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Extraskeletal Ewing's sarcoma.  


We report 2 rare cases of extraskeletal Ewing's sarcoma, one is arising primarily from the posterior mediastinum in a middle-aged man (patient 1), and the other one is arising from the left kidney in a young male patient (patient 2). The CT in the first case showed a large mass of heterogeneous texture, with areas of cystic changes in the right side of the posterior mediastinum, no underlying bony changes or intra-spinal extension, and this mass was diagnosed as lymphoma. The second case showed almost complete replacement of the left kidney by a mass with extension through the renal vein and inferior vena cava, and it was diagnosed as renal cell carcinoma. The histological analysis of these lesions revealed extraskeletal Ewing's sarcoma. PMID:19526172

El-Essawy, Manar T



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



Ewing's sarcoma can express bone morphogenetic protein  

Microsoft Academic Search

Paraffin sections from 6 cases of Ewing's sarcoma were immunostained by ABC method using BMP—McAb for investigating the existence\\u000a of BMP in Ewing's sarcoma. All cases were positive. The result was coincided with human tumor transplants in athymic nude\\u000a mouse by Bauer. It is shown that Ewing's sarcoma can express BMP. So we support the hypothesis that Ewing's sarcoma originates

Zhang Suixiang; Li Defang; Liu Jie; Yang Lianjia; Jin Yan



Ewing’s Sarcoma: Standard and Experimental Treatment Options  

Microsoft Academic Search

Opinion statement  Ewing sarcoma family tumors (EWS), which include classic Ewing’s sarcoma in addition to primitive neuroectodermal tumor and\\u000a Askin tumor, are the second most common variety of primary bone cancer to afflict adolescents and young adults. Multi-disciplinary\\u000a care incorporating advances in diagnosis, surgery, chemotherapy, and radiation has substantially improved the survival rate\\u000a of patients with localized Ewing sarcoma to nearly

Vivek Subbiah; Pete Anderson; Alexander J. Lazar; Emily Burdett; Kevin Raymond; Joseph A. Ludwig



Ewing's Sarcoma and Second Malignancies  

PubMed Central

Ewing's sarcoma (ES) is a rare tumor that is most common in children and young adults. Late effects of ES therapy include second cancers, a tragic outcome for survivors of such a young age. This paper will explore the frequencies and types of malignancies that occur after ES. Additionally, it will review how second malignancies have changed with the shift in treatment from high-dose radiation to chemotherapy regimens including alkylators and epipodophyllotoxins. The risk of additional cancers in ES survivors will also be compared to survivors of other childhood cancers. Finally, the possible genetic contribution to ES and second malignancies will be discussed.

Schiffman, Joshua D.; Wright, Jennifer



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.



Ewing Sarcoma: An Eponym Window to History  

PubMed Central

Ewing sarcoma was named after James R. Ewing, an eminent American pathologist at Cornell who described the first cases in 1921. Although he is best remembered for this singular achievement, Ewing's contributions to the study of cancer were far more profound and influential. He essentially launched oncology as a discipline with the publication of his seminal textbook and founded the major American cancer societies that exist today. His vision of comprehensive cancer centers still drives our research infrastructure. Since his initial report, these organizations have helped us achieve numerous milestones in understanding and treating patients with Ewing sarcoma.

Cripe, Timothy P.



Ewing sarcoma: biology-based therapeutic perspectives.  


Ewing sarcoma, a rare malignancy of childhood and adolescence, has attracted wide research interest. Tumor-specific chromosomal translocations generate aberrant EWS-ETS transcription factors, which alter intracellular signaling networks through gene and protein expression and are considered to be the primary tumor-initiating event. Ewing sarcoma therefore offers insights into principle molecular mechanisms of cancer development and maintenance. Still, despite long-standing research, biology-based targeted treatment strategies for Ewing sarcoma are only beginning to emerge. This article provides an overview of the biological basis and putative targeted treatment options. PMID:22304007

Potratz, Jenny; Jürgens, Heribert; Craft, Alan; Dirksen, Uta



Surgical management of pelvic Ewing's sarcoma  

PubMed Central

Background: Despite advances in adjuvant therapy, Ewing’s sarcoma of the pelvis remains an anatomic site with a poor prognosis due to its relative inaccessibility, complex anatomy, and limited reconstructive options available. This study evaluates the role of surgery in the management of patients with pelvic Ewing’s sarcoma who also have received conventional radiation therapy and chemotherapy. Materials and Methods: From July 1990 to July 2006, we received 10 patients with Ewing’s sarcoma of pelvis at our center. Nine patients were in stage II B and one in Stage III at the time of presentation to us. All patients underwent surgical resection after preoperative chemotherapy with or without radiotherapy, which was given at the discretion of the referral center. Reconstruction was attempted using plate osteosynthesis in four patients, SS wires and screws in three patients, free fibular strut graft in one patient, and none was done in two patients. Results: Functional outcome assessed by Enneking’s criteria revealed excellent outcome in two patients, good outcome in five patients, and poor outcome in two patients. At a mean followup of 10.3 years, seven patients remained free from the disease, and three patients died. The 5- and 10-year cumulative survival (Kaplan Meier method) was 63% and 34%, respectively. Conclusion: This study demonstrates that surgery plus chemotherapy and radiation therapy is helpful for treating patients with pelvic Ewing’s sarcoma, particularly in achieving local control.

Natarajan, Mayil Vahanan; Sameer, M Mohamed; Bose, Jagdish Chandra; Dheep, Kunal



Targeted Therapy of Ewing's Sarcoma  

PubMed Central

Refractory and/or recurrent Ewing's sarcoma (EWS) remains a clinical challenge because the disease's resistance to therapy makes it difficult to achieve durable results with standard treatments that include chemotherapy, radiation, and surgery. Recently, insulin-like-growth-factor-1-receptor (IGF1R) antibodies have been shown to have a modest single-agent activity in EWS. Patient selection using biomarkers and understanding response and resistance mechanisms in relation to IGF1R and mammalian target of rapamycin pathways are areas of active research. Since EWS has a unique tumor-specific EWS-FLI1 t(11;22) translocation and oncogenic fusion protein, inhibition of EWS-FLI1 transcription, translation, and/or protein function may be key to eradicating EWS at the stem-cell level. Recently, a small molecule that blocks the protein-protein interaction of EWS-FLI1 with RNA helicase A has been shown in preclinical models to inhibit EWS growth. The successful application of this first-in-class protein-protein inhibitor in the clinic could become a model system for translocation-associated cancers such as EWS.

Subbiah, Vivek; Anderson, Pete



Spinal intradural extraosseous Ewing's sarcoma  

PubMed Central

Extraosseous Ewing's sarcoma (EES) involving the central nervous system is rare, but can be diagnosed and distinguished from other primitive neuroectodermal tumors (PNET) by identification of the chromosomal translocation (11;22)(q24;q12). We report EES arising from the spinal intradural extramedullary space, based on imaging, histopathological, and molecular data in two men, ages 50 and 60 years old and a review of the literature using PubMed (1970–2009). Reverse transcriptase polymerase chain reaction (RT-PCR) identified the fusion product FL1-EWS. Multimodal therapy, including radiation and alternating chemotherapy including vincristine, cyclophosphamide, doxorubicin and ifosfamide and etoposide led to local tumor control and an initial, favorable therapeutic response. No systemic involvement was seen from the time of diagnosis to the time of last follow-up (26 months) or death (4 years). This report confirms that EES is not confined to the earliest decades of life, and like its rare occurrence as an extra-axial meningeal based mass intracranially, can occasionally present as an intradural mass in the spinal canal without evidence of systemic tumor. Gross total resection followed by multimodal therapy may provide for extended progression free and overall survival.

Mateen, Farrah J.; Nassar, Aziza; Bardia, Aditya; Jatoi, Aminah; Haddock, Michael G.; Buckner, Jan C.; Lachance, Daniel H.



Primary Ewing's sarcoma of the skull.  


Ewing's sarcoma, a highly malignant bone tumour, typically affects the pelvis and the long bones of the lower extremities in children and young adults and primary involvement of the skull is rare. Here, we present a case of primary Ewing's sarcoma of the skull with localised swelling in a young adult that involved the frontoparietal region of the skull and was very aggressive in nature. Even with aggressive surgery, the patient had multiple recurrences within 1 month of surgery and ultimately the patient died. PMID:23370949

Rahman, Asifur; Bhandari, Paawan Bahadur; Hoque, Saif Ul; Wakiluddin, Abu Naim Md



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



An Unusual Location of Extraosseous Ewing's Sarcoma.  


Ewing's sarcoma (ES) is the second most common malignant bone tumor in children and young adults. ES also occurs as a primary soft tissue neoplasm without involvement of bone. We report the second case of extraosseous (EO) ES emerging from the omentum and a review of the relevant literature. EO ES should be included in the differential diagnosis of soft tissue neoplasms in the abdomen. PMID:23898272

Geens, Lisanne; Robays, Johan Van; Geert, Verswijvel; der Speeten, Kurt Van



Chromosome 22 abnormalities in Ewing's sarcoma.  

PubMed Central

A child with disseminated Ewing's sarcoma underwent cytogenetic investigations which showed different structural rearrangements of chromosome 22 at diagnosis (?ring22), and at relapse [t(10;22)], but the classic translocation t(11;22) was not detectable. This case provides further evidence of the importance of chromosome 22 in this disease, while raising some questions about the central importance of the translocation between chromosomes 11 and 22. Images Figure

Davison, E V; Pearson, A D; Emslie, J; Reid, M M; Malcolm, A; Craft, A W



A multidisciplinary study investigating radiotherapy in Ewing’s sarcoma: end results of POG #8346  

Microsoft Academic Search

Purpose: To determine if involved field radiation (IF) is equivalent to standard whole bone radiation (SF) in local tumor control; to establish patterns of failure following treatment; and to determine response, event-free survival (EFS), and overall survival rates from multidisciplinary therapy in Ewing’s sarcoma.Methods and Materials: Between 1983 and 1988, 184 children with Ewing’s sarcoma were enrolled onto Pediatric Oncology

Sarah S Donaldson; Margaret Torrey; Michael P Link; Arvin Glicksman; Louis Gilula; Fran Laurie; John Manning; James Neff; William Reinus; Elizabeth Thompson; Jonathan J Shuster



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



Characteristics of human Ewing/PNET sarcoma models  

PubMed Central

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.

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



Extraosseous Ewing's sarcoma of the pancreas.  


The Ewing's family of tumors (EFT) comprises a molecularly defined group of "small round blue cell tumors", consisting of Ewing's sarcoma of bone (ESB), extraosseous Ewing's sarcoma (EES), peripheral primitive neuroectodermal tumor (pPNET), and Askin's tumor. Characteristic translocations that disrupt the EWSR1 gene located at 22q12 create novel fusion genes that are central to the pathogenesis. The EFT also shares certain clinical characteristics, such as a peak incidence during the teenage years, a tendency to spread rapidly, and responsiveness to the same chemotherapeutic regimens and radiation therapy. Nearly all patients have occult disseminated disease at diagnosis; hence, chemotherapy is routinely used. Improvements in multimodality treatment have had a dramatic impact on outcomes. EES/pPNET has been reported in a variety of sites, including the pancreas, though this is extremely rare. We describe a case of pancreatic EES/pPNET in a 35-year-old woman and provide a brief review of the relevant literature. PMID:21892669

Bose, Prithviraj; Murugan, Paari; Gillies, Elizabeth; Holter, Jennifer L



Primary pediatric endobronchial Ewing sarcoma family of tumors  

PubMed Central

Summary Background: Ewing sarcoma family of tumors is the second most common primary bone tumor of childhood. Extraosseous Ewing sarcoma family of tumors is rare. We present a pediatric case of primary endobronchial Ewing sarcoma family of tumors. Case Report: A 12-year-old boy presented with dyspnea and chest radiography showed right pulmonary atelectasis. Chest computed tomography demonstrated tumor in the right main bronchus. Histopathological examination of the resected tumor demonstrated Ewing sarcoma family of tumors. No other lesions were detected throughout the body and the right main bronchus was thought to be the primary site. As of 1 year and 6 months after further resection of residual tumor followed by chemotherapy and radiotherapy, the patient remains disease-free. Conclusions: Extraosseous Ewing sarcoma family of tumors arises in soft tissues of the trunk or extremities, but primary endobronchial Ewing sarcoma family of tumors has rarely been reported. Although quite rare, Ewing sarcoma family of tumors should be considered among the differential diagnoses for pediatric bronchial tumor.

Hayakawa, Akira; Hirase, Satoshi; Matsunoshita, Natsuki; Yamamoto, Nobuyuki; Kubokawa, Ikuko; Mori, Takeshi; Yanai, Tomoko; Maniwa, Yoshimasa; Iijima, Kazumoto



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.



Perigastric extraskeletal Ewing's sarcoma: A case report  

PubMed Central

Ewing’s sarcoma (ES) is a neoplasm of undifferentiated small round cells, which occurs in the bones and deep soft tissues of children and adolescents. We present a rare case of a 44-year-old woman with gastric ES presenting with epigastric pain and weight loss. Ultrasound and computed tomography scans indicated a solid/cystic mass in the pancreatic tail. At laparotomy, the tumor was found attached to the posterior surface of the stomach, completely free from the pancreas, with no lymphadenopathy or local metastases. The polynodal, partly pseudocystic, dark-red soft tumor was excised. Histopathology revealed an anaplastic small-round-cell tumor with strong membranous CD99 immunoexpression. Additionally, there was patchy immunostaining for S-100 protein, vimentin, protein gene product (PGP) 9.5 and neuron-specific enolase, and weak focal CD117 cytoplasmic immunoreactivity. The patient had no adjuvant chemotherapy; her postoperative recovery was uneventful, and she remains symptom-free, and without any sign of recurrence at 20 mo. To the best of our knowledge, this is only the third ever case of gastric ES.

Colovic, Radoje B; Grubor, Nikica M; Micev, Marjan T; Matic, Slavko V; Atkinson, Henry Dushan Edward; Latincic, Stojan M



Molecular Pathogenesis of Ewing Sarcoma: New Therapeutic and Transcriptional Targets  

PubMed Central

Approximately one-third of sarcomas contain specific translocations. Ewing sarcoma is the prototypical member of this group of sarcomas; it was the first to be recognized pathologically as a singular entity and to have its signature translocation defined cytogenetically, which led to the identification of its key driver alteration, the EWS-FLI1 gene fusion that encodes this aberrant, chimeric transcription factor. Here, we review recent progress in selected areas of Ewing sarcoma research, including the application of genome-wide chromatin immunoprecipitation analyses, to provide a comprehensive view of the EWS-FLI1 target gene repertoire, the identification of EWS-FLI1 target genes that may also point to therapeutically targetable pathways, and data from model systems as they relate to the elusive cell of origin of Ewing sarcoma and its possible similarities to mesenchymal stem cells.

Lessnick, Stephen L.; Ladanyi, Marc



Intradural Extramedullary Ewing's Sarcoma. Recurrence with Acute Clinical Presentation and Literature Review.  


The intradural extramedullary space is an extremely unusual site for the onset of Ewing's sarcoma. We describe a case of recurrence of intradural extramedullary Ewing's sarcoma and review the literature available on this topic. PMID:24007736

Bazzocchi, Alberto; Bacci, Antonella; Serchi, Elena; Salerno, Angela; Salizzoni, Eugenio; Leonardi, Marco



Recent Advances in the Molecular Pathogenesis of Ewing's Sarcoma  

PubMed Central

Tumor development is a complex process resulting from interplay between mutations in oncogenes and tumor suppressors, host susceptibility factors, and cellular context. Great advances have been made by studying rare tumors with unique clinical, genetic, or molecular features. Ewing's sarcoma serves as an excellent paradigm for understanding tumorigenesis because it exhibits some very useful and important characteristics. For example, nearly all cases of Ewing's sarcoma contain the (11;22)(q24;q12) chromosomal translocation that encodes the EWS/FLI oncoprotein. Besides the t(11;22), however, many cases have otherwise simple karyotypes with no other demonstrable abnormalities. Furthermore, it appears that an underlying genetic susceptibility to Ewing's sarcoma, if it exists, must be rare. These two features suggest that EWS/FLI is the primary mutation that drives the development of this tumor. Finally, Ewing's sarcoma is an aggressive tumor that requires aggressive treatment. Thus, improved understanding of the pathogenesis of this tumor will not only be of academic interest, but may also lead to new therapeutic approaches for individuals afflicted with this disease. The purpose of this review is to highlight recent advances in understanding the molecular pathogenesis of Ewing's sarcoma, while considering the questions surrounding this disease that still remain and how this knowledge may be applied to developing new treatments for patients with this highly-aggressive disease.

Toomey, Elizabeth C.; Schiffman, Joshua D.; Lessnick, Stephen L.



Dendritic cell-Ewing's sarcoma cell hybrids enhance antitumor immunity.  


Given the effective immunotherapy of DC-based vaccine in other cancers, we hypothesized DC-based vaccines would induce effective immune responses against Ewing's sarcoma. To verify this hypothesis and develop the most effective dendritic cell vaccine against Ewing's sarcoma, we evaluated the antitumor efficacy of dendritic cell-Ewing's sarcoma hybrids and dendritic cells pulsed with other antigen-loading methods, including cell lysates and the characteristic EWS-FLI1 gene of Ewing's sarcoma, using an A673 cell line as a model. The hybrids were generated by electrofusion with fusion efficiency and viability determined by flow cytometry and fluorescent microscopy analyses. By interferon-gamma secretion assay, the capacity of hybrids to stimulate cytotoxic T-lymphocytes (CTLs) is higher than that of other antigen-loading methods showing stronger tumor antigen-specific CTL cytotoxicity to A673. By in vivo experiment in SCID mice, all dendritic cell-based strategies induced specific immune responses to Ewing's sarcoma after mice-human immune system reconstitution by inoculating human peripheral blood mononuclear cells into the peritoneal cavity of SCID mice. However, the hybrids most inhibited the subcutaneous tumor growth in SCID mice compared with dendritic cells pulsed with other loading methods. The data suggest A673 cells respond to dendritic cell-based immunotherapy. PMID:18563501

Guo, Wei; Guo, Yi; Tang, Shun; Qu, Huayi; Zhao, Hui



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


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



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



Metastasis from scapular Ewing's sarcoma presenting as sutural diastasis: An unusual presentation  

PubMed Central

Ewing’s sarcoma is a malignant non-osteogenic primary tumor of the bone. It is one of the most common primary malignant tumors of bone. Peak incidence is noticed in second decade of life with male preponderance of 1.6:1. It occurs most frequently in long bones and flat bones of pelvic girdles. In 30% cases, Ewing’s sarcoma is multicentric in origin. In 14-50%, multiple metastases are present at the time of diagnosis. CNS spread is rare and isolated CNS involvement is not seen. Skull metastasis of Ewing’s sarcoma is not rare compared to primary Ewing’s sarcoma of the skull, but the actual frequency is unknown. We wish to report a case of “Primary Ewing’s sarcoma of scapula with metastasis to Skull Vault in a Child resulting in sutural diastasis” diagnosed by clinicoradiological examination and confirmed by histopathology.

Asif, Naiyer; Khan, Abdul Qayyum; Siddiqui, Yasir Salam; Mustafa, Hamid



Preferential down-regulation of phospholipase C-? in Ewing’s sarcoma cells transfected with antisense EWS-Fli-1  

Microsoft Academic Search

EWS-Fli-1, a fusion gene found in Ewing’s sarcoma and primitive neuro-ectodermal tumour (PNET), encodes a transcriptional activator and promotes cellular transformation. We have made stable Ewing’s sarcoma cells expressing antisense EWS-Fli-1 transcripts by transfecting the antisense EWS-Fli-1 expression plasmid. These cells showed partial loss of endogenous EWS-Fli-1 proteins and suppression of the cell growth. To elucidate the molecular mechanisms underlying

T Dohjima; T Ohno; Y Banno; Y Nozawa; Y Wen-yi; K Shimizu



Primary Ewing's sarcoma of the spine presenting as acute paraplegia  

PubMed Central

Ewing's sarcoma is a primary bone malignancy with the highest incidence in the second decade of life. Although it mostly affects the metaphyseal region of long growing bones, involvement of spine is not very uncommon especially the sacrum. Nonsacral spinal Ewing's sarcoma is rarer and often mimics a benign condition before spreading extensively. They present with neurologic deficits due to spinal cord compression, but acute onset paraplegia has not been previously reported. A high index of clinical suspicion can clinch the diagnosis early in the course of the disease. A prompt intervention is required to keep neurological damage to a minimum, and a correct combination of surgery, chemotherapy, and radiotherapy is required for better long-term patient outcome. We report a 16-year-old female who presented with acute paraplegia and had an excellent postoperative outcome after radical excision of a D9 Ewing's sarcoma.

Gopalakrishnan, C. V.; Shrivastava, Adesh; Easwer, H. V.; Nair, Suresh



Copy Number Alterations and Methylation in Ewing's Sarcoma  

PubMed Central

Ewing's sarcoma is the second most common bone malignancy affecting children and young adults. The prognosis is especially poor in metastatic or relapsed disease. The cell of origin remains elusive, but the EWS-FLI1 fusion oncoprotein is present in the majority of cases. The understanding of the molecular basis of Ewing's sarcoma continues to progress slowly. EWS-FLI1 affects gene expression, but other factors must also be at work such as mutations, gene copy number alterations, and promoter methylation. This paper explores in depth two molecular aspects of Ewing's sarcoma: copy number alterations (CNAs) and methylation. While CNAs consistently have been reported in Ewing's sarcoma, their clinical significance has been variable, most likely due to small sample size and tumor heterogeneity. Methylation is thought to be important in oncogenesis and balanced karyotype cancers such as Ewing's, yet it has received only minimal attention in prior studies. Future CNA and methylation studies will help to understand the molecular basis of this disease.

Jahromi, Mona S.; Jones, Kevin B.; Schiffman, Joshua D.



Primary Ewing sarcoma of kidney in an elderly.  


Primary Ewing sarcoma of the kidney is a very rare neoplasm that generally occurs in young adults. We report a 69-year-old woman with a history of breast cancer who on a routine annual bone scan was found to have a suspicious area over the right kidney. Computed tomography revealed a 16 by 15-cm mass that was removed by a radical nephrectomy. Pathologic examination confirmed the diagnosis of Ewing sarcoma. Three months later, the patient developed recurrence of the tumor at the nephrectomy site that significantly regressed after chemotherapy. PMID:22797102

Pakravan, Ali; Vo, Thanh-Mai; Sandomirsky, Marianna; Bastani, Bahar



The treatment outcome for adult patients with Ewing's sarcoma.  


Ewing's sarcoma is the second most common bone malignancy in children, but is extremely rare in adults. The outcome of patients with localized disease has improved over the past decades due to better combination chemotherapies, and better methods of local control. Unfortunately, patients with metastatic disease have a very poor outcome with current antineoplastic therapies. In this article, we will review the primary treatment for adult patients with Ewing's sarcoma, both for localized and metastatic disease. The prognostic factors in adult patients with EWS will also be reviewed. PMID:23605781

Ganjoo, Kristen N; Patel, Shreyaskumar



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



Ewing Sarcoma: Its Course and Treatment in 50 Adult Patients  

Microsoft Academic Search

34 patients were treated for Ewing sarcoma with primary presentation. There were 10 females and 24 males with average age of 21 years (range 16–36 years). These patients received radiotherapy ( > 5,000 R) to the primary site and combination chemotherapy with vincristine, cyclophosphamide, doxorubicin and actino-mycin D. Of 19 patients with primary presentation in an extremity, 12 remain alive

J. G. Sinkovics; C. Plager; A. G. Ayala; R. D. Lindberg; M. L. Samuels



18F-FLT Positron Emission Tomography and Diffusion-Weighted Magnetic Resonance Imaging in Planning Surgery and Radiation Therapy and Measuring Response in Patients With Newly Diagnosed Ewing Sarcoma

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



FOXM1 is an oncogenic mediator in Ewing Sarcoma.  


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



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.



Ewing's sarcoma of the ilium mimicking inflammatory arthritis of the hip: a case report  

PubMed Central

Introduction Ewing’s sarcoma is second most common primary malignant bone neoplasm in children and adolescents. We report a case of Ewing’s sarcoma of ilium in an 18-year-old female mimicking clinically and radiologically inflammatory arthritis of hip joint, a rare entity not mentioned in literature. Case presentation An 18-year-old girl presented with pain hip, limp and fever off and on. Patient had restricted range of motion, raised erythrocyte sedimentation rate, leucocytosis and radiograph showed reduced joint space. Magnetic resonance imaging pelvis revealed an altered marrow signal of acetabulum with a large soft tissue component. Histopathology revealed a malignant round cell tumor consistent with Ewing’s sarcoma. Conclusion Classical clinical and radiological presentation of Ewing’s sarcoma of ilium may not be the rule. One should be highly suspicious of the disease even if there is no direct pointer to the disease as was encountered in our case.

Halwai, Manzoor Ahmed; Mir, Bashir Ahmed; Bashir, Arshad; Hussain, Anwar



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



Gastropleural fistula: a rare complication of ewing sarcoma.  


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. PMID:24003412

Bozkurt, Mehmet Abdussamet; Köne?, Osman; Ba?o?lu, Irfan; Al??, Halil



Primary extraosseous intradural spinal Ewing's sarcoma: report of two cases.  


