21% for RT, 0% for S+RT, and 0% for no LC (P=0.0001). OS in patients who received vincristine, doxorubicin, and cyclophosphamide alternating with ifosphamide and etoposide (VDC/IE) chemotherapy was improved (P=0.04). Relapses were documented in 18 patients (excluding patients who received no LC). In total, 44% of patients had all of their metastatic site(s) treated. Patients who received treatment to all extrapulmonary metastases had significantly improved outcomes compared with those who did not receive treatment to all sites: 4-year OS and EFS of 33% and 11%, respectively, versus 0% (P=0.04 and 0.02). CONCLUSIONS:: Our results suggest outcomes for adult patients with metastatic ES are similar to pediatric cohorts in the modern era. VDC/IE chemotherapy and treatment to all metastatic lesions is associated with improved outcomes. PMID:23388557

Ahmed, Safia K; Robinson, Steven I; Okuno, Scott H; Rose, Peter S; Issa Laack, Nadia N

2013-02-01

262

Expression and clinical relevance of MET and ALK in Ewing sarcomas.  

PubMed

Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALK-inhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p = 0.031, z = -2.310, n = 11). In primary tumors (n = 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p = 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p = 0.078) and OS (88 vs. 128 months, p = 0.074) in patients with highest ALK levels (n = 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC50 1.22-3.59 ?mol/L), NVP-TAE684 (IC50 0.15-0.79 ?mol/L) and cabozantinib (IC50 2.69-8.27 ?mol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES. PMID:23335077

Fleuren, Emmy D G; Roeffen, Melissa H S; Leenders, William P; Flucke, Uta E; Vlenterie, Myrella; Schreuder, Hendrik W; Boerman, Otto C; van der Graaf, Winette T A; Versleijen-Jonkers, Yvonne M H

2013-07-15

263

gamma-Glutamyl transpeptidase expression in Ewing's sarcoma cells: up-regulation by interferons.  

PubMed Central

The genetic hallmark of Ewing's sarcoma family of tumours (ET) is the presence of the translocation t(11;22)(q24;q12), which creates the ET fusion gene, leading to cellular transformation. Five human gamma-glutamyl transpeptidase (gamma-GT) genes are located near the chromosomal translocation in ET. gamma-GT is a major enzyme involved in glutathione homoeostasis. Five human cell lines representative of primary or metastatic tumours were investigated to study whether gamma-GT alterations could occur at the chromosomal breaks and rearrangements in ET. As shown by enzymic assays and FACS analyses, all ET cell lines consistently expressed a functional gamma-GT which however did not discriminate steps of ET progression. As shown previously [Sancéau, Hiscott, Delattre and Wietzerbin (2000) Oncogene 19, 3372-3383], ET cells respond to the antiproliferative effects of interferons (IFNs) type I (alpha and beta) and to a much less degree to IFN type II (gamma). IFN-alpha and -beta arrested cells in the S-phase of the cell cycle. We found an enhancement of gamma-GT mRNA species with IFN-alpha and -beta by reverse transcriptase-PCR analyses. This is reflected by up-regulation of gamma-GT protein, which coincides with the increase in gamma-GT-specific enzymic activity. Similarly, IFNs up-regulate the levels of gamma-GT in another IFN-responsive B cell line. Whether this up-regulation of gamma-GT by IFNs is of physiological relevance to cell behaviour remains to be studied.

Bouman, Lena; Sanceau, Josiane; Rouillard, Dany; Bauvois, Brigitte

2002-01-01

264

Dasatinib and Ipilimumab in Treating Patients With Gastrointestinal Stromal Tumors or Other Sarcomas That Cannot be Removed by Surgery or Are Metastatic  

ClinicalTrials.gov

Chondrosarcoma; Clear Cell Sarcoma of the Kidney; Endometrial Stromal Sarcoma; Ewing Sarcoma of Bone; Extraosseous Ewing Sarcoma; Gastrointestinal Stromal Tumor; Mast Cell Sarcoma; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Osteosarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma

2014-05-27

265

[Where does Ewing sarcoma end and begin - two cases of unusual bone tumors with t(20;22)(EWSR1-NFATc2) alteration].  

PubMed

The authors present two cases of Ewing-like sarcoma of the humerus and femur of a 12-year-old boy and a 28-year-old male, respectively. Identical morphology in both tumors consisted of multiple solid nests with a mosaic collection of small, round, uniform cells with clear cytoplasm and no apparent nuclear atypia. A monotonous structural arrangement, including both rich vascularity of bordering septae and significant admixtures of eosinophil leucocytes, resulted in a final organoid "neuroendocrine-like" pattern. Immunohistochemistry revealed diffuse strong CD10, CD99 and CD138 positivity. Detailed molecular analysis in both tumors confirmed translocation t(20;22) resulting in an EWSR1-NFATc2 fusion gene. Additionally, this translocation was accompanied by amplification of the proximal part of the genes and surrounding areas. Clinically, both neoplasms behaved aggressively and they were primarily chemoresistant. Four years later, the patient with the lesion in the humerus developed a massive local recurrence with a disruption of osteosynthesis. The last follow-up disclosed suspicious metastatic deposits in the lung. The boy with the femoral tumor underwent a total femoral prosthesis and there are no signs of local or systemic recurrence after 11 months of follow-up. The authors discuss the taxonomic placement of these rare examples of Ewing-like sarcoma family in the light of new molecular discoveries. Keywords: bone - humerus - femur - small blue round cell tumor - Ewing sarcoma - Ewing-like sarcoma - t(20;22)(EWSR1-NFATc2) - amplification. PMID:24758504

Kinkor, Zden?k; Vane?ek, Tomáš; Svajdler, Marián; Mukenšnabl, Petr; Veselý, Karel; Baxa, Jan; Kokavec, Milan

2014-04-01

266

Immunostaining of the p30\\/32 MIC2 antigen and molecular detection of EWS rearrangements for the diagnosis of Ewing's sarcoma and peripheral neuroectodermal tumor  

Microsoft Academic Search

The identification of Ewing's sarcoma (ES) and peripheral neuroectodermal tumor (PNET) among other small round cell tumors (SRCTs) is a critical issue in musculoskeletal pathology because of the lack of clearly distinctive morphological features. In this study, the authors have compared advantages and limits of two procedures that were recently suggested as additional tools for the identification of ES\\/PNET, the

Katia Scotlandi; Massimo Serra; Maria Cristina Manara; Stefania Benini; Manuela Sarti; Daniela Maurici; Pier-Luigi Lollini; Piero Picci; Franco Bertoni; Nicola Baldini

1996-01-01

267

Treatment of Metastatic Ewing's Sarcoma or Primitive Neuroectodermal Tumor of Bone: Evaluation of Combination Ifosfamide and Etoposide—A Children's Cancer Group and Pediatric Oncology Group Study  

Microsoft Academic Search

Purpose One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes. Methods Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases

James S. Miser; Mark D. Krailo; Nancy J. Tarbell; Michael P. Link; Christopher J. H. Fryer; Douglas J. Pritchard; Mark C. Gebhardt; Paul S. Dickman; Elizabeth J. Perlman; Paul A. Meyers; Sarah S. Donaldson; Sheila Moore; Aaron R. Rausen; Teresa J. Vietti; Holcolmbe E. Grier

268

In vitro radiation studies on Ewing's sarcoma cell lines and human bone marrow: application to the clinical use of total body irradiation (TBI)  

Microsoft Academic Search

Patients with Ewing's sarcoma who present with a central axis or proximal extremity primary and\\/or with metastatic disease have a poor prognosis despite aggressive combination chemotherapy and local irradiation. In this high risk group of patients, total body irradiation (TBI) has been proposed as a systemic adjuvant. To aid in the design of a clinical TBI protocol, the authors have

Timothy J. Kinsella; James B. Mitchell; Scott McPherson; James Miser; Timothy Triche; Eli Glatstein

1984-01-01

269

High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours  

Microsoft Academic Search

Background: The outcome for patients with recurrent or progressive Ewing's sarcoma family of tumours (ESFT) is poor. High dose therapy (HDT) has been used for a number of years in an attempt to improve survival; however, evidence for the efficacy of this treatment remains limited. Patients and methods: Between 1992 and 2004, 33 patients with recurrent or progressive ESFT were

A. McTiernan; D. Driver; M. P. Michelagnoli; A. M. Kilby; J. S. Whelan

2006-01-01

270

Control of a human tumour (Ewing sarcoma) in mice by a single lethal dose of dimethyl-myleran and bone marrow.  

PubMed

A Ewing sarcoma grown in immunosuppressed mice was eradicated with a single lethal dose of dimethylmyleran (DMM) followed by autologous or syngeneic bone marrow. Sarcomas treated 2 weeks after grafting in a phase of rapid proliferation disappeared and large sarcomas treated after 6 or 10 weeks were reduced to necrotic tissue. A human osteosarcoma also regressed distinctly after this therapy while a human colon carcinoma responded poorly. Sub-lethal DMM treatment induced complete remissions in only 62% of the mice. Tumours which display sensitivity in this model may be treated clinically with lethal doses of DMM and autologous marrow transplantations. PMID:7026462

Floersheim, G L; Torhorst, J

1981-06-15

271

Outcome of flat bone sarcomas (other than Ewing's) in children and adolescents: a study of 25 cases.  

PubMed

We analysed the clinical features and outcome of young patients with non-Ewing's flat bone sarcoma treated during the era of contemporary chemotherapy. The characteristics and outcome of 25 patients (15 males and 10 females) with primary or radiation-related flat bone sarcoma treated in the Pediatrics Department at the Institut Gustave Roussy from 1981 to 1999 were reviewed. In all, 20 patients had osteosarcoma, four chondrosarcoma and one malignant fibrous histiocytoma. The age at diagnosis ranged from 2 to 23 years (median, 15 years). Nine tumours were located in the craniofacial bones, 11 in the pelvis and five in flat bones at other sites. Four patients had metastatic disease at diagnosis. Radiation-associated flat bone osteosarcoma was diagnosed in 10 out of 25 cases. The projected overall survival and event-free survival (EFS) rates at 5 years were 45.1 and 34.3% for all the 25 patients. The EFS rate of patients with second bone sarcoma was similar to that of patients with de novo flat bone sarcoma (P=0.1). The aim of treatment was curative for 24 patients, 23 of whom were treated with intensive chemotherapy regimens and 19 with surgery. Significant adverse prognostic factors on survival included incomplete surgical resection (P=0.001) and use of regimens without pre- and postoperative chemotherapy (P=0.007). Nine of the 25 patients were treated with pre- and postoperative chemotherapy and complete surgical resection. Among them, eight are alive with no disease. Radical surgical resection is the overriding prognostic factor for flat bone sarcomas in young patients. Nevertheless, our results suggest a more favourable outcome since the advent of intensive chemotherapy. PMID:14760373

Minard-Colin, V; Kalifa, C; Guinebretiere, J-M; Brugieres, L; Dubousset, J; Habrand, J-L; Vassal, G; Hartmann, O

2004-02-01

272

LGR5 is Expressed by Ewing Sarcoma and Potentiates Wnt/?-Catenin Signaling  

PubMed Central

Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of putative stem cell origin that predominantly occurs in children and young adults. Although most patients with localized ES can be cured with intensive therapy, the clinical course is variable and up to one third of patients relapse following initial remission. Unfortunately, little is yet known about the biologic features that distinguish low-risk from high-risk disease or the mechanisms of ES disease progression. Recent reports have suggested that putative cancer stem cells exist in ES and may contribute to an aggressive phenotype. The cell surface receptor leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a somatic stem cell marker that functions as an oncogene in several human cancers, most notably colorectal carcinoma. LGR5 is a receptor for the R-spondin (RSPO) family of ligands and RSPO-mediated activation of LGR5 potentiates Wnt/?-catenin signaling, contributing to stem cell proliferation and self-renewal. Given its presumed stem cell origin, we investigated whether LGR5 contributes to ES pathogenesis. We found that LGR5 is expressed by ES and that its expression is relatively increased in cells and tumors that display a more aggressive phenotype. In particular, LGR5 expression was increased in putative cancer stem cells. We also found that neural crest-derived stem cells express LGR5, raising the possibility that expression of LGR5 may be a feature of ES cells of origin. LGR5-high ES cells showed nuclear localization of ?-catenin and robust activation of TCF reporter activity when exposed to Wnt ligand and this was potentiated by RSPO. However, modulation of LGR5 or exposure to RSPO had no impact on proliferation confirming that Wnt/?-catenin signaling in ES cells does not recapitulate signaling in epithelial cells. Together these studies show that the RSPO-LGR5-Wnt-?-catenin axis is present and active in ES and may contribute to tumor pathogenesis.

Scannell, Christopher A.; Pedersen, Elisabeth A.; Mosher, Jack T.; Krook, Melanie Anne; Nicholls, Lauren A.; Wilky, Breelyn A.; Loeb, David M.; Lawlor, Elizabeth R.

2013-01-01

273

Trial of Dasatinib in Advanced Sarcomas  

ClinicalTrials.gov

Rhabdomyosarcoma; Malignant Peripheral Nerve Sheath Tumors; Chondrosarcoma; Sarcoma, Ewing's; Sarcoma, Alveolar Soft Part; Chordoma; Epithelioid Sarcoma; Giant Cell Tumor of Bone; Hemangiopericytoma; Gastrointestinal Stromal Tumor (GIST)

2013-05-28

274

Lysyl Oxidase Is Downregulated by the EWS/FLI1 Oncoprotein and Its Propeptide Domain Displays Tumor Supressor Activities in Ewing Sarcoma Cells  

PubMed Central

Ewing sarcoma is the second most common bone malignancy in children and young adults. It is driven by oncogenic fusion proteins (i.e. EWS/FLI1) acting as aberrant transcription factors that upregulate and downregulate target genes, leading to cellular transformation. Thus, identificating these target genes and understanding their contribution to Ewing sarcoma tumorigenesis are key for the development of new therapeutic strategies. In this study we show that lysyl oxidase (LOX), an enzyme involved in maintaining structural integrity of the extracellular matrix, is downregulated by the EWS/FLI1 oncoprotein and in consequence it is not expressed in Ewing sarcoma cells and primary tumors. Using a doxycycline inducible system to restore LOX expression in an Ewing sarcoma derived cell line, we showed that LOX displays tumor suppressor activities. Interestingly, we showed that the tumor suppressor activity resides in the propeptide domain of LOX (LOX-PP), an N-terminal domain produced by proteolytic cleavage during the physiological processing of LOX. Expression of LOX-PP reduced cell proliferation, cell migration, anchorage-independent growth in soft agar and formation of tumors in immunodeficient mice. By contrast, the C-terminal domain of LOX, which contains the enzymatic activity, had the opposite effects, corroborating that the tumor suppressor activity of LOX is mediated exclusively by its propeptide domain. Finally, we showed that LOX-PP inhibits ERK/MAPK signalling pathway, and that many pathways involved in cell cycle progression were significantly deregulated by LOX-PP, providing a mechanistic explanation to the cell proliferation inhibition observed upon LOX-PP expression. In summary, our observations indicate that deregulation of the LOX gene participates in Ewing sarcoma development and identify LOX-PP as a new therapeutic target for one of the most aggressive paediatric malignancies. These findings suggest that therapeutic strategies based on the administration of LOX propeptide or functional analogues could be useful for the treatment of this devastating paediatric cancer.

Garcia-Garcia, Laura; de la Parra, Juan; Alonso, Javier

2013-01-01

275

In vitro antitumor effect of sodium butyrate and zoledronic acid combined with traditional chemotherapeutic drugs: a paradigm of synergistic molecular targeting in the treatment of Ewing sarcoma.  

PubMed

Histone deacetylase inhibitors and bisphosphonates have a promising future in the treatment of cancer as targeted anticancer drugs, particularly when used together or in combination with other cytotoxic agents. However, the effects of these combined treatments have not yet been systematically evaluated in Ewing sarcoma. The in vitro effects on cellular proliferation, viability and survival were investigated in two Ewing sarcoma cell lines, SK-ES-1 and RD-ES. The cell lines were treated with sodium butyrate, a histone deacetylase inhibitor and zoledronic acid, a bisphosphonate, alone, together or in combination with chemotherapeutic drugs recommended for clinical treatment of Ewing sarcoma. The data demonstrated that the combination of sodium butyrate and zoledronic acid had a synergistic cytotoxic effect at 72 h following treatment, persisting for 10-14 days post-treatment, in both cell lines tested. All combinations between sodium butyrate or zoledronic acid and the traditional antineoplastic drugs (doxorubicin, etoposide and vincristine) demonstrated a synergistic cytotoxic effect at 72 h in SK-ES-1 and RD-ES cells, except for the combinations of sodium butyrate with vincristine and of zoledronic acid with doxorubicin, which showed only an additive effect in RD-ES cell lines as compared to each agent alone. These acute effects observed in both Ewing sarcoma cell lines were confirmed by the clonogenic assay. The present data suggest that combining histone deacetylase inhibitors and bisphosphonates with traditional chemotherapeutic drugs is a promising therapeutic strategy for the treatment of Ewing sarcoma, and provides a basis for further studies in this field. PMID:24316794

Dos Santos, Michel Pinheiro; de Farias, Caroline Brunetto; Roesler, Rafael; Brunetto, Algemir Lunardi; Abujamra, Ana Lucia

2014-02-01

276

Two Cases of Spinal, Extraosseous, Intradural Ewing's sarcoma/Peripheral Neuroectodermal Tumor: Radiologic, Pathologic, and Molecular Analysis.  

PubMed

Extraosseous Ewing's sarcoma/peripheral neuroectodermal tumors (ES/PNETs) are rare neoplasms that account for approximately 10%-15% of soft tissue sarcomas in children and 5% of soft tissue sarcomas in adults. Primary spinal, extraosseous, intradural ES/PNETs are even less common. The diagnosis of ES/PNET is extremely challenging, because the tumor can have a nonspecific radiologic appearance, and the histologic features are shared by many other "small round cell tumors." Thus, ES/PNET should be included in the radiologic and pathologic differential diagnosis, even in older patients and in unusual tumor sites. We report two cases of spinal, extraosseous, intradural ES/PNETs in adults who presented with back pain. Magnetic resonance imaging revealed contrast enhancing, intradural lesions in the area of the conus medullaris. The tumor in Case 1 was partially intramedullary, while the tumor in Case 2 was exclusively extramedullary. In both cases, the radiologic and intraoperative surgical impression favored ependymoma. The diagnosis of ES/PNET was established in both cases by histopathologic, immunohistochemical, and molecular analysis. PMID:24678438

Mardekian, Stacey K; Gandhe, Ashish; Miettinen, Markku; Pack, Svetlana; Curtis, Mark T; Abdullaev, Ziedulla

2014-01-01

277

Identification of common and distinctive mechanisms of resistance to different anti-IGF-IR agents in Ewing's sarcoma.  

PubMed

IGF system contributes significantly to many human malignancies. Targeting IGF-I receptor (IGF-IR) has been reported to be active against several tumors, but particular efficacy was observed only against a minority of Ewing's sarcoma patients. Identification of mechanisms of acquired resistance to anti-IGF-IR agents is mandatory to individualize their use in clinics and optimize cure costs. In this study, we compared gene expression profiles of cells made resistant with three different anti-IGF-IR drugs (human antibodies AVE1642, Figitumumab, or tyrosine kinase inhibitor NVP-AEW541) to highlight common and distinctive mechanisms of resistance. Among common mechanisms, we identified two molecular signatures that distinguish sensitive from resistant cells. Annotation analysis indicated some common altered pathways, such as insulin signaling, MAPK pathway, endocytosis, and modulation of some members of the interferon-induced transmembrane protein family. Among distinctive pathways/processes, resistance to human antibodies involves mainly genes regulating neural differentiation and angiogenesis, whereas resistance to NVP-AEW541 is mainly associated with alterations in genes concerning inflammation and antigen presentation. Evaluation of the common altered pathways indicated that resistant cells seem to maintain intact the IGF-IR internalization/degradation route of sensitive cells but constantly down-regulated its expression. In resistant cells, the loss of proliferative stimulus, normally sustained by IGF-I/IGF-IR autocrine loop in Ewing's sarcoma cells, is compensated by transcriptional up-regulation of IGF-II and insulin receptor-A; this signaling seems to favor the MAPK pathway over the v-akt murine thymoma viral oncogene homolog 1 pathway. Overall, complexity of IGF system requires analytical evaluation of its components to select those patients that may really benefit from this targeted therapy and support the idea of cotargeting IGF-IR and insulin receptor-A to increase the efficacy. PMID:22798295

Garofalo, Cecilia; Mancarella, Caterina; Grilli, Andrea; Manara, Maria Cristina; Astolfi, Annalisa; Marino, Maria Teresa; Conte, Alexia; Sigismund, Sara; Carè, Alessandra; Belfiore, Antonino; Picci, Piero; Scotlandi, Katia

2012-09-01

278

Primitive neuroectodermal tumor/Ewing's sarcoma of the urinary bladder: a case report and its molecular diagnosis.  

PubMed

We report a rare case of primitive neuroectodermal tumor/Ewing's sarcoma (PNET/ES) arising from the urinary bladder. A 65-year-old man presented with hematuria and dysuria. Computed tomography revealed an enlarged invasive tumor at the base of the bladder. No additional abnormal findings were disclosed by other diagnostic imaging methods. The surgical specimens showed small round cell tumor with positive staining for MIC2 gene product (CD99). EWS-FLI1 fusion transcripts were detected by reverse transcriptase polymerase chain reaction and direct sequencing, confirming the diagnosis of PNET/ES. The patient developed swollen pelvic lymph nodes as well as multiple lung metastases at 8 months postoperatively. No effective results could be obtained even with systemic chemotherapy consisting of vincristine, ifosfamide, doxorubicin and etoposide (VIDE) based on the EUROpean Ewing tumour Working Initiative of National Groups 1999 (EURO-E.W.I.N.G. 99) multinational trial. The patient died of acute superior mesenteric artery thrombosis at 22 months postoperatively. PNET/ES could have been included in past cases of small cell carcinoma because of the difficulty in its differential diagnosis. Exact diagnosis is crucial for deciding the treatment strategy for rare bladder tumors consisting of small round cells. PMID:21063743

Okada, Yohei; Kamata, Shigeyoshi; Akashi, Takumi; Kurata, Morihito; Nakamura, Takuro; Kihara, Kazunori

2011-08-01

279

G-Protein coupled receptor 64 promotes invasiveness and metastasis in Ewing sarcomas through PGF and MMP1.  