Two cases of primary extraosseous intradural spinal Ewing's sarcoma are reported with a review of the current literature. This rare neoplasm shares features with cerebral primitive neuroectodermal tumors, complicating a correct diagnosis. Gross total resection seems to be the main treatment, although adjuvant therapies could improve the prognosis. In case 1, a 56-year-old man presented with cauda equina syndrome. MRI showed an intradural tumor from L4 to S2. An emergency laminectomy was performed with gross total resection of a hemorrhagic tumor, followed by adjuvant treatment. In the second case, a 25-year-old female developed leg and lumbar pain. MRI study identified a homogeneously enhancing intradural mass at the L2-L3 level. A laminoplasty was performed, followed by tumor resection; no adjuvant treatment was administered afterwards. Immunohistochemical workup confirmed the diagnosis of Ewing's sarcoma in both cases. PMID:23686630

Pancucci, Giovanni; Simal-Julian, Juan Antonio; Plaza-Ramirez, Estela; García-Marcos, Raul; Mayordomo-Aranda, Empar; Botella-Asunción, Carlos



Extraskeletal Ewing's sarcoma presenting as a posterior mediastinal mass.  


The Ewing's sarcoma family of tumors is an uncommon group of malignant neoplasms that may be located in both skeletal and extraskeletal regions. Extraskeletal Ewing's sarcoma (EES) is quite rare and predominantly involves the soft tissues of the trunk or the extremities. Herein, we report the case of a 19-year-old female patient who complained of left arm pain. Simple chest radiography revealed an opacity occupying almost the entire left hemithorax. Diagnostic imaging techniques demonstrated a solid contrast-enhanced mass in the posterior mediastinum. There was an evident mediastinal shift, and the left lung was collapsed. Even though lymphoma was considered as an initial diagnosis, a biopsy was taken and its histopathological analysis revealed EES. In the literature, there have been only a few case reports of ESS located in the mediastinum. We conclude that, although this is an unusual location, EES should be contemplated in the differential diagnosis of mediastinal masses. PMID:22575810

Halefoglu, Ahmet Mesrur



Ewing sarcoma: clinical state-of-the-art.  


Ewing sarcoma, a rare malignancy of childhood and adolescence, has become a model of advances in diagnosis, treatment, and outcome through long-standing research efforts in multinational clinical trials. With modern multimodal regimens consisting of local surgery and/or radiotherapy plus intensive systemic chemotherapy, survival can be achieved for ? 70% of patients with localized disease. However, in the last decade, improvement in survival curves has slowed down. Also, a relapse rate of ? 30% remains unacceptable, since salvage strategies for Ewing sarcoma recurrence are discouraging and prognosis is unfavorable in most cases. Metastatic disease at diagnosis poses a similar challenge, since even if remission is achieved, relapse frequently occurs despite the most intensive treatment. Urgently needed, novel biology-driven treatment options are now beginning to emerge on the horizon, but have not yet reached the standard of care. An overview of the current clinical state-of-the-art is provided in this article. PMID:22295994

Potratz, Jenny; Dirksen, Uta; Jürgens, Heribert; Craft, Alan



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



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


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. PMID:23741264

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



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



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



Ewing Sarcoma Protein: A Key Player in Human Cancer  

PubMed Central

The Ewing sarcoma protein (EWS) is a well-known player in cancer biology for the specific translocations occurring in sarcomas. The EWS-FLI1 gene fusion is the prototypical translocation that encodes the aberrant, chimeric transcription factor, which is a landmark of Ewing tumors. In all described Ewing sarcoma oncogenes, the EWS RNA binding domains are completely missing; thus RNA binding properties are not retained in the hybrid proteins. However, it is currently unknown whether the absence of EWS function in RNA metabolism plays a role in oncogenic transformation or if EWS plays a role by itself in cancer development besides its contribution to the translocation. In this regard, recent reports have highlighted an essential role for EWS in the regulation of DNA damage response (DDR), a process that counteracts genome stability and is often deregulated in cancer cells. The first part of this review will describe the structural features of EWS and its multiple roles in the regulation of gene expression, which are exerted by coordinating different steps in the synthesis and processing of pre-mRNAs. The second part will examine the role of EWS in the regulation of DDR- and cancer-related genes, with potential implications in cancer therapies. Finally, recent advances on the involvement of EWS in neuromuscular disorders will be discussed. Collectively, the information reviewed herein highlights the broad role of EWS in bridging different cellular processes and underlines the contribution of EWS to genome stability and proper cell-cycle progression in higher eukaryotic cells.



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


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



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



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


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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:23878072

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



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



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

PubMed Central

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 identify kinase targets involved in growth and survival of Ewing's sarcoma cells. Results Four Ewing's sarcoma cell lines TC-32, TC-71, SK-ES-1 and RD-ES were tested in high throughput-RNAi screens using a siRNA library targeting 572 kinases. Knockdown of 25 siRNAs reduced the growth of all four Ewing's sarcoma cell lines in replicate screens. Of these, 16 siRNA were specific and reduced proliferation of Ewing's sarcoma cells as compared to normal fibroblasts. Secondary validation and preliminary mechanistic studies highlighted the kinases STK10 and TNK2 as having important roles in growth and survival of Ewing's sarcoma cells. Furthermore, knockdown of STK10 and TNK2 by siRNA showed increased apoptosis. Conclusion In summary, RNAi-based phenotypic profiling proved to be a powerful gene target discovery strategy, leading to successful identification and validation of STK10 and TNK2 as two novel potential therapeutic targets for Ewing's sarcoma.



The first European interdisciplinary ewing sarcoma research summit.  


The European Network for Cancer Research in Children and Adolescents (ENCCA) provides an interaction platform for stakeholders in research and care of children with cancer. Among ENCCA objectives is the establishment of biology-based prioritization mechanisms for the selection of innovative targets, drugs, and prognostic markers for validation in clinical trials. Specifically for sarcomas, there is a burning need for novel treatment options, since current chemotherapeutic treatment protocols have met their limits. This is most obvious for metastatic Ewing sarcoma (ES), where long term survival rates are still below 20%. Despite significant progress in our understanding of ES biology, clinical translation of promising laboratory results has not yet taken place due to fragmentation of research and lack of an institutionalized discussion forum. To fill this gap, ENCCA assembled 30 European expert scientists and five North American opinion leaders in December 2011 to exchange thoughts and discuss the state of the art in ES research and latest results from the bench, and to propose biological studies and novel promising therapeutics for the upcoming European EWING2008 and EWING2012 clinical trials. PMID:22662320

Kovar, Heinrich; Alonso, Javier; Aman, Pierre; Aryee, Dave N T; Ban, Jozef; Burchill, Sue A; Burdach, Stefan; De Alava, Enrique; Delattre, Olivier; Dirksen, Uta; Fourtouna, Argyro; Fulda, Simone; Helman, Lee J; Herrero-Martin, David; Hogendoorn, Pancras C W; Kontny, Udo; Lawlor, Elizabeth R; Lessnick, Stephen L; Llombart-Bosch, Antonio; Metzler, Markus; Moriggl, Richard; Niedan, Stephan; Potratz, Jenny; Redini, Françoise; Richter, Günther H S; Riedmann, Lucia T; Rossig, Claudia; Schäfer, Beat W; Schwentner, Raphaela; Scotlandi, Katia; Sorensen, Poul H; Staege, Martin S; Tirode, Franck; Toretsky, Jeffrey; Ventura, Selena; Eggert, Angelika; Ladenstein, Ruth



The First European Interdisciplinary Ewing Sarcoma Research Summit  

PubMed Central

The European Network for Cancer Research in Children and Adolescents (ENCCA) provides an interaction platform for stakeholders in research and care of children with cancer. Among ENCCA objectives is the establishment of biology-based prioritization mechanisms for the selection of innovative targets, drugs, and prognostic markers for validation in clinical trials. Specifically for sarcomas, there is a burning need for novel treatment options, since current chemotherapeutic treatment protocols have met their limits. This is most obvious for metastatic Ewing sarcoma (ES), where long term survival rates are still below 20%. Despite significant progress in our understanding of ES biology, clinical translation of promising laboratory results has not yet taken place due to fragmentation of research and lack of an institutionalized discussion forum. To fill this gap, ENCCA assembled 30 European expert scientists and five North American opinion leaders in December 2011 to exchange thoughts and discuss the state of the art in ES research and latest results from the bench, and to propose biological studies and novel promising therapeutics for the upcoming European EWING2008 and EWING2012 clinical trials.

Kovar, Heinrich; Alonso, Javier; Aman, Pierre; Aryee, Dave N. T.; Ban, Jozef; Burchill, Sue A.; Burdach, Stefan; De Alava, Enrique; Delattre, Olivier; Dirksen, Uta; Fourtouna, Argyro; Fulda, Simone; Helman, Lee J.; Herrero-Martin, David; Hogendoorn, Pancras C. W.; Kontny, Udo; Lawlor, Elizabeth R.; Lessnick, Stephen L.; Llombart-Bosch, Antonio; Metzler, Markus; Moriggl, Richard; Niedan, Stephan; Potratz, Jenny; Redini, Francoise; Richter, Gunther H. S.; Riedmann, Lucia T.; Rossig, Claudia; Schafer, Beat W.; Schwentner, Raphaela; Scotlandi, Katia; Sorensen, Poul H.; Staege, Martin S.; Tirode, Franck; Toretsky, Jeffrey; Ventura, Selena; Eggert, Angelika; Ladenstein, Ruth



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.



Radiotherapy for Lung Metastases in a Patient With Ewing Sarcoma  

PubMed Central

Purpose. To assess the benefit of therapy for multiple lung metastases in a young female patient previously treated with operation, local radiotherapy and chemotherapy. Patient: Lung metastases occurred in a young female patient 13 months after finishing combined treatment of a Ewing sarcoma of the left eleventh rib. Primary treatment had included surgical removal, 51 Gy local radiotherapy and chemotherapy. Method. 20 Gy total dose was applied to the lungs of both sides in two courses with an additional 15 Gy to the mediastinum. Results and Discussion. Complete radiological regression was achieved at the end of therapy which was maintained during the follow-up period of 16 months.

Naszaly, A.



Pulmonary Coccidiomycosis Masquerading as Refractory Metastatic Ewing Sarcoma.  


We report the case of a patient who presented with a large pelvic mass, which was biopsy-proven to be Ewing sarcoma. The patient was also found to have 18 pulmonary lesions on a staging CT that were presumed to represent metastatic disease. After induction chemotherapy, a PET/CT scan revealed a marked reduction in his pelvic mass along with improvement in nearly all his pulmonary lesions except 2, which increased in size. The mixed response to chemotherapy was unusual and the decision was made to resect one of the growing lesions. Fungal culture from the excised lesion grew Coccidioides immitis. PMID:23588326

Stieglitz, Elliot; Hsiang, Michelle S; Simko, Jeffry P; Hirose, Shinjiro; Goldsby, Robert E



Skull-base Ewing sarcoma with multifocal extracranial metastases.  


Intracranial occurrence of Ewing sarcoma (ES) is unusual, with a skull-base location being anecdotal. We report a 29-year-old man who presented with rapidly progressive ophthalmoplegia, and was found to be harboring an infiltrative lesion involving the sphenoid sinus, sella, and clivus. He underwent trans-sphenoidal decompression of the lesion which was histologically suggestive of ES. He developed paraparesis 2 weeks after commencing adjuvant therapy. Imaging revealed two thoracic extradural lesions and florid vertebral and pulmonary metastases. This is the first report in indexed literature of a primary intracranial ES on the skull-base with disseminated extracranial disease. PMID:23361288

Thakar, Sumit; Furtado, Sunil; Ghosal, Nandita; Dilip, Jethwani; Mahadevan, Anita; Hegde, Alangar


NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma.  


Ewing sarcoma is a high-grade round cell sarcoma that affects bones and soft tissues in children and young adults. Its diagnosis can be challenging, and the differential diagnoses include a wide variety of small round cell tumors. CD99 and FLI-1 are the currently accepted immunohistochemical markers for Ewing sarcoma, but their accuracy has been controversial. NKX2.2 is a homeodomain-containing transcription factor that plays a critical role in neuroendocrine/glial differentiation. The NKX2.2 gene was recently identified as a target of EWS-FLI-1, the fusion protein specific to Ewing sarcoma, and was shown to be differentially upregulated in Ewing sarcoma on the basis of array-based gene expression analysis. However, the immunohistochemical diagnostic potential of this marker has not been tested. We immunostained representative sections of 30 genetically confirmed Ewing sarcomas and 130 non-Ewing small round cell tumors by using an antibody to NKX2.2. Nuclear staining in at least 5% of the cells was deemed positive. Twenty-eight (93%) of the 30 Ewing sarcomas were positive for NKX2.2. The staining was diffuse (>50%) in all the positive cases and was moderate or strong in intensity for most cases (25 of 28). NKX2.2 was also positive in 14 non-Ewing tumors, including all the olfactory neuroblastomas and a minor subset of small cell carcinomas, synovial sarcomas, mesenchymal chondrosarcomas, and malignant melanomas. All the other non-Ewing tumors tested were negative for this marker. NKX2.2 is a valuable marker for Ewing sarcoma, with a sensitivity of 93% and a specificity of 89%, and aids in the differential diagnosis of small round cell tumors. PMID:22446943

Yoshida, Akihiko; Sekine, Shigeki; Tsuta, Koji; Fukayama, Masashi; Furuta, Koh; Tsuda, Hitoshi



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: [Department of Radiation Oncology, Massachusetts General Hospital-Harvard Medical School, Boston, MA (United States)



Primary Ewing’s sarcoma of cranial bones: analysis of ten patients  

Microsoft Academic Search

Objective  Ewing’s sarcomas are the second most common bone tumors in children and primary involvement of the cranium is uncommon. We\\u000a analyzed retrospectively the data of ten patients with this rare subset of disease, who had been treated at our institute\\u000a since 2005. Our aim was to assess the outcomes, recurrence rates and the selection of appropriate treatment methods.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  The patients

Pravin Shashikant Salunke; Kirti Gupta; Vinod Malik; Narendra Kumar; Lauren E. Henke; Chunyu Cai; Wei-Shen Chen; John D. Pfeifer



Pathology of Ewing's sarcoma/PNET: Current opinion and emerging concepts  

PubMed Central

Ewing’s sarcoma/PNET are small round cell tumors showing a varying degree of neuroectodermal differentiation. They are one of the commonest tumors of childhood and occur in bone and within soft tissues. Traditionally, light microscopy with the aid of immunohistochemical stains was suitable for diagnosis. But now translocation analyses are being used not only for the diagnosis and classification of small round cell tumors, but to ascertain their prognostic significance, detect micrometastasis, and monitor minimal residual disease, with potential for targeted therapy. This article analyzes the pathology, biology, and molecular aspects of Ewing’s sarcoma/PNET and discusses their clinical and therapeutic implications.

Desai, Saral S; Jambhekar, Nirmala A



Neutrality of miniSTR D22S1045 marker by Ewing's sarcoma phenotype.  


Neutrality investigations of markers with forensic use are important to see if a phenotypic trait is being expressed in relation to the alleles of the marker. MiniSTR marker D22S1045 (locus 22q12.3) is localized near the breakpoint region of the EWS gene (22q12.2), which leads to the development of Ewing's Sarcoma. Analyzing allele frequencies and linkage disequilibrium in Ewing's sarcoma patients and non-affected populations, we found that the marker mD22S1045 was neutral when related to Ewing's Sarcoma. PMID:24112992

Silva, Deborah S B S; Raimann, Paulo E; Moro, Tatiane; Picanço, Juliane B; Abujamra, Ana L; de Farias, Caroline B; Roesler, Rafael; Brunetto, Algemir L; Alho, Clarice S



Vaginal metastasis of a Ewing Sarcoma five years after resection of the primary tumor.  


A 35-year-old female presented with pain and swelling of the left wrist. A diagnosis of Ewing sarcoma was made and she underwent neoadjuvant chemotherapy and surgery. Macroscopic viable areas remained on the map of the surgical specimen; as such, she was classified as a poor responder and received high dose adjuvant chemotherapy. She remained disease-free for five years, until age 40. A vaginal polyp was then detected during a routine gynaecologic examination. It was removed and histopathology revealed metastatic Ewing sarcoma. To our knowledge, this is the first reported case of a vaginal metastasis of Ewing sarcoma. PMID:22612902

Vanel, Noemie; Vierling, Victoire; Kreshak, Jennifer; Gambarotti, Marco; Cocchi, Stefania; Tranfaglia, Cristina; Vanel, Daniel



Vaginal metastasis of a Ewing sarcoma five years after resection of the primary tumor  

PubMed Central

A 35-year-old female presented with pain and swelling of the distal left radius. A diagnosis of Ewing sarcoma was made and she underwent neoadjuvant chemotherapy and surgery. Macroscopic viable areas remained on the map of the surgical specimen; as such, she was classified as a poor responder and received high dose adjuvant chemotherapy. She remained disease-free for five years, until age 40. A vaginal polyp was then detected during a routine gynaecologic examination. It was removed and histopathology revealed metastatic Ewing sarcoma. To our knowledge, this is the first reported case of a vaginal metastasis of Ewing sarcoma.



A novel role for keratin 17 in coordinating oncogenic transformation and cellular adhesion in ewing sarcoma.  


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. PMID:24043308

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



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.



Cardiac metastases of Ewing sarcoma detected by 18F-FDG PET/CT.  


Positron emission tomography (PET) is widely used in the diagnostic evaluation and staging of different malignant tumors. The role of PET/computed tomographic scan in detecting distant metastases in the workup of Ewing sarcoma in children or young adults is less well defined. We report a case of a boy affected by a metastatic Ewing sarcoma with cardiac asymptomatic metastasis detected by F-FDG PET/computed tomography. PMID:22395217

Coccia, Paola; Ruggiero, Antonio; Rufini, Vittoria; Maurizi, Palma; Attinà, Giorgio; Marano, Riccardo; Natale, Luigi; Leccisotti, Lucia; Calcagni, Maria L; Riccardi, Riccardo



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



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



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.



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.



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



The Tre2 Oncoprotein, Implicated in Ewing’s Sarcoma, Interacts with Two Components of the Cytoskeleton  

Microsoft Academic Search

The product of the Tre2 oncogene, structurally related to the Ypt\\/RabGTPase-activating proteins (Ypt\\/RabGAP), is involved in various human cancers,\\u000a including Ewing’s sarcoma. In order to identify proteins interacting with the GAP part of this protein, we performed yeast\\u000a two-hybrid screening of two libraries. Two components of the cytoskeleton were thus identified, whose interaction with the\\u000a GAP region was confirmed by

Christophe Dechamps; Stephane Bach; Daniel Portetelle; Micheline Vandenbol



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

Microsoft Academic Search

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

Bharat Rekhi; Sajid Qureshi; Ranjan Basak; Sangeeta B Desai; Seema Medhi; Purna Kurkure; Santosh Menon; Amita Maheshwari; Nirmala A Jambhekar



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



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



Small cell osteosarcoma with Ewing sarcoma breakpoint region 1 gene rearrangement detected by interphase fluorescence in situ hybridization.  


Because of its characteristic morphologic appearance, small cell osteosarcoma (SCO) can be confused with other small round cell malignancies of the bone, most importantly with Ewing sarcoma, making this distinction difficult. A specific tool used in separating SCO from Ewing sarcoma has been the detection of Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangements in Ewing sarcoma and their absence in SCO. However, there are rare case reports that have documented the existence of EWSR1 gene rearrangement in SCO. In this report, we describe another case of SCO with an EWSR1 gene rearrangement detected by interphase fluorescence in situ hybridization. Our finding adds support to the existing evidence that SCO is a tumor that can be characterized by EWSR1 gene arrangements. Therefore, we caution the pathology community not to rely solely on molecular studies in distinguishing SCO from Ewing sarcoma. PMID:22971270

Dragoescu, Ema; Jackson-Cook, Colleen; Domson, Gregory; Massey, Davis; Foster, William C



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



Ewing's Sarcoma: Development of RNA Interference-Based Therapy for Advanced Disease  

PubMed Central

Ewing's sarcoma tumors are associated with chromosomal translocation between the EWS gene and the ETS transcription factor gene. These unique target sequences provide opportunity for RNA interference(i)-based therapy. A summary of RNAi mechanism and therapeutically designed products including siRNA, shRNA and bi-shRNA are described. Comparison is made between each of these approaches. Systemic RNAi-based therapy, however, requires protected delivery to the Ewing's sarcoma tumor site for activity. Delivery systems which have been most effective in preclinical and clinical testing are reviewed, followed by preclinical assessment of various silencing strategies with demonstration of effectiveness to EWS/FLI-1 target sequences. It is concluded that RNAi-based therapeutics may have testable and achievable activity in management of Ewing's sarcoma.

Simmons, Olivia; Maples, Phillip B.; Senzer, Neil; Nemunaitis, John



Huntsman Cancer Institute researchers discover possible new treatment for Ewing sarcoma

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.


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



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



Ewing sarcoma of the tibia mimicking fibrous dysplasia.  


Ewing sarcoma (ES) family of tumors is the second most common primary bone malignancy in children. It usually presents as an aggressive looking lesion often located in the meta-diaphyseal region of long bones, with bone destruction, permeation, cortical thinning and/or destruction, periosteal reaction, and large soft-tissue mass. The purpose of this study is to illustrate the occurrence of a fibrous dysplasia (FD)-appearing ES of the tibia. These cases underscore the potential difficulties encountered in the diagnosis of ES. In this study, we performed a retrospective review of children who presented with an otherwise benign-appearing lesion of the tibia, suggestive of FD, which proved to be ES after biopsy. As a result, all patients presented with a history of indolent lower extremity pain of several months of duration, without significant swelling or constitutional symptoms. Plain films revealed an otherwise benign-appearing/FD-like lesion without bone destruction and mild cortical thinning, little or no periosteal reaction. Magnetic resonance imaging revealed the intramedullary extension of the lesion without significant cortical or periosteal involvement and no soft tissue mass. Lesions were hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging. All patients underwent open incisional biopsy and after cytogenetic and molecular studies, the diagnosis of ES was confirmed. We conclude that ES is a deadly malignant tumor if left untreated or if mismanaged. Although it usually presents as an aggressive-looking lesion, at times it may mimic FD and has a benign-looking appearance, making the diagnosis unlikely and challenging. Summation of these cases demonstrates that the potential reasons for misdiagnoses include a low level of suspicion, an atypical site occurrence, a benign radiographic appearance, and a lack of or insufficient histologic specimens. PMID:22094991

Arkader, Alexandre; Myung, Karen S; Stanley, Philip; Mascarenhas, Leo



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



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


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



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


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. PMID:23178492

Sankar, S; Bell, R; Stephens, B; Zhuo, R; Sharma, S; Bearss, D J; Lessnick, S L



Targeting the Insulin-Like Growth Factor 1 Receptor in Ewing's Sarcoma: Reality and Expectations  

PubMed Central

Ewing's sarcoma family of tumours comprises a group of very aggressive diseases that are potentially curable with multimodality treatment. Despite the undoubted success of current treatment, approximately 30% of patients will relapse and ultimately die of disease. The insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the genesis, growth, proliferation, and the development of metastatic disease in Ewing's sarcoma. In addition, IGF1-R has been validated, both in vitro and in vivo, as a potential therapeutic target in Ewing's sarcoma. Phase I studies of IGF-1R monoclonal antibodies reported several radiological and clinical responses in Ewing's sarcoma patients, and initial reports of several Phase II studies suggest that about a fourth of the patients would benefit from IGF-1R monoclonal antibodies as single therapy, with approximately 10% of patients achieving objective responses. Furthermore, these therapies are well tolerated, and thus far severe toxicity has been rare. Other studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies are expected. Despite, the initial promising results, not all patients benefit from IGF-1R inhibition, and consequently, there is an urgent need for the identification of predictive markers of response.

Olmos, David; Martins, Ana Sofia; Jones, Robin L.; Alam, Salma; Scurr, Michelle; Judson, Ian R.



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

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.


BCL11B Is Up-Regulated by EWS/FLI and Contributes to the Transformed Phenotype in Ewing Sarcoma  

PubMed Central

The EWS/FLI translocation product is the causative oncogene in Ewing sarcoma and acts as an aberrant transcription factor. EWS/FLI dysregulates gene expression during tumorigenesis by abnormally activating or repressing genes. The expression levels of thousands of genes are affected in Ewing sarcoma, however, it is unknown which of these genes contribute to the transformed phenotype. Here we characterize BCL11B as an up-regulated EWS/FLI target that is necessary for the maintenance of transformation in patient derived Ewing sarcoma cells lines. BCL11B, a zinc finger transcription factor, acts as a transcriptional repressor in Ewing’s sarcoma and contributes to the EWS/FLI repressed gene signature. BCL11B repressive activity is mediated by the NuRD co-repressor complex. We further demonstrate that re-expression of SPRY1, a repressed target of BCL11B, limits the transformation capacity of Ewing sarcoma cells. These data define a new pathway downstream of EWS/FLI required for oncogenic maintenance in Ewing sarcoma.

Wiles, Elizabeth T.; Lui-Sargent, Bianca; Bell, Russell; Lessnick, Stephen L.



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

PubMed Central

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.

Jedlicka, Paul



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


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



Establishment and characterization of a clonal human extraskeletal Ewing's sarcoma cell line, EES1.  


Ewing's sarcoma, a small round cell sarcoma arising in soft tissue as well as the bone, is one of the most malignant tumors in children and young adults. Few established cell lines of extraskeletal Ewing's sarcoma (EES) have been reported, which made it difficult to examine the biological features of EES. Therefore, we have established a new clonal cell line of EES. We report its morphological characters, results of chromosomal and immunohistochemical analysis. A piece of tumor obtained from the 18-year-old female patient with EES was xenografted in a nude mouse. In vitro subcultured cells were then obtained from this xenograft. A clonal cell line was subsequently established by limiting dilution and designated EES1. EES1 cells had a doubling time of 24 hours. In the xenografted tumor, the cells expressed vimentin, CD99 (MIC2), neuron specific enolase (NSE) and cytokeratin. The original tumor cells also expressed vimentin, CD 99, and NSE, but was negative for cytokeratin. The morphological and immunohistochemical features of this cell line established, except for cytokeratin expression, were consistent with those of the primary tumor. Cytogenetic analysis of EES1 revealed chromosomal translocation of t(11; 12)(q24;ql2). The chimeric fusion of the Ewing's sarcoma gene in band 22q12 with the Friend leukemia virus integration-1 gene in band 11q24 was also demonstrated. Fluorescence in situ hybridization further confirmed the presence of translocation involving the Ewing's sarcoma gene in both the primary tumor and EES1 cells. In conclusion, we have established a human EES cell line EES1, which will provide a useful model for studying various aspects of human EES. PMID:17077599

Hatori, Masahito; Doi, Hideyuki; Watanabe, Mika; Sasano, Hironobu; Hosaka, Masami; Kotajima, Satoshi; Urano, Fumihiko; Hata, Junichi; Kokubun, Shoichi



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



Incidence and management of secondary malignancies in patients with retinoblastoma and Ewing's sarcoma  

SciTech Connect

Childhood cancer survivors at highest risk of developing a secondary malignancy are those with hereditary retinoblastoma. The majority of such secondary cancers will be sarcomas, most commonly of bone. One-third of these occur outside a typical radiation field, commonly in an extremity. Bone sarcoma is also the most commonly reported secondary cancer to develop among survivors of Ewing's sarcoma. In this group, radiation doses greater than 60 Gy as well as alkylating agent chemotherapy have been identified as contributors to the increased risk. The prognosis for patients with a secondary sarcoma has been poor, with few cures reported to date. However, an aggressive, combined modality approach, including radical resection, postoperative radiation, and adjuvant chemotherapy, may improve the survival rate.

Smith, L.M.; Donaldson, S.S. (Department of Radiation Oncology, Stanford University Medical Center, CA (United States))



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



Multimodal Treatment of Primary Extraskeletal Ewing's Sarcoma of the Chest Wall: Report of 2 Cases  

PubMed Central

Extraskeletal Ewing's sarcoma (EES) is a type of Ewing's sarcoma that arises in soft tissue and is now regarded as a member of a family of small round cell neoplasms of bone and soft tissue, including primitive neuroectodermal tumors (PNETs). EES occurs predominantly in adolescents and young adults between the ages of 10 and 30 years. The disease follows an aggressive course with a high recurrence rate. The presence of a distant metastasis is also common. EES arises in the soft tissue of either the trunk or extremities. We recently experienced two cases of EES that occurred in the chest wall. The two patients underwent wide resection and combined radiochemotherapy. There was no evidence of disease 30 and 22 months, respectively, after surgery. Although extremely rare, EES should be considered in the differential diagnosis of chest wall tumors. We report two cases of EES with a brief review of the literature.

Lee, Woo Surng; Chee, Hyun Keun; Hwang, Jae Joon; Kim, Jun Seok; Lee, Song Am; Hwang, Eun Gu; Cho, Yo Han; Chon, Gyu Rak



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


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



Differentiating Lymphoblastic Lymphoma and Ewing's Sarcoma: Lymphocyte Markers and Gene Rearrangement  

Microsoft Academic Search

We encountered a child with an intraosseous small round cell tumor that was negative for LCA, CD20 (L26), and CD3 and positive for vimentin, CD99 (MIC-2), and periodic acid-Schiff. The tumor exhibited rosette-like formations. This case was initially interpreted as Ewing's sarcoma (ES); however, additional studies revealed positivity for CD79a, CD43, and TdT expression, and an immunoglobulin heavy chain gene

Metin Ozdemirli; Julie C. Fanburg-Smith; Dan-Paul Hartmann; Norio Azumi; Markku Miettinen



Biochemical and Genetic Characterization of the HBA71 Ewing's Sarcoma Cell Surface Antigen1  

Microsoft Academic Search

Monoclonal antibody HBA71 detects a cell surface antigen of human Ewing's sarcomas and peripheral neuroepitheliomas that distinguishes these tumors from other small round cell tumors of childhood and adolescence. In the present study, we show that monoclonal antibody HBA71 reacts with polypeptides of M, 32,000 and 30,000 and that the HBA71-coding gene segregates with human chromosomes X and Y in

Erich J. Fellinger; Pilar Garin-Chesa; Sai L. Su; Paula DeAngelis; Wolfgang J. Rettig


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


EWS-FLI1 Suppresses NOTCH-Activated p53 in Ewing's Sarcoma  

Microsoft Academic Search

Although p53 is the most frequently mutated gene in cancer, half of human tumors retain wild-type p53, whereby it is unknown whether normal p53 function is compromised by other cancer-associated alterations. One example is Ewing's sarcoma family tumors (ESFT), where 90% express wild-type p53. ESFT are characterized by EWS-FLI1 oncogene fusions. Studying 6 ESFT cell lines, silencing of EWS-FLI1 in

Jozef Ban; Max Kauer; Karl-Ludwig Schaefer; Christopher Poremba; Gunhild Jug; Raphaela Schwentner; Oskar Smrzka; Karin Muehlbacher; Dave N. T. Aryee; Heinrich Kovar



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


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. PMID:24124617

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



Ewing sarcoma arising after treatment of diffuse large B-cell lymphoma.  


We report the case of a patient in whom the diagnosis of Ewing sarcoma arising from a soft tissue was made after successful treatment of diffuse large B-cell lymphoma. A 65-year-old woman presented with a rapidly growing mass in her left scapular region 8 years after successful chemotherapy with the cyclophosphamide, hydroxydaunomycin hydrochloride, vincristine, prednisolone regimen for diffuse large B-cell lymphoma. Computed tomographic examination and magnetic resonance imaging of the thorax revealed an intramuscular tumour measuring 40 mm in size in the left scapular region. Histopathological examination of an open biopsy specimen revealed a small round cell tumour that showed positive staining for CD99. Fluorescence in situ hybridization showed a split signal by a break-apart probe for the EWS gene in chromosome 22q12. Reverse transcriptase-polymerase chain reaction confirmed the expression of EWS-FLI1 fusion transcripts. Based on these findings, the patient was diagnosed as having secondary Ewing sarcoma. Despite adjuvant chemotherapy, however, she died of pulmonary metastases 2 years after the diagnosis of Ewing sarcoma. Therapy-related haematological malignancies with balanced translocations have been reported previously. A mechanism similar to that underlying the development of secondary malignancy might explain the occurrence of this solid cancer. PMID:23475435

Hiramoto, Nobuhiro; Kobayashi, Yukio; Nomoto, Junko; Maruyama, Dai; Watanabe, Takashi; Tochigi, Naobumi; Furuta, Koh; Takeda, Ken; Chuman, Hirokazu; Yagyu, Shigeki; Hosoi, Hajime; Tobinai, Kensei



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



Targeting of EWS\\/FLI-1 by RNA interference attenuates the tumor phenotype of Ewing's sarcoma cells in vitro  

Microsoft Academic Search

The defining cytogenetic abnormality of Ewing's sarcoma is the presence of a balanced t(11;22) translocation expressing the EWS\\/FLI-1 chimeric fusion protein. The effect of EWS\\/FLI-1 appears to be dominant negative since over-expression of EWS does not overcome the sarcoma phenotype. Previous studies have shown that EWS\\/FLI-1 as well as related sarcoma fusion proteins are necessary and sufficient to induce transformation

Howard A. Chansky; Fariba Barahmand-pour; Qi Mei; Waqqar Kahn-Farooqi; Anna Zielinska-Kwiatkowska; Michael Blackburn; Kari Chansky; Ernest U. Conrad; James D. Bruckner; Theodore K. Greenlee; Liu Yang



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.



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

PubMed Central

Background Cancer 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 relapse remains frequent and is usually fatal. Methodology/Principal Findings We have isolated a subpopulation of Ewing's sarcoma cells, from both human cell lines and human xenografts grown in immune deficient mice, which express high aldehyde dehydrogenase (ALDHhigh) activity and are enriched for clonogenicity, sphere-formation, and tumor initiation. The ALDHhigh cells are resistant to chemotherapy in vitro, but this can be overcome by the ATP binding cassette transport protein inhibitor, verapamil. Importantly, these cells are not resistant to YK-4-279, a small molecule inhibitor of EWS-FLI1 that is selectively toxic to Ewing's sarcoma cells both in vitro and in vivo. Conclusions/Significance Ewing's sarcoma contains an ALDHhigh stem-like population of chemotherapy-resistant cells that retain sensitivity to EWS-FLI1 inhibition. Inhibiting the EWS-FLI1 oncoprotein may prove to be an effective means of improving patient outcomes by targeting Ewing's sarcoma stem cells that survive standard chemotherapy.

Gul, Naheed; Katuri, Varalakshmi; O'Neill, Alison; Kong, Yali; Brown, Milton L.; Toretsky, Jeffrey A.; Loeb, David M.



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



Hemiarthroplasty of the Elbow with a Vascularized Fibular Graft after Excision of Ewing's Sarcoma of the Proximal Ulna: a Case Report  

Microsoft Academic Search

We report an 8-year-old girl with a Ewing's sarcoma in the right proximal ulna. The patient pre- sented with pain in her right elbow, and plain radiographs showed destructive changes with a periosteal reaction in the proximal third of the ulna. A biopsy confirmed the diagnosis of Ewing's sarcoma. For preoperative chemotherapy, the patient received two courses of vincristine, doxo-

Kenji Kimura; Shinichiro Tatezaki; Takeshi Ishii; Tsukasa Yonemoto; Takeo Shigehara



Expression of the EWS\\/FLI-1 Oncogene in Murine Primary Bone-Derived Cells Results in EWS\\/FLI-1Dependent, Ewing Sarcoma-Like Tumors  

Microsoft Academic Search

Ewing sarcoma is the second most common malignant pediatric bone tumor. Over 80% of Ewing sarcoma contain the oncogene EWS\\/FLI-1, which encodes the EWS\\/FLI-1 oncoprotein, a hybrid transcription factor comprised of NH2-terminal sequences from the RNA-binding protein EWS and the DNA-binding and COOH-terminal regions of the Ets transcription factor FLI-1. Although numerous genes are dysregulated by EWS\\/FLI-1, advances in Ewing

Yeny Castillero-Trejo; Susan Eliazer; Lilin Xiang; James A. Richardson



Unusual presentation of Ewing sarcoma in the adrenal gland: a secondary malignancy from a survivor of Burkitt lymphoma.  


The occurrence of Ewing sarcoma as a secondary malignancy is an extremely rare event in long-term cancer survivors. In addition, the occurrence of Ewing sarcoma in the adrenal gland is highly unusual. In this case report, we treated a 20-year-old male patient with cyclophosphamide, doxorubicin, vincristine, dexamethasone, and methotrexate and cytarabine chemotherapy following a diagnosis of Stage IV Burkitt lymphoma. Following complete remission, he had been maintained for 2 years without evidence of disease. However, a regular follow-up computed tomography scan found a left adrenal gland mass and a biopsy revealed positive membrane-localized mic-2 expression (CD99) and the presence of the translocation of the EWSR1 gene. To our knowledge, this is the first case report of Ewing sarcoma occurring in the adrenal gland of a patient who was treated with cyclophosphamide, doxorubicin, vincristine, dexamethasone/methotrexate and cytarabine chemotherapy for Burkitt lymphoma. PMID:23564674

Lim, Sung Hee; Lee, Ji Yoon; Lee, Ji Young; Kim, Ji Hoon; Choi, Ki Hong; Hyun, Ji Yeon; Ko, Young Hyeh; Lee, Jeeyun; Kim, Seok Jin; Kim, Won Seok



Divergent Ewing's sarcoma EWS\\/ETS fusions confer a common tumorigenic phenotype on NIH3T3 cells  

Microsoft Academic Search

Ewing's sarcomas express chimeric transcription factors resulting from a fusion of the amino terminus of the EWS gene to the carboxyl terminus of one of five ETS proteins. While the majority of tumors express EWS\\/FLI1 fusions, some Ewing's tumors contain variant chimeras such as EWS\\/ETV1 that have divergent ETS DNA-binding domains. In spite of their structural differences, both EWS\\/ETS fusions

Andrew D Thompson; Michael A Teitell; Afsane Arvand; Christopher T Denny



Antagonism Pattern Detection between MicroRNA and Target Expression in Ewing's Sarcoma  

PubMed Central

MicroRNAs (miRNAs) have emerged as fundamental regulators that silence gene expression at the post-transcriptional and translational levels. The identification of their targets is a major challenge to elucidate the regulated biological processes. The overall effect of miRNA is reflected on target mRNA expression, suggesting the design of new investigative methods based on high-throughput experimental data such as miRNA and transcriptome profiles. We propose a novel statistical measure of non-linear dependence between miRNA and mRNA expression, in order to infer miRNA-target interactions. This approach, which we name antagonism pattern detection, is based on the statistical recognition of a triangular-shaped pattern in miRNA-target expression profiles. This pattern is observed in miRNA-target expression measurements since their simultaneously elevated expression is statistically under-represented in the case of miRNA silencing effect. The proposed method enables miRNA target prediction to strongly rely on cellular context and physiological conditions reflected by expression data. The procedure has been assessed on synthetic datasets and tested on a set of real positive controls. Then it has been applied to analyze expression data from Ewing’s sarcoma patients. The antagonism relationship is evaluated as a good indicator of real miRNA-target biological interaction. The predicted targets are consistently enriched for miRNA binding site motifs in their 3?UTR. Moreover, we reveal sets of predicted targets for each miRNA sharing important biological function. The procedure allows us to infer crucial miRNA regulators and their potential targets in Ewing’s sarcoma disease. It can be considered as a valid statistical approach to discover new insights in the miRNA regulatory mechanisms.

Martignetti, Loredana; Laud-Duval, Karine; Tirode, Franck; Pierron, Gaelle; Reynaud, Stephanie; Barillot, Emmanuel; Delattre, Olivier; Zinovyev, Andrei



[Primary Ewing's sarcoma of the mandible. A clinico-pathological and immunohistochemical case study].  


A rare case of Ewing's sarcoma, originating in the mandible, is reported. The symptomatologic and radiological aspects is often aspecific. For this reason the diagnostic-therapeutic routine is presented and the difficulty of clinical diagnosis is accentuated. In these cases it may be appropriate to make use of immunohistochemical analysis such as the research of markers like the NSE (Neuro-Specific Enolase). This will be useful to reach an accurate preoperative diagnosis and in order to adopt a correct therapeutic protocol. PMID:9221322

Zavaglia, V; Nori, A; Campanati, G; Goteri, G



The Tre2 oncoprotein, implicated in Ewing's sarcoma, interacts with two components of the cytoskeleton.  


The product of the Tre2 oncogene, structurally related to the Ypt/RabGTPase-activating proteins (Ypt/RabGAP), is involved in various human cancers, including Ewing's sarcoma. In order to identify proteins interacting with the GAP part of this protein, we performed yeast two-hybrid screening of two libraries. Two components of the cytoskeleton were thus identified, whose interaction with the GAP region was confirmed by GST-pulldown, co-immunoprecipitation, and colocalisation experiments. The proteins found to interact with the GAP region are the light regulatory chain of myosin II (Myl2) and LOC91256, a protein containing ankyrin repeats. PMID:16555005

Dechamps, Christophe; Bach, Stephane; Portetelle, Daniel; Vandenbol, Micheline



Coverage of Megaprosthesis with Human Acellular Dermal Matrix after Ewing's Sarcoma Resection: A Case Report  

PubMed Central

A 23-year-old female with Ewing's Sarcoma underwent tibial resection and skeletal reconstruction using proximal tibial allograft prosthetic reconstruction with distal femur endoprosthetic reconstruction and rotating hinge. Human acellular dermal matrix, (Alloderm, LifeCell, Branchburg, NJ, USA), was used to wrap the skeletal reconstruction. Soft tissue reconstruction was completed with a rotational gastrocnemius muscle flap and skin graft. Despite prolonged immobilization, the patient quickly regained full range of motion of her skeletal reconstruction. Synthetic mesh, tapes and tubes are used to perform capsule reconstruction of megaprosthesis. This paper describes the role of human acellular dermal matrix in capsule reconstruction around a megaprosthesis.

Whitfield, Robert M.; Rinard, Jeremy; King, David



A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma  

Microsoft Academic Search

Many sarcomas and leukemias carry nonrandom chromosomal translocations encoding tumor-specific mutant fusion transcription factors that are essential to their molecular pathogenesis. Ewing's sarcoma family tumors (ESFTs) contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precludes standard structure-based small-molecule inhibitor design. EWS-FLI1 binding to RNA helicase A (RHA) is

Hayriye V Erkizan; Yali Kong; Melinda Merchant; Silke Schlottmann; Julie S Barber-Rotenberg; Linshan Yuan; Ogan D Abaan; Tsu-hang Chou; Sivanesan Dakshanamurthy; Milton L Brown; Aykut Üren; Jeffrey A Toretsky



Primary Ewing's sarcoma of vulva: a case report and a review of the literature.  


Ewing sarcomas/peripheral primitive neuroectodermal tumors (ES/pPNET) are extremely rare in the vulva. A review of the literature reveals only 14 previously reported possible cases. Here we reported a case of primary extraskeletal Ewing's sarcoma (EES) of the vulva in a 37-year-old woman. Characteristic histologic features of ES/pPNET were present in this case, including a monomorphic population of small round blue cells with cytoplasmic glycogen confirmed by periodic acid-Schiff, membrane staining with CD99 and nuclear staining with FLI-1. After surgery, the patient was found to have pulmonary metastasis and then received six cycles of polychemotherapy. She is still alive with stable disease after 1 year of follow up. Our findings underline the crucial role of immunohistochemical techniques in the differential diagnosis of small round cell tumors in these unusual locations. We also give a summary about the clinical and pathological features of the primary ES/pPNET in the vulva reported previously in the literature. PMID:23106919

Che, Shao-Min; Cao, Pei-Long; Chen, Hong-Wei; Liu, Zi; Meng, Du



Intensive combined modality therapy including low-dose TBI in high-risk Ewing's sarcoma patients  

SciTech Connect

Twenty-four high-risk Ewing's sarcoma patients were treated on an intensive combined modality protocol including low-dose fractionated total body irradiaiton (TBI) and autologous bone marrow infusion (ABMI). Twenty patients (83%) achieved a complete clinical response to the primary and/or metastatic sites following induction therapy. The median disease-free interval was 18 months, and nine patients remain disease-free with a follow-up of 22 to 72 months. Local failure as a manifestation of initial relapse occurred in only three patients (15%), each having synchronous distant failure. Eight patients failed initially with only distant metastases, usually within 1-2 years following a complete clinical response. Two patterns of granulocyte recovery following consolidative therapy (including TBI and ABMI) were recognized. The time to platelet recovery was different for the groups with early and late granulocyte recovery. Patients with late recovery did not tolerate maintenance chemotherapy. However, there was no difference in disease-free and overall survival, when comparing the groups with early and late granulocyte recovery. It is concluded that these high-risk Ewing's sarcoma patients remain a poor-prognosis group in spite of intensive combined modality therapy including low-dose TBI. The control of microscopic systemic disease remains the major challenge to improving the cure rate. A new combined modality protocol with high-dose 'therapeutic' TBI (800 rad/2 fractions) is being used and the protocol design is outlined.

Kinsella, T.J.; Glaubiger, D.; Diesseroth, A.; Makuch, R.; Waller, B.; Pizzo, P.; Glatstein, E.



PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma  

PubMed Central

Ewing's sarcoma family tumors (ESFTs) are aggressive malignancies which frequently harbor characteristic EWS-FLI1 or EWS-ERG genomic fusions. Here we report that these fusion products interact with the DNA damage response protein and transcriptional co-regulator PARP-1. ESFT cells, primary tumor xenografts and tumor metastases were all highly sensitive to PARP1 inhibition. Addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolamide resulted in complete responses of all treated tumors in an EWS-FLI1-driven mouse xenograft model of ESFT. Mechanistic investigations revealed that DNA damage induced by expression of EWS-FLI1 or EWS-ERG fusion genes was potentiated by PARP1 inhibition in ESFT cell lines. Notably, EWS-FLI1 fusion genes acted in a positive feedback loop to maintain the expression of PARP1, which was required for EWS-FLI-mediated transcription, thereby enforcing oncogene-dependent sensitivity to PARP-1 inhibition. Together, our findings offer a strong preclinical rationale to target the EWS-FLI1: PARP1 intersection as a therapeutic strategy to improve the treatment of Ewing's sarcoma family tumors.

Brenner, J. Chad; Feng, Felix Y.; Han, Sumin; Patel, Sonam; Goyal, Siddharth V.; Bou-Maroun, Laura M.; Liu, Meilan; Lonigro, Robert; Prensner, John R.; Tomlins, Scott A.; Chinnaiyan, Arul M.



siRNA associated with immunonanoparticles directed against cd99 antigen improves gene expression inhibition in vivo in Ewing's sarcoma.  


Ewing's sarcoma is a rare, mostly pediatric bone cancer that presents a chromosome abnormality called EWS/Fli-1, responsible for the development of the tumor. In vivo, tumor growth can be inhibited specifically by delivering small interfering RNA (siRNA) associated with nanoparticles. The aim of the work was to design targeted nanoparticles against the cell membrane glycoprotein cd99, which is overexpressed in Ewing's sarcoma cells to improve siRNA delivery to tumor cells. Biotinylated poly(isobutylcyanoacrylate) nanoparticles were conceived as a platform to design targeted nanoparticles with biotinylated ligands and using the biotin-streptavidin coupling method. The targeted nanoparticles were validated in vivo for the targeted delivery of siRNA after systemic administration to mice bearing a tumor model of the Ewing's sarcoma. The expression of the gene responsible of Ewing's sarcoma was inhibited at 78% ± 6% by associating the siRNA with the cd99-targeted nanoparticles compared with an inhibition of only 41% ± 9% achieved with the nontargeted nanoparticles. PMID:23657987

Ramon, A L; Bertrand, J R; de Martimprey, H; Bernard, G; Ponchel, G; Malvy, C; Vauthier, C



SDF-1 Stimulates Vasculogenesis and Enhances Ewing's Sarcoma Tumor Growth in the Absence of VEGF  

PubMed Central

Stromal cell-derived Factor-1? (SDF-1?) stimulates the migration of bone marrow (BM) cells, similar to Vascular Endothelial Growth Factor (VEGF). We previously demonstrated that inhibition of VEGF165 by small interfering RNA inhibited Ewing’s sarcoma tumor growth, tumor vessel formation and recruitment of BM cells to the tumor. To determine the importance of BM cells in tumor vessel development, we investigated the effects of SDF-1? on VEGF-inhibited TC/siVEGF7-1 Ewing’s tumor neovasculature formation and growth. The effect of SDF-1? on CD34+ progenitor cell chemotaxis was determined in vivo. Using a BM transplantation model with GFP+ transgenic mice as BM donors and nude mice as recipients, we evaluated the effect of SDF-1? on the recruitment of BM-derived cells to VEGF165-inhibited TC/siVEGF7-1 tumors, as well as its effect on neovasculature development, vessel morphology and tumor growth. SDF-1? stimulated the migration of CD34+ progenitor cells to Matrigel plugs in vivo and promoted the retainment of BM-derived pericytes in close association with perfused, functional tumor vessels. Intratumor inoculation of Ad-SDF-1? into TC/siVEGF7-1 tumors resulted in increased SDF-1 and PDGF-BB expression, augmented tumor growth, an increase in the number of large, lumen-bearing vascular structures, and enhanced vessel pericyte coverage, with no change in VEGF165. SDF-1? stimulates BM cell chemotaxis and the association of these cells with functional tumor vessels. Furthermore, SDF-1? enhances tumor neovascularization and growth with no alteration in VEGF165. Our work suggests that SDF-1-mediated vasculogenesis may represent an alternate pathway that could potentially be utilized by tumors to sustain growth and neovasculature expansion after anti-VEGF therapy.

Reddy, Krishna; Zhou, Zhichao; Jia, Shu-Fang; Lee, Tim H.; Morales-Arias, Jaime; Cao, Ying; Kleinerman, Eugenie S.



The clinical use of biomarkers as prognostic factors in Ewing sarcoma  

PubMed Central

Ewing Sarcoma is the second most common primary bone sarcoma with 900 new diagnoses per year in Europe (EU27). It has a poor survival rate in the face of metastatic disease, with no more than 10% survival of the 35% who develop recurrence. Despite the remaining majority having localised disease, approximately 30% still relapse and die despite salvage therapies. Prognostic factors may identify patients at higher risk that might require differential therapeutic interventions. Aside from phenotypic features, quantitative biomarkers based on biological measurements may help identify tumours that are more aggressive. We audited the research which has been done to identify prognostic biomarkers for Ewing sarcoma in the past 15 years. We identified 86 articles were identified using defined search criteria. A total of 11,625 patients were reported, although this number reflects reanalysis of several cohorts. For phenotypic markers, independent reports suggest that tumour size > 8 cm and the presence of metastasis appeared strong predictors of negative outcome. Good histological response (necrosis > 90%) after treatment appeared a significant predictor for a positive outcome. However, data proposing biological biomarkers for practical clinical use remain un-validated with only one secondary report published. Our recommendation is that we can stratify patients according to their stage and using the phenotypic features of metastases, tumour size and histological response. For biological biomarkers, we suggest a number of validating studies including markers for 9p21 locus, heat shock proteins, telomerase related markers, interleukins, tumour necrosis factors, VEGF pathway, lymphocyte count, and a number of other markers including Ki-67.