PubMed

Metastatic spread in Ewing sarcomas (ES) is frequent and haematogenous. G-protein coupled receptor 64 (GPR64), an orphan receptor with normal expression restricted to human epididymis is specifically over-expressed in ES among sarcoma, but also up-regulated in a number of carcinomas derived from prostate, kidney or lung. Inhibition of GPR64 expression in ES by RNA interference impaired colony formation in vitro and suppressed local tumour growth and metastasis in Rag2(-/-) ?C (-/-) mice. Microarray analysis after GPR64 knock down revealed a GPR64-mediated repression of genes involved in neuronal development like SLIT, drosophila, homolog of, 2 (SLIT2), and genes regulating transcription including pre-B cell leukemia homeobox 2 (PBX2). Concurrently, the suppression of GPR64 increased ES susceptibility to TRAIL induced apoptosis. Moreover, a GPR64-mediated induction of placental growth factor (PGF) in ES was observed. PGF suppression by RNA interference resulted in a reduction of metastatic growth similar to that observed after GPR64 knock down. Importantly, inhibition of GPR64 as well as PGF expression was associated with a reduced expression of matrix metalloproteinase (MMP) 1 and invasiveness in vitro. Furthermore, MMP1 knock down abrogated lung metastasis in Rag2(-/-) ?C (-/-) mice. Thus, GPR64 expression in ES maintains an immature phenotype that is less sensitive to TRAIL-induced apoptosis and via its up-regulation of PGF and MMP1 orchestrates and promotes invasiveness and metastatic spread. PMID:23338946

Richter, Günther H S; Fasan, Annette; Hauer, Kristina; Grunewald, Thomas G P; Berns, Colette; Rössler, Sabine; Naumann, Ivonne; Staege, Martin S; Fulda, Simone; Esposito, Irene; Burdach, Stefan

2013-05-01

280

Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling.  

PubMed

Identification of patient selection criteria and understanding of the potential mechanisms involved in the development of resistance are crucial for an appropriate and successful design of clinical trials with anti-insulin-like growth factor (IGF)-1R therapies. Few Ewing's sarcomas are highly sensitive to IGF-1R targeting and understanding the reason why, may hold the secret to improve successful treatments. In this paper, we show that a major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production. Resistant cells are able to switch from IGF-1/IGF-1R to IGF-2/IR-A dependency to maintain sustained activation of AKT and ERK1/2, proliferation, migration and metastasis. These cells also showed higher proliferative response to insulin, in keeping with a switch towards insulin pathways sustaining proliferation and malignancy, rather than metabolism. Our findings demonstrate a role for IR-A in eliciting intrinsic and adaptive resistance to anti-IGF-1R therapies. Thus, we indicate that tumors with low IGF-1R:IR ratio are unlikely to greatly benefit from anti-IGF-1R therapies and that the efficacy of anti-IGF-1R therapies should be evaluated in relationship to the IR-A:IGF-1R ratio in cancer cells. Moreover, we provide evidences supporting IR-A as an important target in sarcoma therapy. PMID:21278796

Garofalo, C; Manara, M C; Nicoletti, G; Marino, M T; Lollini, P-L; Astolfi, A; Pandini, G; López-Guerrero, J A; Schaefer, K-L; Belfiore, A; Picci, P; Scotlandi, K

2011-06-16

281

Interval compressed vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide in patients with advanced Ewing's and other Small Round Cell Sarcomas  

PubMed Central

Background To evaluate tolerability and maintenance of dose intensity of 2 weekly treatment with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide (VDC/IE) in patients with advanced small round cell sarcomas including Ewing family tumours (EFT), desmoplastic small round cell tumours (DSRCT) and undifferentiated high grade round cell sarcomas (UHGRCS). Methods Retrospective review of 16 patients treated at a single centre with VDC/IE. Dose received, treatment delay, toxicity and clinical outcome were recorded for each cycle up to a maximum of 14 cycles. Results A total 193 cycles of VDC/IE were administered to 10 patients with EFT, 4 with DSRCT and 2 with UHGRCS. Median age was 22 years with 75% over 18 years. Metastases were present in 14 patients. The mean duration of each cycle was 16.7 days. Febrile neutropenia occurred in 14 % of cycles, and grade 3/4 haematologic toxicity including anaemia and thrombocytopenia in 16 % and 11 % of cycles respectively. Seven patients had a dose reduction. Five patients discontinued VDC/IE early due to toxicity. Conclusions This schedule of VDC/IE is feasible in patients with EFT and DSRCT including adults and those with metastases. Its comparison with other standard regimens for these diseases is justified.

2012-01-01

282

Distinct Transcriptional Signature and Immunoprofile of CIC-DUX4-Fusion Positive Round Cell Tumors Compared to EWSR1-Rearranged Ewing Sarcomas - Further Evidence Toward Distinct Pathologic Entities  

PubMed Central

Round cell sarcomas harboring CIC-DUX4 fusions have recently been described as highly aggressive soft tissue tumors of children and young adults. Due to partial morphologic and immunohistochemical overlap with Ewing sarcoma (ES), CIC-DUX4-positive tumors have generally been classified as Ewing sarcoma-like and managed similarly, however, a systematic comparison at the molecular and immunohistochemical levels between these two groups has not yet been conducted. Based on an initial observation that CIC-DUX4-positive tumors show nuclear immunoreactivity for WT1 and ETS transcription factors, FLI1 and ERG, we performed a detailed immunohistochemical and molecular analysis including these markers, to further investigate the relationship between CIC-DUX4 tumors and ES. The study group included 21 CIC-DUX4-positive sarcomas and 20 EWSR1-rearranged ES. Immunohistochemically, CIC-DUX4 sarcomas showed membranous CD99 positivity in 18 (86%) cases, but only 5 (24%) with a diffuse pattern, while WT1 and FLI1 were strongly positive in all cases. ERG was positive in 18% of cases. All ES expressed CD99 and FLI1, while ERG positivity was only seen in EWSR1-ERG fusion positive ES. WT1 was negative in all ES. Expression profiling validated by q-PCR revealed a distinct gene signature associated with CIC-DUX4 fusion, with upregulation of ETS transcription factors (ETV4, ETV1 and ETV5) and WT1, among top overexpressed genes compared to ES, other sarcomas and normal tissue. In conclusion, the distinct gene signature and immunoprofile of CIC-DUX4 sarcomas suggest a distinct pathogenesis from ES. The consistent WT1 expression may provide a useful clue in the diagnosis in the context of round cell sarcomas negative for EWSR1-rearrangement.

Specht, Katja; Sung, Yun-Shao; Zhang, Lei; Richter, Gunther H. S.; Fletcher, Christopher D.; Antonescu, Cristina R.

2014-01-01

283

Ewing Sarcoma tumor cells express CD34: implications for autologous stem cell transplantation  

Microsoft Academic Search

The significance of tumor cell contamination in marrow and peripheral blood stem cell (PBSC) collections of patients with solid tumors remains controversial. Various methods have been developed to purge tumor cells from autologous stem cell products, including CD34+ selection. PBSC harvests from patients with Ewing family of tumors (EFT) were analyzed for contaminating tumor cells prior and after CD34+ selection

I Yaniv; J Stein; D Luria; I J Cohen; E Liberzon; S Manor; A Grunshpan; Y Sverdlov; Y Kodman; J Issakov; M Feinmesser; R Zaizov; S Avigad

2007-01-01

284

Detection of EWS-FLI-1 fusion in Ewing's sarcoma\\/peripheral primitive neuroectodermal tumor by fluorescence in situ hybridization using formalin-fixed paraffin-embedded tissue  

Microsoft Academic Search

The balanced translocation t(11;22)(q24;q12) is specific for the Ewing's sarcoma\\/peripheral primitive neuroectodermal tumors (ESPNETs) and results in the EWSFLI-1 fusion transcript, which can be detected by reverse transcription polymerase chain reaction (RT-PCR). Recent studies also have used fluorescence in situ hybridization (FISH) to show the translocation; however, most of these have been performed on cell lines or touch preparations and

Shimareet Kumar; Svetlana Pack; Dhruv Kumar; Robert Walker; Martha Quezado; Zhengping Zhuang; Paul Meltzer; Maria Tsokos

1999-01-01

285

Molecular diagnosis of Ewing sarcoma\\/primitive neuroectodermal tumor in routinely processed tissue: a comparison of two FISH strategies and RT-PCR in malignant round cell tumors  

Microsoft Academic Search

Ewing sarcoma\\/primitive neuroectodermal tumor (EWS\\/PNET) is a diagnostically challenging malignant round cell tumor with signature translocations involving the EWS gene. These translocations are detectable with both reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) in formalin-fixed paraffin-embedded tissue. However, RT-PCR is less sensitive in formalin-fixed paraffin-embedded than frozen tissue. Similarly, commercial FISH probes have recently become available,

Robert S Bridge; Veena Rajaram; Louis P Dehner; John D Pfeifer; Arie Perry

2006-01-01

286

Sequence-Specific Knockdown of EWS-FLI1 by Targeted, Nonviral Delivery of Small Interfering RNA Inhibits Tumor Growth in a Murine Model of Metastatic Ewing's Sarcoma  

Microsoft Academic Search

The development of effective, systemic therapies for meta- static cancer is highly desired. We show here that the systemic delivery of sequence-specific small interfering RNA (siRNA) against the EWS-FLI1 gene product by a targeted, nonviral delivery system dramatically inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. The nonviral delivery system uses a cyclodextrin-containing polycation to bind and

Siwen Hu-Lieskovan; Jeremy D. Heidel; Derek W. Bartlett; Mark E. Davis; Timothy J. Triche

287

Simultaneous inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways augment the sensitivity to actinomycin D in Ewing sarcoma  

Microsoft Academic Search

Purpose  Ewing sarcoma cells, of which over 85% retain chimeric fusion gene EWS\\/Fli-1, are by and large more resistant to chemotherapeutics\\u000a compared to nonneoplastic cells. The purpose of this study is to determine the role of EWS\\/Fli-1 fusion and its downstream\\u000a targets regarding the cells’ resistance against actinomycin D (ActD), which is one of the most commonly used antitumor agents\\u000a in

Takatoshi Yamamoto; Takatoshi Ohno; Kazuhiko Wakahara; Akihito Nagano; Gou Kawai; Mitsuru Saitou; Iori Takigami; Aya Matsuhashi; Kazunari Yamada; Katsuji Shimizu

2009-01-01

288

A Pivotal Role for Heat Shock Protein 90 in Ewing Sarcoma Resistance to Anti-Insulin-like Growth Factor 1 Receptor Treatment: In vitro and In vivo Study  

Microsoft Academic Search

Ewing Sarcoma (ES) shows several deregulated autocrine loops mediating cell survival and proliferation. Therefore, their blockade is a promising therapeutic approach. We previously reported the in vitro effect of insulin-like growth factor 1receptor (IGF1 R)\\/KIT pathway blockade on ES cell lines, and we now extend our observations to changes induced by this treatment in interacting proteins\\/networks. A proteo- mic analysis

Ana Sofia Martins; JoseLuis Ordonez; Alfredo Garcia-Sanchez; David Herrero; Daniel Osuna; Carlos Mackintosh; Gemma Caballero; Ana Pastora Otero; Christopher Poremba; Juan Madoz-Gurpide; Enrique de Alava

2008-01-01

289

Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators  

Microsoft Academic Search

CD99 is a unique 32-kDa cell surface molecule with broad cellular expression but still poorly understood biological functions. In cancer cells, CD99 is highly expressed in virtually all Ewing's sarcoma (ES). Engagement of CD99 induces fast homotypic aggregation of ES cells and caspase-independent apoptosis. In this study, we analysed signal transduction after CD99 engagement on ES cells. Findings obtained with

Vanessa Cerisano; Yan Aalto; Stefania Perdichizzi; Ghislaine Bernard; Maria Cristina Manara; Stefania Benini; Giovanna Cenacchi; Paola Preda; Giovanna Lattanzi; Bálint Nagy; Sakari Knuutila; Mario Paolo Colombo; Alain Bernard; Piero Picci; Katia Scotlandi

2004-01-01

290

Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing's sarcoma via inhibition of cell migration  

PubMed Central

Background Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties. Methods Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 ?g/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology. Results ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and ?9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases. Conclusion These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs.

2014-01-01

291

ABT-869 Inhibits Proliferation of Ewing Sarcoma cells and Suppresses PDGFR? and c-KIT Signaling Pathways  

PubMed Central

Ewing Sarcoma (EWS) family of tumors is one of the most common tumors diagnosed in children and adolescents and is characterized by a translocation involving the EWS gene. Despite advances in chemotherapy, the prognosis of metastatic EWS is poor with an overall survival of less than 30% after 5 years. EWS tumor cells express the receptor tyrosine kinases, platelet-derived growth factor receptor (PDGFR) and c-KIT. ABT-869 is a multi-targeted small molecule inhibitor that targets Fms-like tyrosine kinase-3 (FLT-3), c-KIT, vascular endothelial growth receptors (VEGFR) and PDGFRs. To determine the potential therapeutic benefit of ABT-869 in EWS cells, we examined the effects of ABT-869 on EWS cell lines and xenograft mouse models. ABT-869 inhibited the proliferation of two EWS cell lines, A4573 and TC71, at an IC50 of 1.25 ?M and 2 ?M after 72 hours of treatment, respectively. Phosphorylation of PDGFR?, c-KIT, and ERKs was also inhibited. To examine the effects of ABT-869 in vivo, the drug was given to mice injected with EWS cells. We observed inhibition of growth of EWS tumor cells in a xenograft mouse model and prolonged survival in a metastatic mouse model of EWS. Therefore, our in vitro and in vivo studies demonstrate that ABT-869 inhibits proliferation of EWS cells through inhibition of PDGFR? and c-KIT pathways.

Ikeda, Alan K.; Judelson, Dejah R.; Federman, Noah; Glaser, Keith B.; Landaw, Elliot M.; Denny, Christopher T; Sakamoto, Kathleen M.

2010-01-01

292

Chemotherapy-related toxicity in patients with non-metastatic Ewing sarcoma: influence of sex and age.  

PubMed

Influence of age and sex on chemotherapy-related toxicity was evaluated in children (3-9 years), adolescents (10-17 years), and adults (up to 40 years) with localized Ewing sarcoma (ES) enrolled in the ISG/SSG III protocol. Treatment was based on vincristine, doxorubicin, cyclophosphamide, ifosfamide, dactinomycin, and etoposide. High-dose chemotherapy with busulfan and melphalan was given in poor responder patients. The analysis was based on 2191 courses of standard chemotherapy and 230 patients. A lower risk of G4 leukopenia and thrombocytopenia, hospitalization, febrile neutropenia, and red blood cell (RBC) transfusions was observed in males. Use of granulocyte colony-stimulating factor (G-CSF) was more frequent in adults, while children more often received RBC transfusions. A significant correlation between sex and chemotherapy-related toxicity was observed in the study, whereas no significant differences in terms of bone marrow toxicity can be expected according to patient age. Further studies should analyse the role of pharmacokinetics, pharmacogenomics, and clinical characteristics. PMID:24091100

Paioli, Anna; Luksch, Roberto; Fagioli, Franca; Tamburini, Angela; Cesari, Marilena; Palmerini, Emanuela; Abate, Massimo Eraldo; Marchesi, Emanuela; Balladelli, Alba; Pratelli, Loredana; Ferrari, Stefano

2014-02-01

293

Frailty modeling of age-incidence curves of osteosarcoma and Ewing sarcoma among individuals younger than 40 years  

PubMed Central

The Armitage—Doll model with random frailty can fail to describe incidence rates of rare cancers influenced by an accelerated biological mechanism at some, possibly short, period of life. We propose a new model to account for this influence. Osteosarcoma and Ewing sarcoma are primary bone cancers with characteristic age-incidence patterns that peak in adolescence. We analyze SEER incidence data for whites younger than 40 years diagnosed during the period 1975?2005, with an Armitage—Doll model with compound Poisson frailty. A new model treating the adolescent growth spurt as the accelerated mechanism affecting cancer development is a significant improvement over that model. We also model the incidence rate conditioning on the event of having developed the cancers before the age of 40 years and compare the results with those predicted by the Armitage—Doll model. Our results support existing evidence of an underlying susceptibility for the two cancers among a very small proportion of the population. In addition, the modeling results suggest that susceptible individuals with a rapid growth spurt acquire the cancers sooner than they otherwise would have, if their growth had been slower. The new model is suitable for modeling incidence rates of rare diseases influenced by an accelerated biological mechanism.

Valberg, Morten; Grotmol, Tom; Tretli, Steinar; Veier?d, Marit B.; Devesa, Susan S.; Aalen, Odd O.

2014-01-01

294

Ewing sarcoma-peripheral neuroectodermal tumor of the kidney with a FUS-ERG fusion transcript.  

PubMed

The Ewing family of tumors (EFTs) represents a neoplastic entity characterized by specific chromosomal rearrangements. The most commonly detected translocation involves fusion of EWSR1 to one of the genes encoding ETS family of transcription factors, usually FLI1 or ERG. In rare cases, FUS or FEV has been shown to substitute for EWSR1. The detection of specific translocations by fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), or both has become a diagnostic hallmark for the EFTs. We report here a case of small round blue cell tumor detected in the kidney of a 3-year-old girl. The use of FISH in combination with RT-PCR led to identification of a novel FUS-ERG fusion transcript in the tumor, with FUS exons 1-5 fused in-frame to ERG exons 6-9. The results from the molecular analyses were critical for reaching a final diagnostic conclusion of Ewing tumor-peripheral neuroectodermal tumor and hence had important therapeutic implications for the patient. PMID:19737655

Berg, Thomas; Kalsaas, Ann-Hilde; Buechner, Jochen; Busund, Lill-Tove

2009-10-01

295

Identification of a self-association domain in the Ewing's sarcoma protein: a novel function for arginine-glycine-glycine rich motifs?  

PubMed Central

The Ewing’s sarcoma (EWS) protein is a ubiquitously expressed RNA chaperone. The EWS protein localizes predominantly to the nucleus. Previous reports have suggested that the EWS protein is capable of dimerizing. However, to date this has not been confirmed. Here, using a novel panel of recombinant proteins, we have performed an in vitro biomolecular interaction analysis of the EWS protein. We have demonstrated that all three arginine-glycine-glycine (RGG) motifs are capable of binding directly to the survival motor neuron protein, a Tudor domain containing EWS binding partner. We have also confirmed EWS is capable of self-associating, and we have mapped this binding domain to the RGG motifs. We have also found that self-association may be required for EWS nuclear import. This is the first direct evidence of RGG domains being involved in self-association and has implications on all RGG-containing proteins.

Shaw, Debra J.; Morse, Robert; Todd, Adrian G.; Eggleton, Paul; Lorson, Christian L.; Young, Philip J.

2010-01-01

296

Morphoproteomic Profiling of the Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Desmoplastic Small Round Cell Tumor (EWS/WT1), Ewing's Sarcoma (EWS/FLI1) and Wilms' Tumor(WT1)  

PubMed Central

Background Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma in adolescents and young adults. The hallmark of this disease is a EWS-WT1 translocation resulting from apposition of the Ewing’s sarcoma (EWS) gene with the Wilms’ tumor (WT1) gene. We performed morphoproteomic profiling of DSRCT (EWS-WT1), Ewing’s sarcoma (EWS-FLI1) and Wilms’ tumor (WT1) to better understand the signaling pathways for selecting future targeted therapies. Methodology This pilot study assessed patients with DSRCT, Wilms’ tumor and Ewing’s sarcoma. Morphoproteomics and immunohistochemical probes were applied to detect: p-mTOR (Ser2448); p-Akt (Ser473); p-ERK1/2 (Thr202/Tyr204); p-STAT3 (Tyr 705); and cell cycle-related analytes along with their negative controls. Principal Findings In DSRCT the PI3K/Akt/mTOR pathway is constitutively activated by p-Akt (Ser 473) expression in the nuclear compartment of the tumor cells and p-mTOR phosphorylated on Ser 2448, suggesting mTORC2 (rictor+mTOR) as the dominant form. Ewing’s sarcoma had upregulated p-Akt and p-mTOR, predominantly mTORC2. In Wilm’s tumor, the mTOR pathway is also activated with most tumor cells moderately expressing p-mTOR (Ser 2448) in plasmalemmal and cytoplasmic compartments. This coincides with the constitutive activation of one of the downstream effectors of the mTORC1 signaling pathway, namely p-p70S6K (Thr 389). There was constitutive activation of the Ras/Raf/ERK pathway p-ERK 1/2 (Thr202/Tyr204) expression in the Wilms tumor and metastatic Ewing’s sarcoma, but not in the DSRCT. Conclusion Morphoproteomic tumor analyses revealed constitutive activation of the mTOR pathway as evidenced by: (a) expression of phosphorylated (p)-mTOR, p-p70S6K; (b) mTORC 2 in EWS and DSRCT; (c) ERK signaling was seen in the advanced setting indicating these as resistance pathways to IGF1R related therapies. This is the first morphoproteomic study of such pathways in these rare malignancies and may have potential therapeutic implications. Further study using morphoproteomic assessments of these tumors are warranted.