The CXCR4-CXCL12 axis in Ewing sarcoma: promotion of tumor growth rather than metastatic disease  

PubMed Central

Background Chemokine receptor CXCR4, together with its ligand CXCL12, plays critical roles in cancer progression, including growth, metastasis and angiogenesis. Ewing sarcoma is a sarcoma with poor prognosis despite current therapies, particularly for patients with advanced-stage disease. Lungs and bone (marrow), organs of predilection for (primary/metastatic) Ewing sarcoma, represent predominant CXCL12 sources. Methods To gain insight into the role of the CXCR4-CXCL12 axis in Ewing sarcoma, CXCR4, CXCL12 and hypoxia-inducible factor-1? protein expression was studied in therapy-naïve and metastatic tumors by immunohistochemistry. CXCR4 function was assessed in vitro, by flow cytometry and proliferation/ cell viability assays, in the presence of recombinant CXCL12 and/or CXCR4-antagonist AMD3100 or under hypoxic conditions. Results Whereas CXCR4 was predominantly expressed by tumor cells, CXCL12 was observed in both tumor and stromal areas. Survival analysis revealed an (expression level-dependent) negative impact of CXCR4 expression (p?Ewing sarcoma growth was suggested by our observations that i) CXCR4 expression correlated positively with tumor volume at diagnosis (p?=?0.013), ii) CXCL12 was present within the microenvironment of virtually all cases, iii) CXCL12 induced proliferation of CXCR4-positive Ewing sarcoma cell lines, which could be abrogated by AMD3100. CXCR4 expression was not correlated with occurrence of metastatic disease. Also, therapy-naïve tumors demonstrated higher CXCR4 expression as compared to metastases (p?=?0.027). Evaluation of in vivo hypoxia-inducible factor-1? expression and culture of cells under hypoxic conditions revealed no role for hypoxia in CXCR4 expression. Conclusions Together, our results imply a crucial role for the CXCR4-CXCL12 axis in auto- and/or paracrine growth stimulation. Integration of CXCR4-targeting strategies into first- and/or second-line treatment regimens may represent a promising treatment option for Ewing sarcoma.



Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study  

PubMed Central

Summary Background Figitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signalling for sarcoma subtypes, including Ewing’s sarcoma, and early reports show antitumour activity of IGF-1R-targeting drugs in these diseases. Methods Between January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumour phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing’s sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumour activity (best response by Response Evaluation Criteria in Solid Tumours [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with, number NCT00474760. Findings 29 patients, 16 of whom had Ewing’s sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6·1, range 1–24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumours. 28 patients were assessed for response; two patients, both with Ewing’s sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilisation (six with Ewing’s sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer. Interpretation Figitumumab is well tolerated and has antitumour activity in Ewing’s sarcoma, warranting further investigation in this disease. Funding Pfizer Global Research and Development.

Olmos, David; Postel-Vinay, Sophie; Molife, L Rhoda; Okuno, Scott H; Schuetze, Scott M; Paccagnella, M Luisa; Batzel, Gretchen N; Yin, Donghua; Pritchard-Jones, Kathryn; Judson, Ian; Worden, Francis P; Gualberto, Antonio; Scurr, Michelle; de Bono, Johann S; Haluska, Paul



Small-molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing's sarcoma.  


Ewing's sarcoma family of tumors (EFT) is characterized by the presence of chromosomal translocations leading to the expression of oncogenic transcription factors such as, in the majority of cases, EWS/FLI1. Because of its key role in Ewing's sarcoma development and maintenance, EWS/FLI1 represents an attractive therapeutic target. Here, we characterize PHLDA1 as a novel direct target gene whose expression is repressed by EWS/FLI1. Using this gene and additional specific well-characterized target genes such as NROB1, NKX2.2 and CAV1, all activated by EWS/FLI1, as a read-out system, we screened a small-molecule compound library enriched for FDA-approved drugs that modulated the expression of EWS/FLI1 target genes. Among a hit-list of nine well-known drugs such as camptothecin, fenretinide, etoposide and doxorubicin, we also identified the kinase inhibitor midostaurin (PKC412). Subsequent experiments demonstrated that midostaurin is able to induce apoptosis in a panel of six Ewing's sarcoma cell lines in vitro and can significantly suppress xenograft tumor growth in vivo. These results suggest that midostaurin might be a novel drug that is active against Ewing's cells, which might act by modulating the expression of EWS/FLI1 target genes. PMID:22323082

Boro, Aleksandar; Prêtre, Kathya; Rechfeld, Florian; Thalhammer, Verena; Oesch, Susanne; Wachtel, Marco; Schäfer, Beat W; Niggli, Felix K



Mandibular Ewing sarcoma with chromosomal translocation t(21;22)(q22;q12).  


Ewing sarcoma (ES) is a primary bone malignant neoplasm and is the second most common primary malignancy of the bone found in childhood and adolescence after osteosarcoma. ES has an annual frequency in the population younger than 20 years of approximately 2.9 per million. ES occurs most frequently in the long bones of the extremities and pelvis and very rarely in the jaw. Recently, it was revealed that chromosomal translocation t(11;22)(q24;q12), which fuses the EWS gene on chromosome 22 and the FLI-1 gene on chromosome 11, occurs in most cases of ES. We report here a rare case of mandibular ES in a 10-year-old child with chromosomal translocation t(21;22)(q22;q12) in which the EWS gene is fused with the ERG gene on chromosome 21. PMID:23851834

Shibasaki, Maiko; Iwai, Toshinori; Maegawa, Jiro; Inayama, Yoshiaki; Yokosuka, Tomoko; Yokota, Shumpei; Ohta, Shinsuke; Matsui, Yoshiro; Mitsudo, Kenji; Tohnai, Iwai



Local control of Ewing's sarcoma of bone with radiotherapy and combination chemotherapy  

SciTech Connect

Between 1964 and 1977, 94 patients with Ewing's sarcoma of bone were treated at the National Cancer Institute. They received 5000 rad to the whole bone and progressively more aggressive chemotherapy protocols. The patients were divided according to site of primary lesion into central, proximal and distal lesions, with 19%, 33% and 57%, respectively, alive and well. The local control rate is high (93%), with good functional results in the distal lesions, and no changes are needed in radiation therapy dose or volume. Control is not as satisfactory for central and proximal lesions and efforts need to be made to increase control at these sites. We are at present attempting to define more accurately the extent of soft tissue disease, increasing the dose to 6000 rad for central lesions, and using a more aggressive chemotherapy program, in the hope of increasing the local control in these more aggressive tumors.

Tepper, J.; Glaubiger, D.; Lichter, A.; Wackenhut, J.; Glatstein, E.



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.



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



Small Interfering RNAs Expressed from a Pol III Promoter Suppress the EWS\\/Fli-1 Transcript in an Ewing Sarcoma Cell Line  

Microsoft Academic Search

The EWS\\/Fli-1 fusion gene encodes an oncogenic fusion protein. The fusion is a product of the translocation t(11;22) (q24;q12), which is detected in 85% of Ewing sarcoma and primitive neuroectodermal tumor cells. Utilizing intracellularly expressed 21- to 23-nucleotide small interfering RNAs (siRNAs) targeting the EWS\\/Fli-1 fusion transcript in an Ewing sarcoma cell line, we achieved a greater than 80% reduction

Taikoh Dohjima; Nan Sook Lee; Haitang Li; Takatoshi Ohno; John J. Rossi



The Ewing's sarcoma fusion protein, EWS-FLI, binds Runx2 and blocks osteoblast differentiation.  


Ewing's sarcomas are highly aggressive round cell tumors of bone and soft tissues that afflict children and young adults. The majority of these tumors harbor the t(11;22) translocation and express the fusion protein EWS-FLI. Modern molecular profiling experiments indicate that Ewing's tumors originate from mesenchymal precursors in young individuals. EWS-FLI alters the morphology of mesenchymal cells and prevents lineage specification; however, the molecular mechanisms for differentiation arrest are unclear. We recently showed that EWS-FLI binds Runx2, a master regulator of osteoblast differentiation. In this report, we demonstrate that FLI sequences within EWS-FLI are responsible for interactions with Runx2. EWS-FLI blocks the expression of osteoblastic genes in a multipotent progenitor cell line that requires Runx2 to integrate bone morphogenic protein (Bmp)2 signaling while increasing proliferation and altering cell morphology. These results demonstrate that EWS-FLI blocks the ability of Runx2 to induce osteoblast specification of a mesenchymal progenitor cell. Disrupting interactions between Runx2 and EWS-FLI1 may promote differentiation of the tumor cell. PMID:20665663

Li, Xiaodong; McGee-Lawrence, Meghan E; Decker, Matthew; Westendorf, Jennifer J



Xenograft and genetically engineered mouse model systems of osteosarcoma and Ewing's sarcoma: tumor models for cancer drug discovery.  


Introduction: There are > 75 histological types of solid tumors that are classified into two major groups: bone and soft-tissue sarcomas. These diseases are more prevalent in children, and pediatric sarcomas tend to be highly aggressive and rapidly progressive. Sarcomas in adults may follow a more indolent course, but aggressive tumors are also common. Sarcomas that are metastatic at diagnosis, or recurrent following therapy, remain refractory to current treatment options with dismal overall survival rates. A major focus of clinical trials, for patients with sarcoma, is to identify novel and more effective therapeutic strategies targeted to genomic or proteomic aberrations specific to the malignant cells. Critical to the understanding of the potential for targeted therapies are models of disease that are representative of clinical disease and predictive of relevant clinical responses. Areas covered: In this article, the authors discuss the use of mouse xenograft models and genetically engineered mice in cancer drug discovery. The authors provide a special focus on models for the two most common bone sarcomas: osteosarcoma (OS) and Ewing's sarcoma (ES). Expert opinion: Predicting whether a new anticancer agent will have a positive therapeutic index in patients with OS and ES remains a challenge. The use of mouse sarcoma models for understanding the mechanisms involved in the response of tumors to new treatments is an important step in the process of drug discovery and the development of clinically relevant therapeutic strategies for these diseases. PMID:23844615

Sampson, Valerie B; Kamara, Davida F; Kolb, E Anders



Extraosseous Ewing sarcoma of the vagina 1 1 The views expressed herein are those of the authors and do not reflect the official policy or opinion of the Department of Defense, or the United States Army or Navy  

Microsoft Academic Search

Background: Ewing sarcoma is a highly malignant childhood bone neoplasm. Extraosseous presentations of Ewing sarcomas include the trunk, extremities, uterus, cervix, and vagina.Case: A 35-year-old woman, gravida 3, para 3, presented with a painless vaginal mass. After surgical excision, pathology results diagnosed an extraosseous Ewing sarcoma. Chemotherapy was given, followed by external beam and vaginal intracavitary brachytherapy, then more chemotherapy.

John Farley; John D O’Boyle; Jason Heaton; Stephen Remmenga



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



Ewing's sarcoma/primitive neuroectodermal tumor arising from the adrenal gland: a case report and literature review.  


We report a rare case of Ewing's sarcoma (ES)/primitive neuroectodermal tumor (PNET) arising from the adrenal gland. A 17-year-old Japanese woman presented with left upper abdominal pain and high fever. Computed tomography and magnetic resonance imaging revealed a 15×10 cm tumor replacing the adrenal gland. Preoperative diagnosis was an adrenocortical carcinoma. Resection of the tumor was performed. We obtained the final diagnosis of ES/PNET by immunohistochemical molecular study with positive staining for the MIC2 gene product (CD99) and a Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangement. Local recurrence was observed one month after the surgery. The patient was then treated with systemic chemotherapy and localized radiotherapy. PMID:24158076

Sasaki, Takeshi; Onishi, Takehisa; Yabana, Tadashi; Hoshina, Akira


Efficacy of siRNA Nanocapsules Targeted Against the EWS–Fli1 Oncogene in Ewing Sarcoma  

Microsoft Academic Search

The EWS–Fli1 fusion gene encodes for a chimeric oncogenic transcription factor considered to be the cause of the Ewing sarcoma. The efficiency\\u000a of small interfering RNAs (siRNAs) targeted toward the EWS–Fli1 transcript (at the junction point type 1) was studied, free\\u000a or encapsulated into recently developed polyisobutylcyanoacrylate aqueous core nanocapsules. Because this mRNA sequence is\\u000a only present in cancer cells,

Nedjma Toub; Jean-Rémi Bertrand; Ali Tamaddon; Hind Elhamess; Hervé Hillaireau; Andrei Maksimenko; Jean Maccario; Claude Malvy; Elias Fattal; Patrick Couvreur



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




Microsoft Academic Search

In this paper, the case of a 12-year old girl with a clinical manifestation simulating Ewings Sarcoma is presented. Supplementary studies with light microscopy, immunophenotypic, and cytogenetic evaluation confirm pre-B lymphoblastic lymphoma, with t(1;19)(q23:p13) translocation. The characteristics of this neoplasia, and the importance of complementary inmunophenotypic, and cytogenetic studies, to perform an accurate diagnosis are discussed.

Javier Fox; Jorge López; Amaranto Suárez; Greti Terselich; Martha Vizcaíno; Lyda Rengifo; Elvira Castro; Carlos Saavedra; Juan Carlos Mejía; Gonzalo Guevara; Fernando Mejía


Superficial primitive neuroectodermal tumor\\/Ewing sarcoma (PN\\/ES): same tumor as deep PN\\/ES or new entity?  

Microsoft Academic Search

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

Torsten Ehrig; Steven D. Billings; Julie C. Fanburg-Smith



Ewing’s sarcoma  


... bones of the trunk. The tumor often spreads ( metastasis ) to the lungs and other bones. Spread at ... to locate the primary tumor and any spread (metastasis) often include: Biopsy of the tumor Bone scan ...


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

SciTech Connect

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 studied in the in vitro radiation response of two established cell lines of Ewing's sarcoma and human bone marrow CFUc. The Ewing's lines showed a larger D/sub 0/ and anti-n compared to the bone marrow CFU. No repair of potentially lethal radiation damage (PLDR) was found after 4.5 Gy in plateau phase Ewing's sarcoma cells. A theoretical split dose survival curve for both the Ewing's sarcoma lines and human bone marrow CFUc using this TBI schedule shows a significantly lower surviving fraction (10/sup -4/-10/sup -5/) for the bone marrow CFUc. Based on these in vitro results, two 4.0 Gy fractions separated by 24 hours is proposed as the TBI regimen. Because of the potentially irreversible damage to bone marrow, autologous bone marrow transplantation following the TBI is felt to be necessary. The details of this clinical protocol in high risk Ewing's sarcoma patients are outlined.

Kinsella, T.J.; Mitchell, J.B.; McPherson, S.; Miser, J.; Triche, T.; Glatstein, E.



Ewing's sarcoma: A case report of a 52-year-old woman with recurrent tumor and literature review  

PubMed Central

Ewing’s sarcoma is the second most common primary sacral tumor. Ewing’s sarcomas are rare, aggressive tumors with a tendency towards recurrence following resection and early metastasis. Although peak incidences are between the ages of 10 and 20 years, patients of younger or older age account for almost 30% of the cases. We report the case of a 52-year-old healthy female who presented with a 2-week history of pain in her right posterior thigh that was unable to be relieved by non-steroidal anti-inflammatory medicine and physical therapy. Magnetic resonance imaging demonstrated an irregular right presacral mass and core needle biopsy revealed a small, round blue cell neoplasm. Staging workup was normal and an open biopsy was positive for the ES translocation (22q12). The patient was treated with 17 cycles of vincristine, adriamycin and cytoxan with mesna rescue, alternating with ifosfamide and etoposide in addition to external beam radiation. Post-treatment imaging demonstrated complete resolution of the tumor. Six weeks post-treatment the patient presented with a recurrent tumor. This case emphasizes the importance of timely establishment of initial diagnosis, early metastasis in treatment responsive patients and under-utilization of positron emission tomography-computed tomography (PET-CT) during the treatment to detect sub-clinical metastasis.




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: [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)



Should Aggressive Surgical Local Control Be Attempted in All Patients with Metastatic or Pelvic Ewing's Sarcoma?  

PubMed Central

In previous reports, patients with Ewing's sarcoma received radiation therapy (XRT) for definitive local control because metastatic disease and pelvic location were thought to preclude aggressive local treatment. We sought to determine if single-site metastatic disease should be treated differently from multicentric-metastatic disease. We also wanted to reinvestigate the impact of XRT, pelvic location, and local recurrence on outcomes. Our results demonstrated a significant difference in overall survival (OS) between patients with either localized disease or a single-metastatic site and patients with multicentric-metastatic disease (P = 0.004). Local control was also found to be an independent predictor of outcomes as demonstrated by a significant difference in OS between those with and without local recurrence (P = 0.001). Axial and pelvic location did not predict a decreased OS. Based on these results, we concluded that pelvic location and the diagnosis of metastatic disease at diagnosis should not preclude aggressive local control, except in cases of multicentric-metastatic disease.

Thorpe, Steven W.; Weiss, Kurt R.; Goodman, Mark A.; Heyl, Alma E.; McGough, Richard L.



Ewing tumours and synovial sarcomas have critical features of karyotype evolution in common with epithelial tumours.  


We have analysed the accumulated cytogenetic data on karyotypic evolution in Ewing tumours (ET) and synovial sarcomas (SS). Both tumour types frequently show balanced translocations, t(11;22) and t(X;18), respectively, that result in specific fusion genes. The analyses revealed +8, +12, +1q, and 16q- as important secondary changes to t(11;22) in ET and the imbalances showed a distinct temporal order. By principal component analysis, one major karyotypic pathway dominated by gains and one minor dominated by losses were identified. The kartyotypic evolution pattern in SS was less distinct. Both ET and SS showed a power law distribution of the number of acquired aberrations, which in both tumour types conformed to a distribution with an exponent equal to 1. Similar distributions are frequently found in epithelial tumours. ET and SS differ in this respect from other malignancies with balanced translocations resulting in fusion genes, which typically show a power law distribution of the number of acquired aberrations with exponents close to 2. This suggests that chromosome changes in ET and SS may develop through mechanisms more similar to those in epithelial tumours lacking recurrent balanced rearrangements than in haematological malignancies characterised by balanced translocations leading to fusion genes. PMID:15800948

Höglund, Mattias; Gisselsson, David; Mandahl, Nils; Mitelman, Felix



Improved outlook for Ewing's sarcoma with combination chemotherapy (vincristine, actinomycin D and cyclophosphamide) and radiation therapy.  


Vincristine, actinomycin D, and cyclophosphamide (VAC) were administered to 14 patients with Ewing's sarcoma. The primary tumors were treated with radiation therapy and concurrent chemotherapy. Nine patients had no visible metastases at diagnosis: two died following the development of pulmonary metastases and the rest have been free of disease for periods varying from 4 months to 4 1/2 years following completion of treatment. This contrasts with a 27% survival in patients previously treated at this center with single agent chemotherapy. Five other patients had demonstrable metastases at diagnosis: VAC chemotherapy achieved complete regression of pulmonary metastases in three for 9, 9+ and 24+ months, respectively. Following disappearance of tumor in the latter two, pulmonary irradiation was administered in an attempt to consolidate the response, but tumor recurred 6 months later. These patients eventually died of widespread disease although survival appeared prolonged in comparison to that seen in past experience. Chemotherapy was well tolerated, although three patients developed hemorrhagic cystitis, necessitating discontinuation of cyclophosphamide. The data suggest the potential for prolonged control and an increase in the cure rate with this therapeutic approach. PMID:991106

Jaffe, N; Paed, D; Traggis, D; Salian, S; Cassady, J R



Ewing sarcoma gene EWS is essential for meiosis and B lymphocyte development  

PubMed Central

Ewing sarcoma gene EWS encodes a putative RNA-binding protein with proposed roles in transcription and splicing, but its physiological role in vivo remains undefined. Here, we have generated Ews-deficient mice and demonstrated that EWS is required for the completion of B cell development and meiosis. Analysis of Ews–/– lymphocytes revealed a cell-autonomous defect in precursor B lymphocyte (pre–B lymphocyte) development. During meiosis, Ews-null spermatocytes were deficient in XY bivalent formation and showed reduced meiotic recombination, resulting in massive apoptosis and complete arrest in gamete maturation. Inactivation of Ews in mouse embryonic fibroblasts resulted in premature cellular senescence, and the mutant animals showed hypersensitivity to ionizing radiation. Finally, we showed that EWS interacts with lamin A/C and that loss of EWS results in a reduced lamin A/C expression. Our findings reveal essential functions for EWS in pre–B cell development and meiosis, with proposed roles in DNA pairing and recombination/repair mechanisms. Furthermore, we demonstrate a novel role of EWS in cellular senescence, possibly through its interaction and modulation of lamin A/C.

Li, Hongjie; Watford, Wendy; Li, Cuiling; Parmelee, Alissa; Bryant, Mark A.; Deng, Chuxia; O'Shea, John; Lee, Sean Bong



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


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



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



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))



The Ewing sarcoma protein regulates DNA damage-induced alternative splicing.  


The Ewing sarcoma (EWS) protein is a member of the TET (TLS/EWS/TAF15) family of RNA- and DNA-binding proteins whose expression is altered in cancer. We report that EWS depletion results in alternative splicing changes of genes involved in DNA repair and genotoxic stress signaling, including ABL1, CHEK2, and MAP4K2. Chromatin and RNA crosslinking immunoprecipitation results indicate that EWS cotranscriptionally binds to its target RNAs. This association is reduced upon irradiation of cells with ultraviolet light, concomitant with transient enrichment of EWS in nucleoli and with alternative splicing changes that parallel those induced by EWS depletion and that lead to reduced c-ABL protein expression. Consistent with the functional relevance of EWS-mediated alternative splicing regulation in DNA damage response, EWS depletion reduces cell viability and proliferation upon UV irradiation, effects that are attenuated by restoring c-ABL expression. These results provide insights into posttranscriptional mechanisms of DNA damage response by a TET protein. PMID:21816343

Paronetto, Maria Paola; Miñana, Belén; Valcárcel, Juan



Adult Ewing Sarcoma: Survival and Local Control Outcomes in 102 Patients with Localized Disease  

PubMed Central

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.

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



Enhanced poly(adenosine diphosphate ribose) polymerase activity and gene expression in Ewing's sarcoma cells  

SciTech Connect

Ewing's sarcoma (ES) is a highly malignant childhood bone tumor and is considered curable by moderate doses of radiotherapy. The addition of chemical inhibitors of the activity of the nuclear enzyme poly(adenosine diphosphate ribose) (poly(ADPR)) polymerase to ES cells in culture results in increased cell killing, a phenomenon called inhibitor sensitization. Since poly(ADPR) polymerase is thought to be associated with DNA repair, it has been suggested that ES cells and other inhibitor-sensitized cells may have a reduced capacity for polymer synthesis resulting in deficient postirradiation recovery. We present here the unexpected observation that in comparison to other cell lines tested, ES cells exhibit a high enzyme activity, higher constitutive levels of the protein, and elevated levels of its mRNA transcript for poly(ADPR) polymerase. No gross amplifications or rearrangements of the gene were observed; however, regulation of poly(ADPR) polymerase in these tumor cells takes place at the level of the gene transcript.

Prasad, S.C.; Thraves, P.J.; Bhatia, K.G.; Smulson, M.E.; Dritschilo, A. (Georgetown Univ. Medical Center, Washington, DC (USA))



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.



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



Cyclophosphamide-hydroxycamptothecin as second-line chemotherapy for advanced Ewing's sarcoma: Experience of a single institution.  


AIM: To investigate the feasibility and efficacy of cyclophosphamide (CTX)-hydroxycamptothecin (HCPT) as second-line chemotherapy on advanced Ewing's sarcoma. METHODS: From April 2009 to November 2010, 27 patients with advanced Ewing's sarcoma who had progressive disease after the first-line chemotherapy regimen of vincristine, dactinomycin and cyclophosphamide and ifosfamide and etoposide were retrospectively reviewed in this analysis. CTX was given (0.6?g/m(2) , i.v. push day 1) and HCPT (6?mg/m(2) , i.v. drip days 1-5) as second-line chemotherapy every 3 weeks. The primary end-point was overall response rate, the secondary end-point included progression-free, overall survival, disease control rate and toxicities. RESULTS: A total of 134 cycles were given, median four cycles per patient (range 2-6). Overall response rate was 30% and disease control rate was 82%, with two complete response (8%), six partial remission (22%) and 14 stable disease (52%). The median time to progression and overall survival time were 7 months (95% CI 3-10) and 11 months (95% CI 5-18), respectively. Major severe toxicities (grade 3 and 4) were: nausea/vomiting (17%), alopecia (17%); leukopenia (27%) in total cycles. Mild toxicities (grade 1 or 2) were leukopenia (73%), nausea/vomiting (83%), hepatic lesion (14%) and anemia (44%). CONCLUSION: A CTX-HCPT regimen can control disease progression effectively and the side effects can be tolerable for Chinese advanced Ewing's sarcoma patients. Further assessment is necessary to confirm the safety and efficacy of this treatment. PMID:23176372

Han, Kun; Sun, Yuanjue; Zhang, Jianjun; He, Aina; Zheng, Shui'er; Shen, Zan; Yao, Yang



Ewing sarcoma-primitive neuroectodermal tumor of the uterus: a clinicopathologic, immunohistochemical and ultrastructural study of one case  

Microsoft Academic Search

Introduction  Ewing sarcoma-primitive neuroectodermal tumors (ES\\/PNET) constitute a family of neoplasms characterized by a continuum of\\u000a neuroectodermal differentiation. ES\\/PNET of the uterus is rare. There are 43 cases published in the English literature as\\u000a far as we know. We describe an additional case.\\u000a \\u000a \\u000a \\u000a \\u000a Case report  A 56-year-old woman presented with a 2-month history of irregular menopausal vaginal bleeding. After surgical excision, microscopic,

Ya-Li RenXiu-Ying; Xiu-Ying Tang; Ting Li



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:



Cytotoxic T-lymphocyte antigen-4 genetic variants and risk of Ewing's sarcoma.  


Despite the knowledge of many genetic alterations present in Ewing's sarcoma (ES), the complexity of this disease precludes placing its biology into a simple conceptual framework. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) can decrease T-cell activation and attenuate antitumor responses. Polymorphisms in the CTLA-4 gene have been shown to be associated with different diseases. Here, we investigated the association of four CTLA-4 gene polymorphisms, -1661A/G (rs4553808), -318C/T (rs5742909), +49G/A (rs231775), and CT60A/G (rs3087243), with ES in the Chinese population. A total of 308 ES cases and 362 healthy controls were recruited and CTLA-4 polymorphisms were tested by polymerase chain reaction-restriction fragment length polymorphism. Results showed that frequencies of the CTLA-4 gene +49AA genotype, +49A allele, and GTAG haplotype were significantly increased in ES patients compared to healthy controls (odds ratio [OR]=2.42, 95% confidence interval [CI] 1.43-4.09, p<0.001; OR 1.38, 95% CI 1.11-1.73, p=0.005, and OR=1.46, 95% CI 1.06-2.02, p=0.020, respectively). We further compared CTLA-4 polymorphisms in ES patients based on different clinical parameters and data revealed that ES patients with metastasis had higher numbers of the +49AA genotype than those without metastasis (p=0.004). These results indicated that the CTLA-4 polymorphism could be a risk factor for ES and suggested a potential role of CTLA-4 in the metastasis of this malignancy. PMID:23480667

Feng, Dapeng; Yang, Xinghai; Li, Shufeng; Liu, Tielong; Wu, Zhipeng; Song, Yuanlin; Wang, Jian; Gao, Wenwu; Huang, Quan; Huang, Wending; Zheng, Wei; Xiao, Jianru



Integrated multimodal genetic testing of Ewing sarcoma-a single-institution experience.  


Ewing sarcoma (ES) is an aggressive malignant small round cell tumor that arises in bone or soft tissue of adolescents and young adults. A characteristic molecular finding in ES is EWSR1 gene fusion with ETS (erythroblast transformation-specific) family genes including FLI1 (~90%) and ERG (>5%). Here we report our experience using integrated clinicopathologic, cytogenetic, fluorescence in situ hybridization (FISH), and reverse transcriptase polymerase chain reaction (RT-PCR) analyses of 32 pediatric patients with ES diagnosed in a single institution between 2005 and 2011. Diagnostic EWSR1 rearrangements were detected in 30 (93.8%) of 32 patients. Cytogenetics detected t(11;22) (n = 14) and t(21;22) (n = 1) in 15 (46.9%) patients. FISH detected EWSR1 rearrangements in 27 (96.4%) of 28 patients tested. RT-PCR was positive in 27 (84.4%) of 32 patients, including 24 EWSR1-FLI1 and 3 EWSR1-ERG. RT-PCR defined breakpoints and fusion partners in 7 cases with EWSR1 rearrangements detected by FISH. Sanger sequencing further delineated breakpoints in 21 (77.8%) of 27 RT-PCR positive cases. In summary, conventional cytogenetic analysis provided a global view but had a lower detection rate and longer turnaround time than other methods. FISH is a rapid method and theoretically can detect all EWSR1 rearrangements, but it cannot identify all partners and is not completely specific for ES. RT-PCR and sequencing are more sensitive and useful in identifying fusion partners and refining breakpoints; however, these methods can be compromised by poor RNA preservation and primer design. In conclusion, an integrated approach that uses all methods capable of detecting EWSR1 rearrangements has value in the workup of suspected cases of ES. PMID:23706910

Warren, Mikako; Weindel, Michael; Ringrose, Jo; Venable, Clint; Reyes, Adriana; Terashima, Keita; Rao, Pulivarthi; Chintagumpala, Murali; Hicks, M John; Lopez-Terrada, Dolores; Lu, Xin-Yan



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



IGF1R signaling in Ewing sarcoma is shaped by clathrin-/caveolin-dependent endocytosis.  


Receptor endocytosis is critical for cell signaling. IGF1R mediates an autocrine loop that is de-regulated in Ewing Sarcoma (ES) cells. Here we study the impact of IGF1R internalization, mediated by clathrin and caveolin-1 (CAV1), in ES signaling. We used clathrin and CAV1-siRNA to interfere in clathrin- and caveolin-dependent endocytosis. Chlorpromazine (CPMZ) and methyl-beta-cyclo-dextrin (MCD) were also used in order to inhibit clathrin- and caveolin-dependent endocytosis, respectively. We analyzed IGF1R internalization and co-localization with clathrin and CAV1 upon ligand binding, as well as the status of the IGF1R pathway, cellular proliferation, and the apoptosis of interfered and inhibited ES cells. We performed a high-throughput tyrosine kinase phosphorylation assay to analyze the effects of combining the IGF1R tyrosine kinase inhibitor AEW541 (AEW) with CPMZ or MCD on the intracellular phospho-proteome. We observed that IGF1R is internalized upon ligand binding in ES cells and that this process is dependent on clathrin or CAV1. The blockage of receptor internalization inhibited AKT and MAPK phosphorylation, reducing the proliferative rate of ES cells and increasing the levels of apoptosis. Combination of AEW with CPMZ or MCD largely enhanced these effects. CAV1 and clathrin endocytosis controls IGF1R internalization and signaling and has a profound impact on ES IGF1R-promoted survival signaling. We propose the combination of tyrosine-kinase inhibitors with endocytosis inhibitors as a new therapeutic approach to achieve a stronger degree of receptor inhibition in this, or other neoplasms dependent on IGF1R signaling. PMID:21611203

Martins, Ana Sofia; Ordóñez, José Luis; Amaral, Ana Teresa; Prins, Frans; Floris, Giuseppe; Debiec-Rychter, Maria; Hogendoorn, Pancras C W; de Alava, Enrique



miR-125b develops chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor  

PubMed Central

Background Diverse functions of microRNAs (miRNAs), including effects on tumorigenesis, proliferation, and differentiation, have been reported, and several miRNAs have also been demonstrated to play an important role in apoptosis. In this study, we investigated the possible role that miRNAs may play in the development of chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor (EWS). Methods We screened doxorubicin (Dox)-resistant EWS cells to identify any distinct miRNA sequences that may regulate the chemoresistance of EWS cells. The effects of miRNAs were evaluated using a chemosensitivity assay. The possible target genes of the miRNAs were predicted using a web-based prediction program. Results We found miR-125b to be upregulated in two different Dox-resistant EWS cell lines. The upregulation of miR-125b was also confirmed in the EWS tumors having survived chemotherapy regimen which includes doxorubicin. When miR-125b was knocked down in EWS cells, both the Dox-resistant and parental cells showed an enhanced sensitivity to doxorubicin, which was associated with the upregulation of the pro-apoptotic molecules, p53 and Bak. Inversely, the overexpression of miR-125b in parental EWS cells resulted in enhanced drug resistance, not only to doxorubicin, but also to etoposide and vincristine. Conclusions Our findings suggest that miR-125b may play a role in the development of chemoresistance in EWS by suppressing the expression of the apoptotic mediators, such as p53 and Bak.



Long-term Survivors of Childhood Ewing Sarcoma: Report From the Childhood Cancer Survivor Study  

PubMed Central

Background The survival of Ewing sarcoma (ES) patients has improved since the 1970s but is associated with considerable future health risks. Methods The study population consisted of long-term (?5-year) survivors of childhood ES diagnosed before age 21 from 1970 to 1986. Cause-specific mortality was evaluated in eligible survivors (n = 568), and subsequent malignant neoplasms, chronic health conditions, infertility, and health status were evaluated in the subset participating in the Childhood Cancer Survivor Study (n = 403). Outcomes were compared with the US population and sibling control subjects (n = 3899). Logistic, Poisson, or Cox proportional hazards models, with adjustments for sex, age, race/ethnicity, and potential intrafamily correlation, were used. Statistical tests were two-sided. Results Cumulative mortality of ES survivors was 25.0% (95% confidence interval [CI] = 21.1 to 28.9) 25 years after diagnosis. The all-cause standardized mortality ratio was 13.3 (95% CI = 11.2 to 15.8) overall, 23.1 (95% CI = 17.6 to 29.7) for women, and 10.0 (95% CI = 7.9 to 12.5) for men. The nonrecurrence-progression non-external cause standardized mortality ratio (subsequent non-ES malignant neoplasms and cardiac and pulmonary causes potentially attributable to ES treatment) was 8.7 (95% CI = 6.2 to 12.0). Twenty-five years after ES diagnosis, cumulative incidence of subsequent malignant neoplasms, excluding nonmelanoma skin cancers, was 9.0% (95% CI = 5.8 to 12.2). Compared with siblings, survivors had an increased risk of severe, life-threatening, or disabling chronic health conditions (relative risk = 6.0, 95% CI = 4.1 to 9.0). Survivors had lower fertility rates (women: P = .005; men: P < .001) and higher rates of moderate to extreme adverse health status (P < .001). Conclusion Long-term survivors of childhood ES exhibit excess mortality and morbidity.

Goodman, Pamela; Leisenring, Wendy; Ness, Kirsten K.; Meyers, Paul A.; Wolden, Suzanne L.; Smith, Stephanie M.; Stovall, Marilyn; Hammond, Sue; Robison, Leslie L.; Oeffinger, Kevin C.



EWS-FLI-1-targeted cytotoxic T-cell killing of multiple tumor types belonging to the Ewing Sarcoma Family of Tumors*  

PubMed Central

Purpose The Ewing Sarcoma Family of Tumors (ESFTs) comprises a group of aggressive, malignant bone and soft tissue tumors that predominantly affect children and young adults. These tumors frequently share expression of the EWS-FLI-1 translocation, which is central to tumor survival but not present in healthy cells. In this study, we examined EWS-FLI-1 antigens for their capacity to induce immunity against a range of ESFT types. Design Computer prediction analysis of peptide binding, HLA-A2.1 stabilization assays, and induction of Cytotoxic T-Lymphocytes (CTL) in immunized HLA-A2.1 transgenic mice were used to assess the immunogenicity of native and modified peptides derived from the fusion region of EWS-FLI-1 type 1. CTL-killing of multiple ESFT family members in vitro, and control of established xenografts in vivo, was assessed. We also examined whether these peptides could induce human CTLs in vitro. Results EWS-FLI-1 type 1 peptides were unable to stabilize cell surface HLA-A2.1 and induced weak CTL activity against Ewing Sarcoma cells. In contrast, peptides with modified anchor residues induced potent CTL killing of Ewing Sarcoma cells presenting endogenous (native) peptides. The adoptive transfer of CTL specific for the modified peptide YLNPSVDSV resulted in enhanced survival of mice with established Ewing Sarcoma xenografts. YLNPSVDSV-specific CTL displayed potent killing of multiple ESFT types in vitro: Ewing Sarcoma, pPNET, Askin’s Tumor, and Biphenotypic Sarcoma. Stimulation of human Peripheral Blood Mononuclear Cells with YLNPSVDSV peptide resulted in potent CTL-killing. Conclusions These data show that YLNPSVDSV peptide is a promising antigen for ESFT immunotherapy and warrants further clinical development.

Evans, Christopher H.; Liu, Fangjun; Porter, Ryan M.; O'Sullivan, Regina P.; Merghoub, Taha; Lunsford, Elaine P.; Robichaud, Kyle; Van Valen, Frans; Lessnick, Stephen L.; Gebhardt, Mark C.; Wells, James W.



Primary vulvar Ewing sarcoma/primitive neuroectodermal tumor: a report of 2 cases and review of the literature.  


Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) family of tumor is a very aggressive malignant round cell tumor characterized by translocations involving EWS-FLI1 genes. They are increasingly recognized in extraosseous sites as a result of improvements in diagnostic tools. In this paper, we report 2 additional cases arising in vulva of young adults who have been treated aggressively and have survived fore more than 7 and 4 years successively. Histologic examination showed small round (blue) cell morphology in both cases. The tumor cells contained glycogen and were positive for CD99 and vimentin and negative for keratins, lymphoid markers, S-100, synaptophysin, chromogranin, and desmin. Reverse transcriptase polymerase chain reaction analysis from paraffin-embedded tissue revealed EWS-FLI1 fusion product in 1 case. Collectively, 13 cases of vulvar ES/PNET have been reported in the literature. Only 8 cases have detailed follow-up information with an average follow-up data of 28 months. Ewing sarcoma/PNET should be considered in the differential diagnosis of any undifferentiated tumors involving the lower gynecologic tract and all axillary tests including molecular tests should be performed for correct diagnosis because prolonged survival is possible for this dreadful disease after complete surgical resection, followed by adjuvant therapy. PMID:19820381

Cetiner, Handan; Kir, Gözde; Gelmann, Edward P; Ozdemirli, Metin



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

PubMed Central

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 the EWS/FLI oncoprotein, present in the vast majority of Ewing tumors, was characterized over ten years ago, it has never been exploited as a target of therapy. Previously, this target has been intractable to modulation with traditional small-molecule library screening approaches. Here we describe a gene expression–based approach to identify compounds that induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid path to clinical application. Methods and Findings A gene expression signature for the EWS/FLI off state was determined with microarray expression profiling of Ewing sarcoma cell lines with EWS/FLI-directed RNA interference. A small-molecule library enriched for FDA-approved drugs was screened with a high-throughput, ligation-mediated amplification assay with a fluorescent, bead-based detection. Screening identified cytosine arabinoside (ARA-C) as a modulator of EWS/FLI. ARA-C reduced EWS/FLI protein abundance and accordingly diminished cell viability and transformation and abrogated tumor growth in a xenograft model. Given the poor outcomes of many patients with Ewing sarcoma and the well-established ARA-C safety profile, clinical trials testing ARA-C are warranted. Conclusions We demonstrate that a gene expression–based approach to small-molecule library screening can identify, for rapid clinical testing, candidate drugs that modulate previously intractable targets. Furthermore, this is a generic approach that can, in principle, be applied to the identification of modulators of any tumor-associated oncoprotein in the rare pediatric malignancies, but also in the more common adult cancers.

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



Gene expression profile of ewing sarcoma cell lines differing in their EWS-FLI1 fusion type.  


The t(11;22)(q24;q12) translocation is present in up to 95% of Ewing tumor patients and results in the formation of an EWS-FLI-1 fusion gene that encodes a chimeric transcription factor. Many alternative forms of EWS-FLI-1 exist because of variations in the location of the EWS and FLI-1 genomic breakpoints. Previous reports have shown that the type 1 fusion is associated with a significantly better prognosis than the other fusion types. It has been suggested that the observed clinical discrepancies result from different transactivation potentials of the various EWS-FLI-1 fusion proteins. In an attempt to identify genes whose expression levels are differentially modulated by structurally different EWS-FLI-1 transcription factors, we have used microarray technology to interrogate 19,000 sequence genes to compare gene expression profile of type 1 or non-type 1 Ewing sarcoma cell lines. Data analysis showed few qualitative differences on gene expression; expression of only 41 genes (0.215% of possible sequences analyzed) differed significantly between Ewing tumor cell lines carrying EWS-FLI-1 fusion type 1 with respect to those with non-type 1 fusion. PMID:16217257

Bandrés, Eva; Malumbres, Raquel; Escalada, Alvaro; Cubedo, Elena; González, Iranzu; Honorato, Beatriz; Zarate, Ruth; García-Foncillas, Jesus; de Alava, Enrique



Molecular localization of the t(11;22)(q24;q12) translocation of Ewing sarcoma by chromosomal in situ suppression hybridization.  

PubMed Central

Chromosome translocations are associated with a variety of human leukemias, lymphomas, and solid tumors. To localize molecular markers flanking the t(11;22) (q24;q12) breakpoint that occurs in virtually all cases of Ewing sarcoma and peripheral neuroepithelioma, high-resolution chromosomal in situ suppression hybridization was carried out using a panel of cosmid clones localized and ordered on chromosome 11q. The location of the Ewing sarcoma translocation breakpoint was determined relative to the nearest two cosmid markers on 11q, clones 23.2 and 5.8, through the analysis of metaphase chromosome hybridization. By in situ hybridization to interphase nuclei, the approximate physical separation of these two markers was determined. In both Ewing sarcoma and peripheral neuroepithelioma, cosmid clone 5.8 is translocated from chromosome 11q24 to the derivative chromosome 22 and a portion of chromosome 22q12 carrying the leukemia inhibitory factor gene is translocated to the derivative chromosome 11. The physical distance between the flanking cosmid markers on chromosome 11 was determined to be in the range of 1000 kilobases, and genomic analysis using pulsed-field gel electrophoresis showed no abnormalities over a region of 650 kilobases in the vicinity of the leukemia inhibitory factor gene on chromosome 22. This approach localizes the Ewing sarcoma breakpoint to a small region on chromosome 11q24 and provides a rapid and precise technique for the molecular characterization of chromosomal aberrations. Images

Selleri, L; Hermanson, G G; Eubanks, J H; Lewis, K A; Evans, G A



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



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

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



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.



Prognostic and therapeutic relevance of the IGF pathway in Ewing's sarcoma patients.  


The optimal target and timing of drugs interfering with the insulin-like growth factor (IGF) signaling system in Ewing's sarcoma (ES) remain undetermined. We examined the expression of IGF signaling proteins in ES samples taken before and after chemotherapy, and speculate about the optimal way of treating ES patients in the future. Tumor material (36 initial biopsies and 24 resection specimens after neoadjuvant chemotherapy) and follow-up data of 41 patients treated for ES at the Radboud University Nijmegen Medical Centre were analyzed. Immunohistochemical staining was done for IGF1, IGF2, IGFBP3, IGF-1R, phosphorylated AKT (pAKT), phosphorylated mTOR (pmTOR), and phosphorylated ERK (pERK), and staining intensity was scored semiquantitatively. Change of protein expression during treatment, correlations of effector cascade signaling, and influence on progression-free (PFS) and overall survival (OS) were tested. All potential targets were widely expressed at both time points. After chemotherapy, pmTOR expression decreased significantly (p?=?0.021) while IGFBP3 increased (p?=?0.005). Correlations exist between IGF-1R and pERK (??=?0.286, p?=?0.031), IGF-1R and pAKT (??=?0.269, p?=?0.045), pAKT and pERK (??=?0.460, p?=?0.000), and pERK and pmTOR (??=?0.273, p?=?0.038). In therapy-naive samples, combined expression of pAKT, pmTOR, and pERK predicted worse PFS (median, 11 vs. 32 months; p?=?0.039) and OS (median, 18 vs. 83 months; p?=?0.023). We identify an unfavorable prognostic group of ES patients with widely activated IGF-effector cascades, demonstrate cooperation between the different downstream pathways, and show how expression of IGF-related proteins may change after exposure to chemotherapy. These findings should be taken into account when designing future trials with IGF-targeting agents. We suggest the prospective exploration of chemotherapy and multi-target tyrosine kinase inhibitors in the first-line setting. PMID:23292309

van de Luijtgaarden, A C M; Versleijen-Jonkers, Y M H; Roeffen, M H S; Schreuder, H W B; Flucke, U E; van der Graaf, W T A



Wnt5a promotes ewing sarcoma cell migration through upregulating CXCR4 expression  

PubMed Central

Background As one of the malignant tumors most often affecting children and young adults, Ewing sarcoma (ES) is characterized by early metastasis contributing to unfavorable prognosis. However, the molecular mechanisms responsible for ES metastasis remain poorly understood. In this study, we aimed to explore whether Wnt5a, a putative pro-metastatic factor, plays a role in ES metastasis. Methods Expression of Wnt5a and CXCR4 was determined by real-time PCR or Western blot in 15 ES specimens and 4 ES cell lines, A-673, RD-ES, SK-N-MC and SK-ES-1. Expression of Wnt antagonists, SFRP1, SFRP2 and SFRP5, and some components in noncanonical Wnt pathway (p-JNK, p-cJUN and p-PKC) was also analyzed in this study. Methylation status of SFRP1, SFRP2 and SFRP5 was detected by Methylation-specific PCR (MSP). Wnt5a shRNA and pcDNA3.1 SFRP5 vector were used to abrogate Wnt5a expression and overexpress SFRP5 in ES cells, respectively. Results Wnt5a expression was positively correlated with CXCR4 expression in ES specimens. Levels of both Wnt5a mRNA and CXCR4 mRNA were significantly higher in specimens from ES patients with metastasis at diagnosis compared with specimens from those without metastasis. Recombinant Wnt5a enhanced CXCR4 expression in ES cells, which was accompanied by increased ES cell migration, whereas Wnt5a shRNA has opposite effects. SFRP5 was methylated and silenced in ES cells, and both recombinant SFRP5 and pcDNA3.1 SFRP5 vector suppressed CXCR4 expression as well as ES cell migration. Wnt5a shRNA and recombinant SFRP5 inhibited phosphorylation of JNK and cJUN, and JNK inhibitor also reduced CXCR4 expression and cell migration in ES cells. Conclusions Wnt5a increases ES cell migration via upregulating CXCR4 expression in the absence of Wnt antagonist SFRP5, suggesting that Wnt5a overexpression and SFRP5 deficiency may jointly promote ES metastasis.



Trial of Dasatinib in Advanced Sarcomas

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)



Candida tropicalis arthritis of the elbow in a patient with Ewing's sarcoma that successfully responded to itraconazole  

PubMed Central

Fungal infections are rarely responsible for arthritis. Few cases of fungal arthritis have been reported, even in immunocompromised hosts susceptible to low-virulence organisms. Herein, the authors report the first case of Candida tropicalis arthritis in a child with a solid tumor. A 13-year-old boy with Ewing's sarcoma developed arthritis in his elbow during the neutropenic period after chemotherapy. Despite treatment with broad-spectrum antibiotics, his condition did not improve and serial blood cultures failed to reveal any causative organisms. After surgical drainage, culture of the joint fluid revealed the presence of C. tropicalis. Itraconazole treatment was started and after 3 months of therapy, the patient completely recovered full elbow function.

Kim, Seung Youn; Lim, Jung Sub; Kim, Dong Hwan; Lee, Hyeon Jeong; Cho, Joong Bum; Lee, Jun Ah



Pathobiologic Markers of the Ewing Sarcoma Family of Tumors: State of the Art and Prediction of Behaviour  

PubMed Central

Over the past three decades, the outcome of Ewing sarcoma family tumor (ESFT) patients who are nonmetastatic at presentation has improved considerably. The prognosis of patients with metastatic disease at the time of diagnosis and recurrence after therapy remains dismal. Drug-resistant disease at diagnosis or at relapse remains a major cause of mortality among patients diagnosed with ESFT. In order to improve the outcome for patients with potential relapse, there is an urgent need to find reliable markers that either predict tumor behaviour at diagnosis or identify therapeutic molecular targets at the time of recurrence. An improved understanding of the cell of origin and the molecular pathways that regulate tumorigenicity in ESFT should aid us in the search for novel therapies for ESFT. The purpose of this paper is thus to outline current concepts of sarcomagenesis in ESFT and to discuss ESFT patterns of differentiation and molecular markers that might affect prognosis or direct future therapeutic development.

Pinto, Alfredo; Dickman, Paul; Parham, David



Plerixafor plus G-CSF in combination with chemotherapy for stem cell mobilization in a pediatric patient with Ewing's sarcoma.  


Some malignant tumors in childhood require high-dose chemotherapy with stem cell support to achieve a cure. In patients heavily pretreated with myelosuppressive chemotherapy or irradiation, granulocyte colony-stimulating factor (G-CSF) may fail to mobilize stem cells from the bone marrow. Based on the experience with lymphoma and myeloma patients in whom peripheral blood-derived stem cell (PBSC) collection following mobilization with G-CSF failed, we successfully employed plerixafor in a 14-year-old female diagnosed with Ewing's sarcoma in early relapse treated with three lines of chemotherapy in whom PBSC could not be mobilized using either G-CSF alone or G-CSF following chemotherapy. No side effects were observed. Plerixafor may be an effective and safe agent for stem cell collection in pediatric patients with solid tumors, although new studies addressed to evaluate its effectiveness and safety are needed. PMID:22566276

Vives, Susana; Sancho, Juan-Manuel; Almazán, Francisco; Juncà, Jordi; Grifols, Joan-Ramon; Ribera, Josep-Maria



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.



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


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



Primary cutaneous Ewing sarcoma\\/primitive neuroectodermal tumour: a clinicopathological analysis of seven cases highlighting diagnostic pitfalls and the role of FISH testing in diagnosis  

Microsoft Academic Search

Aims:To perform a clinicopathological analysis of a series of primary cutaneous Ewing sarcomas\\/primitive neuroectodermal tumours (ES\\/PNET) to highlight the pathological features, discuss the differential diagnosis, emphasise the role of molecular testing (particularly fluorescence in situ hybridisation, FISH) in diagnosis and outline the patients’ clinical course.Methods:Seven cases of primary cutaneous ES\\/PNET were identified from the authors’ consultation files.Results:The patients were aged

M V Shingde; M Buckland; K J Busam; S W McCarthy; J Wilmott; J F Thompson; R A Scolyer



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



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



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


Caveolin-1 promotes resistance to chemotherapy-induced apoptosis in Ewing's sarcoma cells by modulating PKC? phosphorylation  

PubMed Central

Caveolin-1 (CAV1) has been implicated in the regulation of several signaling pathways and in oncogenesis. Previously, we identified CAV1 as a key determinant of the oncogenic phenotype and tumorigenic activity of cells from tumors of the Ewing’s Sarcoma Family (ESFT). However, the possible CAV1 involvement in the chemotherapy resistance commonly presented by an ESFT subset has not been established to date. This report shows that CAV1 expression determines the sensitivity of ESFT cells to clinically relevant chemotherapeutic agents. Analyses of endogenous CAV1 levels in several ESFT cells and ectopic CAV1 expression into ESFT cells expressing low endogenous CAV1 showed that the higher the CAV1 levels, the greater their resistance to drug treatment. Moreover, results from antisense- and shRNA-mediated gene expression knockdown and protein re-expression experiments demonstrated that CAV1 increases the resistance of ESFT cells to doxorubicin (Dox)- and cisplatin (Cp)-induced apoptosis by a mechanism involving the activating phosphorylation of PKC?. CAV1 knockdown in ESFT cells led to decreased phospho(Thr638)-PKC? levels and a concomitant sensitization to apoptosis, which were reversed by CAV1 re-expression. These results were recapitulated by PKC? knockdown and re-expression in ESFT cells in which CAV1 was previously knocked down, thus demonstrating that phospho(Thr638)-PKC? acts downstream of CAV1 to determine the sensitivity of ESFT cells to chemotherapeutic drugs. These data, along with the finding that CAV1 and phospho(Thr638)-PKC? are co-expressed in ~45% of ESFT specimens tested, imply that targeting CAV1 and/or PKC? may allow the development of new molecular therapeutic strategies to improve the treatment outcome for ESFT patients.