Jiang, Yunyun; Buryanek, Jamie; Hayes-Jordan, Andrea

2013-01-01

297

A Novel Chimera Gene between EWSand E1AF, Encoding the Adenovirus E1A Enhancer-Binding Protein, in Extraosseous Ewing's Sarcoma  

Microsoft Academic Search

Ewing's sarcoma\\/PNET, a tumor of the bone and soft tissue, is one of the most common causes of tumor death among youths. This tumor does not have specific phenotypes, but does have characteristic chromosomal translocations. Furthermore, the expression ofEWS\\/FLI-1orEWS\\/ERGchimeric genes was found to be generated through a t(11;22)(q24;q12) or a t(21;22)(q22;q12) translocation. In this study, we identified a new chimera

Fumihiko Urano; Akihiro Umezawa; Wei Hong; Haruhito Kikuchi; Jun-ichi Hata

1996-01-01

298

Hypoxia shifts activity of neuropeptide Y in Ewing sarcoma from growth-inhibitory to growth-promoting effects  

PubMed Central

Ewing sarcoma (ES) is an aggressive malignancy driven by an oncogenic fusion protein, EWS-FLI1. Neuropeptide Y (NPY), and two of its receptors, Y1R and Y5R are up-regulated by EWS-FLI1 and abundantly expressed in ES cells. Paradoxically, NPY acting via Y1R and Y5R stimulates ES cell death. Here, we demonstrate that these growth-inhibitory actions of NPY are counteracted by hypoxia, which converts the peptide to a growth-promoting factor. In ES cells, hypoxia induces another NPY receptor, Y2R, and increases expression of dipeptidyl peptidase IV (DPPIV), an enzyme that cleaves NPY to a shorter form, NPY3-36. This truncated peptide no longer binds to Y1R and, therefore, does not stimulate ES cell death. Instead, NPY3-36 acts as a selective Y2R/Y5R agonist. The hypoxia-induced increase in DPPIV activity is most evident in a population of ES cells with high aldehyde dehydrogenase (ALDH) activity, rich in cancer stem cells (CSCs). Consequently, NPY, acting via Y2R/Y5Rs, preferentially stimulates proliferation and migration of hypoxic ALDHhigh cells. Hypoxia also enhances the angiogenic potential of ES by inducing Y2Rs in endothelial cells and increasing the release of its ligand, NPY3-36, from ES cells. In summary, hypoxia acts as a molecular switch shifting NPY activity away from Y1R/Y5R-mediated cell death and activating the Y2R/Y5R/DPPIV/NPY3-36 axis, which stimulates ES CSCs and promotes angiogenesis. Hypoxia-driven actions of the peptide such as these may contribute to ES progression. Due to the receptor-specific and multifaceted nature of NPY actions, these findings may inform novel therapeutic approaches to ES.

Galli, Susana; Izycka-Swieszewska, Ewa; Earnest, Joshua Patrick; Shabbir, Asim; Everhart, Lindsay M.; Wang, Shuo; Martin, Samantha; Horton, Meredith; Mahajan, Akanksha; Christian, David; O'Neill, Alison; Wang, Hongkun; Zhuang, Tingting; Czarnecka, Magdalena; Johnson, Michael D.; Toretsky, Jeffrey A.; Kitlinska, Joanna

2013-01-01

299

Dose-Intensified Compared With Standard Chemotherapy for Nonmetastatic Ewing Sarcoma Family of Tumors: A Children's Oncology Group Study  

PubMed Central

Purpose The Ewing sarcoma family of tumors (ESFT) is a group of malignant tumors of soft tissue and bone sharing a chromosomal translocation affecting the EWS locus. The Intergroup INT-0091 demonstrated the superiority of a regimen of vincristine, cyclophosphamide, doxorubicin (VDC), and dactinomycin alternating with ifosfamide and etoposide (IE) over VDC for patients with nonmetastatic ESFT of bone. The goal of this study was to determine whether a dose-intensified regimen of VDC alternating with IE would further improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue. Methods Patients with previously untreated, nonmetastatic ESFT of bone or soft tissue were eligible. They were randomly assigned to receive standard doses of VDC/IE over 48 weeks or a dose-intensified regimen of VDC/IE over 30 weeks. Results Four hundred seventy-eight patients met eligibility requirements: 231 patients received the standard regimen; 247 patients received the intensified regimen. The 5-year event-free survival (EFS) and overall survival rates for all eligible patients were 71.1% (95% CI, 67.7% to 75.0%) and 78.6% (95% CI, 74.6% to 82.1%), respectively. There was no significant difference (P = .57) in EFS between patients treated with the standard (5-year EFS, 72.1%; 95% CI, 65.8% to 77.5%) or intensified regimen (5-year EFS, 70.1%; 63.9% to 75%). Patients with soft tissue tumors accounted for 20% of the study population; there was no difference in outcome between patients with soft tissue and bone primary sites. Conclusion Dose escalation of alkylating agents as tested in this trial did not improve the outcome for patients with nonmetastatic ESFT of bone or soft tissue.

Granowetter, Linda; Womer, Richard; Devidas, Meenakshi; Krailo, Mark; Wang, Chenguang; Bernstein, Mark; Marina, Neyssa; Leavey, Patrick; Gebhardt, Mark; Healey, John; Shamberger, Robert Cooper; Goorin, Allen; Miser, James; Meyer, James; Arndt, Carola A.S.; Sailer, Scott; Marcus, Karen; Perlman, Elizabeth; Dickman, Paul; Grier, Holcombe E.

2009-01-01

300

WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells.  

PubMed

Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of children and young adults in which finding effective new targeted therapies is imperative. Here, we report an in-depth preclinical study of the investigational cullin-RING ubiquitin ligase (CRL) inhibitor MLN4924 in ES, as we have recently demonstrated the implication of a CRL component in the ES pathogenesis. First, our results support a high sensitivity of ES cells to MLN4924 growth inhibition both in vitro (14 ES cell lines tested, median IC50=81?nM) and in tumor xenografts (tumor regression achieved with 60?mg/kg BID, subcutaneously, n=9). Second, we report a dual mechanism of action of MLN4924 in ES cells: while a wide range of MLN4924 concentrations (?30-300?nM) trigger a G2 arrest that can only be rescued by WEE1 kinase inhibition or depletion, saturating doses of the drug (>300?nM) cause a delay in S-phase progression concomitant with unbalanced CDK2-Cyclin E and CDK2-Cyclin A relative levels (accumulation of the first and depletion of the latter). The aberrant presence of CDC6 in the nucleus at late S-phase cell cycle stage confirmed the loss of CDK2-Cyclin A-specific functions. Remarkably, other mechanisms explored (P27 accumulation and DNA damage signaling pathways) were found unable to explain MLN4924 effects, strengthening the specificity of our findings and suggesting the absence of functionality of some CRL substrates accumulated in response to MLN4924. This study renders a rationale for clinical trials and contributes molecular mechanisms for a better understanding of this promising antitumoral agent. PMID:22641220

Mackintosh, C; García-Domínguez, D J; Ordóñez, J L; Ginel-Picardo, A; Smith, P G; Sacristán, M P; de Álava, E

2013-03-14

301

1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma.  

PubMed

Despite extensive characterization of the role of the EWS-ETS fusions, little is known about secondary genetic alterations and their clinical contribution to Ewing sarcoma (ES). It has been demonstrated that the molecular structure of EWS-ETS lacks prognostic value. Moreover, CDKN2A deletion and TP53 mutation, despite carrying a poor prognosis, are infrequent. In this scenario identifying secondary genetic alterations with a significant prevalence could contribute to understand the molecular mechanisms underlying the most aggressive forms of ES.We screened a 67 ES tumor set for copy number alterations by array comparative genomic hybridization. 1q gain (1qG), detected in 31% of tumor samples, was found markedly associated with relapse and poor overall and disease-free survival and demonstrated a prognostic value independent of classical clinical parameters. Reanalysis of an expression dataset belonging to an independent tumor set (n=37) not only validated this finding but also led us to identify a transcriptomic profile of severe cell cycle deregulation in 1qG ES tumors. Consistently, a higher proliferation rate was detected in this tumor subset by Ki-67 immunohistochemistry. CDT2, a 1q-located candidate gene encoding a protein involved in ubiquitin ligase activity and significantly overexpressed in 1qG ES tumors, was validated in vitro and in vivo proving its major contribution to this molecular and clinical phenotype. This integrative genomic study of 105 ES tumors in overall renders the potential value of 1qG and CDT2 overexpression as prognostic biomarkers and also affords a rationale for the application of already available new therapeutic compounds selectively targeting the protein-ubiquitin machinery. PMID:21822310

Mackintosh, C; Ordóñez, J L; García-Domínguez, D J; Sevillano, V; Llombart-Bosch, A; Szuhai, K; Scotlandi, K; Alberghini, M; Sciot, R; Sinnaeve, F; Hogendoorn, P C W; Picci, P; Knuutila, S; Dirksen, U; Debiec-Rychter, M; Schaefer, K-L; de Álava, E

2012-03-01

302

Influence of the Internalization Pathway on the Efficacy of siRNA Delivery by Cationic Fluorescent Nanodiamonds in the Ewing Sarcoma Cell Model  

PubMed Central

Small interfering RNAs (siRNAs) are powerful tools commonly used for the specific inhibition of gene expression. However, vectorization is required to facilitate cell penetration and to prevent siRNA degradation by nucleases. We have shown that diamond nanocrystals coated with cationic polymer can be used to carry siRNAs into Ewing sarcoma cells, in which they remain traceable over long periods, due to their intrinsic stable fluorescence. We tested two cationic polymers, polyallylamine and polyethylenimine. The release of siRNA, accompanied by Ewing sarcoma EWS-Fli1 oncogene silencing, was observed only with polyethylenimine. We investigated cell penetration and found that the underlying mechanisms accounted for these differences in behavior. Using drugs selectively inhibiting particular pathways and a combination of fluorescence and electronic microscopy, we showed that siRNA gene silencing occurred only if the siRNA:cationic nanodiamond complex followed the macropinocytosis route. These results have potential implications for the design of efficient drug-delivery vectors.

Alhaddad, Anna; Durieu, Catherine; Dantelle, Geraldine; Le Cam, Eric; Malvy, Claude; Treussart, Francois; Bertrand, Jean-Remi

2012-01-01

303

Anti-VEGFR2 and anti-IGF-1R-Adnectins inhibit Ewing's sarcoma A673-xenograft growth and normalize tumor vascular architecture.  

PubMed

Increasing experimental evidence suggests that IGF-1 may modulate tumor angiogenesis via activation of the expression of VEGF in Ewing sarcomas and rhabdomyosarcomas. This study investigates the effects of the PEGylated Adnectins™ CT-322, a VEGFR2-inhibitor and AT580Peg40, an IGF-1R inhibitor, as monotherapy and in combination in a murine A673 xenograft tumor model. The combination of Adnectins CT-322 and AT580Peg40 revealed a 83% reduction in tumor growth, a nearly 5 times lower vessel density, less necrotic areas and less appearance of intussusceptive angiogenesis. Monotherapy with IGF-1R or CT-322 revealed equally a significant inhibition of tumor and vessel growth. Combinatory inhibition of IGF-1R and VEGFR2 shows a downregulation of IGF-binding protein 2 and a compensatory upregulation of VEGF levels. Immunohistological analysis showed remodeling vascular effects of CT-322-treatment or combination therapy. The vascular architecture in Adnectin-treated tumors was characterized by a strong normalization of vasculature. 3D-evaluation in microvascular corrosion casts showed significantly higher intervascular and interbranching distances in Adnectin-treated tumors. CT-322-treatment and combinatory inhibition reveal a significant reduction of intussusceptive angiogenesis. These pronounced effects on tumor vasculature suggest potential therapeutic benefit of combinatorial IGF1- and VEGF-pathways inhibition in Ewing's sarcoma. PMID:22914877

Ackermann, Maximilian; Morse, Brent A; Delventhal, Vera; Carvajal, Irvith M; Konerding, Moritz A

2012-12-01

304

Let-7a functions as a tumor suppressor in Ewing's sarcoma cell lines partly by targeting cyclin-dependent kinase 6.  

PubMed

MicroRNAs play an important role in the development and progression of Ewing's sarcoma (ES). Especially, the expression of let-7a has been reported to be significantly downregulated in various cancers, and can affect the initiation and maintenance of tumor progression. However, the relative effects of let-7a on ES cells and relative mechanisms are largely unknown. In this study, we identified the underexpression of let-7a in human ES cells comparing with the human mesenchymal stem cells. Then, we sought to compensate for its loss through exogenous transfection with let-7a mimic into ES cell lines A673 and SK-ES-1. Restored let-7a expression inhibited cell proliferation, migration, as well as invasion; arrested cell cycle progression; and induced cell apoptosis of both cell lines. Moreover, bioinformatic prediction suggested that cyclin-dependent kinase 6 (CDK6), which is overexpressed and functions as an oncoprotein in ES cells, is a putative target gene of let-7a. Using mRNA and protein expression analysis and luciferase assays, we further identified the target role of CDK6. Finally, we found that restored CDK6 expression in ES cells that had been treated with let-7a mimic before could partly dampen let-7a-mediated tumor suppression. Taken together, our results showed that let-7a acted as a tumor suppressor in ES by targeting CDK6, and it may provide novel diagnostic and therapeutic options for human Ewing sarcoma clinical operation in future. PMID:24383407

Zhang, Zhongzu; Huang, Lu; Yu, Zhiming; Chen, Xiang; Yang, Dong; Zhan, Ping; Dai, Min; Huang, Shanhu; Han, Zhimin; Cao, Kai

2014-03-01

305

Long-range restriction map of human chromosome 22q11-22q12 between the lambda immunoglobulin locus and the Ewing sarcoma breakpoint  

SciTech Connect

A long-range restriction map of the region between the immunoglobulin lambda locus and the Ewing sarcoma breakpoint has been constructed using the rare-cutting enzymes NotI, NruI, AscI, and BsiWI. The map spans approximately 11,000 kb and represents about one-fifth of the long arm of chromosome 22. Thirty-nine markers, including seven NotI junction clones as well as numerous genes and anonymous sequences, were mapped to the region with a somatic cell hybrid panel. These probes were then used to produce the map. The seven NotI junction clones each identified a possible CpG island. The breakpoints of the RAJ5 hybrid and the Ewing sarcoma t(11;22) were also localized in the resulting map. This physical map will be useful in studying chromosomal rearrangements in the region, as well as providing the details to examine the fidelity of the YAC and cosmid contigs currently under construction. Comparisons of this physical map to genetic and radiation hybrid maps are discussed. 52 refs., 7 figs., 3 tabs.

McDermid, H.E. (Univ. of Alberta, Edmonton (Canada)); Budarf, M.L.; Emanuel, B.S. (Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States) Children's Hospital of Philadelphia, PA (United States))

1993-11-01

306

Multimodality imaging features, metastatic pattern and clinical outcome in adult extraskeletal Ewing sarcoma: experience in 26 patients.  

PubMed

Objective: To describe the multimodality imaging features, metastatic pattern and clinical outcome in adult extraskeletal Ewing sarcoma (EES). Methods: In this institutional review board-approved, health insurance portability and accountability act-compliant retrospective study, we included 26 patients (17 females and 9 males; mean age, 36 years; range, 18-85 years) with pathologically confirmed EES seen at our institute between 1999 and 2011, who had imaging of primary tumour. Imaging of primary tumour in all 26 patients and follow-up imaging in 23 was reviewed by two radiologists in consensus. Clinical data were extracted from electronic medical records. Results: The most common primary sites were the torso (n?=?13), extremities (n?=?10) and head and neck (HN) region (n?=?3). The mean tumour size was 9?cm (range, 3-22?cm); tumours of the torso were larger than those of other areas (p?>?0.05). Compared with the skeletal muscle, tumours were isodense on CT (21/21), hypointense (n?=?5) to isointense (n?=?14) on T1 weighted image, hyperintense on T2 weighted image (19/19) and were fluorine-18 fludeoxyglucose ((18)F-FDG)-avid [10/10; mean maximum standardized uptake value of 7 (range, 3-11)]. Necrosis (15/26), haemorrhage (5/26) and adjacent organ invasion (14/26) were present without calcification. Median follow-up was 16 months. 5 patients had local recurrence (torso, 3; extremity, 1; and HN, 1). Metastases developed in 11 patients (torso, 7; extremities, 3; and HN, 1; p?>?0.05); 8 at presentation, most commonly to lung (9/11), peritoneum (4/11), muscles (4/11) and lymph nodes (4/11). Nine patients (torso, 7; extremity, 1; and HN, 1) died (10 months median survival) (p?>?0.05). Conclusion: Adult EESs are large tumours, which frequently invade adjacent organs and metastasize to the lung. EESs of the torso are larger, have more frequent metastases and poorer outcomes. Advances in knowledge: Adult EESs of the torso have poor outcomes compared with other EESs. PMID:24734938

Somarouthu, B S; Shinagare, A B; Rosenthal, M H; Tirumani, H; Hornick, J L; Ramaiya, N H; Tirumani, S H

2014-06-01

307

miR-34a predicts survival of Ewing's sarcoma patients and directly influences cell chemo-sensitivity and malignancy.  

PubMed

Identification of factors to detect chemotherapy-resistant tumours at diagnosis is a first priority for risk-adapted therapy in the oncology of children and young adults, where more individualized, effective, and less toxic treatments are highly desirable. In this study, we analysed the miRNAs discriminating Ewing's sarcoma (EWS) patients with different clinical outcomes in order to identify new indicators of prognosis. miRNA expression was investigated in 49 primary EWSs by using the Agilent human miRNA microarray v.2 and/or qRT-PCR. Statistical power of the samples studied for miRNA expression was verified, indicating adequate sample size. Microarray analysis defined a signature of five miRNAs (miR-34a, miR-23a, miR-92a, miR-490-3p, and miR-130b) as an independent predictor of risk for disease progression and survival. Validation analysis in the extended sample set indicated that both miR-34a and miR-490-3p achieved sufficient statistical power to predict prognosis. Results were particularly robust for miR-34a, which appeared associated with either event-free or overall survival and emerged as a significant predictor also after multivariate analysis. Patients with the highest expression of miR-34a did not experience adverse events in 5 years; in contrast, patients with the lowest expression recurred within 2 years. High expression of miR34a can be detected also in paraffin-embedded tissues by in situ hybridization, thus contributing to an easy routine evaluation of this miRNA. Functional analysis of miR-34a in EWS cell lines indicated that when miR-34a expression was enforced, cells were less proliferative, less malignant, and sensitized to doxorubicin and vincristine. Expression of miR-34a could be increased in p53wt cells by treatment with nutlin-3a. Accordingly, nutlin-3a synergizes with doxorubicin. Overall, our data indicate that miR-34a expression is a strong predictor of outcome in EWS. Restoration of miR-34a activity may be useful to decrease malignancy and increase tumour sensitivity to current drugs, so sparing excessive long-term toxicity to EWS patients. PMID:21960059

Nakatani, Fumihiko; Ferracin, Manuela; Manara, Maria Cristina; Ventura, Selena; Del Monaco, Valentina; Ferrari, Stefano; Alberghini, Marco; Grilli, Andrea; Knuutila, Sakari; Schaefer, Karl-Ludwig; Mattia, Gianfranco; Negrini, Massimo; Picci, Piero; Serra, Massimo; Scotlandi, Katia

2012-04-01

308

Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing's sarcoma.  

PubMed

According to the published report on current practice of hematopoietic SCT in Europe, high-dose therapy (HDT) with autologous stem cell support is a standard of care in paediatric patients with high risk (HR) or relapsed Ewing's sarcoma (ES). Randomized trials, however, have not confirmed the value of this procedure yet. In this retrospective analysis we intended to evaluate the role of HDT as a consolidation therapy in first remission of ES. A total of 102 patients were included in the analysis and divided according to the following risk factors: metastatic disease at presentation, feasibility of surgery and histological response after induction. Forty-one patients were classified as standard risk (SR) patients, while the remaining 61 children, with at least one risk factor, were classified as HR patients. HR group patients were non-randomized and qualified according to the decision of the local clinician to give a conventional consolidation (CC) or to perform high-dose chemotherapy and radiotherapy in selected patients. Twenty-six children were given CC while 35 patients were treated with HDT. The HDT consisted of oral BU 4 mg/kg p.o. in divided doses daily for 4 days (total dose 16 mg/kg) followed by melphalan 140 mg/m(2) i.v. on day -2. Probability of relapse-free survival (RFS) in median observation time was significantly worse in HR patients who were given CC therapy as compared with children with HR features receiving high-dose chemotherapy (0.27 vs 0.66 (P = 0.008); OS 0.31 vs 0.71 (P = 0.007), respectively). Patients from the SR group had a probability of RFS of 0.72 and OS of 0.75, and the difference between SR and HR patients after HDT was NS (P = 0.37). Our observation confirms that the consolidation of the first-line treatment with BU and melphalan improves the outcome in ES patients with HR features. PMID:22609883

Drabko, K; Raciborska, A; Bilska, K; Styczynski, J; Ussowicz, M; Choma, M; Wojcik, B; Zaucha-Prazmo, A; Gorczynska, E; Skoczen, S; Wozniak, W; Chybicka, A; Wysocki, M; Gozdzik, J; Kowalczyk, J

2012-12-01

309

Combined use of expression and CGH arrays pinpoints novel candidate genes in Ewing sarcoma family of tumors  

PubMed Central

Background Ewing sarcoma family of tumors (ESFT), characterized by t(11;22)(q24;q12), is one of the most common tumors of bone in children and young adults. In addition to EWS/FLI1 gene fusion, copy number changes are known to be significant for the underlying neoplastic development of ESFT and for patient outcome. Our genome-wide high-resolution analysis aspired to pinpoint genomic regions of highest interest and possible target genes in these areas. Methods Array comparative genomic hybridization (CGH) and expression arrays were used to screen for copy number alterations and expression changes in ESFT patient samples. A total of 31 ESFT samples were analyzed by aCGH and in 16 patients DNA and RNA level data, created by expression arrays, was integrated. Time of the follow-up of these patients was 5–192 months. Clinical outcome was statistically evaluated by Kaplan-Meier/Logrank methods and RT-PCR was applied on 42 patient samples to study the gene of the highest interest. Results Copy number changes were detected in 87% of the cases. The most recurrent copy number changes were gains at 1q, 2, 8, and 12, and losses at 9p and 16q. Cumulative event free survival (ESFT) and overall survival (OS) were significantly better (P < 0.05) for primary tumors with three or less copy number changes than for tumors with higher number of copy number aberrations. In three samples copy number imbalances were detected in chromosomes 11 and 22 affecting the FLI1 and EWSR1 loci, suggesting that an unbalanced t(11;22) and subsequent duplication of the derivative chromosome harboring fusion gene is a common event in ESFT. Further, amplifications on chromosomes 20 and 22 seen in one patient sample suggest a novel translocation type between EWSR1 and an unidentified fusion partner at 20q. In total 20 novel ESFT associated putative oncogenes and tumor suppressor genes were found in the integration analysis of array CGH and expression data. Quantitative RT-PCR to study the expression levels of the most interesting gene, HDGF, confirmed that its expression was higher than in control samples. However, no association between HDGF expression and patient survival was observed. Conclusion We conclude that array CGH and integration analysis proved to be effective methods to identify chromosome regions and novel target genes involved in the tumorigenesis of ESFT.