Tirado, Oscar M.; MacCarthy, Caitlin M.; Fatima, Naheed; Villar, Joaquin; Mateo-Lozano, Silvia; Notario, Vicente



Superficial small round-cell tumors with special reference to the Ewing's sarcoma family of tumors and the spectrum of differential diagnosis.  


Superficial/cutaneous small round-cell tumors comprise a heterogeneous group of neoplasms including sarcoma, carcinoma, melanoma, and lymphomas. Among superficial sarcomas, the Ewing's sarcoma family of tumors (ESFT) represents a poorly understood rare variant, having a behavioral difference characterized by a relative favorable prognosis. Several problems are still to be resolved in superficial ESFT, including the differential diagnosis between ESFT of bone (intraosseous or periosteal) with superficial infiltration and superficial ESFT with bone infiltration, especially in the fingers. Our aim is to review the most common types of small round-cell tumors included in the differential diagnosis of superficial ESFT, analyzing the histopathology, phenotype, and molecular alterations of each entity. PMID:23327732

Machado, Isidro; Traves, Victor; Cruz, Julia; Llombart, Beatriz; Navarro, Samuel; Llombart-Bosch, Antonio



DNA Methylation and Gene Expression Profiling of Ewing Sarcoma Primary Tumors Reveal Genes That Are Potential Targets of Epigenetic Inactivation  

PubMed Central

The role of aberrant DNA methylation in Ewing sarcoma is not completely understood. The methylation status of 503 genes in 52 formalin-fixed paraffin-embedded EWS tumors and 3 EWS cell lines was compared to human mesenchymal stem cell primary cultures (hMSCs) using bead chip methylation analysis. Relative expression of methylated genes was assessed in 5-Aza-2-deoxycytidine-(5-AZA)-treated EWS cell lines and in a cohort of primary EWS samples and hMSCs by gene expression and quantitative RT-PCR. 129 genes demonstrated statistically significant hypermethylation in EWS tumors compared to hMSCs. Thirty-six genes were profoundly methylated in EWS and unmethylated in hMSCs. 5-AZA treatment of EWS cell lines resulted in upregulation of expression of hundreds of genes including 162 that were increased by at least 2-fold. The expression of 19 of 36 candidate hypermethylated genes was increased following 5-AZA. Analysis of gene expression from an independent cohort of tumors confirmed decreased expression of six of nineteen hypermethylated genes (AXL, COL1A1, CYP1B1, LYN, SERPINE1,) and VCAN. Comparing gene expression and DNA methylation analyses proved to be an effective way to identify genes epigenetically regulated in EWS. Further investigation is ongoing to elucidate the role of these epigenetic alterations in EWS pathogenesis.

Patel, Nikul; Black, Jennifer; Chen, Xi; Marcondes, A. Mario; Grady, William M.; Lawlor, Elizabeth R.; Borinstein, Scott C.



Biomarkers in Ewing Sarcoma: The Promise and Challenge of Personalized Medicine. A Report from the Children's Oncology Group  

PubMed Central

A goal of the COG Ewing Sarcoma (ES) Biology Committee is enabling identification of reliable biomarkers that can predict treatment response and outcome through the use of prospectively collected tissues and correlative studies in concert with COG therapeutic studies. In this report, we aim to provide a concise review of the most well-characterized prognostic biomarkers in ES, and to provide recommendations concerning design and implementation of future biomarker studies. Of particular interest and potentially high clinical relevance are studies of cell-cycle proteins, sub-clinical disease, and copy number alterations. We discuss findings of particular interest from recent biomarker studies and examine factors important to the success of identifying and validating clinically relevant biomarkers in ES. A number of promising biomarkers have demonstrated prognostic significance in numerous retrospective studies and now need to be validated prospectively in larger cohorts of equivalently treated patients. The eventual goal of refining the discovery and use of clinically relevant biomarkers is the development of patient specific ES therapeutic modalities.

Shukla, Neerav; Schiffman, Joshua D.; Reed, Damon; Davis, Ian J.; Womer, Richard B.; Lessnick, Stephen L.; Lawlor, Elizabeth R.



Matrix metalloproteinase-9 silencing by RNA interference triggers the migratory-adhesive switch in Ewing's sarcoma cells.  


Enhanced expression of (pro)matrix metalloproteinase-9 (MMP-9) is associated with human tumor invasion and/or metastasis. COH cells derived from a highly invasive and metastatic Ewing's sarcoma constitutively express proMMP-9. Transfection of a double stranded RNA that targets the MMP-9 mRNA into COH cells depleted the corresponding mRNA and protein as demonstrated by reverse transcriptase-PCR, enzyme-linked immunosorbent assay, and gelatin zymography. proMMP-9 extinction resulted in the following: (i) decreased spreading on extracellular matrix (fibronectin, laminin, collagen IV)-coated surfaces, (ii) inhibition of migration toward fibronectin, and (iii) induced aggregation, which was specifically disrupted by a function-blocking E-cadherin antibody. MMP-9 knockdown concomitantly resulted in increased levels of surface E-cadherin, redistribution at the plasma membrane of beta-catenin, and its physical association with E-cadherin. Moreover, induction of E-cadherin-mediated adhesion was associated with RhoA activation and changes in paxillin cytoskeleton. Finally, an inhibitor of gelatinolytic activity of pro-MMP9 did not reduce COH cell migration confirming that the enzymatic property of COH MMP-9 was not required for migration toward fibronectin. Overall, our observations define a novel critical role for proMMP-9 in providing a cellular switch between stationary and migratory cell phases. PMID:12847101

Sancéau, Josiane; Truchet, Sandrine; Bauvois, Brigitte



Identification of target genes for the Ewing's sarcoma EWS/FLI fusion protein by representational difference analysis.  

PubMed Central

The EWS/FLI-1 fusion gene results from the 11;22 chromosomal translocation in Ewing's sarcoma. The product of the gene is one of a growing number of structurally altered transcription factors implicated in oncogenesis. We have employed a subtractive cloning strategy of representational difference analysis in conjunction with a model transformation system to identify genes transcribed in response to EWS/FLI. We have characterized eight transcripts that are dependent on EWS/FLI for expression and two transcripts that are repressed in response to EWS/FLI. Three of the former were identified by sequence analysis as stromelysin 1, a murine homolog of cytochrome P-450 F1 and cytokeratin 15. Stromelysin 1 is induced rapidly after expression of EWS/FLI, suggesting that the stromelysin 1 gene may be a direct target gene of EWS/FLI. These results demonstrate that expression of EWS/FLI leads to significant changes in the transcription of specific genes and that these effects are at least partially distinct from those caused by expression of germ line FLI-1. The representational difference analysis technique can potentially be applied to investigate transformation pathways activated by a broad array of genes in different tumor systems.

Braun, B S; Frieden, R; Lessnick, S L; May, W A; Denny, C T



Sorafenib in Treating Patients With Soft Tissue Sarcomas (Extremity Sarcoma Closed to Entry as of 5/30/07)

Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Osteosarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma



VEGF 165 expression in the tumor microenvironment influences the differentiation of bone marrow-derived pericytes that contribute to the Ewing’s sarcoma vasculature  

Microsoft Academic Search

We previously demonstrated that bone marrow (BM) cells migrate to Ewing’s tumors and differentiate into endothelial cells\\u000a within the tumor vasculature. Recent evidence suggests that the roles of BM cells in tumors are more diverse. We investigated\\u000a whether non-endothelial cell types critical for tumor vessel development are also derived from migrated BM cells. We utilized\\u000a BM transplantation with GFP+ transgenic

Krishna Reddy; Ying Cao; Zhichao Zhou; Ling Yu; Shu-Fang Jia; Eugenie S. Kleinerman



Potential Downstream Target Genes of Aberrant ETS Transcription Factors Are Differentially Affected in Ewing's Sarcoma and Prostate Carcinoma  

PubMed Central

FLI1 and ERG, the major ETS transcription factors involved in rearrangements in the Ewing’s sarcoma family of tumors (ESFT) and in prostate carcinomas (PCa), respectively, belong to the same subfamily, having 98% sequence identity in the DNA binding domain. We therefore decided to investigate whether the aberrant transcription factors in both malignancies have some common downstream targets. We crossed a publicly available list of all putative EWSR1-FLI1 target genes in ESFT with our microarray expression data on 24 PCa and 6 non-malignant prostate tissues (NPT) and choose four genes among the top-most differentially expressed between PCa with (PCa ERG+) and without (PCa ETS-) ETS fusion genes (HIST1H4L, KCNN2, ECRG4 and LDOC1), as well as four well-validated direct targets of the EWSR1-FLI1 chimeric protein in ESFT (NR0B1, CAV1, IGFBP3 and TGFBR2). Using quantitative expression analysis in 16 ESFT and seven alveolar rhabdomyosarcomas (ARMS), we were able to validate the four genes previously described as direct targets of the EWSR1-FLI1 oncoprotein, showing overexpression of CAV1 and NR0B1 and underexpression of IGFBP3 and TGFBR2 in ESFT as compared to ARMS. Although none of these four genes showed significant expression differences between PCa ERG+ and PCa ETS-, CAV1, IGFBP3 and TGFBR2 were less expressed in PCa in an independent series of 56 PCa and 15 NPT, as also observed for ECRG4 and LDOC1, suggesting a role in prostate carcinogenesis in general. On the other hand, we demonstrate for the first time that both HIST1H4L and KCNN2 are significantly overexpressed in PCa ERG+ and that ERG binds to the promoter of these genes. Conversely, KCNN2 was found underexpressed in ESFT relative to ARMS, suggesting that the EWSR1-ETS oncoprotein may have the opposite effect of ERG rearrangements in PCa. We conclude that aberrant ETS transcription factors modulate target genes differently in ESFT and PCa.

Ribeiro, Franclim R.; Barros-Silva, Joao D.; Almeida, Mafalda; Costa, Vera L.; Cerveira, Nuno; Skotheim, Rolf I.; Lothe, Ragnhild A.; Henrique, Rui; Jeronimo, Carmen; Teixeira, Manuel R.



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



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


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



The boy who refused an IV: a case report of subcutaneous clodronate for bone pain in a child with Ewing Sarcoma  

PubMed Central

Background Bone pain in malignancy can be challenging to treat. Bisphosphonates have been found to be useful in adults with bone pain, but there are no reports of their use in children for this indication. In pediatric palliative medicine there are hurdles in translating knowledge gained primarily in adult studies into application in children. Obstacles exist in initially determining whether the evidence supports using a drug in children, and once a drug is chosen, then determining the optimal route of delivery. There is very little data to guide pediatric practitioners in this situation. Case Presentation A 9 year old boy with disseminated Ewing Sarcoma presented with extremity pain not responsive to a combination of opiates, gabapentin and non-steroidal anti-inflammatory drugs. Clodronate, a bisphosphonate, was added to the regimen to treat bone pain. It was given subcutaneously every 4 weeks with a good response and no side effects. Conclusion This case report describes the use of a bisphosphonate, clodronate, given subcutaneously to a child with Ewing sarcoma with effective relief of bone pain. It describes how the care team encountered the challenges inherent in translating adult therapy into a pediatric regimen. Furthermore the report details how a regimen was developed to address this child's concerns regarding medication administration. Further effort needs to be made at finding solutions to address the lack of good evidence for pediatric palliative therapies.

Siden, Harold



Ewing sarcoma fusion protein EWSR1/FLI1 interacts with EWSR1 leading to mitotic defects in zebrafish embryos and human cell lines  

PubMed Central

The mechanism whereby the fusion of EWSR1 with the ETS transcription factor FLI1 contributes to malignant transformation in Ewing sarcoma remains unclear. We demonstrate that injection of human or zebrafish EWSR1/FLI1 mRNA into developing zebrafish embryos leads to mitotic defects with multipolar and disorganized mitotic spindles. Expression of human EWSR1/FLI1 in HeLa cells also results in mitotic defects, along with mislocalization of Aurora kinase B, a key regulator of mitotic progression. Since these mitotic abnormalities mimic those observed with knockdown of EWSR1 in zebrafish embryos and HeLa cells, we investigated whether EWSR1/FLI1 interacts with EWSR1 and interferes with its function. EWSR1 coimmunoprecipitates with EWSR1/FLI1, and overexpression of EWSR1 rescues the mitotic defects in EWSR1/FLI1-transfected HeLa cells. This interaction between EWSR1/FLI1 and EWSR1 in Ewing sarcoma may induce mitotic defects leading to genomic instability and subsequent malignant transformation.

Embree, Lisa J.; Azuma, Mizuki; Hickstein, Dennis D.



Molecular Pathology of Sarcomas  

Microsoft Academic Search

Bone and soft tissue sarcomas are an infrequent group of tumours with a prevalence of 4 in 100000 peo- ple\\/year. Sarcomas, such as synovial sarcoma, Ewing's sarcoma and osteosarcoma, are more usual in adolescents or in young adults. Neoplasias such as leiomyosarcoma or liposarcoma are more frequent in patients over 55 years. One rele- vant topic is related to sarcomagenesis

Daniel Osuna; Enrique de Álava



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


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



Superficial primitive neuroectodermal tumor/Ewing sarcoma (PN/ES): same tumor as deep PN/ES or new entity?  


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



Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma.  


Lysine-specific demethylase 1 (GeneID 23028), a flavin-dependent monoamine oxidoreductase and a histone demethylase, serves as an epigenetic coregulator of transcription. Lysine-specific demethylase 1 is up-regulated in neuroblastoma and in bladder, breast, colorectal, gastric, lung, and neuroendocrine cancers, and its overexpression drives the cell cycle of otherwise nontransformed human cells, suggesting oncogenic properties. Lysine-specific demethylase 1 was recently reported to be also overexpressed in several different mesenchymal tumors. We investigated lysine-specific demethylase 1 expression in over 500 sarcomas by gene expression profiling and tissue microarray-coupled immunohistochemical analyses and confirmed lysine-specific demethylase 1 overexpression in rhabdomyosarcoma and synovial sarcoma. We also show for the first time that lysine-specific demethylase 1 is also overexpressed in chondrosarcoma, Ewing's sarcoma, and osteosarcoma wherein it localizes in cell nuclei. We further show that a US Food and Drug Administration-approved drug that inhibits lysine-specific demethylase 1 also inhibits chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma cell growth in vitro. These data suggest that lysine-specific demethylase 1 plays a role in sarcoma pathology and that lysine-specific demethylase 1 inhibition strategies might represent a novel means to inhibiting growth of lysine-specific demethylase 1-overexpressing sarcomas. PMID:22245111

Bennani-Baiti, Idriss M; Machado, Isidro; Llombart-Bosch, Antonio; Kovar, Heinrich



Bee-sting, a non-resolving wound and a progressive mass over the right eye preceding the ultimate diagnosis of frontal bone Ewing's sarcoma.  


A healthy young lady suffered a bee-sting over her right eyelid which was followed by pain, redness and swelling at, above and beyond the right eyelid. Although the initial swelling subsided, the patient noticed a small 'lump', superior to the eyelid which persisted after the rest of the swelling disappeared. This lump subsequently progressed over a span of 3 months and then caused ulceration of the overlying skin. Further testing revealed the lump to be an Ewing's sarcoma arising from the frontal bone. The patient was treated with standard chemotherapy (16 cycles of vincristine, doxorubicin, cyclophosphamide alternating with cycles of ifosfamide and etoposide) and radiotherapy and has remained disease-free 18-months after completion of treatment. This report reminds the reader about a not-so-uncommon mode of presentation of malignancies, that is, they being discovered after attention drawn by a rather common injury or trauma. PMID:22761215

Gupta, Manoj Kumar; Rastogi, Madhup; Seam, Rajeev Kumar; Revannasiddaiah, Swaroop



Pediatric soft tissue sarcomas.  


After a brief discussion of the rarity of soft tissue sarcomas in children and of the limited ability of magnetic resonance imaging to provide a tissue diagnosis, this article discusses the incidence, presentation, treatment, prognosis, and imaging characteristics of the more common and unusual pediatric soft tissue sarcomas. It begins with extensive discussion of rhabdomyosarcoma, synovial sarcoma, and congenital/infantile fibrosarcoma. It then presents a more abbreviated discussion of uncommon tumors such as alveolar soft part sarcoma, epithelioid sarcoma, extraosseous Ewing's sarcoma, granulocytic sarcoma, hemangiopericytoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, and undifferentiated sarcoma. PMID:21963167

Stein-Wexler, Rebecca



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



Single-chain Antibodies to the EWS NH2 Terminus Structurally Discriminate between Intact and Chimeric EWS in Ewing's Sarcoma and Interfere with the Transcriptional Activity ofEWS In vivo  

Microsoft Academic Search

The chimeric protein EWS-FLI1, arising from chromosomal translocation in Ewing's sarcoma family tumors (ESFT), acts as an aberrant tumorigenic transcription factor. The trans- forming activity of EWS-FLI1 minimally requires an ETS DNA binding domain and the EWS NH2 terminus. Proteins interacting with the EWS portion differ between germ-line and chimeric EWS despite their sharing identical sequences in this domain. We

Dave N. T. Aryee; Michael Kreppel; Radostina Bachmaier; Aykut Uren; Karin Muehlbacher; Stefan Wagner; Heimo Breiteneder; Jozef Ban; Jeffrey A. Toretsky; Heinrich Kovar


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.




R1507, an Anti-Insulin-Like Growth Factor-1 Receptor (IGF-1R) Antibody, and EWS/FLI-1 siRNA in Ewing's Sarcoma: Convergence at the IGF/IGFR/Akt Axis  

PubMed Central

A subset of patients with Ewing's sarcoma responds to anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies. Mechanisms of sensitivity and resistance are unknown. We investigated whether an anti-IGF-1R antibody acts via a pathway that could also be suppressed by small interfering (si) RNA against the EWS/FLI-1 fusion protein, the hallmark of Ewing's sarcoma. The growth of two Ewing's sarcoma cell lines (TC-32 and TC-71) was inhibited by the fully human anti-IGF-1R antibody, R1507 (clonogenic and MTT assays). TC-32 and TC-71 cells express high levels of IGF-2, while RD-ES and A4573 Ewing's cell lines, which were less responsive to R1507 in our assays, express low or undetectable IGF-2, respectively. TC-71 cells also expressed high levels of IGF-1R, and R1507 decreased steady-state levels of this receptor by internalization/degradation, an effect which was associated with a decrease in p-IGF-1R, p-IRS-1, and p-Akt. EWS/FLI-1 siRNA also decreased p-Akt, due to its ability to increase IGF-BP3 levels and subsequently decrease IGF-1 and IGF-2 levels, thus inhibiting signaling through p-IGF-1R. This inhibition correlated with growth suppression and apoptosis. The attenuation of Akt activation was confirmed in TC-71 and HEK-293 (human embryonic kidney) cells by transfecting them with IGF-1R siRNA. We conclude that antibodies and siRNA to IGF-1R, as well as siRNA to EWS/FLI-1, act via intersecting IGF/IGF-1R signals that suppress a common point in this pathway, namely the phosphorylation of Akt.

Rodon, Jordi; Sun, Michael; Kuenkele, Klaus-Peter; Parsons, Henrique A.; Trent, Jonathan C.; Kurzrock, Razelle



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:; 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)



Sensitive Ewing sarcoma and neuroblastoma cell lines have increased levels of BAD expression and decreased levels of BAR expression compared to resistant cell lines.  


The purpose of the study is to compare the mRNA expression of pro-apoptotic and anti-apoptotic genes by using the GeneSystem 320 (Capital Genomix Inc., Gaithersburg, MD) to examine the differential expression in Ewing sarcoma and neuroblastoma cell lines. This is an alternate method for which internal controls have been built into the system for comparing mRNA. The tumor cell lines were chosen based on their previously characterized Fas-resistance or Fas-sensitive properties in order to determine the differences in their response to apoptotic signals. Two representative pro-apoptotic genes (BAD and SMAC) and one anti-apoptotic gene (BAR) were chosen for the study. The results of mRNA expression were correlated with protein expression by Western analysis. BAD was highly expressed in the Fas-sensitive cell lines while SMAC was equally expressed in both Fas-sensitive and Fas-resistant cell lines. On the other hand, BAR was highly expressed in Fas-resistant cell lines and minimally expressed in the Fas-sensitive cell lines. Our data suggests that levels of BAD and BAR mRNA expression predict sensitivity to apoptosis. PMID:16690206

Lee, Betty; Galli, Susanna; Tsokos, Maria



Toxicity of high-dose chemotherapy with etoposide, thiotepa and CY in treating poor-prognosis Ewing's sarcoma family tumors: the experience of the Bambino Gesù Children's Hospital.  


We report the toxicity of high-dose chemotherapy (HDC) based on etoposide, thiotepa and CY (ETC) in children with poor-prognosis Ewing's sarcoma family tumors (ESFTs). A total of 26 patients with high-risk ESFT (metastasis or axis localization or tumor volume >200 ml or necrosis <95%) were reviewed. The conditioning was based on etoposide (600 mg/m(2)), thiotepa (750 mg/m(2)) and CY (120 mg/kg) followed by autologous BM or PBSC rescue. The conditioning regimen was well tolerated, without any toxic deaths. The median time from transplant to a neutrophil count of >0.5 x 10(9)/l was 10 days (range 6-27) and 22.5 days (range 9-114) for a plt count of >50 x 10(9)/l. Oral mucositis was recorded in 20 patients, grade 1/2 in 19 and grade 3 in the last patient. Diarrhea grade 1/2 was recorded in four patients and grade 1/2 liver toxicity in four patients. Sepsis was documented in four cases and skin toxicity in three. Lung and tubular toxicity, respectively, were reported in one patient each. We conclude that the ETC regimen presented a limited and manageable toxicity. Further studies would confirm the role of ETC in high-risk ESFT. PMID:20098456

Ilari, I; De Ioris, M A; Milano, G M; Pessolano, R; De Lurentis, C; De Sio, L; Fidani, P; Jenkner, A; Cozza, R



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



A practical approach to the clinical diagnosis of Ewing's sarcoma/primitive neuroectodermal tumour and other small round cell tumours sharing EWS rearrangement using new fluorescence in situ hybridisation probes for EWSR1 on formalin fixed, paraffin wax embedded tissue  

PubMed Central

Background: Over 90% of Ewing’s sarcoma/primitive neuroectodermal tumour (ES/PNET) cases have the t(11;22) chromosomal rearrangement, which is also found in other small round cell tumours, including desmoplastic small round cell tumour (DSRCT) and clear cell sarcoma (CCS). Although this rearrangement can be analysed by fluorescence in situ hybridisation (FISH) using routinely formalin fixed, paraffin wax embedded (FFPE) tissues when fresh or frozen tissues are not available, a sensitive and convenient detection method is needed for routine clinical diagnosis. Aims: To investigate the usefulness of newly developed probes for detecting EWS rearrangement resulting from chromosomal translocations using FISH and FFPE tissue in the clinical diagnosis of ES/PNET, DSRCT, and CCS. Methods: Sixteen ES/PNETs, six DSRCTs, and six CCSs were studied. Three poorly differentiated synovial sarcomas, three alveolar rhabdomyosarcomas, and three neuroblastomas served as negative controls. Interphase FISH analysis was performed on FFPE tissue sections with a commercially available EWSR1 (22q12) dual colour, breakapart rearrangement probe. Results: One fused signal and one split signal of orange and green, demonstrating rearrangement of the EWS gene, was detected in 14 of 16 ES/PNETs, all six DRSCTs, and five of six CCSs, but not in the negative controls. Conclusions: Interphase FISH using this newly developed probe is sensitive and specific for detecting the EWS gene on FFPE tissues and is of value in the routine clinical diagnosis of ES/PNET, DSRCT, and CCS.

Yamaguchi, U; Hasegawa, T; Morimoto, Y; Tateishi, U; Endo, M; Nakatani, F; Kawai, A; Chuman, H; Beppu, Y; Endo, M; Kurotaki, H; Furuta, K



Targeting PI3K/Akt represses Hypoxia inducible factor-1alpha activation and sensitizes Rhabdomyosarcoma and Ewing's sarcoma cells for apoptosis.  


BACKGROUND: Hypoxia inducible factor alpha (HIF-1alpha) 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-1alpha activation as well as apoptosis resistance in various adult tumors. However the relevance of PI3K/Akt signaling in HIF-1alpha 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-1alpha 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-1alpha 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 muM) significantly decreased the protein expression as well as DNA binding activity of HIF-1alpha 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-1alpha as well as HIF1alpha-mediated apoptosis resistance in RMS and ES cells under hypoxia. PMID:23590596

Kilic-Eren, Mehtap; Boylu, Tulin; Tabor, Vedrana



Loss of connexin43 expression in Ewing's sarcoma cells favors the development of the primary tumor and the associated bone osteolysis.  