2009-01-01

310

Superficial primitive neuroectodermal tumor/Ewing sarcoma (PN/ES): same tumor as deep PN/ES or new entity?  

PubMed

Primitive neuroectodermal tumor/Ewing sarcoma (PN/ES) is a single clinical, morphologic, and molecular small round cell tumor entity. These are generally found in deep soft tissue or bone of young male patients, with poor behavior. Location in dermis is unexpected; only rare cases are reported. Cases coded as "dermal," "cutaneous," or "skin" PN/ES were retrieved from our consultation files. Only primary dermal cases were included. Those otherwise diagnosed or with incomplete material were excluded. There were 13 dermal PN/ES cases, consisting of 10 women and 3 men. Ages ranged from 2 to 67 years (mean, 28 years). Locations included groin or thigh (4), back or shoulder (3), neck (1), chest (1), scalp (1), forehead (1), hand (1), and foot (1). Most cases were small (0.5-2.3 centimeters) and painful, and persisted for less than 1 year. All were located within the dermis. Three caused pedunculation; 9 also involved superficial subcutis. All but 1 of the metastasizing tumors were round and encapsulated. All were composed of round to oval cells with a vague rosetting pattern, slightly overlapping nuclei, finely stippled chromatin, clear to eosinophilic cytoplasm, and collagenous stroma. Median mitotic activity was 8 per 10 high-power fields. Necrosis was present in three cases. All had globular periodic acid Schiff positivity and distinctive cytoplasmic membrane CD99 reactivity. One case studied was positive for Fli-1. All were negative for leukocyte common antigen, Tdt, CD3, CD20, CD79, CK20, pankeratin, epithelial membrane antigen, chromogranin, neurofilament protein, carcinoembryonic antigen, desmin, actin, diffuse S100 protein, and HMB45. Nine cases with material for reverse transcription-polymerase chain reaction revealed 1 positive type 2 translocation (EWS exon 7 to Fli-1 exon 5), 4 negative, and 4 "unable to amplify." Treatment was by wide excision; 9 received chemotherapy and 6 radiation. Follow-up of 11 (85%) cases revealed the following: 1 metastasis to stomach and death at 3 years; 10 years without disease (median, 9.0 years). Cutaneous PN/ES is a superficial round cell tumor in older women, with better prognosis than deep PN/ES. These may have a hitherto unrecognized variant genetic abnormality. PMID:17498589

Ehrig, Torsten; Billings, Steven D; Fanburg-Smith, Julie C

2007-06-01

311

Suitability of imaging methods (X-ray, CT, MRI) in the diagnostics of Ewing's sarcoma in children - analysis of own material  

PubMed Central

Summary Background: Ewing sarcoma is a malignant, small round cell bone tumor, presenting predominantly in children and adolescents. Ewing sarcoma may develop in every bone; diaphyses of long bones, ribs and flat bones are the main locations. Local and systemic clinical symptoms are nonspecific - pain, swelling, fever or ill-being. The aim of the study was to assess the role of radiography, computed tomography and magnetic resonance imaging in the analysis of bone lesions in children and young adults with Ewing sarcoma. Material/Methods: Twenty-seven patients, aged between 1 year and 10 months, and 17 years and 2 months, with histologically verified Ewing sarcoma of the bone, referred to the Radiological Department of University Hospital No 6., John Paul II Upper Silesian Centre for Child Health Katowice, in the period from 1996 to 2007, were included in the study.Plain radiography was performed in every child, CT in 20 and MRI in 12 individuals. Tumour location, extension of the tumour, soft tissue mass, and periosteal reaction were taken into consideration in the evaluation of the lesion. In some cases, pathological features of the MRI and CT were compared. The prevalence of some radiological features was compared to the literature data. Results: The most common site of tumor was: ribs (6 children), femoral bone (6 children), pelvis (4 children) and tibia (3 children). In 2 children, a primary tumor was diagnosed in the spine (multifocal in 1 child). X-rays revealed: periosteal reaction in 17 children (63%), soft tissue involvement in 19 children (70%), permeative component in 16 children (59%), and sclerotic component in 5 children (19%). In 10 children (37%), periosteal reaction was not detected. The examination revealed: soft tissue calcifications in 7 cases (26%), a well-delineated focus of destruction within bones in 3 children (11%), cortical thickening in 4 children (15%), cortical destruction in 4 children (15%), saucerisation in 3 children (11%), bone expansion in 3 children (11%), pathological fracture in 2 children (7%), cystic component in 1 child (4%), and vertebra plana in 1 child (4%).Reaction of tumors after i.v. contrast administration, shown on CT, was visible in 16 children – it was useful for a better description of the tumor and extension of the mass within the soft tissue. All MRI examinations (12 children) showed a heterogenous mass with ill-defined borders and a violated cortex. Low signal intensity of the tumor in a T1-weighted image and high signal intensity in a T2-weighted image was shown as well. Heterogenous enhancement of signal intensity on T1-weighted images could be observed after i.v. contrast administration. MRI examinations showed: tumor in an adjacent soft tissue in 11 children, and involvement of the epiphyseal plate or of the joint cavity in 6 children. Conclusions: X-ray and MRI are essential in diagnostics. CT examination is more useful to estimate periosteal reactions and destruction of bone and marrow cavity, especially in flat bones. However, to recognise a malignancy, it is necessary to perform a histopathological examination. In doubtful cases, the examination has to be verified as well.

Kuleta-Bosak, Elzbieta; Kluczewska, Ewa; Machnik-Broncel, Joanna; Madziara, Wojciech; Ciupinska-Kajor, Monika; Sojka, Dorota; Rogala, Wojciech; Juszczyk, Jan; Wilk, Robert

2010-01-01

312

Prognostic Factors for Patients with Ewing sarcoma (EWS) at First Recurrence Following Multimodality Therapy - A Report from the Children's Oncology Group  

PubMed Central

Background The prognosis for patients with recurrent Ewing sarcoma is very poor with 5-year survival of 13%. Methods To evaluate prognostic factors for these patients we studied patients initially treated on the multi-institutional study INT0091. Results Two hundred and sixty-two patients experienced disease recurrence. The median time to first recurrence was 1.3 years (0 to 7.4 years), 1.4 years (0 to 7.4 years) for patients with initially localized disease and 1 year (0 to 6 years) for patients with initially metastatic disease. Time to first recurrence from date of initial diagnosis was a predictor of post-recurrence survival (p<0.0001). Twenty-one percent of patients, with recurrent or progressive disease ? 2 years from initial diagnosis, had an estimated 5 year survival of 30% (vs. 7% estimated 5 year survival with an earlier recurrence). No statistical difference was detected between patients whose disease recurred < 1 year and between 1–2 years from initial diagnosis. A stepwise relative risk model and backwards stepwise regression was used to explore factors significantly associated with risk for post-recurrence death. Significant risk factors for death after recurrence included recurrence at combined local and distant sites, elevated LDH at initial diagnosis and initial recurrence less than two years after diagnosis. Isolated pulmonary recurrence was not predictive of survival after recurrence. Conclusion Patients with a longer disease control interval represent the subset of patients most likely to survive following recurrence of Ewing sarcoma. All patients with recurrence would benefit from collaborative trials to investigate new therapeutic options.

Leavey, Patrick J.; Mascarenhas, Leo; Marina, Neyssa; Chen, Zhengjia; Krailo, Mark; Miser, James; Brown, Ken; Tarbell, Nancy; Bernstein, Mark L.; Granowetter, Linda; Gebhardt, Mark; Grier, Holcombe E.

2009-01-01

313

Intraoral use of extraoral implants for oral rehabilitation of a pediatric patient after resection of ewing sarcoma of the mandible and reconstruction with iliac osteocutaneous free flap.  

PubMed

Large osseous defects secondary to resection of the mandibular segment may lead to significant facial deformity, functional disabilities, and associated psychologic problems. The therapeutic approach is more complicated in pediatric patients because it must not interfere with normal craniofacial growth process. Here, we present a clinical report to emphasize the application of extraoral short implants with magnetic abutments used for mandible of a growing patient reconstructed with free iliac flap after resection of Ewing sarcoma. A 5-year-old boy, complaining of an ulcerated mass of the anterior mandibular area and floor of the mouth, was referred to our clinic. Incisional biopsy from the lesion confirmed the diagnosis of Ewing sarcoma. After resection, free iliac osteocutaneous flap, with a 6.5 × 4.0-cm skin paddle and based on the deep circumflex iliac vessels, was used to reconstruct the mandibular integrity and to cover the floor of the mouth simultaneously. Nine months after the operation, the patient was referred for oral rehabilitation. Prosthodontic plan included the placement of 5 extraoral implants with magnetic abutment and fabrication of an implant-retained overdenture. Magnetic abutment was preferred not to interfere with the expected craniofacial growth. During a follow-up period, radiographic images showed no pathologic signs with consideration of overall bone loss and recurrence of the tumor; 12 months after the initiation of prosthetic loading, no peri-implant bone loss was observed. In conclusion, this reported case would be an example for the management of challenging pediatric mandibular tumor cases in terms of resection, reconstruction and dental rehabilitation. PMID:24699098

Aksu, Ali Emre; Dursun, Erhan; Calis, Mert; Ersu, Bahadir; Safak, Tunc; Tözüm, Tolga F

2014-05-01

314

Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing's Sarcoma Family Tumors  

PubMed Central

SUMMARY Purpose Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R). Experimental Design Patients received cixutumumab, 6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Median follow up was 8.9 months. Results Twenty patients (17 with Ewing’s sarcoma [EWS], 3 with desmoplastic small-round-cell tumor [DSCRT]) were enrolled). Twelve patients (60%) were men; median age, 24 years; median number of prior systemic therapies in metastatic setting, 6. The most frequent toxicities were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%) (mostly grade 1–2). Seven of 20 patients (35%) achieved stable disease (SD) >5 months or complete/partial (CR/PR) responses. Tumor regression of over 20% (23%, 23%, 27%, 100%, 100%) occurred in 5/17 (29%) patients with EWS, and they remained on study for 8 to 27 months. One of six EWS patients who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR. Four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which was controlled while maintaining drug dose. Conclusion Cixutumumab combined with temsirolimus was well tolerated and showed preliminary evidence of durable antitumor activity in heavily-pretreated EWS family tumors.

Naing, Aung; LoRusso, Patricia; Fu, Siqing; Hong, David S.; Anderson, Pete; Benjamin, Robert S.; Ludwig, Joseph; Chen, Helen X.; Doyle, Laurence A.; Kurzrock, Razelle

2013-01-01

315

Stages of Ewing Sarcoma  

MedlinePLUS

... shrink the tumor before surgery or radiation therapy. Radiation therapy Radiation therapy is a cancer treatment that uses high-energy ... them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the ...

316

RT-PCR evaluation of peripheral blood, bone marrow and peripheral blood stem cells in children and adolescents undergoing VACIME chemotherapy for Ewing's sarcoma and alveolar rhabdomyosarcoma.  

PubMed

Peripheral blood stem cell support allows dose intensification of multiple cycle chemotherapy for metastatic tumors, including pediatric sarcomas. The VACIME protocol (vincristine, adriamycin, cyclophosphamide, ifosfamide, mesna and etoposide) utilizes peripheral blood stem cells (PBSC) collected following the treatment cycle as support for subsequent dose- and time-intensive chemotherapy. A critical assumption is that PBSC collected in this manner will be purged of residual tumor cells in vivo. We tested this assumption using sensitive reverse-transcriptase polymerase chain reaction (RT-PCR) to assess the presence of the characteristic translocations of the Ewing's sarcoma family of tumors (ESFT) and alveolar rhabdomyosarcoma (ARMS), t(11;22), and t(2;13), respectively. We used RT-PCR to evaluate 122 samples of peripheral blood (PB), bone marrow (BM) and PBSC collected from 12 pediatric patients with metastatic ESFT and ARMS. The samples included pre-therapy BM and PB, as well as BM, PB, and PBSC collections at various times in the VACIME treatment course. Molecular evidence of tumor contamination was detected in 1/40 PBSC collections from 12 patients. In all patients, we documented clearance of disease by RT-PCR in peripheral blood and bone marrow by week 9 of the VACIME protocol. In vivo purging in combination with the intensive VACIME regime appears to be effective in removing tumor cells from PBSC, bone marrow, and peripheral blood as detected by RT-PCR. PMID:10482938

Thomson, B; Hawkins, D; Felgenhauer, J; Radich, J

1999-09-01

317

Preliminary Efficacy of the Anti-Insulin-Like Growth Factor Type 1 Receptor Antibody Figitumumab in Patients With Refractory Ewing Sarcoma  

PubMed Central

Purpose Patients with Ewing sarcoma (ES) with metastases and those who relapse fare poorly and receive therapies that carry significant toxicity. This phase 1/2 study was conducted to evaluate the efficacy of figitumumab in advanced ES. Patients and Methods Patients with sarcoma 10 to 18 years old were enrolled in two dose escalation cohorts (20 and 30 mg/Kg intravenously every 4 weeks) in the phase 1 portion of the study. Patients with ES 10 years old or older were enrolled in the phase 2 portion of the study. The primary phase 2 objective was objective response rate (ORR). Results Thirty-one patients with ES (n = 16), osteosarcoma (n = 11), or other sarcomas (n = 4) were enrolled in the phase 1 portion of the study. Dose escalation proceeded to 30 mg/kg every 4 weeks with no dose-limiting toxicity identified. In the phase 2 portion of the study, 107 patients with ES received figitumumab at 30 mg/kg every 4 weeks for a median of 2 cycles (range, 1 to 16). Sixty three percent of phase 2 patients had received at least three prior treatment regimens. Of 106 evaluable patients, 15 had a partial response (ORR, 14.2%) and 25 had stable disease. Median overall survival was 8.9 months. Importantly, patients with a pretreatment circulating free insulin-like growth factor (IGF) -1 lower than 0.65 ng/mL (n = 14) had a median OS of 3.6 months, whereas those with a baseline free IGF-1 ? 0.65 ng/mL (n = 84) had a median OS of 10.4 months (P < .001). Conclusion Figitumumab had modest activity as single agent in advanced ES. A strong association between pretreatment serum IGF-1 and survival benefit was identified.

Juergens, Heribert; Daw, Najat C.; Geoerger, Birgit; Ferrari, Stefano; Villarroel, Milena; Aerts, Isabelle; Whelan, Jeremy; Dirksen, Uta; Hixon, Mary L.; Yin, Donghua; Wang, Tao; Green, Stephanie; Paccagnella, Luisa; Gualberto, Antonio

2011-01-01

318

The dual inhibitory effect of thiostrepton on FoxM1 and EWS/FLI1 provides a novel therapeutic option for Ewing's sarcoma  

PubMed Central

The poor prognosis of Ewing’s sarcoma (EWS), together with its high lethal recurrence rate and the side-effects of current treatments, call for novel targeted therapies with greater curative effectiveness and substantially reduced side-effects. The oncogenic chimeric protein EWS/FLI1 is the key malignancy driver in most EWSs, regulating numerous target genes, many of which influence cell cycle progression. It has often been argued that targeting proteins regulated directly or indirectly by EWS/FLI1 may provide improved therapeutic options for EWS. In this context, our study examined FoxM1, a key cell cycle regulating transcription factor, reported to be expressed in EWS and influenced by EWS/FLI1. Thiostrepton, a naturally occurring small molecule, has been shown to selectively inhibit FoxM1 expression in cancer cells. We demonstrate that in EWS, in addition to inhibiting FoxM1 expression, thiostrepton downregulates the expression of EWS/FLI1, both at the mRNA and protein levels, leading to cell cycle arrest and, ultimately, to apoptotic cell death. We also show that thiostrepton treatment reduces the tumorigenicity of EWS cells, significantly delaying the growth of nude mouse xenograft tumors. Results from this study demonstrate a novel action of thiostrepton as inhibitor of the expression of the EWS/FLI1 oncoprotein in vitro and in vivo, and that it shows greater efficacy against EWS than against other tumor types, as it is active on EWS cells and tumors at concentrations lower than those reported to have effective inhibitory activity on tumor cells derived from other cancers. Owing to the dual action of this small molecule, our findings suggest that thiostrepton may be particularly effective as a novel agent for the treatment of EWS patients.

SENGUPTA, ANIRUDDHA; RAHMAN, MAHBUBUR; MATEO-LOZANO, SILVIA; TIRADO, OSCAR M.; NOTARIO, VICENTE

2013-01-01

319

?-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing's sarcoma  

PubMed Central

Owing to its essential role in cancer, insulin-like growth factor type 1 receptor (IGF-1R)–targeted therapy is an exciting approach for cancer treatment. However, when translated into clinical trials, IGF-1R–specific antibodies did not fulfill expectations. Despite promising clinical responses in Ewing’s sarcoma (ES) phase I/II trials, phase III trials were discouraging, requiring bedside-to-bench translation and functional reevaluation of the drugs. The anti-IGF-1R antibody figitumumab (CP-751,871; CP) was designed as an antagonist to prevent ligand–receptor interaction but, as with all anti-IGF-1R antibodies, it induces agonist-like receptor down-regulation. We explored this paradox in a panel of ES cell lines and found their sensitivity to CP was unaffected by presence of IGF-1, countering a ligand blocking mechanism. CP induced IGF-1R/?-arrestin1 association with dual functional outcome: receptor ubiquitination and degradation and decrease in cell viability and ?-arrestin1–dependent ERK signaling activation. Controlled ?-arrestin1 suppression initially enhanced CP resistance. This effect was mitigated on further ?-arrestin1 decrease, due to loss of CP-induced ERK activation. Confirming this, the ERK1/2 inhibitor U0126 increased sensitivity to CP. Combined, these results reveal the mechanism of CP-induced receptor down-regulation and characteristics that functionally qualify a prototypical antagonist as an IGF-1R–biased agonist: ?-arrestin1 recruitment to IGF-1R as the underlying mechanism for ERK signaling activation and receptor down-regulation. We further confirmed the consequences of ?-arrestin1 regulation on cell sensitivity to CP and demonstrated a therapeutic strategy to enhance response. Defining and suppressing such biased signaling represents a practical therapeutic strategy to enhance response to anti-IGF-1R therapies.

Zheng, Huiyuan; Shen, Hongchang; Oprea, Iulian; Worrall, Claire; Stefanescu, Radu; Girnita, Leonard

2012-01-01

320

Targeting PI3K/Akt represses Hypoxia inducible factor-1? activation and sensitizes Rhabdomyosarcoma and Ewing's sarcoma cells for apoptosis  

PubMed Central

Background Hypoxia inducible factor-1 ? (HIF-1?) has been identified as an important novel target in apoptosis resistance of pediatric tumors such as Rhabdomyosarcoma (RMS) and Ewing’s sarcoma (ES). Evidence suggests that PI3K/Akt signaling plays a role in regulation of HIF-1? activation as well as apoptosis resistance in various adult tumors. However the relevance of PI3K/Akt signaling in HIF-1b? activation and apoptosis resistance in childhood tumors has not been addressed yet. Thus, this study was to investigate whether PI3K/Akt signaling is involved in hypoxia induced activation of HIF-1? as well as in resistance to hypoxia-induced apoptosis in childhood tumors such as RMS and ES. Methods Constitutive activation of PI3K/Akt signaling was analyzed by Western blotting. Hypoxic activation of HIF-1? was determined by Western Blot analysis and electrophoretic mobility shift assay. Apoptosis was determined by flow cytometric analysis of the propidium iodine stained nuclei of cells treated with PI3K inhibitor LY294002 in combination with either TNF-related apoptosis-inducing ligand (TRAIL) or doxorubicin. Results This study demonstrated that PI3K/Akt signaling was constitutively activated in RMS and ES cell lines, A204 and A673, respectively. Targeting PI3K/Akt signaling by the inhibitor LY294002 (30 ?M) significantly decreased the protein expression as well as DNA binding activity of HIF-1? and restored the apoptosis-inducing ability of cells in hypoxia Additionally, pretreatment with LY294002 sensitized A204 and A673 cells to TRAIL or doxorubicin induced apoptosis under hypoxia. Conclusion These results suggest that the constitutively active PI3K/Akt signaling contributes to hypoxic activation of HIF-1? as well as HIF1?-mediated apoptosis resistance in RMS and ES cells under hypoxia.

2013-01-01

321

Depsipeptide (Romidepsin) in Treating Patients With Metastatic or Unresectable Soft Tissue Sarcoma  

ClinicalTrials.gov

Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Malignant Mesenchymoma; Adult Neurofibrosarcoma; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Gastrointestinal Stromal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

2014-06-09

322

The role of surgical margins in treatment of Ewing's sarcoma family tumors: Experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy  

SciTech Connect

Purpose: To evaluate the importance of surgical margins for local and systemic control of Ewing's sarcoma family tumors (ESFT). Methods and Materials: Between 1979 and 1999, 512 patients with ESFTs entered 4 different adjuvant and neoadjuvant studies performed at a single institution. Of these patients, 335 were treated with surgery alone (196) or surgery followed by radiotherapy at doses of 44.8 Gy (139). We compared their outcome with that of the 177 patients who were locally treated by radiotherapy at 60 Gy. Results: Local control (88.8% vs. 80.2%, p < 0.009) and 5-year disease-free survival (63.8% vs. 47.6%, p < 0.0007) were significantly better in patients treated with surgery and, among them, in those with adequate surgical margins (96.6% vs. 71,7%, p < 0.0008, and 69.6% vs. 46.3%, p < 0.0002). Nonetheless, better results were observed only in extremity tumors. Conclusions: Surgery is better than radiotherapy in cases of extremity ESFT with achievable adequate surgical margins, and in cases of inadequate surgical margins, adjuvant reduced-dose radiotherapy is ineffective. Therefore, when inadequate margins are expected, patients are better treated with full-dose radiotherapy from the start.

Bacci, Gaetano [Section of Chemotherapy, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy)]. E-mail: gaetano.bacci@ior.it; Longhi, Alessandra [Section of Chemotherapy, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy); Briccoli, Antonio [Section of Thoracic Surgery, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy); Bertoni, Franco [Laboratory for Pathology, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy); Versari, Michela [Section of Chemotherapy, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy); Picci, Piero [Laboratory for Oncologic Research, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy)

2006-07-01

323

High Expression of Complement Component 5 (C5) at Tumor Site Associates with Superior Survival in Ewing's Sarcoma Family of Tumour Patients  

PubMed Central

Background. Unlike in most adult-onset cancers, an association between typical paediatric neoplasms and inflammatory triggers is rare. We studied whether immune system-related genes are activated and have prognostic significance in Ewing's sarcoma family of tumors (ESFTs). Method. Data analysis was performed on gene expression profiles of 44 ESFT patients, 11 ESFT cell lines, and 18 normal skeletal muscle samples. Differential expression of 238 inflammation and 299 macrophage-related genes was analysed by t-test, and survival analysis was performed according to gene expression. Results. Inflammatory genes are activated in ESFT patient samples, as 38 of 238 (16%) inflammatory genes were upregulated (P < 0.001) when compared to cell lines. This inflammatory gene activation was characterized by significant enrichment of macrophage-related gene expression with 58 of 299 (19%) of genes upregulated (P < 0.001). High expression of complement component 5 (C5) correlated with better event-free (P = 0.01) and overall survival (P = 0.004) in a dose-dependent manner. C5 and its receptor C5aR1 expression was verified at protein level by immunohistochemistry on an independent ESFT tumour tissue microarray. Conclusion. Immune system-related gene activation is observed in ESFT patient samples, and prognostically significant inflammatory genes (C5, JAK1, and IL8) for ESFT were identified.

Savola, Suvi; Klami, Arto; Myllykangas, Samuel; Manara, Cristina; Scotlandi, Katia; Picci, Piero; Knuutila, Sakari; Vakkila, Jukka

2011-01-01

324

EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells  

PubMed Central

Cancer stem cells (CSCs) display plasticity and self-renewal properties reminiscent of normal tissue stem cells, but the events responsible for their emergence remain obscure. We recently identified CSCs in Ewing sarcoma family tumors (ESFTs) and showed that they retain mesenchymal stem cell (MSC) plasticity. In the present study, we addressed the mechanisms that underlie ESFT CSC development. We show that the EWS-FLI-1 fusion gene, associated with 85%–90% of ESFTs and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2, and NANOG in human pediatric MSCs (hpMSCs) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSCs expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWS-FLI-1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene, SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a CSC phenotype.

Riggi, Nicolo; Suva, Mario-Luca; De Vito, Claudio; Provero, Paolo; Stehle, Jean-Christophe; Baumer, Karine; Cironi, Luisa; Janiszewska, Michalina; Petricevic, Tanja; Suva, Domizio; Tercier, Stephane; Joseph, Jean-Marc; Guillou, Louis; Stamenkovic, Ivan

2010-01-01

325

Epithelial cell adhesion molecules and epithelial mesenchymal transition (EMT) markers in Ewing's sarcoma family of tumors (ESFTs). Do they offer any prognostic significance?  

PubMed

Epithelial marker and adhesion molecule expression has been reported in Ewing's sarcoma family of tumors (ESFTs), although the prognostic significance has not been assessed systematically. We performed immunohistochemical analysis of epithelial cell adhesion molecule and epithelial mesenchymal transition markers on 415 genetically confirmed ESFTs. Survival analyses were performed in 217 patients. The atypical histological subtype expressed a high proportion of the epithelial markers compared with conventional and PNET variants. We observed that expression of desmoplakin (p?

Machado, Isidro; López-Guerrero, José A; Navarro, Samuel; Alberghini, Marco; Scotlandi, Katia; Picci, Piero; Llombart-Bosch, Antonio

2012-09-01

326

The Ews/Fli-1 fusion gene switches the differentiation program of neuroblastomas to Ewing sarcoma/peripheral primitive neuroectodermal tumors.  

PubMed

Neuroblastoma (NB) and the Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (PNET) family are pediatric cancers derived from neural crest cells. Although NBs display features of the sympathetic nervous system, ES/PNETs express markers consistent with parasympathetic differentiation. To examine the control of these differentiation markers, we generated NB x ES/PNET somatic cell hybrids. NB-specific markers were suppressed in the hybrids, whereas ES/PNET-specific markers were unaffected. These results suggested that the Ews/Fli-1 fusion gene, resulting from a translocation unique to ES/PNETs, might account for the loss of NB-specific markers. To test this hypothesis, we generated two different NB cell lines that stably expressed the Ews/Fli-1 gene. We observed that heterologous expression of the Ews/Fli-1 protein led to the suppression of NB-specific markers and de novo expression of ES/PNET markers. To determine the extent of changes in differentiation, we used the Affymetrix GeneChip Array system to observe global transcriptional changes of genes. This analysis revealed that the gene expression pattern of the Ews/Fli-1-expressing NB cells resembled that observed in pooled ES/PNET cell lines and differed significantly from the NB parental cells. Therefore, we propose that Ews/Fli-1 contributes to the etiology of ES/PNET by subverting the differentiation program of its neural crest precursor cell to a less differentiated and more proliferative state. PMID:14973077

Rorie, Checo J; Thomas, Venetia D; Chen, Pengchin; Pierce, Heather Hanson; O'Bryan, John P; Weissman, Bernard E

2004-02-15

327

Intra-patient dose escalation in Ewing's sarcoma treated with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide: a retrospective review  

PubMed Central

Background Data suggests that males experience less toxicity and poorer survival than females treated for Ewing’s sarcoma. We instituted an intra-patient dose escalation (DE) policy with Vincristine/Doxorubicin/Cyclophosphamide (VDC) alternating with Ifosfamide/Etoposide (IE) based on hematological nadirs and report its feasibility and safety. Methods A retrospective review of adherence to DE guidelines and toxicities was conducted for patients who received DE with VDC/IE over 3 years at a single cancer center. Absolute neutrophil counts (ANC) was collected on days 8, 12 and 15 for cycles 1–6. DE of 10%/cycle was applied if ANC?>?1.5×109/L and platelet?>?100×109/L on all blood results. The primary endpoint was the proportion of patients who received appropriate DE. The secondary endpoint was to assess morbidity, changes in hematologic nadirs between gender and age and a comparison with a prior cohort of ESFT patients who did not receive DE. Gender comparisons were assessed via independent 2-sample t-tests assuming unequal variances. Within cycle changes in hematologic nadirs were assessed using repeated measures ANOVA. Relapse free survival and overall survival (OS) curves were estimated using the Kaplan-Meier method. Results 23 patients were identified (mean age: 27; range 17–54). 91 decisions for DE were made (1 decision excluded because of progressive disease) with 90% concordance with guidelines. No adverse outcomes occurred as a result of the inappropriate escalation. Grade 3/4 febrile neutropenia (FN) during VDC and IE was 26.1% (6/23 patients) and 17.4% respectively with no difference for those who were DE. Males were less neutropenic after C1 and C3 of VDC compared to females (P-value C1?=?0.003; C3?=?0.005). VDC was associated with greater neutropenia on day 8 whereas IE had greater neutropenia on day 12 (P-value <0.001). During VDC, a non statistical difference in neutropenia was seen for individuals aged 15–25 (n?=?13) compared with older individuals (P-value?=?0.09). OS comparison for those with localized disease with a prior cohort who were not DE showed similar outcomes (P-value?=?0.37). Conclusions DE is deliverable without increased adverse outcomes. Males have less myelosuppression during VDC, and should be especially considered for DE.

2013-01-01

328

Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged ewing sarcomas: further evidence toward distinct pathologic entities.  

PubMed

Round cell sarcomas harboring CIC-DUX4 fusions have recently been described as highly aggressive soft tissue tumors of children and young adults. Due to partial morphologic and immunohistochemical overlap with Ewing sarcoma (ES), CIC-DUX4-positive tumors have generally been classified as ES-like and managed similarly; however, a systematic comparison at the molecular and immunohistochemical levels between these two groups has not yet been conducted. Based on an initial observation that CIC-DUX4-positive tumors show nuclear immunoreactivity for WT1 and ETS transcription factors, FLI1 and ERG, we performed a detailed immunohistochemical and molecular analysis including these markers, to further investigate the relationship between CIC-DUX4 tumors and ES. The study group included 21 CIC-DUX4-positive sarcomas and 20 EWSR1-rearranged ES. Immunohistochemically, CIC-DUX4 sarcomas showed membranous CD99 positivity in 18 (86%) cases, but only 5 (24%) with a diffuse pattern, while WT1 and FLI1 were strongly positive in all cases. ERG was positive in 18% of cases. All ES expressed CD99 and FLI1, while ERG positivity was only seen in EWSR1-ERG fusion positive ES. WT1 was negative in all ES. Expression profiling validated by q-PCR revealed a distinct gene signature associated with CIC-DUX4 fusion, with upregulation of ETS transcription factors (ETV4, ETV1, and ETV5) and WT1, among top overexpressed genes compared to ES, other sarcomas and normal tissue. In conclusion, the distinct gene signature and immunoprofile of CIC-DUX4 sarcomas suggest a distinct pathogenesis from ES. The consistent WT1 expression may provide a useful clue in the diagnosis in the context of round cell sarcomas negative for EWSR1 rearrangement. © 2014 Wiley Periodicals, Inc. PMID:24723486

Specht, Katja; Sung, Yun-Shao; Zhang, Lei; Richter, Günther H S; Fletcher, Christopher D; Antonescu, Cristina R

2014-07-01

329

Soft Tissue Sarcoma in Children  

MedlinePLUS

... most common of which are rhabdomyosarcoma , osteosarcoma and Ewing sarcoma . Each year, approximately 900 children are diagnosed with ... soft tissue sarcoma After treatment for soft tissue sarcoma http://www.curesearch.org/Articleview2.aspx?id=9614 ... CureSearch Contact Us Feedback

330

Use of a fluorescence lifetime imaging microscope in an apoptosis assay of Ewing's sarcoma cells with a vital fluorescent probe.  

PubMed

A fluorescence lifetime imaging microscope (FLIM) was applied to study early-stage apoptotic cells stained with a SYTO13 dye. The fluorescence lifetime of SYTO13 in healthy cells was 3.8+/-0.3ns but was reduced to 2.4+/-0.4 and 1.9+/-0.2ns after a 3-h period of incubation with SYTO13 when doxorubicin, a known inducer of apoptosis, was added to human Ewing's family tumor cells at final concentrations of 250 and 500nM, respectively, in a dose-dependent experiment. On the other hand, in a time-dependent experiment, the fluorescence lifetime decreased to 2.5+/-0.5 and 1.7+/-0.4ns at a doxorubicin concentration of 750nM after 2 and 4h, respectively. A possible explanation for these results is self-quenching induced by a change in interprobe distance that arises from the condensation of DNA during apoptosis. In this study, the FLIM system was employed to investigate early-stage apoptosis that involves only small morphological changes, suggesting the potential advantage of this method for evaluating small biological effects in living cells. PMID:17543878

Li, Xu; Uchimura, Tomohiro; Kawanabe, Satoshi; Imasaka, Totaro

2007-08-15

331

The dual inhibitory effect of thiostrepton on FoxM1 and EWS/FLI1 provides a novel therapeutic option for Ewing's sarcoma.  

PubMed

The poor prognosis of Ewing's sarcoma (EWS), together with its high lethal recurrence rate and the side?effects of current treatments, call for novel targeted therapies with greater curative effectiveness and substantially reduced side?effects. The oncogenic chimeric protein EWS/FLI1 is the key malignancy driver in most EWSs, regulating numerous target genes, many of which influence cell cycle progression. It has often been argued that targeting proteins regulated directly or indirectly by EWS/FLI1 may provide improved therapeutic options for EWS. In this context, our study examined FoxM1, a key cell cycle regulating transcription factor, reported to be expressed in EWS and influenced by EWS/FLI1. Thiostrepton, a naturally occurring small molecule, has been shown to selectively inhibit FoxM1 expression in cancer cells. We demonstrate that in EWS, in addition to inhibiting FoxM1 expression, thiostrepton downregulates the expression of EWS/FLI1, both at the mRNA and protein levels, leading to cell cycle arrest and, ultimately, to apoptotic cell death. We also show that thiostrepton treatment reduces the tumorigenicity of EWS cells, significantly delaying the growth of nude mouse xenograft tumors. Results from this study demonstrate a novel action of thiostrepton as inhibitor of the expression of the EWS/FLI1 oncoprotein in vitro and in vivo, and that it shows greater efficacy against EWS than against other tumor types, as it is active on EWS cells and tumors at concentrations lower than those reported to have effective inhibitory activity on tumor cells derived from other cancers. Owing to the dual action of this small molecule, our findings suggest that thiostrepton may be particularly effective as a novel agent for the treatment of EWS patients. PMID:23857410

Sengupta, Aniruddha; Rahman, Mahbubur; Mateo-Lozano, Silvia; Tirado, Oscar M; Notario, Vicente

2013-09-01

332

High-dose chemotherapy and autologous peripheral blood stem cell transplantation in the treatment of children and adolescents with Ewing sarcoma family of tumors  

PubMed Central

Purpose We performed a pilot study to determine the benefit of high-dose chemotherapy and autologous peripheral blood stem cell transplantation (HDCT/autoPBSCT) for patients with Ewing sarcoma family of tumors. Methods We retrospectively analyzed the data of patients who received HDCT/autoPBSCT at Korea Cancer Center Hospital. Patients with relapsed, metastatic, or centrally located tumors were eligible for the study. Results A total of 9 patients (3 male, 6 female), with a median age at HDCT/autoPBSCT of 13.4 years (range, 7.1 to 28.2 years), were included in this study. Patients underwent conventional chemotherapy and local control either by surgery or radiation therapy, and had achieved complete response (CR, n=7), partial response (n=1), or stable disease (n=1) prior to HDCT/autoPBSCT. There was no transplant-related mortality. However, the median duration of overall survival and event-free survival after HDCT/autoPBSCT were 13.3 months (range, 5.3 to 44.5 months) and 6.2 months (range, 2.1 to 44.5 months), respectively. At present, 4 patients are alive and 5 patients who experienced adverse events (2 metastasis, 2 local recur, and 1 progressive disease) survived for a median time of 2.8 months (range, 0.1 to 10.7 months). The 2-year survival after HDCT/autoPBSCT was 44.4%±16.6% and disease status at the time of HDCT/autoPBSCT tended to influence survival (57.1%±18.7% of cases with CR vs. 0% of cases with non-CR, P=0.07). Conclusion Disease status at HDCT/autoPBSCT tended to influence survival. Further studies are necessary to define the role of HDCT/autoPBSCT and to identify subgroup of patients who might benefit from this investigational treatment.

Seo, Juhee; Kim, Dong Ho; Lim, Jung Sub; Koh, Jae-Soo; Yoo, Ji Young; Kong, Chang-Bae; Song, Won Seok; Cho, Wan Hyeong; Jeon, Dae-Geun; Lee, Soo-Yong

2013-01-01

333

Prognostic factors and clinical outcome of patients with Ewing's sarcoma family of tumors in adults: multicentric study of the Anatolian Society of Medical Oncology.  

PubMed

The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with Ewing sarcoma family of tumors (ESFT). Data of patients with ESFTs followed up at different cancer centers in Turkey between 2001 and 2010 were retrospectively analyzed. The median age of 114 patients was 26 years (range 14-66). The median follow-up was 20 months (range 1-118 months). Tumor size was between 1.5 and 14 cm (median 8 cm). Eighty-six percent of patients had localized disease at presentation, and 14 % had metastatic disease. Local therapy was surgery alone in 31 % of patients, surgery combined with radiotherapy in 41 % and radiotherapy alone in 18 %. Approximately 70 % of patients were treated with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, alternating with ifosfamide and etoposide every 3 weeks. In patients with localized disease at presentation, the 5-year disease-free survival and overall survival were 60 and 65 %, respectively. At univariate analysis, patients with tumor size ? 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size ? 8 cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. ESFTs are aggressive tumors with a high incidence of local recurrence and distant metastasis. Multimodality treatment consisting of adequate surgical resection, aggressive chemotherapy (VAC alternating with IE) and radiotherapy is recommended for patients with ESFTs. PMID:23345116

Arpaci, Erkan; Yetisyigit, Tarkan; Seker, Metin; Uncu, Dogan; Uyeturk, Ummugul; Oksuzoglu, Berna; Demirci, Umut; Coskun, Ugur; Kucukoner, Mehmet; Is?kdogan, Abdurrahman; Inanc, Mevlude; Alkis, Necati; Ozkan, Metin

2013-03-01

334

?-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing's sarcoma.  

PubMed

Owing to its essential role in cancer, insulin-like growth factor type 1 receptor (IGF-1R)-targeted therapy is an exciting approach for cancer treatment. However, when translated into clinical trials, IGF-1R-specific antibodies did not fulfill expectations. Despite promising clinical responses in Ewing's sarcoma (ES) phase I/II trials, phase III trials were discouraging, requiring bedside-to-bench translation and functional reevaluation of the drugs. The anti-IGF-1R antibody figitumumab (CP-751,871; CP) was designed as an antagonist to prevent ligand-receptor interaction but, as with all anti-IGF-1R antibodies, it induces agonist-like receptor down-regulation. We explored this paradox in a panel of ES cell lines and found their sensitivity to CP was unaffected by presence of IGF-1, countering a ligand blocking mechanism. CP induced IGF-1R/?-arrestin1 association with dual functional outcome: receptor ubiquitination and degradation and decrease in cell viability and ?-arrestin1-dependent ERK signaling activation. Controlled ?-arrestin1 suppression initially enhanced CP resistance. This effect was mitigated on further ?-arrestin1 decrease, due to loss of CP-induced ERK activation. Confirming this, the ERK1/2 inhibitor U0126 increased sensitivity to CP. Combined, these results reveal the mechanism of CP-induced receptor down-regulation and characteristics that functionally qualify a prototypical antagonist as an IGF-1R-biased agonist: ?-arrestin1 recruitment to IGF-1R as the underlying mechanism for ERK signaling activation and receptor down-regulation. We further confirmed the consequences of ?-arrestin1 regulation on cell sensitivity to CP and demonstrated a therapeutic strategy to enhance response. Defining and suppressing such biased signaling represents a practical therapeutic strategy to enhance response to anti-IGF-1R therapies. PMID:23188799

Zheng, Huiyuan; Shen, Hongchang; Oprea, Iulian; Worrall, Claire; Stefanescu, Radu; Girnita, Ada; Girnita, Leonard

2012-12-11

335

Loss of connexin43 expression in Ewing's sarcoma cells favors the development of the primary tumor and the associated bone osteolysis.  

PubMed

Ewing's sarcoma (ES) is a primary bone tumor characterized by a chromosomic translocation between the EWS gene and a member of the ETS gene family, mainly FLI1, which leads to an aberrant transcription factor EWS-FLI1 that promotes tumorigenicity. Gap junctions are intercellular channels composed of transmembrane proteins (connexin: Cx), that allow direct intercellular communication between adjacent cells. Numerous studies have shown that tumorigenesis may be associated with a loss of gap junctional intercellular communication (GJIC). Loss of Cx43 expression was observed at the protein and mRNA levels in ES cell lines compared to those measured in human mesenchymal stem cells. A673 ES cells stably transfected with an shRNA targeting EWS-FLI1 showed an increase in Cx43 expression (at the mRNA, protein and transcriptional levels) and GJIC. In an osteolytic murine model of ES, the overexpression of Cx43 in ES cells dramatically reduced tumor growth, leading to a significant increase in animal survival. In vitro assays showed that Cx43 overexpression increases the p27 level with an associated marked decrease of Rb phosphorylation, consistent with the observed blockade of the cell cycle in G0/G1 phase. In addition, the bone microarchitectural parameters, assessed by micro-CT analysis, showed an increased bone volume when Cx43 expression was enhanced. Histological analysis demonstrated that the overexpression of Cx43 in ES tumor cells inhibits osteoclast activity and therefore bone resorption. Our study demonstrated that the loss of Cx43 expression in ES cells plays a crucial role in the development of the primary tumor and the associated bone osteolysis. PMID:23313578

Talbot, Julie; Brion, Régis; Picarda, Gaëlle; Amiaud, Jérome; Chesneau, Julie; Bougras, Gwenola; Stresing, Verena; Tirode, Franck; Heymann, Dominique; Redini, Françoise; Verrecchia, Franck

2013-04-01

336

Central Nervous System Involvement in Children with Sarcoma  

Microsoft Academic Search

Objectives: To summarize and analyze the experience in CNS involvement (CNSI) in children with sarcomas treated in the above-mentioned institutions. Patients and Methods: From 1990 to 2001, all medical charts were retrospectively reviewed: 19 sarcoma patients (12 boys and 7 girls) were diagnosed with CNSI (4 osteogenic sarcomas, 11 Ewing sarcomas, 2 rhabdomyosarcomas, 1 alveolar soft part sarcoma and 1

S. Postovsky; S. Ash; I. N. Ramu; Y. Yaniv; R. Zaizov; B. Futerman; R. Elhasid; A. Ben Barak; A. Halil; M. W. Ben Arush

2003-01-01

337

Formation and Rupture of the Internal Carotid Artery Aneurysm after Multiple Courses of Intensity-Modulated Radiation Therapy for Management of the Skull Base Ewing Sarcoma/PNET: Case Report  

PubMed Central

Background?Aneurysm formation after stereotactic irradiation of skull base tumors is rare. The formation and rupture of an internal carotid artery (ICA) aneurysm in a patient with skull base Ewing sarcoma/primitive neuroectodermal tumor (PNET), who underwent surgery followed by multiple courses of intensity-modulated radiation therapy (IMRT) and chemotherapy, is described. Case Description?A 25-year-old man presented with a sinonasal tumor with intraorbital and intracranial growth. At that time cerebral angiography did not reveal any vascular abnormalities. The lesion was resected subtotally. Histopathologic diagnosis was Ewing sarcoma/PNET. The patient underwent multiple courses of chemotherapy and three courses of IMRT at 3, 28, and 42 months after initial surgery. The total biologically effective dose delivered to the right ICA was 220.2 Gy. Seven months after the third IMRT, the patient experienced profound nasal bleeding that resulted in hypovolemic shock. Angiography revealed a ruptured right C4–C5 aneurysm and irregular stenotic changes of the ICA. Lifesaving endovascular trapping of the right ICA was done. The patient recovered well after surgery but died due to tumor recurrence 6 months later. Conclusion?Excessive irradiation of the ICA may occasionally result in aneurysm formation, which should be borne in mind during stereotactic irradiation of malignant skull base tumors.