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



Primary spinal extradural Ewing's sarcoma (primitive neuroectodermal tumor): Report of a case and meta-analysis of the reported cases in the literature  

PubMed Central

Background: Primary spinal primitive neuroectodermal tumors (PNET) and/or spinal extraskeletal Ewing's sarcoma family tumors (ESET) are rare lesions appearing in the spinal extradural space. One hundred forty-one primary spinal PNETs, including 29 intramedullary lesions, have been reported in the literature. Encountering a case of primary epidural EES/peripheral PNET (pPNET) in sacral level, which is the fifth one occurring at this level in the literature, we have tried to conduct a meta-analysis of the reported cases. Case Description: A 44-year-old lady with epidural EES/pPNET is reported here. She was once operated for L5/S1 herniated disc, which did not ameliorate her symptoms. The clinical, imaging, surgical, and histopathologic characteristics of our case are presented and wide search of the literature is also done. All the reports were level 3 or less evidences and most of the series had missing parts. 106 cases of primary intraspinal (extradural/extramedullary-intradural) EES/pPNET and 29 cases of primary intramedullary PNET (CNS-PNET) have been reported in the literature. The most common clinical presentation in both entities was muscle weakness proportionate to the tumor location. Distant metastasis occurred in 38 of 99 (38%) cases of primary intraspinal EES/pPNET, while the rate of metastasis was 48% in patients with PNETs occurring in the intramedullary region (P > 0.05). One-year survival rate of the patients who underwent chemo-radiation after total or subtotal resection was better than those who did not receive chemotherapy or radiotherapy, or did not have total or subtotal resection. However, this difference was not repeated in 2-year survival rate in any of the tumor groups. Conclusion: It seems that total or subtotal removal of the tumor and adjuvant chemo- and radiation therapy can improve the outcome in these patients.

Saeedinia, Saeed; Nouri, Mohsen; Alimohammadi, Meysam; Moradi, Hedieh; Amirjamshidi, Abbas



?-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing's sarcoma.  


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



R1507, a Monoclonal Antibody to the Insulin-Like Growth Factor 1 Receptor, in Patients With Recurrent or Refractory Ewing Sarcoma Family of Tumors: Results of a Phase II Sarcoma Alliance for Research Through Collaboration Study  

PubMed Central

Purpose The type 1 insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the pathogenesis of the Ewing sarcoma family of tumors (ESFT). We conducted a multicenter phase II study of the fully human IGF-1R monoclonal antibody R1507 in patients with recurrent or refractory ESFT. Patients and Methods Patients ? 2 years of age with refractory or recurrent ESFT received R1507 at doses of 9 mg/kg intravenously one a week or 27 mg/kg intravenously every three weeks. Response was measured by using WHO criteria. Tumor imaging was performed every 6 weeks for 24 weeks and then every 12 weeks. Results From December 2007 through April 2010, 115 eligible patients from 31 different institutions were enrolled. The median age was 25 years (range, 8 to 78 years). The location of the primary tumor was bone in 57% of patients and extraskeletal in 43% of patients. A total of 109 patients were treated with R1507 9 mg/kg/wk, and six patients were treated with 27 mg/kg/3 wk. The overall complete response/partial response rate was 10% (95% CI, 4.9% to 16.5%). The median duration of response was 29 weeks (range, 12 to 94 weeks), and the median overall survival was 7.6 months (95% CI, 6 to 9.7 months). Ten of 11 responses were observed in patients who presented with primary bone tumors (P = .016). The most common adverse events of grades 3 to 4 were pain (15%), anemia (8%), thrombocytopenia (7%), and asthenia (5%). Conclusion R1507 was a well-tolerated agent that had meaningful and durable benefit in a subgroup of patients with ESFT. The identification of markers that are predictive of a benefit is necessary to fully capitalize on this approach.

Pappo, Alberto S.; Patel, Shreyaskumar R.; Crowley, John; Reinke, Denise K.; Kuenkele, Klaus-Peter; Chawla, Sant P.; Toner, Guy C.; Maki, Robert G.; Meyers, Paul A.; Chugh, Rashmi; Ganjoo, Kristen N.; Schuetze, Scott M.; Juergens, Heribert; Leahy, Michael G.; Geoerger, Birgit; Benjamin, Robert S.; Helman, Lee J.; Baker, Laurence H.



A Tetraspanin-Family Protein, T-Cell Acute Lymphoblastic Leukemia-Associated Antigen 1, Is Induced by the Ewing's Sarcoma-Wilms' Tumor 1 Fusion Protein of Desmoplastic Small Round-Cell Tumor  

PubMed Central

Recurrent chromosomal translocations in neoplasms often generate hybrid genes that play critical roles in tumorigenesis. Desmoplastic small round-cell tumor (DSRCT) is an aggressive malignancy associated with the chromosomal translocation t(11;22)(p13;q12). This translocation generates a chimeric transcription factor, EWS-WT1, which consists of the transcriptional activation domain of the Ewing’s sarcoma (EWS) protein and the DNA binding domain of the Wilms’ tumor 1 (WT1) protein. One of the splice variants, EWS-WT1(-KTS) lacks three amino acid residues (Lys-Thr-Ser) in the DNA binding domain and transforms NIH3T3 cells. Therefore, it is likely that aberrant gene expression caused by EWS-WT1(-KTS) is involved in the malignant phenotype of DSRCT. Microarray analysis of 9600 human genes revealed that a gene encoding a tetraspanin-family protein, T-cell acute lymphoblastic leukemia-associated antigen 1 (TALLA-1), was induced in EWS-WT1(-KTS)-expressing cell clones. This induction was EWS-WT1(-KTS)-specific, and more importantly, TALLA-1 protein was expressed in the three independent cases of DSRCT. Tetraspanin-family genes encode transmembrane proteins that regulate various cell processes such as cell adhesion, migration and metastasis. Our findings provide a novel insight into the malignant phenotype of DSRCT, suggesting that TALLA-1 is a useful marker for diagnosis and a potential target for the therapy of DSRCT.

Ito, Emi; Honma, Reiko; Imai, Jun-ichi; Azuma, Sakura; Kanno, Takayuki; Mori, Shigeo; Yoshie, Osamu; Nishio, Jun; Iwasaki, Hiroshi; Yoshida, Koichi; Gohda, Jin; Inoue, Jun-ichiro; Watanabe, Shinya; Semba, Kentaro



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



EWS–ETS oncoproteins: The linchpins of Ewing tumors  

Microsoft Academic Search

Ewing tumors, which comprise Ewing's sarcoma and peripheral primitive neuroectodermal tumors, are highly aggressive and mostly affect children and adolescents. Their molecular signature is a chromosomal translocation leading to the generation of EWS–ETS (or very rarely FUS–ETS) fusion proteins that are capable of transforming cells. These oncoproteins act as aberrant transcription factors due to the fusion of an ETS DNA

Ralf Janknecht



Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma

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



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



Local recurrence, rate and sites of metastases, and time to relapse as a function of treatment regimen, size of primary and surgical history in 62 patients presenting with non-metastatic Ewing's sarcoma of the pelvic bones  

SciTech Connect

This report reviews the experience of 62 patients who presented between 1972 and 1978 with non-metastatic Ewing's sarcoma of the pelvis and were entered on IESS I. Seventeen patients (27%) developed a local recurrence, 38 patients (61%) demonstrated metastases and 21 (34%) neither. In the dose range 4000 rad to 6000 rad no dose response could be detected for local control of tumor. Forty-six patients (74%) had a biopsy or exploratory surgery only, 5 patients (8%) had an incomplete resection and 11 patients (18%) has a complete resection of their tumor. In the 46 patients having a biopsy only, 13 developed a local recurrence (28%) as compared to 2 of 11 patients undergoing a complete resection (18%). The most common sites for metastases were lung in 19 patients (31%) and bone in 23 patients (37%). No significant difference was noted in the frequency of overall metastases or metastases to any site between those patients receiving one of the three treatment regimens used in IESS I: VAC and Adriamycin (regime I), VAC alone (regimen II) and VAC plus bilateral pulmonary irradiation (regimen III). At a median follow-up of 135 weeks no significant difference in median survival could be detected in patients with pelvic primaries between regimens I, II and III. The possible reasons for the poor prognosis of pelvic primary patients are discussed together with treatment policies that might improve the survival of this group of patients.

Evans, R.; Nesbit, M.; Askin, F.; Burgert, O.; Cangir, A.; Foulkes, M.; Gehan, E.; Gilula, L.; Kissane, J.; Makley, J.



A tetraspanin-family protein, T-cell acute lymphoblastic leukemia-associated antigen 1, is induced by the Ewing's sarcoma-Wilms' tumor 1 fusion protein of desmoplastic small round-cell tumor.  


Recurrent chromosomal translocations in neoplasms often generate hybrid genes that play critical roles in tumorigenesis. Desmoplastic small round-cell tumor (DSRCT) is an aggressive malignancy associated with the chromosomal translocation t(11;22)(p13;q12). This translocation generates a chimeric transcription factor, EWS-WT1, which consists of the transcriptional activation domain of the Ewing's sarcoma (EWS) protein and the DNA binding domain of the Wilms' tumor 1 (WT1) protein. One of the splice variants, EWS-WT1(-KTS) lacks three amino acid residues (Lys-Thr-Ser) in the DNA binding domain and transforms NIH3T3 cells. Therefore, it is likely that aberrant gene expression caused by EWS-WT1(-KTS) is involved in the malignant phenotype of DSRCT. Microarray analysis of 9600 human genes revealed that a gene encoding a tetraspanin-family protein, T-cell acute lymphoblastic leukemia-associated antigen 1 (TALLA-1), was induced in EWS-WT1(-KTS)-expressing cell clones. This induction was EWS-WT1(-KTS)-specific, and more importantly, TALLA-1 protein was expressed in the three independent cases of DSRCT. Tetraspanin-family genes encode transmembrane proteins that regulate various cell processes such as cell adhesion, migration and metastasis. Our findings provide a novel insight into the malignant phenotype of DSRCT, suggesting that TALLA-1 is a useful marker for diagnosis and a potential target for the therapy of DSRCT. PMID:14633590

Ito, Emi; Honma, Reiko; Imai, Jun-ichi; Azuma, Sakura; Kanno, Takayuki; Mori, Shigeo; Yoshie, Osamu; Nishio, Jun; Iwasaki, Hiroshi; Yoshida, Koichi; Gohda, Jin; Inoue, Jun-Ichiro; Watanabe, Shinya; Semba, Kentaro



Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX2 signaling pathways  

Microsoft Academic Search

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

Jin-Taek Hwang; Joohun Ha; Ock Jin. Park



Searching for molecular targets in sarcoma.  


Sarcoma are about 1% of cancers. Within that 1% are widely varied tumors now divided into types and subtypes. Sarcoma occur in patients of all ages with frequency spread evenly over the human age range. Although the specific cell of origin of many sarcoma remains unclear, sarcoma are all tumors of mesenchymal origin. The mesenchymal stem cell, a pluripotent cell, which gives rise to varied differentiated cells including osteocytes, adipocytes, chondrocytes, muscle cells, fibroblasts, neural cells and stromal cells, is the most likely ultimate cell of origin for sarcoma. When mesenchymal stem cell genetics go awry and malignant transformation occurs sarcoma including osteosarcoma, Ewing's sarcoma, chondrosarcoma, rhabdomyosarcoma, synovial sarcoma fibrosarcoma, liposarcoma and many others can initiate. Our knowledge of sarcoma genetics is increasing rapidly. Two general groups, sarcoma arising from chromosomal translocations and sarcoma with very complex genetics, can be identified. Genes that are frequently mutated in sarcoma include TP53, NF1, PIK3CA, HDAC1, IDH1 and 2, KDR, KIT and MED12. Genes that are frequently amplified in sarcoma include CDK4, YEATS4, HMGA2, MDM2, JUN, DNM3, FLT4, MYCN, MAP3K5, GLI1 and the microRNAs miR-214 and miR-199a2. Genes that are upregulated in sarcoma include MUC4, CD24, FOXL1, ANGPTL2, HIF1?, MDK, cMET, TIMP-2, PRL, PCSK1, IGFR-1, TIE1, KDR, TEK, FLT1 and several microRNAs. While some alterations occur in specific subtypes of sarcoma, others cross several sarcoma types. Discovering and developing new therapeutic approaches for these relentless diseases is critical. The detailed knowledge of sarcoma genetics may allow development of sarcoma subtype-targeted therapeutics. PMID:22387046

Teicher, Beverly A



Surgery for Ewing Tumors  


... tumors Next Topic Radiation therapy for Ewing tumors Surgery for Ewing tumors Several types of surgery can ... be reconstructed after surgery. Possible side effects of surgery The short-term side effects of surgery can ...


70. Systemic Administration of siRNA Against EWS-FLI1 Using a Targeted, Non-Viral Formulation Inhibits Growth in a Disseminated Murine Model of Ewing's Sarcoma  

Microsoft Academic Search

Despite aggressive therapy, 40% of patients with localized Ewing's family of tumors (EFT) and 80% of patients with detectable metastasis die due to tumor progression. More specific and effective treatments are needed, especially for high-risk cases. EWS-FLI1, the chimeric gene product of a chromosome translocation found in more than 90% of EFT, is crucial for maintaining EFT tumor growth. Endogenous

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



Uncommon sarcomas of the uterine cervix: a review of selected entities  

PubMed Central

Sarcomas constitute less than 1% of all cervical malignancies. With over 150 reported cases, rhabdomyosarcomas represent the most commonly reported sarcoma at this location. In this report, a select group of the more uncommon sarcomas of the uterine cervix are reviewed, including all previously reported examples of leiomyosarcoma, liposarcoma, alveolar soft part sarcoma, Ewing sarcoma/primitive neuroectodermal tumor, undifferentiated endocervical sarcoma, and malignant peripheral nerve sheath tumor (MPNST). Emphasis is placed on any distinctive clinicopathologic features of these entities at this unusual location.

Fadare, Oluwole



Gemcitabine in Bone Sarcoma Resistant to Doxorubicin-Based Chemotherapy  

PubMed Central

Subjects and Methods: Seven patients with progressive localized or metastatic chemo-resistant osteosarcoma were treated by gemcitabine.The protocol included gemcitabine 1000 mg/m2/w for 7 consecutive weeks, followed by 1 week rest. If no progression was observed,maintenance by gemcitabine 1000 mg/m2/w for 3 weeks every 28 days was given until failure was clinically or radiologically evident. Results. The true objective response rate was 0%. However, disease stabilization and clinical benefit response were observed in five patients (70%) for 13–96 weeks. Discussion. Postponing the inevitable death with a relatively non-toxic treatment, is, in our opinion, an important issue especially in young patients.Thus it may be justified and warranted to investigate the activity of gemcitabine in a larger group of patients with bone sarcomas.

Meller, Isaac; Kollender, Yehuda; Issakov, Josephine; Flusser, Gideon; Inbar, Moshe



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



Expandable Non-invasive Prostheses - an Alternative to Pediatric Patients with Bone Sarcoma  

Microsoft Academic Search

In the paper the problem of joint arthroplasty in children who have not reached their maturity is raised. The arthroplasty concerns replacement of a joint that does not function due to bone sarcoma that a child suffers from. Osteosarcoma and Ewing's sarcoma are the most common types of pediatric bone cancer and they afflict mainly long bones, i.e. femur and

Piotr Borkowski; Marek Pawlikowski; Konstanty Skalski



EWS-ETS oncoproteins: the linchpins of Ewing tumors.  


Ewing tumors, which comprise Ewing's sarcoma and peripheral primitive neuroectodermal tumors, are highly aggressive and mostly affect children and adolescents. Their molecular signature is a chromosomal translocation leading to the generation of EWS-ETS (or very rarely FUS-ETS) fusion proteins that are capable of transforming cells. These oncoproteins act as aberrant transcription factors due to the fusion of an ETS DNA binding domain to a highly potent EWS (or FUS) transactivation domain. Accordingly, many EWS-ETS target genes have been identified whose dysregulation could contribute to the development of tumor formation. Furthermore, EWS-ETS oncoproteins may impact on RNA splicing or affect other proteins through disturbing their ability to form functional complexes. The molecular knowledge gained so far from studying EWS-ETS oncoproteins has not only broadened our understanding of Ewing tumors but also improved the diagnosis of these highly undifferentiated tumors. In addition, several potential prognostic markers have been uncovered and novel therapies are suggested that may improve the still dismal survival rate of Ewing tumor patients. PMID:16202544

Janknecht, Ralf



Microsatellite Instability in Sarcoma: Fact or Fiction?  

PubMed Central

Microsatellite instability (MSI) is a unique molecular abnormality, indicative of a deficient DNA mismatch repair (MMR) system. Described and characterized in the colorectal cancer literature, the MSI-positive phenotype is predictive of disease susceptibility, pathogenesis, and prognosis. The clinical relevance of MSI in colorectal cancer has inspired similar inquisition within the sarcoma literature, although unfortunately, with very heterogeneous results. Evolving detection techniques, ill-defined sarcoma-specific microsatellite loci and small study numbers have hampered succinct conclusions. The literature does suggest that MSI in sarcoma is observed at a frequency similar to that of sporadic colorectal cancers, although there is little evidence to suggest that MSI-positive tumors share distinct biological attributes. Emerging evidence in Ewing sarcoma has demonstrated an intriguing mechanistic role of microsatellite DNA in the activation of key EWS/FLI-target genes. These findings provide an alternative perspective to the biological implications of microsatellite instability in sarcoma and warrant further investigation using sophisticated detection techniques, sensitive microsatellite loci, and appropriately powered study designs.

Monument, Michael J.; Lessnick, Stephen L.; Schiffman, Joshua D.; Randall, Rl. Tx.



Clinical relevance of molecular genetics to paediatric sarcomas  

PubMed Central

The application of cytogenetic and molecular genetic analyses to paediatric sarcomas has identified a number of characteristic changes associated with types and subtypes of sarcomas. This has led to increased understanding of the underlying molecular biology of some sarcomas and provided an important adjunct to standard morphological and immunohistochemical diagnoses. Characteristic genetic abnormalities, particularly specific chromosome translocations and associated fusion genes, have diagnostic and in some cases prognostic value. There is also the potential to detect micrometastastic disease. Fusion genes are most readily detected by fluorescence in situ hybridisation and reverse transcription?PCR technologies. The expression profiles of tumours with specific fusion genes are characteristically similar and the molecular signatures of sarcomas are also proving to be of diagnostic and prognostic value. Furthermore, fusion genes and other emerging molecular events associated with sarcomas represent potential targets for novel therapeutic approaches which are desperately required to improve the outcome of children with certain categories of sarcoma, including rhabdomyosarcomas and the Ewing's family of tumours. Increased understanding of the molecular biology of sarcomas is leading towards more effective treatments which may complement or be less toxic than conventional radiotherapy and cytotoxic chemotherapy. Here we review paediatric sarcomas that have associated molecular genetic changes which can increase diagnostic and prognostic accuracy and impact on clinical management.

Slater, Olga; Shipley, Janet



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.




PubMed Central

Sarcoma surgeons face unique challenges in younger patients with significant skeletal growth remaining. The heightened concerns regarding radiation in the very young and the drastic changes expected in the lengths and cross-sectional areas of bones affect the decision-making for both soft-tissue and bone sarcomas in this population. Nonetheless, there is sparse literature focused on sarcoma surgery in this age group. The records of one tertiary regional sarcoma treatment program were reviewed to identify all patients ten years old or younger at the time of local control surgery for limb or limb-girdle sarcomas. Demographic information, diagnosis, surgery performed, complications, and general outcomes were gleaned from the medical records. 43 patients were identified, including 15 with osteosarcomas, 11 Ewing’s sarcoma family tumors, five rhabdomyosarcomas, and two synovial sarcomas, among others. Location of tumors varied widely, but demonstrated a predilection for the upper extremity more than is typical in adolescents with the same tumor types. Survival was favorable overall, with only five patients dying from disease. Most patients continued to function well at latest follow-up, but 16 experienced additional surgical interventions following the index procedure. Sarcoma surgery in the younger growing child presents challenges for the surgeon, patient, and parents, but is usually successful in the long-term.

Israelsen, Ryan B; Ilium, Benjamin E; Crabtree, Susie; Randall, R Lor; Jones, Kevin B



SK-NEP-1 and Rh1 are Ewing family tumor lines.  


The utility of preclinical models of childhood cancers is contingent upon reliably classifying them with their corresponding clinical counterparts. Molecular tools such as gene expression profiling allow researchers to confirm the similarity between clinical tumors and preclinical models. We describe the use of gene expression profiling to show that SK-NEP-1, a cell line previously thought to represent anaplastic Wilms tumor, is instead related to Ewing sarcoma. RT-PCR confirmed that SK-NEP-1 expresses EWS-FLI1 gene fusion transcripts characteristic of Ewing sarcoma, and DNA sequencing demonstrated the joining of exon 7 of EWS with exon 5 of FLI1 for these transcripts. Rh1, which was previously categorized as an alveolar rhabdomyosarcoma cell line, also has a gene expression profile suggestive of Ewing sarcoma and expresses EWS-FLI1 fusion transcripts in which exon 7 of EWS is joined with exon 6 of FLI1. These examples illustrate the importance of molecularly characterizing pediatric preclinical models used for testing new agents. PMID:17154184

Smith, Malcolm A; Morton, Christopher L; Phelps, Doris; Girtman, Kevin; Neale, Geoffrey; Houghton, Peter J



Development of IGF-IR inhibitors in pediatric sarcomas  

Microsoft Academic Search

For approximately two decades, the insulin-like growth factor (IGF) has been implicated in the pathogenesis of numerous pediatric\\u000a malignancies, including osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma. In the past, major toxicities have limited the\\u000a clinical development of IGF-targeted therapies. However, recent interest has been heightened by the availability of increasingly\\u000a specific small molecules and antibodies directed at IGF-I receptor. Preclinical data

E. Anders Kolb; Richard Gorlick



Ewing Marion Kauffman Foundation  

NSDL National Science Digital Library

Founded in 1966, the Kauffman Foundation was the brainchild of Ewing Kauffman who displayed a great curiosity about the world and who also happened to be a great believer in the importance of philanthropy. Over the past forty years, the Foundation has worked on a variety of initiatives, including work on supporting early education, entrepreneurship, and school reform. On the homepage, visitors will find five primary sections, including "Advancing Innovation", "Education", and "Research & Policy". The first place to start is the "Research & Policy" area. Here, visitors can find data reports and analysis papers on national entrepreneurship trends and technology innovation strategies. In each section, visitors can also view media clips featuring commentary from Kauffman Foundation scholars and experts. Moving on, the "Grants" area is a great way to learn about grant opportunities and recipients listed by date and name. Finally, the "Stay Connected" area contains a place where visitors can sign up to receive their various e-newsletters.


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


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.



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



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



[Targeted treatment of rare connective tissue tumors and sarcomas].  


The recent progress of the biology of the locally aggressive sarcomas of soft tissues and related connective tissue tumors enabled to reclassify molecular and histological entities of the disease. Six subgroups of sarcomas are identified with specific molecular alterations, the targeted treatments of which are the object of this article: 1) sarcomas with specific translocations with fusion oncogenes (DFSP, PVNS); 2) sarcomas with tyrosine kinase mutations (KIT in GIST); 3) tumors with deletion of tumor suppressor genes (TSC in the PEComes, NF1 involved in type 1 neurofibromatosis; 4) sarcomas with MDM2/CDK4 amplification in the 12q13-15 amplicon, i.e. well differentiated or dedifferentiated liposarcomas; 5) sarcomas with complex genetics present more unrefined genetic changes (leiomyosarcomas, osteosarcomas). On top these 5 groups, desmoids tumors characterized by alterations of the Wnt, beta catenin, APC, and giant cell tumors of the bone, in which RANK/RANKL operates a complex interaction between the cellular stroma and giant tumor cells. The identification of these abnormal ways of road marking to licence the development of effective targeted therapeutic agents against certain rare histological connective subcategories of sarcomas and tumors with local aggressiveness, in particular DFSP, PVNS, GCST, PEComes, endometrial stromal sarcomas, Ewing sarcomas, etc. Imatinib is used in the treatment of DFSP, characterized by a translocation of the gene PDGF, or in pigmented villonodular synovitis (PVNS), a tumor of soft part also locally aggressive, caused by an abnormality of the gene coding for the M-CSF. Several clinical trials of phase I and II trials demonstrated the antitumor activity of anti-IGF1R antibodies in Ewing, whose fusion gene downregulates IGFBP3. Inhibitors of MDM2 are in the course of clinical evaluation in liposarcomas. Inhibitors of mTOR (sirolimus, temsirolimus) demonstrated an antitumoral activity in the PEComas. The molecular characterization of sarcomas allowed to develop therapeutic targeted to correct the responsible abnormalities. Translational research is and will be an essential tool for the development of new treatments and the identification of the mechanisms of answer and resistance set up by these tumors. PMID:20497911

Cassier, P; Pissaloux, D; Alberti, L; Ray-Coquard, I; Blay, J-Y



Neurologic Complications of Sarcoma  

Microsoft Academic Search

Sarcomas are a heterogeneous group of tumors that rarely involve the nervous system. Neurologic effects of sarcoma are more\\u000a often due to tumors outside of the central nervous system. However, as long-term survival rates in childhood sarcoma improves,\\u000a reports of late neurologic complications have increased. With recent advances in treating local sarcomas with targeted molecular\\u000a therapies, the incidence of late

Santosh Kesari; Lara J. Kunschner


What's New in Ewing Tumor Research and Treatment?  


... 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 ...


Vascular sarcomas.  