Tamura, Manabu; Kogo, Kasei; Masuo, Osamu; Oura, Yoshinori; Matsumoto, Hiroyuki; Fujita, Koji; Nakao, Naoyuki; Uematsu, Yuji; Itakura, Toru; Chernov, Mikhail; Hayashi, Motohiro; Muragaki, Yoshihiro; Iseki, Hiroshi

2013-01-01

338

Targeted therapy for sarcomas.  

PubMed

Sarcomas are tumors of mesenchymal origin that make up approximately 1% of human cancers. They may arise as primary tumors in either bone or soft tissue, with approximately 11,280 soft tissue tumors and 2,650 bone tumors diagnosed each year in the United States. There are at least 50 different subtypes of soft tissue sarcoma, with new ones described with ever-increasing frequency. One way to look at sarcomas is to divide them into categories on the basis of their genetic make-up. One group of sarcomas has an identifiable, relatively simple genetic signature, such as the X:18 translocation seen in synovial sarcoma or the 11:22 translocation seen in Ewing's sarcoma. These specific abnormalities often lead to the presence of fusion proteins, such as EWS-FLI1 in Ewing's sarcoma, which are helpful as diagnostic tools and may become therapeutic targets in the future. Another group of sarcomas is characterized by complex genetic abnormalities as seen in leiomyosarcoma, osteosarcoma, and undifferentiated sarcoma. It is important to keep these distinctions in mind when contemplating the development of targeted agents for sarcomas. Different abnormalities in sarcoma could be divided by tumor subtype or by the molecular or pathway abnormality. However, some existing drugs or drugs in development may interfere with or alter more than one of the presented pathways. PMID:24669185

Forscher, Charles; Mita, Monica; Figlin, Robert

2014-01-01

339

General Information about Ewing Sarcoma  

MedlinePLUS

... a doctor who specializes in treating children with cancer. The pediatric oncologist works with other health care providers who ... Pediatrician . Surgical oncologist or orthopedic oncologist . Radiation oncologist . Pediatric nurse ... Some cancer treatments cause side effects months or years after ...

340

Insulin-Like Growth Factor 1 Receptor as a Therapeutic Target in Ewing Sarcoma: Lack of Consistent Upregulation or Recurrent Mutation and a Review of the Clinical Trial Literature  

PubMed Central

The insulin-like growth factor 1 receptor (IGF-1R) has been considered an important therapeutic target in Ewing sarcoma (ES), generating a need to identify the subset of patients most likely to respond to IGF-1R inhibitors. We assessed IGF-1R expression in ES cell lines and patient tumors to understand the variable clinical responses to anti-IGF-1R therapy. Using ligand-binding displacement, we measured between 13,000 and 40,000 receptors per cell in ES cell lines. We used ELISA to quantify IGF-1R in patient tumors, which expressed 4.8%??± 3.7 to 20.0%??± 0.2 of the levels in a positive control cell line overexpressing IGF-1R. Flow cytometry showed markedly reduced IGF-1R expression in ES cell lines compared to a standard positive control cell line. The IGF1R gene was sequenced in 47 ES tumor samples and 8 ES cell lines; only one tumor sample showed a nonsynonymous mutation, R1353H, in a region with low functional impact. Finally, we assessed IGF-1R pathway activity in the ES stem cell (ESSC) population, to characterize its potential for resistance to anti-IGF-1R therapy, using Luminex technology. We found no significant differences in IGF-1R pathway activity between ESSCs and the total cell population. Overall, our findings suggest that IGF-1R as a therapeutic target in this sarcoma may require reevaluation.

O'Neill, Alison; Shah, Nilay; Zitomersky, Naamah; Ladanyi, Marc; Shukla, Neerav; Uren, Aykut; Loeb, David; Toretsky, Jeffrey

2013-01-01

341

Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma  

ClinicalTrials.gov

Childhood Alveolar Soft-part Sarcoma; Childhood Angiosarcoma; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Gliosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Neurofibrosarcoma; Childhood Synovial Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Osteosarcoma

2014-06-16

342

RT-PCR evaluation of peripheral blood, bone marrow and peripheral blood stem cells in children and adolescents undergoing VACIME chemotherapy for Ewing’s sarcoma and alveolar rhabdomyosarcoma  

Microsoft Academic Search

Peripheral blood stem cell support allows dose intensification of multiple cycle chemotherapy for metastatic tumors, including pediatric sarcomas. The VACIME protocol (vincristine, adriamycin, cyclophosphamide, ifosfamide, mesna and etoposide) utilizes peripheral blood stem cells (PBSC) collected following the treatment cycle as support for subsequent dose- and time-intensive chemotherapy. A critical assumption is that PBSC collected in this manner will be purged

B Thomson; D Hawkins; J Felgenhauer; JP Radich

1999-01-01

343

Expression of C-kit in Ewing Family of Tumors: A Comparison of Different Immunohistochemical Protocols  

Microsoft Academic Search

Ewing sarcoma is a small round blue cell tumor with a high incidence of metastasis and poor survival. The tyrosine kinase receptor, c-kit, is a growth factor receptor that is expressed in a variety of tumors including Ewing sarcoma. Blockade of c-kit by imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ) has been successfully used in the treatment of

Atif Ahmed; Enid Gilbert-Barness; Atilano Lacson

2004-01-01

344

Fenretinide Cytotoxicity for Ewing's Sarcoma and Primitive Neuroectodermal Tumor Cell Lines Is Decreased by Hypoxia and Synergistically Enhanced by Ceramide Modulators  

Microsoft Academic Search

Patients with disseminated Ewing's family of tumors (ESFT) often experience drug-resistant relapse. We hypothesize that targeting minimal residual disease with the cytotoxic retinoid N-(4-hydroxyphenyl) reti- namide (4-HPR; fenretinide) may decrease relapse. We determined the following: (a) 4-HPR cytotoxicity against 12 ESFT cell lines in vitro ;( b) whether 4-HPR increased ceramide species (saturated and desaturated ceramides); (c) whether physiological hypoxia

Sandeep Batra; C. Patrick Reynolds; Barry J. Maurer

2004-01-01

345

74. Specific Delivery of hTRAIL and Inhibition of Ewing's Sarcoma Growth by Transplantation of Viral Vector-Transduced Bone Marrow-Derived Mesenchymal Stem Cells (MSC)  

Microsoft Academic Search

For the majority of pediatric patients with soft tissue tumors, some form of selective systemic therapy is required. Here we show that bone marrow-derived non-hematopoietic mesenchymal stem cells (MSCs) integrate into pediatrics soft tissue sarcoma xenografts as stromal fibroblasts. Importantly, exogenously administered MSC preferentially engraft at the sites of disseminated tumor nodules throughout the body. These findings suggest the development

Jeffrey S. Bartlett; Wenfang Shi; Carmel Lawrencia

2005-01-01

346

Imaging pediatric bone sarcomas.  

PubMed

Primary malignant bone tumors are rare and account for about 6% of all new pediatric cancer cases per year in the United States. Identification of the lesion not uncommonly occurs as a result of imaging performed for trauma. Clinical and standard imaging characteristics of the various tumor types are evolving in concert with treatment advancements and clinical trial regimens. This article reviews the 3 most common pediatric bone sarcomas-osteosarcoma, Ewing sarcoma, and chondrosarcoma-and their imaging as applicable to contemporary disease staging and monitoring, and explores the roles of evolving imaging techniques. PMID:21807172

Kaste, Sue C

2011-07-01

347

Targeted therapies for bone sarcomas  

PubMed Central

Bone sarcomas include a very large number of tumour subtypes, which originate form bone and more particularly from mesenchymal stem cell lineage. Osteosarcoma, Ewing's sarcoma and chondrosarcoma, the three main bone sarcoma entities develop in a favourable microenvironment composed by bone cells, blood vessels, immune cells, based on the ‘seed and soil theory'. Current therapy associates surgery and chemotherapy, however, bone sarcomas remain diseases with high morbidity and mortality especially in children and adolescents. In the past decade, various new therapeutic approaches emerged and target the tumour niche or/and directly the tumour cells by acting on signalling/metabolic pathways involved in cell proliferation, apoptosis or drug resistance. The present review gives a brief overview from basic to clinical assessment of the main targeted therapies of bone sarcoma cells.

Heymann, Dominique; Redini, Francoise

2013-01-01

348

[Soft tissue sarcoma: postoperative chemotherapy].  

PubMed

In high-grade musculoskeletal sarcomas, adjuvant chemotherapy is often performed to prevent distant metastases. The efficacy of chemotherapy varies according to the histological type of sarcoma. Prognoses are poor in patients with osteosarcoma, Ewing's sarcoma, or rhabdomyosarcoma, when surgery alone is performed. However, because these sarcomas are chemosensitive, their prognoses are improved with adjuvant chemotherapy. On the other hand, the efficacy of chemotherapy is not statistically demonstrated in non-round cell sarcomas, e. g., malignant fibrous histiocytoma. Nowadays, several kinds of antitumor agents are usually used for adjuvant chemotherapy, and many authors have reported various kinds of regimens and their clinical results. Commonly used drugs include adriamycin, ifosfamide, cisplatin, methotrexate, cyclophosphamide, dacarbazine, vincristine, and actinomycin-D. Recently, high-dose chemotherapy combined with autologous peripheral blood or bone marrow stem cell transplantation has been begun in patients who do not respond to standard chemotherapy, and a better prognosis is expected. PMID:15446551

Goto, Takahiro; Kosaku, Hidemi; Kobayashi, Hiroshi; Hozumi, Takahiro; Kondo, Taiji

2004-09-01

349

Analysis of Prognostic Factors of Pediatric-Type Sarcomas in Adult Patients  

Microsoft Academic Search

Objective: Pediatric-type sarcomas such as Ewing’s sarcoma (EWS)\\/primitive neuroectodermal tumor family and rhabdomyosarcoma are relatively uncommon in adult patients. Optimal treatment strategies for this population and prognosis in adult patients compared with pediatric patients remain controversial. Methods: We retrospectively reviewed pediatric-type sarcoma patients older than 15 years at a single institution. Results: A total of 84 consecutive patients between 1995

Hee Kyung Ahn; Ji Eun Uhm; Jeeyun Lee; Do Hoon Lim; Sung Wook Seo; Ki-Sun Sung; Su Jin Lee; Duk Joo Lee; Kyung Kee Baek; Won-Seog Kim; Joon Oh Park

2011-01-01

350

[Radiotherapy and Ewing tumor in children].  

PubMed

Despite high local control rate in Ewing's sarcoma the exact indication of radiation therapy is still controversial as well as the choice of the target volume and the optimal dose of radiation. The importance of the quality of radiotherapy has been stressed in recently published data and has shown a significant impact on long term local control with adequate radiation therapy. The dramatic improvement of precision allowed by the conformal therapy and three dimensional dosimetry allow to expect a decrease of late effects expected for second malignancies. However, late sequellae and radio-induced osteosarcoma still remain the major side effects after radiotherapy. The authors discuss the results of the main trials on Ewing's sarcoma on the choice of dose and target volume. Surgery is still the preferred choice for small tumors if the foreseen outcome is identical. PMID:7549114

Carrie, C; Helfre, S; Bouffet, E; Brunat-Mentigny, M

1995-07-01

351

Endosialin expression in side populations in human sarcoma cell lines.  

PubMed

The Hoechst 33342 exclusion side population (SP) assay is a validated method used to identify cells with stem cell-like properties. When isolated from tumors, SP cells have been shown to have high malignant potential. SPs have been found in both carcinomas and sarcomas. The molecular profile of sarcoma SP is poorly understood. The purpose of the present study was to determine whether endosialin is a suitable therapeutic target for sarcomas. Six cell lines (HT-1080 fibrosarcoma, SJSA-1 and HOS osteosarcoma, A-673 and SK-ES-1 Ewing sarcoma) were used for the SP analysis. Flow cytometry was used to count and examine the cells. Results showed for the first time that endosialin (CD248), which was previously identified as a sarcoma marker, is expressed in sarcoma SP cells. This observation supports the hypothesis that endosialin is a promising therapeutic target for sarcomas. PMID:22740905

Rouleau, Cecile; Sancho, Jose; Campos-Rivera, Juanita; Teicher, Beverly A

2012-02-01

352

Cancer stem cells in pediatric sarcomas.  

PubMed

Sarcomas represent a clinically and biologically diverse group of malignant connective tissue tumors. Despite aggressive conventional therapy, a large proportion of sarcoma patients experience disease recurrence which will ultimately result in mortality. The presence of a unique population of cells, referred to as cancer stem cells (CSCs), have been proposed to be responsible for refractory responses to current chemotherapies as well underlying the basis for metastasis and relapse of disease - clinical corollaries to what has been termed the CSC hypothesis. The presence of CSCs have been suggested in a variety of hematologic and solid malignancies, and only more recently in sarcomas. Based on our current understanding of normal stem cell biology and evidence obtained from the study of malignant hematopoietic and solid tumors, researchers have identified candidate cell surface markers (CD133, CD117, Stro-1), biochemical markers (aldehyde dehydrogenase activity), and cytological characteristics (side population and spherical colony formation) that may identify putative sarcoma CSCs. In this review, we explore the current state of evidence that may suggest the existence of sarcoma CSCs. We present research in osteosarcoma, the Ewing's sarcoma family of tumors, rhabdomyosarcoma, as well as other sarcoma subtypes to describe commonly used molecular and biochemical markers, as well as techniques, used in the identification, isolation, and characterization of candidate sarcoma CSCs. We will also discuss the current controversies and challenges that face research in sarcoma CSC. PMID:23819111

Dela Cruz, Filemon S

2013-01-01

353

Molecular classification of soft tissue sarcomas and its clinical applications  

PubMed Central

Sarcomas are a heterogeneous group of tumors that are traditionally classified according to the morphology and type of tissue that they resemble, such as rhabdomyosarcoma, which resembles skeletal muscle. However, the cell of origin is unclear in numerous sarcomas. Molecular genetics analyses have not only assisted in understanding the molecular mechanism in sarcoma pathogenesis but also demonstrated new relationships within different types of sarcomas leading to a more proper classification of sarcomas. Molecular classification based on the genetic alteration divides sarcomas into two main categories: (i) sarcomas with specific genetic alterations; which can further be subclassified based on a) reciprocal translocations resulting in oncogenic fusion transcripts (e.g. EWSR1-FLI1 in Ewing sarcoma) and b) specific oncogenic mutations (e.g. KIT and PDGFRA mutations in gastrointestinal stromal tumors) and (ii) sarcomas displaying multiple, complex karyotypic abnormalities with no specific pattern, including leiomyo-sarcoma, and pleomorphic liposarcoma. These specific genetic alterations are an important adjunct to standard morphological and immunohistochemical diagnoses, and in some cases have a prognostic value, e. g., Ewing family tumors, synovial sarcoma, and alveolar rhabdomyosarcoma. In addition, these studies may also serve as markers to detect minimal residual disease and can aid in staging or monitor the efficacy of therapy. Furthermore, sarcoma-specific fusion genes and other emerging molecular events may also represent potential targets for novel therapeutic approaches such as Gleevec for dermatofibrosarcoma protuberans. Therefore, increased understanding of the molecular biology of sarcomas is leading towards development of newer and more effective treatment regimens. The review focuses on recent advances in molecular genetic alterations having an impact on diagnostics, prognostication and clinical management of selected sarcomas.

Jain, Shilpa; Xu, Ruliang; Prieto, Victor G; Lee, Peng

2010-01-01

354

Molecular classification of soft tissue sarcomas and its clinical applications.  

PubMed

Sarcomas are a heterogeneous group of tumors that are traditionally classified according to the morphology and type of tissue that they resemble, such as rhabdomyosarcoma, which resembles skeletal muscle. However, the cell of origin is unclear in numerous sarcomas. Molecular genetics analyses have not only assisted in understanding the molecular mechanism in sarcoma pathogenesis but also demonstrated new relationships within different types of sarcomas leading to a more proper classification of sarcomas. Molecular classification based on the genetic alteration divides sarcomas into two main categories: (i) sarcomas with specific genetic alterations; which can further be subclassified based on a) reciprocal translocations resulting in oncogenic fusion transcripts (e.g. EWSR1-FLI1 in Ewing sarcoma) and b) specific oncogenic mutations (e.g. KIT and PDGFRA mutations in gastrointestinal stromal tumors) and (ii) sarcomas displaying multiple, complex karyotypic abnormalities with no specific pattern, including leiomyo-sarcoma, and pleomorphic liposarcoma. These specific genetic alterations are an important adjunct to standard morphological and immunohistochemical diagnoses, and in some cases have a prognostic value, e. g., Ewing family tumors, synovial sarcoma, and alveolar rhabdomyosarcoma. In addition, these studies may also serve as markers to detect minimal residual disease and can aid in staging or monitor the efficacy of therapy. Furthermore, sarcoma-specific fusion genes and other emerging molecular events may also represent potential targets for novel therapeutic approaches such as Gleevec for dermatofibrosarcoma protuberans. Therefore, increased understanding of the molecular biology of sarcomas is leading towards development of newer and more effective treatment regimens. The review focuses on recent advances in molecular genetic alterations having an impact on diagnostics, prognostication and clinical management of selected sarcomas. PMID:20490332

Jain, Shilpa; Xu, Ruliang; Prieto, Victor G; Lee, Peng

2010-01-01

355

Effect of Indirect Nonequilibrium Atmospheric Pressure Plasma on Anti-Proliferative Activity against Chronic Chemo-Resistant Ovarian Cancer Cells In Vitro and In Vivo  

PubMed Central

Purpose Nonequilibrium atmospheric pressure plasma (NEAPP) therapy has recently been focused on as a novel medical practice. Using cells with acquired paclitaxel/cisplatin resistance, we elucidated effects of indirect NEAPP-activated medium (NEAPP-AM) exposure on cell viability and tumor growth in vitro and in vivo. Methods Using chronic paclitaxel/cisplatin-resistant ovarian cancer cells, we applied indirect NEAPP-exposed medium to cells and xenografted tumors in a mouse model. Furthermore, we examined the role of reactive oxygen species (ROS) or their scavengers in the above-mentioned EOC cells. Results We assessed the viability of NOS2 and NOS3 cells exposed to NEAPP-AM, which was prepared beforehand by irradiation with NEAPP for the indicated time. In NOS2 cells, viability decreased by approximately 30% after NEAPP-AM 120-sec treatment (P<0.01). The growth-inhibitory effects of NEAPP-AM were completely inhibited by N-acetyl cysteine treatment, while L-buthionine-[S, R]-sulfoximine, an inhibitor of the ROS scavenger used with NEAPP-AM, decreased cell viability by 85% after NEAPP-AM 60-sec treatment(P<0.05) and by 52% after 120 sec, compared to the control (P<0.01). In the murine subcutaneous tumor-formation model, NEAPP-AM injection resulted in an average inhibition of the NOS2 cell-inoculated tumor by 66% (P<0.05) and NOS2TR cell-inoculated tumor by 52% (P<0.05), as compared with the control. Conclusion We demonstrated that plasma-activated medium also had an anti-tumor effect on chemo-resistant cells in vitro and in vivo. Indirect plasma therapy is a promising treatment option for EOC and may contribute to a better patient prognosis in the future.

Utsumi, Fumi; Kajiyama, Hiroaki; Nakamura, Kae; Tanaka, Hiromasa; Mizuno, Masaaki; Ishikawa, Kenji; Kondo, Hiroki; Kano, Hiroyuki; Hori, Masaru; Kikkawa, Fumitaka

2013-01-01

356

Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways  

SciTech Connect

5-Fluorouracil (5-FU) is one of the widely used chemotherapeutic drugs targeting various cancers, but its chemo-resistance remains as a major obstacle in clinical settings. In the present study, HT-29 colon cancer cells were markedly sensitized to apoptosis by both 5-FU and genistein compared to the 5-FU treatment alone. There is an emerging evidence that genistein, soy-derived phytoestrogen, may have potential as a chemotherapeutic agent capable of inducing apoptosis or suppressing tumor promoting proteins such as cyclooxygenase-2 (COX-2). However, the precise mechanism of cellular cytotoxicity of genistein is not known. The present study focused on the correlation of AMPK and COX-2 in combined cytotoxicity of 5-FU and genistein, since AMPK is known as a primary cellular homeostasis regulator and a possible target molecule of cancer treatment, and COX-2 as cell proliferation and anti-apoptotic molecule. Our results demonstrated that the combination of 5-FU and genistein abolished the up-regulated state of COX-2 and prostaglandin secretion caused by 5-FU treatment in HT-29 colon cancer cells. These appear to be followed by the specific activation of AMPK and the up-regulation of p53, p21, and Bax by genistein. Under same conditions, the induction of Glut-1 by 5-FU was diminished by the combination treatment with 5-FU and genistein. Furthermore, the reactive oxygen species (ROS) was found as an upstream signal for AMPK activation by genistein. These results suggested that the combination of 5-FU and genistein exert a novel chemotherapeutic effect in colon cancers, and AMPK may be a novel regulatory molecule of COX-2 expression, further implying its involvement in cytotoxicity caused by genistein.

Hwang, Jin-Taek [Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University College of Medicine, Seoul 130-701 (Korea, Republic of); Ha, Joohun [Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University College of Medicine, Seoul 130-701 (Korea, Republic of); Park, Ock Jin [Department of Food and Nutrition, Hannam University, 133 Ojeong-dong Daedeok-gu, Daejeon 306-791 (Korea, Republic of)]. E-mail: ojpark@hannam.ac.kr

2005-07-01

357

La TEP\\/TDM au FDG(18F) apparaît plus sensible que la scintigraphie osseuse planaire et tomographique aux bisphosphonates(99mTc) dans la récidive du sarcome d’Ewing à localisations ostéomédullaires. À propos d’une observation de sarcome d’Ewing à localisation initiale mandibulaire et récidive sternale chez un enfant de 13 ans et revue de la littérature  

Microsoft Academic Search

Today, bone scintigraphy still remains a mainstay imaging modality for the baseline work-up, the follow-up and the diagnosis of recurrence by osteomedullary metastases in Ewing's sarcoma (ES). We describe the case of a 13-year-old teenager diagnosed with an Ewing's sarcoma of mandible associated to a right sixth rib metastasis. Initial bone scintigraphy displayed a mandibular hot spot related to the

A. Girma; F. Paycha; P. Carrier; M. Razzouk; A. Deville; M. Piche; C. Boyer; J. Darcourt

2009-01-01

358

Bone Marrow Subsets Differentiate into Endothelial Cells and Pericytes Contributing to Ewing's Tumor Vessels  

PubMed Central

Hematopoietic progenitor cells arising from bone marrow (BM) are known to contribute to the formation and expansion of tumor vasculature. However, whether different subsets of these cells have different roles in this process is unclear. To investigate the roles of BM-derived progenitor cell subpopulations in the formation of tumor vasculature in a Ewing’s sarcoma model, we used a functional assay based on endothelial cell and pericyte differentiation in vivo. Fluorescence-activated cell sorting of human cord blood/BM or mouse BM from gfp-transgenic mice was used to isolate human CD34+/CD38?, CD34+/CD45+, and CD34?/CD45+, and mouse Sca1+/Gr1+, Sca1?/Gr1+, VEGFR1+ and VEGFR2+ cells. Each of these progenitor subpopulations was separately injected intravenously into nude mice bearing Ewing’s sarcoma tumors. Tumors were resected one week later, and analyzed using immunohistochemistry and confocal microscopy for the presence of migrated progenitor cells expressing endothelial, pericyte or inflammatory cell surface markers. We demonstrated two distinct patterns of stem cell infiltration. Human CD34+/CD45+ and CD34+/CD38? and murine VEGFR2+ and Sca1+/Gr1+ cells migrated to Ewing’s tumors, co-localized with the tumor vascular network and differentiated into cells expressing either endothelial markers (mouse CD31 or human vascular endothelial cadherin), or the pericyte markers desmin and ?-smooth muscle actin. By contrast, human CD34?/CD45+ and mouse Sca1?/Gr1+ cells migrated predominantly to sites outside of the tumor vasculature, and differentiated into monocytes/macrophages expressing F4/80 or CD14. Our data indicate that only specific BM stem/progenitor subpopulations participate in Ewing’s sarcoma tumor vasculogenesis.

Reddy, Krishna; Zhou, Zhichao; Schadler, Keri; Jia, Shu-Fang; Kleinerman, Eugenie S.

2008-01-01

359

ERG expression in epithelioid sarcoma: a diagnostic pitfall.  

PubMed

ERG transcription factor is constitutively expressed in endothelial cells. Because benign and malignant vascular endothelia retain the ERG expression, ERG is considered a useful marker for angiosarcomas and related tumors. ERG is also expressed in a subset of prostate carcinomas and Ewing sarcomas due to ERG-involved translocations; therefore, this marker is also of high interest in the study of these malignancies. In this study, we evaluated 109 epithelioid sarcomas for ERG expression, on the basis of an initial observation of an ERG-positive case. We also studied expression of other endothelial antigens in epithelioid sarcoma. ERG was expressed in 38% of epithelioid sarcomas (41/109), usually with a uniform nuclear staining, similar to that seen in angiosarcomas. However, all epithelioid sarcomas were negative for ERG gene rearrangement indicating that ERG expression is not likely related to ERG-involving translocations in epithelioid sarcoma. Other endothelial markers, CD31, claudin 5, and Prox1, were absent in epithelioid sarcomas. The only exception was a pulmonary metastasis of epithelioid sarcoma showing focal CD31 expression, which probably resulted from antigen adsorption onto tumor cell surfaces. However, podoplanin was commonly (7/9) expressed in epithelioid sarcoma; therefore, this marker is not useful in distinguishing epithelioid sarcoma from angiosarcoma. INI1/SMARCB1 gene product was absent in all epithelioid sarcomas (considered here a definitional feature) but was absent from only 1 epithelioid angiosarcoma, indicating its relative specificity for epithelioid sarcoma in this differential diagnostic setting. ERG expression is fairly common in epithelioid sarcoma and should be recognized as a diagnostic pitfall in the differential diagnosis of epithelioid sarcoma and epithelioid angiosarcoma. General lack of endothelial cell-specific markers in epithelioid sarcoma helps in this distinction. PMID:23774169

Miettinen, Markku; Wang, Zengfeng; Sarlomo-Rikala, Maarit; Abdullaev, Ziedulla; Pack, Svetlana D; Fetsch, John F

2013-10-01

360

1982 Maurice Ewing Medalist  

NASA Astrophysics Data System (ADS)

It is a pleasure to present the citation for this year's Maurice Ewing medalist, John Ewing.John was born in Texas and completed his early education there. During or shortly after high school, he spent 1 year working on a farm. Working on a farm included tinkering with tractors, automobiles, and various other machines. John has told me that this one year of fooling around with machines gave him better training in instrumentation than he subsequently obtained at more hallowed institutions, such as Harvard, where he obtained a B.S. degree in physics. John subsequently took some graduate courses at Columbia. At Columbia a course in mathematics for physics students (which was a disguised course in applied quantum mechanics) had to compete for John's attention with adventures at sea with Maurice Ewing. Adventures at sea won out. Joining John in his march out of graduate school were a number of others who went on to become illustrious scientists.

Talwani, Manik

361

Novel peptide binds EWS-FLI1 and reduces the oncogenic potential in Ewing tumors  

PubMed Central

Ewing tumor is driven by the oncogenic EWS-FLI1 fusion protein that functions as an aberrant transcription factor. The identification of EWS-FLI1 protein partners is essential to enhance its vulnerability as a therapeutic target. We utilized phage display library screening against recombinant EWS-FLI1 protein. We identified 27 unique Ewing Sarcoma binding peptides. The cytotoxicity evaluation of these peptides with in EWS-FLI1 containing cell lines yielded one potent peptide called ESAP1 (TMRGKKKRTRAN). ESAP1 binds EWS-FLI1 with 0.202 micromolar affinity as measured in surface plasmon resonance. The minimal interaction region of ESAP1 is characterized and found that the lysine residues are critical for cellular cytotoxicity. ESAP1 reduces the transcriptional activity of EWS-FLI1 as well as disrupts cell cycle kinetics in Ewing tumor cells. These findings provide both a novel experimental probe and a potential therapeutic scaffold for Ewing tumor.

Erkizan, Hayriye V; Scher, Lauren J; Gamble, S Ellen; Barber-Rotenberg, Julie S; Sajwan, Kamal P; Uren, Aykut

2011-01-01

362

Advances in therapy for pediatric sarcomas.  

PubMed

Pediatric sarcomas are relatively rare malignancies individually. As a group they are typically approached with combination chemotherapies in addition to local control. Fortunately, these malignancies have been approached through careful clinical trial collaboration to define risk groups and appropriately deliver local control measures and systemic therapies. Although local disease is typically approached with curative intent, therapy typically lasts over 6 months and has significant associated morbidities. It is more difficult to cure metastatic disease or induce sustained remissions. In this article, we discuss recent advances in the understanding of the disease process and highlight recent and future cooperative group trials in osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, nonrhabdomyosarcoma soft tissue sarcomas, and desmoid tumor as well as discuss promising therapeutic approaches such as epigenetics and immunotherapy. PMID:24894064

Weiss, Aaron; Gill, Jonathan; Goldberg, John; Lagmay, Joanne; Spraker-Perlman, Holly; Venkatramani, Rajkumar; Reed, Damon

2014-08-01

363

High-dose chemotherapy with autologous peripheral blood stem cell transplantation for bone and soft-tissue sarcomas  

Microsoft Academic Search

The role of high-dose chemotherapy (HDCT) with PBSCT in the treatment of bone and soft-tissue sarcomas is not established. In total, 27 patients (15 female, median age at TPL 30.6 years (range: 13–59)) were analyzed (Ewing sarcoma family n=8, osteosarcoma n=6, MPNST (malignant peripheral nerve sheath tumor) n=4, synovial sarcoma n=3, liposarcoma n=2, leiomyosarcoma n=2, rhabdomyosarcoma n=1, meningosarcoma n=1). Following

B Kasper; T Lehnert; L Bernd; G Mechtersheimer; H Goldschmidt; A D Ho; G Egerer

2004-01-01

364

Chromatin H3K27me3/H3K4me3 histone marks define gene sets in high-grade serous ovarian cancer that distinguish malignant, tumour-sustaining and chemo-resistant ovarian tumour cells.  

PubMed

In embryonic stem (ES) cells, bivalent chromatin domains containing H3K4me3 and H3K27me3 marks silence developmental genes, while keeping them poised for activation following differentiation. We have identified gene sets associated with H3K27me3 and H3K4me3 marks at transcription start sites in a high-grade ovarian serous tumour and examined their association with epigenetic silencing and malignant progression. This revealed novel silenced bivalent marked genes, not described previously for ES cells, which are significantly enriched for the PI3K (P<10(-7)) and TGF-? signalling pathways (P<10(-5)). We matched histone marked gene sets to gene expression sets of eight normal fallopian tubes and 499 high-grade serous malignant ovarian samples. This revealed a significant decrease in gene expression for the H3K27me3 and bivalent gene sets in malignant tissue. We then correlated H3K27me3 and bivalent gene sets to gene expression data of ovarian tumour 'stem cell-like' sustaining cells versus non-sustaining cells. This showed a significantly lower expression for the H3K27me3 and bivalent gene sets in the tumour-sustaining cells. Similarly, comparison of matched chemo-sensitive and chemo-resistant ovarian cell lines showed a significantly lower expression of H3K27me3/bivalent marked genes in the chemo-resistant compared with the chemo-sensitive cell line. Our analysis supports the hypothesis that bivalent marks are associated with epigenetic silencing in ovarian cancer. However it also suggests that additional tumour specific bivalent marks, to those known in ES cells, are present in tumours and may potentially influence the subsequent development of drug resistance and tumour progression. PMID:23128397

Chapman-Rothe, N; Curry, E; Zeller, C; Liber, D; Stronach, E; Gabra, H; Ghaem-Maghami, S; Brown, R

2013-09-19

365

Epithelioid Sarcoma  

PubMed Central

Epithelioid sarcoma is a rare, highgrade, soft tissue tumor that has a known propensity for local recurrence, regional lymph node involvement, and distant metastases. We review the clinical and histological presentations of epithelioid sarcoma. Because epithelioid sarcoma presents innocuously, it is often mistaken as a benign process, which can result in insufficient treatment. Therefore, we emphasize the need for clinicians to consider this diagnosis when a slowgrowing tumor is found on the distal extremity of a young male as the malignancy inherently portends a poor prognosis. Prognostic factors, such as local recurrence, regional metastatic disease, and tumor width, are discussed along with current treatment modalities, which include radical excision, sentinel lymph node biopsy, and radiation.

Sobanko, Joseph F.; Meijer, Lindsay; Nigra, Thomas P.

2009-01-01

366

Postradiation sarcoma of bone: review of 78 Mayo Clinic cases  

SciTech Connect

Postradiation sarcoma of bone is an uncommon but serious sequela of radiation therapy. Seventy-eight Mayo Clinic patients have been treated for sarcomas arising in irradiated bones. They received their initial radiotherapy for a wide variety of nonneoplastic and neoplastic conditions, both benign and malignant. Thirty-five sarcomas arose in bone that was normal at the time of radiotherapy, and 43 arose in irradiated preexisting osseous lesions. The latent period between radiotherapy and diagnosis of sarcoma averaged 14.3 years. Ninety percent of the postradiation sarcomas were either osteosarcomas or fibrosarcomas; chondrosarcoma, malignant (fibrous) histiocytoma, malignant lymphoma, Ewing's tumor, and metastasizing chondroblastoma also occurred. Prompt radical surgery, when feasible, is usually the treatment of choice for the sarcoma. About 30% of patients with sarcomas of the extremities or craniofacial bones survived 5 years without recurrence; there were no disease-free survivors among patients with tumors of the vertebral column, pelvis, or shoulder girdle. The low risk of sarcoma following radiotherapy for the treatment of cancer should not be a contraindication to its use in these patients; however, radiation therapy for benign bone tumors should be reserved for lesions that are not amenable to surgical treatment. An unusual case is also reported herein in which a fibrosarcoma was discovered in the humerus of a patient who had received radiotherapy 55 years previously for a verified osteosarcoma in the same site.

Weatherby, R.P.; Dahlin, D.C.; Ivins, J.C.

1981-05-01

367

Kaposi Sarcoma  

Cancer.gov

DCEG researchers conduct studies on Kaposi sarcoma (KS). Infection with KS-associated herpesvirus (KSHV, also known as human herpesvirus-8 [HHV-8]) is necessary for KS to occur, but other factors, such as HIV infection, greatly increase the risk of the disease.

368

Kaposi's Sarcoma.  

National Technical Information Service (NTIS)

14 cases of Kaposi's sarcoma, a disease very rarely found in China, are reported. The patients were chiefly natives of Xinjiang Uighur Autonomous Region and were mainly of the Uighur, Kazakh and Mongolian minority nationalities with only 1 Han. The author...

J. Liu Y. Huang C. Nie K. Xu

1981-01-01

369

A Phase II multicenter, open-label, clinical and pharmokinetic trial of PM00104 in patients with advanced Ewing Family of Tumors.  

PubMed

Ewing sarcoma is a rare connective tissue tumor characterized by the translocation of the EWS gene, mainly between chromosome 11 and 22, giving rise to gene re-arrangements between the EWS gene and various members of the ETS gene family. Multi-agent chemotherapy has improved the outcome for patients with localized Ewing sarcoma, but survival of patients with recurrent/metastatic disease remains poor. An exploratory two-stage, single-arm Phase II multicenter trial of the synthetic alkaloid, PM00104, was conducted in patients with recurrent Ewing sarcoma. The primary end point of the trial was objective response rate. PM00104 was administered at a dose of 2 mg/m(2) on Days 1, 8 and 15 of a 4 week cycle. Seventeen patients were recruited. No objective responses were reported in the 16 patients evaluable for efficacy. Recruitment was closed without proceeding to the second stage of the trial. Four patients achieved stable disease as best response, and in two of these patients the stabilization was longer than 4 months. The median progression-free survival was 1.8 months (95 % CI, 0.9-3.5 months) and median overall survival was not reached (95%CI, 56.2 % at censored data). Pharmacokinetics in patients with Ewing sarcoma was similar to that previously reported in other patient populations. PM00104 showed modest activity in Ewing sarcoma at 2 mg/m(2) on a weekly schedule. There remains an unmet need for effective therapies for patients with advanced/metastatic Ewing sarcoma. PMID:24173965

Jones, Robin L; Ferrari, Stefano; Blay, Jean Yves; Navid, Fariba; Lardelli, Pilar; Alfaro, Vicente; Siguero, Mariano; Soman, Neelesh; Chawla, Sant P

2014-02-01

370

Comorbidity in Adult Bone Sarcoma Patients: A Population-Based Cohort Study  

PubMed Central

Background. Comorbidity is an important prognostic factor for survival in different cancers; however, neither the prevalence nor the impact of comorbidity has been investigated in bone sarcoma. Methods. All adult bone sarcoma patients from western Denmark treated at the Aarhus Sarcoma Centre in the period from 1979 to 2008 were identified through a validated population-based database. Charlson Comorbidity Index scores were computed, using discharge diagnoses from the Danish National Patient Registry. Survival was assessed as overall and disease-specific mortality. The impact of comorbidity was examined as rates according to the level of comorbidity as well as uni- and multivariately using proportional hazard models. Results. A total of 453 patients were identified. The overall prevalence of comorbidity was 19%. The prevalence increased with age and over the study period. In patients with Ewing/osteosarcoma, comorbidity was not associated with an increased overall or disease-specific mortality. However, patients with bone sarcomas other than Ewing/osteosarcoma had increased overall mortality. Independent prognostic factors for disease-specific survival were age, tumor size, stage at diagnosis, soft tissue involvement, grade, and surgery. Conclusion. The prevalence of comorbidity in bone sarcoma patients is low. Comorbidity impaired survival in patients with non-Ewing/nonosteosarcoma, histology. This emphasizes the importance of not only treating the sarcoma but also comorbidity.

Aggerholm-Pedersen, Ninna; Keller, Johnny; Baerentzen, Steen; Safwat, Akmal

2014-01-01

371

Comorbidity in adult bone sarcoma patients: a population-based cohort study.  

PubMed

Background. Comorbidity is an important prognostic factor for survival in different cancers; however, neither the prevalence nor the impact of comorbidity has been investigated in bone sarcoma. Methods. All adult bone sarcoma patients from western Denmark treated at the Aarhus Sarcoma Centre in the period from 1979 to 2008 were identified through a validated population-based database. Charlson Comorbidity Index scores were computed, using discharge diagnoses from the Danish National Patient Registry. Survival was assessed as overall and disease-specific mortality. The impact of comorbidity was examined as rates according to the level of comorbidity as well as uni- and multivariately using proportional hazard models. Results. A total of 453 patients were identified. The overall prevalence of comorbidity was 19%. The prevalence increased with age and over the study period. In patients with Ewing/osteosarcoma, comorbidity was not associated with an increased overall or disease-specific mortality. However, patients with bone sarcomas other than Ewing/osteosarcoma had increased overall mortality. Independent prognostic factors for disease-specific survival were age, tumor size, stage at diagnosis, soft tissue involvement, grade, and surgery. Conclusion. The prevalence of comorbidity in bone sarcoma patients is low. Comorbidity impaired survival in patients with non-Ewing/nonosteosarcoma, histology. This emphasizes the importance of not only treating the sarcoma but also comorbidity. PMID:24723789

Aggerholm-Pedersen, Ninna; Maretty-Nielsen, Katja; Keller, Johnny; Baerentzen, Steen; Safwat, Akmal

2014-01-01

372

New drug developments for patients with metastatic soft tissue sarcoma.  

PubMed

For the subgroup of patients with inoperable gastrointestinal stromal tumors, progress has been made by the rapid development and approval of the targeted therapy imatinib mesylate. Small round cell sarcomas (SRCT), such as Ewing/primitive neuroectodermal tumor, desmoplastic SRCT, and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies that are treated with multimodality dose-intensive neoadjuvant protocols regardless of size or overt metastatic disease. However, the number of effective cytotoxic agents for the treatment of patients with metastatic so-called adult soft tissue sarcoma is limited, especially when patients have failed anthracycline- and ifosfamide-based chemotherapy. PMID:15946590

Hartmann, Jörg Thomas; Patel, Shreyaskumar

2005-07-01

373

Pediatric Sarcoma in Central America: Outcomes, Challenges and Plans for Improvement  

PubMed Central

Background Children with cancer in middle-income countries have inferior outcomes to those in high-income countries. The magnitude and drivers for this survival gap are not well understood. We sought to describe patterns of clinical presentation, magnitude of treatment abandonment, and survival in children with sarcoma in Central America. Methods Retrospective review of hospital-based registries from national pediatric oncology referral centers. Patients with newly diagnosed osteosarcoma, Ewing sarcoma (Ewing), rhabdomyosarcoma (RMS), and soft tissue sarcomas (STS) between 1/1/00-12/31/09 were included. Survival analysis was performed using standard definitions of overall and event-free survival (OS and EFS) and with abandonment included as an event (AOS and AEFS). Results A total of 785 new cases of pediatric sarcoma were reported (264 osteosarcoma, 175 Ewing, 240 RMS, and 106 STS). Metastatic disease at presentation was high (osteosarcoma 38%, Ewing 39%, RMS 29% and STS 21%). Treatment abandonment rate was high, particularly among patients with extremity bone sarcomas (osteosarcoma 30%, Ewing 15%, RMS 25% and STS 15%). Of 559 patients experiencing a first event, 59% had either relapse or progressive disease. The 4-year OS was 40% (SE±3%) and EFS was 30% (SE±2%), but further decreased to 31% (SE±2%) and 24% (SE±2%), when abandonment was taken into account. Conclusion High rate of metastases and treatment abandonment, and difficulty with upfront treatment effectiveness are important contributors to poor survival of children with pediatric sarcomas in Central America. Initiatives for early diagnosis, psychosocial support, quality improvement, and multidisciplinary care are warranted to improve outcomes.

Friedrich, Paola; Ortiz, Roberta; Strait, Kelly; Fuentes, Soad; Gamboa, Yessica; Arambu, Ingrid; Ah-Chu-Sanchez, Maria; London, Wendy; Rodriguez-Galindo, Carlos; Antillon-Klussmann, Federico; Baez, Fulgencio

2012-01-01

374

Sarcoma Immunotherapy  

PubMed Central

Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis.

Gouw, Launce G.; Jones, Kevin B.; Sharma, Sunil; Randall, R. Lor

2011-01-01

375

Granulocytic Sarcoma  

Microsoft Academic Search

\\u000a Granulocytic sarcoma (GS) is a rare solid malignant tumor, which consists of extramedullary primitive precursors of white\\u000a blood cells including myeloblasts, promyelocytes and myelocytes (Puiet al. 1994). It is most commonly associated with acute myeloid leukemia (AML), in which 2.5–8% of patients will develop GS before, during\\u000a or after the onset of systemic leukemia (Pui et al. 1994; Liu et

Clara G. C. Ooi; Ali Guermazi

376

Mesenchymal Stromal Cell Dependent Regression of Pulmonary Metastasis from Ewing's  

PubMed Central

Introduction: Ewing’s sarcoma (ES) is the second most common bone tumor in children. Survival has not improved over the last decade and once pulmonary metastatic disease is present, survival is dismal. Mesenchymal stromal cell (MSC) therapy has shown potential benefit for Kaposi’s sarcoma; however, the role of progenitor cell therapies for cancer remains controversial. MSC treatment of ES or pulmonary metastatic disease has not been demonstrated. We have developed an orthotopic xenograft model of ES in which animals develop spontaneous pulmonary metastases. Within this model, we demonstrate the use of MSCs to target ES lung metastasis. Materials and Methods: Human ES cells were transfected with luciferase and injected into the rib of nude mice. Development of pulmonary metastases was confirmed by imaging. After flow cytometry based characterization, MSCs were injected into the tail vein of nude mice with established local ES tumor or pulmonary metastasis. Mice were treated with intravenous MSCs weekly followed by bioluminescent imaging. Results: The intravenous injection of MSCs in an ES model decreases the volume of pulmonary metastatic lesions; however, no effect on primary chest wall tumor size is observed. Thus verifying the MSC preferential homing to the lung. MSCs are found to “home to” the pulmonary parenchyma and remain engrafted up to 5?days after delivery. Discussion: MSC treatment of ES slows growth of pulmonary metastasis. MSCs have more affinity for pulmonary metastasis and can effect a greater decrease in tumor growth in the lungs compared to the primary tumor site.

Hayes-Jordan, Andrea; Wang, Yong Xin; Walker, Peter; Cox, Charles S.

2014-01-01

377

T1-201 chloride scintigraphy for bone tumors and soft part sarcomas  

SciTech Connect

The author investigated T1-201 chloride as a tumor scanning agent of both tumors and soft part sarcomas. Six bone tumors (2 with Ewing sarcoma, 3 with osteosarcoma and 1 with giant cell tumor) and 3 soft part sarcoma (1 with liposarcoma and 2 with malignant fibrous histiocytoma (MFH)) were examined. All but one MFH were untreated primary cases. The diagnosis was determined from biopsy specimen. One patient with Ewing sarcoma had bone metastases. All cases were subsequently received chemotherpeutic agents. Surgery or local irradiation were also used in treatment. T1-201 scintigraphy were performed with intravenous administration of 2 mCi of T1-201 chloride before initiation of therapy. In addition, follow-up examinations were done in 4 patients (2 with Ewing sarcoma and 2 with osteosarcoma) to study the effect of chemotherapy on T1-201 uptake by the tumor. Tc-99m bone scans were available for comparison in 6 tumor. Ga-67 citrate scans were also examined for the 3 soft part sarcomas. The untreated tumors even in the metastatic lesions of Ewing sarcoma were distinctly visualized with T1-201 in all cases. The distribution of T1-201 in the tumors was sometimes different from that of Tc-99m and similar to that of Ga-67. Of 3 out of the 4 follow-up patients, the post-therapy scan showed reduction in T1-201 uptake more markedly than Tc-99m uptake during effective chemotherapy. The other one patient had not responded to the treatment so that the scan showed no changes in T1-201 uptake. These findings indicate that the tumor imaging with T1-201 is useful in the diagnosis of these malignant tumors and may be of value in assessing the response of bone tumors to chemotherapy.

Terui, S.; Oyamada, H.; Nishikawa, K.; Beppu, Y.; Fukuma, H.

1984-01-01

378

ASSESSMENT OF DAILY PHYSICAL ACTIVITY IN PEDIATRIC PATIENTS TREATED FOR MALIGNANT TUMORS (SARCOMAS) AND ACUTE LEUKAEMIA  

Microsoft Academic Search

Introduction: Ewing's sarcoma and Osteosarcoma have a peak incidence during the second decade of life (1), whereas leukaemia is the most common of all cancer di- agnoses in children and adolescents. The diseases lead to a loss of physical fitness that often forces patients to rest in bed. Chemotherapy requirements and restrictions to the ward during in-patient treatment generate a

Müller Carsten; Winter Corinna; Brinkmann Anja

379

Early decrements in bone density after completion of neoadjuvant chemotherapy in pediatric bone sarcoma patients  

Microsoft Academic Search

BACKGROUND: Bone mineral density (BMD) accrual during childhood and adolescence is important for attaining peak bone mass. BMD decrements have been reported in survivors of childhood bone sarcomas. However, little is known about the onset and development of bone loss during cancer treatment. The objective of this cross-sectional study was to evaluate BMD in newly diagnosed Ewing's and osteosarcoma patients

Carsten Müller; Corinna C Winter; Dieter Rosenbaum; Joachim Boos; Georg Gosheger; Jendrik Hardes; Volker Vieth

2010-01-01

380

Paratesticular Sarcomas in Brazil  

Microsoft Academic Search

Purpose: Paratesticular sarcomas are rare and frequently reported as isolated case reports. Studies evaluating the relative frequency of the paratesticular sarcomas are limited, and to the best of our knowledge, this is the first study of paratesticular sarcomas in the Brazilian population. Patients and Methods: Medical records of all patients undergoing treatment for paratesticular sarcomas between 1993 and 2006 were

Fernando Korkes; Marília G. Castro; Frederico R. Romero; Guilherme Godoy; Maria F. Amary; Roni C. Fernandes; Marjo D. Perez

2009-01-01

381

Breast sarcoma.  

PubMed

Breast sarcoma is a very rare mesenchymal tumour and accounts for about 0.5% of the total breast malignancies. We present the case of a 69 years old female who presented with a painful breast lump. The report highlights the pre-operative tests and the operative approach adopted for this patient. Surgical resection is recommended, although debate exists about the extent of surgery. Neo adjuvant chemotherapy and radiotherapy has been advised in certain cases but their role is still not clear. Further work is needed to standardize the treatment. PMID:23552541

Muzaffar, Naveed; Al Gari, Mohammed

2013-04-01

382

Retraction: Primary extraosseous Ewing sarcoma of the lung in children.  

PubMed

ecancer 7 312 (2013) The report in this article of the treatment the patient received is incorrect. Three of the authors (Jean Luc Michel, Clara Fernandez and Audrey Derouet) were unaware that their names had been added to the author list. The three remaining authors (Nidal Alsit, Linda Sakhri and Augustin Pirvu) were not involved with the treatment of the patient. PMID:23858324

2013-01-01

383

General Information about Kaposi Sarcoma  

MedlinePLUS

... also called transplant-related or acquired Kaposi sarcoma. Epidemic Kaposi Sarcoma Epidemic Kaposi sarcoma is found in patients who have ... or bisexual men infected with HIV. Signs of epidemic Kaposi sarcoma can include lesions that form in ...

384

Study the ovarian function in Awassi ewes.  

National Technical Information Service (NTIS)

An experiment was carried out on local Awassi ewes to study the reproductive performance, progesteron concentrations, accuracy of pregnacy diagnosis and other reproduction related criteria of Awassi ewes using radioimunoassay (RIA). A total of 18 nullipar...

M. Zarkawi

1996-01-01

385

Nematode worm egg output by ewes  

Microsoft Academic Search

The results from routine monitoring of parasite burdens in ewe flocks from 1980 to 1991 by the Massey University Veterinary Clinic were analysed. Faecal strongylate nematode egg counts from 401 flock samples were analysed according to ewe age (two-tooth, 16-23 month-old vs mixed-age, greater than 2-year-old ewes) and month of the year. Each flock sample contained faeces from ten ewes

K. J. Stafford; D. M. West; W. E. Pornroy

1994-01-01

386

Epidemic Kaposi Sarcoma  

MedlinePLUS

... type of cancer being treated. Liposomal chemotherapy uses liposomes (very tiny fat particles) to carry anticancer drugs. ... doxorubicin is used to treat Kaposi sarcoma. The liposomes build up in Kaposi sarcoma tissue more than ...

387

Sarcoma Foundation of America  

MedlinePLUS

... cHER2 Immunotherapy to Treat Pediatric Bone Cancer Sarcoma Foundation of America Awards Half Million Dollars in Research ... nbsp   Contact Us       Sarcoma Foundation of America, 9899 Main Street, Suite 204, Damascus, ...

388

[Soft tissue sarcoma--problems of diagnosis and treatment].  

PubMed

Soft tissue sarcomas are a rare group of cancers compromising 1% of all malignancies and there has been a slight increase in incidence. We present 3 cases of soft tissue sarcomas (the tumors were located to the right axilary region, perianal and dorsale face of the left leg) hospitalized in 2nd Surgical Clinic of Emergency Hospital of Craiova and we discuss the difficulties of diagnosis and treatment. The classification and characterization of soft-tissue sarcomas have evolved as the information supplied by histologic analysis has been supplemented with that provided by immunohistochemical analysis. Surgical resection involving wide margins, with or without radiotherapy, offers the best chance of cure in the absence of metastatic disease. There is little evidence that local recurrence increases the likelihood of metastatic spread, although debate on this point continues. Except for rhabdomyosarcomas and Ewing's sarcomas, the use of adjuvant chemotherapy generally does little to influence the natural history of the disease. In conclusion surgical treatment is mainstay of treatment for soft-tissue sarcomas and is usefull the prompt diagnosis for decrease the risk of local recurrence and metastatic disease. PMID:20540243

Me?in?, C; Vasile, I; Vîlcea, I D; Pa?alega, M; Pârv?nescu, H; Calot?, F; Georgescu, C V; Ghilu?i, M; Dumitrescu, T; Mirea, C; Mogoan??, S; Moraru, E

2010-01-01

389

Topotecan and Cyclophosphamide in Adults with Relapsed Sarcoma  

PubMed Central

Background. The combination of topotecan and cyclophosphamide (TC) has activity in pediatric patients with recurrent sarcoma, especially Ewing's sarcoma (EWS). We sought to determine the toxicity of and response to TC in adults with recurrent sarcoma. Patients and Methods. Adults treated with TC from 2005 to 2010 were reviewed who received T = topotecan at 0.75?mg/m2/day (days 1–5) and C = cyclophosphamide at 250?mg/m2/day (days 1–5) every 21 days. Results. Fifteen patients, median age 31 years (range 17.5–56) had nonpleomorphic rhabdomyosarcoma (RMS, n = 6), EWS, n = 5, synovial sarcoma (SS, n = 2) leiomyosarcoma (LMS, n = 1), and desmoplastic small round cell tumour (DSRCT, n = 1). Median time to progression was 2.5 months (range 1.6–13.0). Partial responses were seen in 2/6 RMS and 1/2 SS. Stable disease was seen in 2/5 EWS, 1/2 SS and 1 DSRCT. The most common reason for stopping treatment was progressive disease 12/15, (80%). Hematologic toxicity was common; 7 (47%) patients required blood product transfusion, 5 (33%) patients had fever/neutropenia. At median follow-up time of 7.7 months, all but 1 patient had died of disease. Conclusion: TC combination is tolerable but has only modest activity in adults with recurrent sarcoma. Other regimens deserve exploration for this high-risk group of patients

Blanchette, P.; Hogg, D.; Ferguson, P.; Wunder, J. S.; Swallow, C.; Gladdy, R.; Chung, P.; O'Sullivan, B.; Blackstein, M. E.; Catton, C.; Gupta, A. A.

2012-01-01

390

What's New in Ewing Tumor Research and Treatment?  

MedlinePLUS

... Next Topic Additional resources for Ewing tumors What’s new in Ewing tumor research and treatment? Research on ... institutions across the world. Diagnosis Scientists are developing new techniques to more accurately diagnose Ewing tumors. New ...

391

Metformin as an adjuvant drug against pediatric sarcomas: hypoxia limits therapeutic effects of the drug.  

PubMed

Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts anti-mitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas. PMID:24391834

Garofalo, Cecilia; Capristo, Mariantonietta; Manara, Maria Cristina; Mancarella, Caterina; Landuzzi, Lorena; Belfiore, Antonino; Lollini, Pier-Luigi; Picci, Piero; Scotlandi, Katia

2013-01-01

392

Postradiation sarcomas of bone  

Microsoft Academic Search

Fifty-nine patients with osteogenic sarcomas arising in bones following exposure to x rays and 20 patients with postradiation malignant fibrous histiocytomas of bone arising as a direct consequence of irradiation were studied. These represent 5.5% of all osteogenic sarcomas and 4.9% of all malignant fibrous histiocytomas of bones. The sarcomas may affect any skeletal site, but most commonly they arose

Andrew G. Huvos; Helen Q. Woodard

1988-01-01

393

Microsatellite instability in sarcomas  

Microsoft Academic Search

Background: Microsatellite instability (MIN) has been studied in a variety of carcinomas and gynecologic sarcomas, but never in musculoskeletal\\u000a sarcomas.\\u000a \\u000a \\u000a Methods: We evaluated 16 skeletal and soft tissue sarcomas at nine genetic loci from chromosomal regions 1q, 5q, 7q, 12p, 13q, 17p,\\u000a 19q, and two at 11p—all potential regions of interest regarding musculoskeletal sarcomas.\\u000a \\u000a \\u000a \\u000a \\u000a Results: MIN was identified at one

Stephanie S. Martin; W. Grear Hurt; Lora K. Hedges; Merlin G. Butler; Herbert S. Schwartz

1998-01-01

394

The soft tissue sarcomas  

SciTech Connect

New advances in multimodality therapy of sarcomas in all anatomic sites are thoroughly described. Multimodality therapy with limb-salvage surgery for extremity tumors, sarcomas of the head and neck, trunk, intraabdominal, visceral, and genitourinary tract and cardiopulmonary system are presented. Separate sections are devoted to the management of pediatric sarcomas, pulmonary metastasis and to the pathology and radiobiology, chemotherapy, and immunotherapy of sarcomas. The text also stresses the philosophy of achieving adequate local control without radical amputation by combined surgery and chemo/radiotherapy.

Eilber, F.R.; Morton, D.L.; Sondak, V.K.; Economou, J.S.

1987-01-01

395

[Treatment of primary bone sarcoma of the jaws].  

PubMed

Head and neck bone sarcomas are very uncommon tumors. Therefore, treatment modalities are not clearly established. The medical record of 12 patients with bone sarcoma of the jaw were reviewed. Six patients with osteosarcoma underwent primary chemotherapy followed by wide surgical resection, radiation therapy or combined radiosurgical treatment. The 2 and 5 years survivals were 66% and 40% respectively. Five patients with chondrosarcoma were treated by wide surgical resection alone or combined with postoperative radiotherapy and possibly chemotherapy. All patients were alive; the mean follow-up was 9 years. One patient had Ewing's tumor. Osteosarcoma and chondrosarcoma in head and neck patients have a high rate of local recurrences. Surgery is the mainstay of treatment. Patients with voluminous tumors and high-grade lesions should receive postoperative radiotherapy. The role of chemotherapy has not been defined. PMID:7939361

Barthélémy, I; Coustal, B; Michelet, V; Pinsolle, J; Siberchicot, F; Caix, P; Michelet, F X

1994-01-01

396

Assessment of histological response of paediatric bone sarcomas using FDG PET in comparison to morphological volume measurement and standardized MRI parameters  

Microsoft Academic Search

Purpose  The objective of this study was to evaluate positron emission tomography (PET) using 18F-fluoro-2-deoxy-D-glucose (FDG) in comparison to volumetry and standardized magnetic resonance imaging (MRI) parameters for the assessment\\u000a of histological response in paediatric bone sarcoma patients.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  FDG PET and local MRI were performed in 27 paediatric sarcoma patients [Ewing sarcoma family of tumours (EWS), n?=?16; osteosarcoma (OS), n?=?11] prior

Timm Denecke; Patrick Hundsdörfer; Daniel Misch; Ingo G. Steffen; Stefan Schönberger; Christian Furth; Michail Plotkin; Juri Ruf; Hubertus Hautzel; Brigitte Stöver; Regine Kluge; Uta Bierbach; Sylke Otto; James F. Beck; Christiane Franzius; Günter Henze; Holger Amthauer

2010-01-01

397

Soft Tissue Sarcoma  

MedlinePLUS

... tissue sarcoma is a cancer of these soft tissues. There are many kinds, based on the type of tissue they started in. They may cause a lump ... or have certain genetic diseases. Doctors diagnose soft tissue sarcomas with a ... chemotherapy, or a combination. NIH: National Cancer Institute

398

Mechanisms of sarcoma development  

Microsoft Academic Search

Sarcomas are a rare and diverse group of tumours that are derived from connective tissues, including bone, muscle and cartilage. Although there are instances of hereditary predisposition to sarcomas, the overwhelming majority of such tumours are sporadic. In the past decade, we have gained much insight into the genetic abnormalities that seem to underlie the pathogenesis of these tumours. This

Lee J. Helman; Paul Meltzer

2003-01-01

399

Effect of dystocia on serum haptoglobin in Awassi ewes  

Microsoft Academic Search

Serum haptoglobin concentration was determined in 102 Iraqi Awassi ewes. Blood samples were collected from 82 ewes before the correction of dystocia, 10 ewes with eutocia 2 to 4 h after parturition and 10 nonpregnant ewes during the seasonal anestrus phase. The mean serum haptoglobin concentration was significantly higher (P

D. M. Aziz; M. B. Taha

1997-01-01

400

Effect of dystocia on serum haptoglobin in Awassi ewes.  

PubMed

Serum haptoglobin concentration was determined in 102 Iraqi Awassi ewes. Blood samples were collected from 82 ewes before the correction of dystocia, 10 ewes with eutocia 2 to 4 h after parturition and 10 nonpregnant ewes during the seasonal anestrus phase. The mean serum haptoglobin concentration was significantly higher (P < 0.01) in ewes with dystocia than in ewes with normal births and in the nonpregnant ewes. No significant difference was found between serum haptoglobin concentrations of ewes with ringwomb and ewes with dystocia due to other causes. There was a significant elevation (P < 0.01) of serum haptoglobin in cases treated 24 h after labor compared with those treated during the first 24 h. Significant (P < 0.05) differences were found between serum haptoglobin concentrations in ewes treated surgically and those treated manually. PMID:16728152

Aziz, D M; Taha, M B

1997-09-01

401

Fleming, Ewing, Macelwane awardees announced  

NASA Astrophysics Data System (ADS)

AGU has announced that the 1986 John Adam Fleming Medal for original research and technical leadership in geomagnetism, atmospheric electricity, aeronomy, and related sciences will be presented to George E. Backus of the Scripps Institution of Oceanography (La Jolla, Calif.).In addition, as previously announced, John Imbrie of Brown University (Providence, R.I.) will receive the Maurice Ewing Award, and James B. Macelwane Awards will be presented to Edward M. Stolper of the California Institute of Technology (Pasadena) and Robert A. Weller of Woods Hole Oceanographic Institution (Woods Hole, Mass.).

402

Expression Profiling of t(12;22) Positive Clear Cell Sarcoma of Soft Tissue Cell Lines Reveals Characteristic Up-Regulation of Potential New Marker Genes Including ERBB3  

Microsoft Academic Search

Clear cell sarcoma of soft tissue (CCSST), also known as malignant melanoma of soft parts, represents a rare lesion of the musculoskeletal system usually affecting adolescents and young adults. CCSST is typified by a chromosomal t(12;22)(q13;q12) translocation resulting in a fusion between the Ewing sarcoma gene (EWSR1) and activating transcription factor 1 (ATF1), of which the activity in nontransformed cells

Karl-Ludwig Schaefer; Kristin Brachwitz; Daniel H. Wai; Yvonne Braun; Raihanatou Diallo; Eberhard Korsching; Martin Eisenacher; Reinhard Voss; Frans van Valen; Claudia Baer; Barbara Selle; Laura Spahn; Shuen-Kuei Liao; Kevin A. W. Lee; Pancras C. W. Hogendoorn; Guido Reifenberger; Helmut E. Gabbert; Christopher Poremba

2004-01-01

403

Systemic treatment options for patients with refractory adult-type sarcoma beyond anthracyclines.  

PubMed

For the subgroup of patients with inoperable gastrointestinal stromal tumors, progress has been made by the rapid development and approval of the targeted therapy imatinib mesylate. Small round cell sarcoma, such as Ewing/PNET, desmoplastic small round cell sarcoma and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensitive and neoadjuvant protocols regardless of size or overt metastatic disease. A limited number of effective agents available for the treatment of patients with metastatic adult soft-tissue sarcoma exists, which have failed anthracyline and ifosfamide-based chemotherapy. Most other high-grade (grading >I) so-called adult-type soft-tissue sarcomas such as fibro, lipo, pleomorphic and synovial sarcoma are treated with a anthracycline-based regimen with or without ifosfamide as front-line therapy. In this review, the therapeutic activities of drugs currently available as second-line treatment in patients with metastatic soft tissue sarcoma are summarized, providing an overview of contentious or emerging treatment issues. In relapsed 'adult-type' soft-tissue sarcomas trofosfamide, gemcitabine and ecteinascidin (ET-743) appear to be drugs associated with moderate activity and an acceptable toxicity profile. An interesting finding to be noted is that the different drugs have particular effects in distinct subtypes of soft-tissue sarcoma; however, it has to be taken into account that the number of patients included in those phase II trials are limited. The role of the newer agents (e.g. patupilone derivates, brostallicin) is currently not definable. The so-called selective therapy targeting vascular endothelial growth factor (receptor), epidermal growth factor receptor, c-kit, Raf kinase or platelet-derived growth factor receptor and bcl-2 antisensing, proteasome, protein kinase C/B, and mammalian target of rabamycin inhibition will continue to be tested in gastrointestinal stromal tumors patients refractory to imatinib mesylate as well as in selected sarcoma subtypes. PMID:17264755

Hartmann, Jörg T

2007-03-01

404

Recent developments in salvage chemotherapy for patients with metastatic soft tissue sarcoma.  

PubMed

The number of effective cytotoxic agents for the treatment of patients with metastatic adult soft tissue sarcoma is limited, especially when patients have failed anthracycline- and ifosfamide-based chemotherapy. For the subgroup of patients with inoperable gastrointestinal stromal tumour (GIST), progress has been made via the rapid development and approval of the targeted therapy imatinib. Small round cell tumours (SRCTs), such as Ewing's sarcoma/primitive neuroectodermal tumour, desmoplastic SRCT and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensive, neoadjuvant protocols regardless of size or overt metastatic disease. Most other high-grade (grading >I), so-called 'adult type', soft tissue sarcomas such as fibrosarcoma, liposarcoma, pleomorphic and synovial sarcomas are treated with an anthracycline-based regimen with or without ifosfamide as front-line therapy. In relapsed 'adult type' soft tissue sarcomas, trofosfamide, gemcitabine and trabectedin (ecteinascidin 743) appear to be drugs associated with some activity and an acceptable toxicity profile. A high activity has been reported for the taxanes, in particular for paclitaxel, in vascular sarcomas located in the scalp or face and in Kaposi's sarcoma. It is interesting to note that the different drugs have particular effects in distinct subtypes of soft tissue sarcoma; however, it should be taken into account that the number of patients included in the phase II trials is limited. The role of the newer agents (e.g. epothilones, brostallicin) is currently undefinable. Targeted therapy inhibiting vascular endothelial growth factor receptor, epidermal growth factor receptor, RAF kinase, c-KIT or platelet-derived growth factor receptors will continue to be tested in GIST patients refractory to imatinib and in other sarc