Vascular sarcomas are soft-tissue tumors that arise from the endothelium with a malignant potential. This review discusses the management of epithelioid hemangioendothelioma (EHE) and angiosarcoma. EHE is a vascular tumor of intermediate malignant potential with an indolent course. EHE arising from the liver, lung, or bone tends to be multifocal and the rate of progression is slow and often unpredictable. Treatment should be considered in patients with significant symptomatic deterioration and/or progressive disease on imaging studies. Various cytotoxic and targeted therapies are available for management, with disease stabilization as the most common outcome. Angiosarcoma is an aggressive vascular tumor with a high malignant potential. Multidisciplinary care is critical for the management of localized disease, and the best outcomes are often observed in patients when a combination of systemic and local therapy options is used. Metastatic angiosarcoma is treated primarily with systemic therapy, and several cytotoxic and targeted therapies are available, alone or in combination. The choice of therapy depends on several factors, such as cutaneous location of the tumor, performance status of the patient, toxicity of the treatment, and patient goals. PMID:23852636

Ravi, Vinod; Patel, Shreyaskumar



Chemo Resistance of Breast Cancer Stem Cells.  

National Technical Information Service (NTIS)

There is increasing evidence that breast cancers are driven by a small subcomponent that displays stem cell properties. We hypothesize that these breast cancer stem cells are resistant to chemotherapy and may contribute to tumor relapse. In order to provi...

M. S. Wicha



Chemo Resistance of Breast Cancer Stem Cells.  

National Technical Information Service (NTIS)

This past year was the second year of the DOD award. Over this year we have made substantial progress in achieving the goals outlined in the proposal. In addition, we have found that the enzyme aldehyde dehydrogenase 1 is an excellent marker for cancer st...

M. S. Wicha



Ewing Structure: A Possible Abyssal Impact Crater  

Microsoft Academic Search

We discovered a possible abyssal impact crater about 150 km in diameter that we call the Ewing structure. It lies between the Clarion and Clipperton fracture zones and is about the age of the late\\/middle Miocene boundary, a prominent mass extinction event. The Ewing structure has a weak topographic expression, but 6 cm to over 850-cm thick layers with high

D. H. Abbott; L. Burckle; T. Goldin; J. Hays



Anaplastic sarcoma of the kidney: Case report and literature review.  


Anaplastic sarcoma of the kidney (ASK) is a relatively newly recognized pediatric renal tumor. The present patient, a 13-year-old boy with a large renal mass, underwent surgery. Pathological findings showed proliferation of short spindle-shaped cells with anaplastic features including multiple foci in hyaline cartilage. Complex chromosomal abnormalities were detected in the tumor cells. Postoperative chemotherapy with the regimen for Ewing's sarcoma achieved complete remission but the tumor recurred and the patient died during re-induction chemotherapy. Autopsy indicated the cause of death as duodenal hemorrhage. Because there were no viable tumor cells, the recurrent tumor was considered to have been completely cured by chemotherapy. ASK is a very rare tumor, of unknown pathogenesis, and no standard treatment has yet been established, but the tumor cells may be responsive to chemotherapy. Further study is needed to establish the optimal treatment strategy. PMID:24134767

Watanabe, Noriko; Omagari, Daisuke; Yamada, Tsutomu; Nemoto, Norimichi; Furuya, Takeshi; Sugito, Kiminobu; Koshinaga, Tsugumichi; Yagasaki, Hiroshi; Sugitani, Masahiko



Four year experience of sarcoma of soft tissues and bones in a tertiary care hospital and review of literature  

PubMed Central

Background Sarcoma encompasses an uncommon group of cancer and the data is insufficient from Pakistan. We report our four years experience of Sarcoma of soft tissues and bones. Methods This cross sectional study was carried out at Aga Khan University Hospital from 2004 to 2008. The patients were divided into two groups from the outset i.e. initially diagnosed and relapsed group and separate sub group analysis was conducted. Results Out of 93 newly diagnosed patients, 58 belonged to bone sarcoma and 35 to soft tissue sarcoma group. While for relapsed patients, 5 had soft tissue sarcoma and 9 had bone sarcoma. Mean age was 32.5 years. At presentation, approximately two third patients had localised disease while remaining one third had metastatic disease. The Kaplan Meier estimate of median recurrence free survival was 25 months, 35 months, and 44 months for Osteogenic sarcoma, Ewing's sarcoma and Chondrosarcoma respectively. For Leiomyosarcoma and Synovial sarcoma, it was 20 and 19 months respectively. The grade of the tumour (p = 0.02) and surgical margin status (p = 0.001) were statistically significant for determination of relapse of disease. Conclusion The median recurrence free survival of patients in our study was comparable to the reported literature but with significant lost to follow rate. Further large-scale, multi centre studies are needed to have a more comprehensive understanding of this heterogeneous disease in our population.



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.



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.).


Molecular Alterations in Pediatric Sarcomas: Potential Targets for Immunotherapy  

PubMed Central

Purpose/results/discussion. Recurrent chromosomal translocations are common features of many human malignancies. While such translocations often serve as diagnostic markers, molecular analysis of these breakpoint regions and the characterization of the affected genes is leading to a greater understanding of the causal role such translocations play in malignant transformation. A common theme that is emerging from the study of tumor-associated translocations is the generation of chimeric genes that, when expressed, frequently retain many of the functional properties of the wild-type genes from which they originated. Sarcomas, in particular, harbor chimeric genes that are often derived from transcription factors, suggesting that the resulting chimeric transcription factors contribute to tumorigenesis. The tumor-specific expression of the fusion proteins make them likely candidates for tumor-associated antigens (TAA) and are thus of interest in the development of new therapies. The focus of this review will be on the translocation events associated with Ewing's sarcomas/PNETs (ES), alveolar rhabdomyosarcoma (ARMS), malignant melanoma of soft parts (MMSP) (clear cell sarcoma), desmoplastic small round cell tumor (DSRCT), synovial sarcoma (SS), and liposarcoma (LS), and the potential for targeting the resulting chimeric proteins in novel immunotherapies.

Goletz, Theresa J.; Mackall, Crystal L.; Berzofsky, Jay A.



Epithelioid Sarcoma in the Hand  

Microsoft Academic Search

An illustrative case of epithelioid sarcoma in the hand of a young man, causing considerable diagnostic problems, is presented.Epithelioid sarcoma is a malignant lesion, first described by Enzinger in 1970. Although epithelioid sarcoma is the third commonest soft tissue sarcoma in the upper extremity (Bryan, 1974) it still causes confusion in differential diagnosis, both to the surgeon and to the




GLI1 Is a Central Mediator of EWS/FLI1 Signaling in Ewing Tumors  

PubMed Central

The Ewing Sarcoma Family Tumors (ESFT) consist of the classical pathologic entities of Ewing Sarcoma and peripheral Primitive Neuroectodermal Tumor. Occurring largely in the childhood through young adult years, these tumors have an unsurpassed propensity for metastasis and have no defined cell of origin. The biology of these aggressive malignancies centers around EWS/FLI1 and related EWS/ETS chimeric transcription factors, which are largely limited to this tumor class. Much progress has been made in the identification of a network of loci whose expression is modulated by EWS/FLI1 and its congeners. To date, little progress has been made in reconstructing the sequence of direct and indirect events that produce this network of modulated loci. The recent identification of GLI1 as an upregulated target of EWS/ETS transcription factors suggests a target which may be a more central mediator in the ESFT signaling network. In this paper, we further define the relationship of EWS/FLI1 expression and GLI1 upregulation in ESFT. This relationship is supported with data from primary tumor specimens. It is consistently observed across multiple ESFT cell lines and with multiple means of EWS/FLI1 inhibition. GLI1 inhibition affects tumor cell line phenotype whether shRNA or endogenous or pharmacologic inhibitors are employed. As is seen in model transformation systems, GLI1 upregulation by EWS/FLI1 appears to be independent of Hedgehog stimulation. Consistent with a more central role in ESFT pathogenesis, several known EWS/FLI1 targets appear to be targeted through GLI1. These findings further establish a central role for GLI1 in the pathogenesis of Ewing Tumors.

Joo, Jay; Christensen, Laura; Warner, Kegan; States, Leith; Kang, Hyung-Gyoo; Vo, Kieuhoa; Lawlor, Elizabeth R.; May, William A.



Tissue Microarray Validation of Epidermal Growth Factor Receptor and SALL2 in Synovial Sarcoma with Comparison to Tumors of Similar Histology  

PubMed Central

Histological diagnosis of synovial sarcoma can be difficult. Genome-wide expression profiling has identified a number of genes expressed at higher levels in synovial sarcoma than in other soft tissue tumors, representing excellent candidates for diagnostic immunohistochemical markers. A tissue microarray comprising 77 sarcomas, including 46 synovial sarcomas, was constructed to validate identified markers and investigate their expression in tumors in the differential diagnosis of synovial sarcoma. Immunostaining was performed for two such markers, epidermal growth factor receptor and SAL (drosophila)-like 2 (SALL2), and for fifteen established markers used in the differential diagnosis of sarcomas. As predicted by expression profiling, epidermal growth factor receptor (a potential therapeutic target) and SALL2 stained most cases of synovial sarcoma; staining was significantly less common among other tested sarcomas. Hierarchical clustering analysis applied to immunostaining results for all 18 antibodies showed that synovial sarcomas, leiomyosarcomas, hemangiopericytomas, and solitary fibrous tumors cluster distinctly, and assigned one case with indeterminate histology as a Ewing sarcoma. Digital images from over 2500 immunostained cores analyzed in this study were captured and are made accessible through the accompanying website:

Nielsen, Torsten O.; Hsu, Forrest D.; O'Connell, John X.; Gilks, C. Blake; Sorensen, Poul H.B.; Linn, Sabine; West, Robert B.; Liu, Chih Long; Botstein, David; Brown, Patrick O.; van de Rijn, Matt



Spinal and Paraspinal Ewing Tumors  

SciTech Connect

Purpose: To perform a review of the 40-year University of Florida experience treating spinal and paraspinal Ewing tumors. Patients and Methods: A total of 27 patients were treated between 1965 and 2007. For local management, 21 patients were treated with radiotherapy (RT) alone and 6 with surgery plus RT. All patients with metastatic disease were treated with RT alone. The risk profiles of each group were otherwise similar. The median age was 17 years, and the most frequent subsite was the sacral spine (n = 9). The median potential follow-up was 16 years. Results: The 5-year actuarial overall survival, cause-specific survival, and local control rate was 62%, 62%, and 90%, respectively. For the nonmetastatic subset (n = 22), the 5-year overall survival, cause-specific survival, and local control rate was 71%, 71%, and 89%, respectively. The local control rate was 84% for patients treated with RT alone vs. 100% for those treated with surgery plus RT. Patients who were >14 years old and those who were treated with intensive therapy demonstrated superior local control. Of 9 patients in our series with Frankel C or greater neurologic deficits at presentation, 7 experienced a full recovery with treatment. Of the 27 patients, 37% experienced Common Toxicity Criteria Grade 3 or greater toxicity, including 2 deaths from sepsis. Conclusion: Aggressive management of spinal and paraspinal Ewing tumors with RT with or without surgery results in high toxicity but excellent local control and neurologic outcomes. Efforts should be focused on identifying disease amenable to combined modality local therapy and improving RT techniques.

Indelicato, Daniel J., E-mail: dindelicato@floridaproton.or [Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL (United States); 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 (United States); University of Florida Proton Therapy Institute, Jacksonville, FL (United States); Shahlaee, Amir H. [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 (United States); 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); Pincus, David W. [Department of Neurosurgery, 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 (United States); University of Florida Proton Therapy Institute, Jacksonville, FL (United States)



What Is Kaposi Sarcoma?  


... KSHV infection are more likely to develop KS. Endemic (African) Kaposi sarcoma Endemic KS occurs in people living in Equatorial Africa ... group of people that includes children and women. Endemic KS tends to occur in younger people (usually ...


Epithelioid sarcoma of vulva  

Microsoft Academic Search

Epithelioid sarcoma of vulva is an extremely rare and aggressive tumor. In most patients it is asymptomatic, and the lesions\\u000a are usually mistaken for benign processes, leading to diagnosis at later stages. We report a case of vulvar epithelioid sarcoma\\u000a in a 51-yr-old woman presenting with a nodularity of vulva. Left hemivulvectomy with bilateral inguinal lymph node dissection\\u000a was performed.

Kadri Altundag; Oguz Dikbas; Basak Oyan; Alp Usubutun; Alev Turker



Slope and the choice of birth sites by ewes  

Microsoft Academic Search

An experiment was carried out over 2 years using 140 Marshall Romney (MR) and 110 conventional Romney (CR) ewes to determine if ewes would lamb on steep slopes when given a choiceofsteep and flat areas within the same paddock. A day before their expected peak of lambing, the ewes entered one of two lambing paddocks which had three (paddock 1)

T. W. Knight; L. D. Wilson; P. R. Lynch; H.-U. P. Hockey



To Find a Safe Dose and Show Early Clinical Activity of Weekly Nab-paclitaxel in Pediatric Patients With Recurrent/ Refractory Solid Tumors

Neuroblastoma;; Rhabdomyosarcoma;; Ewing's Sarcoma;; Ewing's Tumor;; Sarcoma, Ewing's;; Sarcomas, Epitheliod;; Sarcoma, Soft Tissue;; Sarcoma, Spindle Cell;; Melanoma;; Malignant Melanoma;; Clinical Oncology;; Oncology, Medical;; Pediatrics, Osteosarcoma;; Osteogenic Sarcoma;; Osteosarcoma Tumor;; Sarcoma, Osteogenic;; Tumors;; Cancer;; Neoplasia;; Neoplasm;; Histiocytoma;; Fibrosarcoma;; Dermatofibrosarcoma



Primary hepatic sarcomas: CT findings  

Microsoft Academic Search

Primary hepatic sarcomas are rare tumors that are difficult to diagnose clinically. Different primary hepatic sarcomas may\\u000a have different clinical, morphologic, and radiological features. In this pictorial review, we summarized computed tomography\\u000a (CT) findings of some relatively common types of hepatic sarcomas, including angiosarcoma, epithelioid hemangioendothelioma\\u000a (EHE), liposarcoma, undifferentiated embryonal sarcoma (UES), leiomyosarcoma, malignant fibrous histiocytoma (MFH), and carcinosarcoma\\u000a (including

Ri-Sheng Yu; Ying Chen; Biao Jiang; Liu-Hong Wang; Xiu-Fang Xu



Prognostic factors predictive of survival and local recurrence for extremity soft tissue sarcoma.  

PubMed Central

OBJECTIVE: The authors sought to identify prognostic factors in the management of extremity soft tissue sarcoma. SUMMARY BACKGROUND DATA: The surgical management of soft tissue sarcoma has evolved because of advances in therapy, resulting in increased limb preservation and quality of life. However, identifying a subset of patients most likely to benefit from adjuvant chemotherapy has been difficult to achieve. METHODS: A retrospective analysis of a prospective data base of 182 patients with extremity sarcomas from 1970 to 1992 was performed. RESULTS: A histologic diagnosis of Ewing's sarcoma, synovial sarcoma, and angiosarcoma was associated with a 13-fold increased risk of death compared with liposarcoma, fibrosarcoma, and malignant peripheral nerve sheath histologic types after having adjusted for the other prognostic factors (p < 0.001). In addition to histologic type, high-grade sarcomas (p = 0.018), sarcomas greater than 10 cm in size (p = 0.006), and age at diagnosis (p = 0.016) were found to be important prognostic factors for survival but not for local recurrence. For the first time to their knowledge, the authors showed that mean mitotic activity has prognostic value after having adjusted for other prognostic factors, such as grade (p = 0.005). The only prognostic factors predictive for local recurrence were whether the patient presented with locally recurrent disease (p = 0.0001) or had microscopically positive margins (p = 0.052). CONCLUSIONS: The use of mitotic activity along with grade, size, histologic type, and age at diagnosis is prognostic for survival in extremity soft tissue sarcoma. The use of an objective pathologic feature, such as mean mitotic activity, is also useful in selecting patients for future systemic neoadjuvant or adjuvant trials and primary therapy.

Singer, S; Corson, J M; Gonin, R; Labow, B; Eberlein, T J



ILK (?1-integrin-linked protein kinase): a novel immunohistochemical marker for Ewing’s sarcoma and primitive neuroectodermal tumour  

Microsoft Academic Search

ILK (?1-integrin-linked protein kinase) is a recently identified 59-kDa serine\\/threonine protein kinase that interacts with\\u000a the cytoplasmic domain of the ?1-integrin containing four ankyrin-like repeats. We have developed a polyclonal antibody against\\u000a ILK and explored the ILK immunoreactivity in normal human cells and tissues. ILK was mainly expressed in cardiac muscle and\\u000a skeletal muscles. Surprisingly, ILK expression was observed in

Doo Hyun Chung; Jong Im Lee; Myeong Cherl Kook; Jeong Ran Kim; Soon Ha Kim; Eun Young Choi; Seong Hoe Park; H. G. Song



Reproductive performance of ewe lambs from ewes from different selection practices with or without induced estrus  

Microsoft Academic Search

Three groups of ewe lambs born in May (experiment 1; n=211) or April (experiment 2; n=174) were used to evaluate the effects of selection line and induction of estrus on pregnancy rate. Experiment 1 was a single factor experiment with induction of estrus as the main effect. In early December, May-born Targhee (n=82) and Rambouillet×Targhee (n=129) ewes were randomly assigned

J. N Stellflug; P. G Hatfield; M. C Wulster-Radcliffe; J. W Walker



Influence of a conspecific image of own vs. different breed on fear reactions of ewes  

Microsoft Academic Search

We observed the influence of slide images of conspecifics on fear reactions of 12 Romanov and 12 Ile-de-France ewes. Each ewe was individually tested twice in isolation: once in the presence of the projected image of an unfamiliar ewe of its own breed, and once when exposed to an image of a ewe of a different breed. Ewes' responses to

M. F. Bouissou; R. H. Porter; L. Boyle; G. Ferreira



Effects of Ewe Oil in Media for Mass Production of Tricephalobus (Nematoda: Rhabditida)  

Microsoft Academic Search

The Media WA 2%, WA 2% + Ewe oil, WA 2% + K2HPO4, SDA (Sabouraud 4% Dextrose Agar), SDA + K2HPO4, SDA + Ewe oil, NA, NA + K2HPO4 and NA + Ewe oil were used for mass production of Tricephalobus. One mL Ewe oil extracted from milk was added to the media 2% WA + Ewe oil and NA




Radiotherapy in Ewing tumors of the vertebrae: Treatment results and local relapse analysis of the Chess 81/86 and EICESS 92 trials  

SciTech Connect

Purpose: Treatment results in patients with Ewing tumors of the vertebrae enrolled in the Cooperative Ewing's Sarcoma Study (CESS) 81, 86, and the European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) 92 trials were analyzed with special emphasis on radiation-associated factors. Patients and Methods: A retrospective analysis was performed on 116 patients with primary tumors of the cervical, thoracic, or lumbar vertebrae treated between 1981 and 1999. Furthermore, a relapse analysis was done on those patients who underwent radiotherapy and subsequently had a local recurrence. Results: A total of 64.6% of the patients received definitive radiotherapy; 27.5% of patients had surgery and radiotherapy. Only 4 patients (3.4%) underwent definitive surgery. Twenty-seven patients presented with metastases at diagnosis. 22.4% of the total group developed a local relapse. Among the subgroup with definitive radiotherapy, local recurrence was seen in 17 of 75 patients (22.6%). Event-free survival and survival at 5 years were 47% and 58%, respectively. Of the 14 evaluable patients with a local relapse after radiotherapy, 13 were in-field. No correlation between radiation dose and local control could be found. Conclusion: Surgery with wide resection margins is rarely possible. The results after definitive radiotherapy in vertebral tumors are comparable to those of other tumor sites when definitive radiotherapy is given. Nearly all local relapses after radiotherapy are in-field.

Schuck, Andreas [Department of Radiotherapy, University Hospital of Muenster, Muenster (Germany)]. E-mail:; Ahrens, Susanne [Department of Pediatric Oncology and Hematology, University Hospital of Muenster, Muenster (Germany); Schorlemer, Ines von [Department of Radiotherapy, University Hospital of Muenster, Muenster (Germany); Kuhlen, Michaela [Department of Pediatric Oncology and Hematology, University Hospital of Muenster, Muenster (Germany); Paulussen, Michael [Department of Pediatric Oncology and Hematology, University Hospital of Muenster, Muenster (Germany); Hunold, Andrea [Department of Pediatric Oncology and Hematology, University Hospital of Muenster, Muenster (Germany); Gosheger, Georg [Department of Orthopedics, University Hospital of Muenster, Muenster (Germany); Winkelmann, Winfried [Department of Orthopedics, University Hospital of Muenster, Muenster (Germany); Dunst, Juergen [Department of Radiotherapy, University Hospital of Halle, Halle (Germany); Willich, Normann [Department of Radiotherapy, University Hospital of Muenster, Muenster (Germany); Juergens, Heribert [Department of Pediatric Oncology and Hematology, University Hospital of Muenster, Muenster (Germany)



Purdy Awarded 2006 Maurice Ewing Medal  

NASA Astrophysics Data System (ADS)

G. Michael Purdy was awarded the Maurice Ewing Medal at the AGU Fall Meeting honors ceremony, which was held on 13 December 2006 in San Francisco, Calif. The medal recognizes significant original contributions to the scientific understanding of the processes in the ocean; for the advancement of oceanographic engineering technology and instrumentation; or outstanding service to marine science.

Purdy, G. Michael; Detrick, Robert S.



Pedlosky receives 2011 Maurice Ewing Medal: Response  

NASA Astrophysics Data System (ADS)

Joseph Pedlosky was awarded the 2011 Maurice Ewing Medal at the AGU Fall Meeting Honors Ceremony, held on 7 December 2011 in San Francisco, Calif. The medal is for “significant original contributions to the scientific understanding of the processes in the ocean; for the advancement of oceanographic engineering, technology, and instrumentation; and for outstanding service to the marine sciences.”

Pedlosky, Joseph



Pedlosky receives 2011 Maurice Ewing Medal: Citation  

NASA Astrophysics Data System (ADS)

Joseph Pedlosky was awarded the 2011 Maurice Ewing Medal at the AGU Fall Meeting Honors Ceremony, held on 7 December 2011 in San Francisco, Calif. The medal is for “significant original contributions to the scientific understanding of the processes in the ocean; for the advancement of oceanographic engineering, technology, and instrumentation; and for outstanding service to the marine sciences.”

Liu, Zhengyu; Cessi, Paola



Rhodotorula minuta fungemia in a ewe lamb  

Technology Transfer Automated Retrieval System (TEKTRAN)

An 8-mo-old crossbred ewe, normal upon physical examination, was humanely euthanized for tissue collection. After approximately three weeks in tissue culture, fungi began budding out of cells obtained from the choroid plexus. After an additional three weeks, budding was observed in kidney cell cul...


Soft Tissue Sarcoma  


... have been exposed to certain chemicals, had radiation therapy or have certain genetic diseases. To diagnose soft tissue sarcomas, doctors must remove and look at a piece of the tumor under a microscope. Treatments include ... chemotherapy or a combination. NIH: National Cancer Institute


Leukosis/Sarcoma Group  

Technology Transfer Automated Retrieval System (TEKTRAN)

The leukosis/sarcoma (L/S) group of diseases designates a variety of transmissible benign and malignant neoplasms of chickens caused by members that belong to the family Retroviridae. Lymphoid leukosis has been the most common form of L/S group of diseases seen in field flocks, although myeloid leuk...


Leukosis/Sarcoma Group  

Technology Transfer Automated Retrieval System (TEKTRAN)

The leukosis/sarcoma (L/S) group of diseases designates a variety of transmissible benign and malignant neoplasms of chickens caused by members that belong to the family Retroviridae. Because the expansion of the literature on this disease, it is no longer feasible to cite all relevant publications ...


Gene Therapy for Sarcoma  

Microsoft Academic Search

Soft tissue sarcomas are mesenchymal tumors which respond poorly to systemic therapy. Recent studies suggest a higher response rate with an increased doxorubicin dosage. However, this was parallel with a profound hematotoxicity in 75% of patients. Transfer of the human multidrug resistance 1 (MDR1) gene to normal hematopoietic stem cells and transplantation may significantly reduce the hematotoxicity of anthracyclin-based chemotherapy.

S. Fruehauf; M. R. Veldwijk; S. Berlinghoff; N. Basara; C. Baum; M. Flasshove; S. Hegewisch-Becker; N. Kröger; T. Licht; T. Moritz; U. R. Hengge; W. Jens Zeller; S. Laufs



Sorafenib for Kaposi's Sarcoma

In this trial, patients with either AIDS-related or non-AIDS-related Kaposi's sarcoma (KS) will be treated with varying doses of the drug sorafenib (Nexavar®) for up to 54 weeks to examine the safety of the drug and determine how it is processed in patients with KS who are receiving antiretroviral therapy.


Recombinant Interferon Gamma in Treating Patients With Soft Tissue Sarcoma

Adult Liposarcoma; Adult Synovial Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Stage IA Adult Soft Tissue Sarcoma; Stage IB Adult Soft Tissue Sarcoma; Stage IIA Adult Soft Tissue Sarcoma; Stage IIB Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma



Understanding the Biology of Bone Sarcoma from Early Initiating Events through Late Events in Metastasis and Disease Progression  

PubMed Central

The two most common primary bone malignancies, osteosarcoma (OS), and Ewing sarcoma (ES), are both aggressive, highly metastatic cancers that most often strike teens, though both can be found in younger children and adults. Despite distinct origins and pathogenesis, both diseases share several mechanisms of progression and metastasis, including neovascularization, invasion, anoikis resistance, chemoresistance, and evasion of the immune response. Some of these processes are well-studies in more common carcinoma models, and the observation from adult diseases may be readily applied to pediatric bone sarcomas. Neovascularization, which includes angiogenesis and vasculogenesis, is a clear example of a process that is likely to be similar between carcinomas and sarcomas, since the responding cells are the same in each case. Chemoresistance mechanisms also may be similar between other cancers and the bone sarcomas. Since OS and ES are mesenchymal in origin, the process of epithelial-to-mesenchymal transition is largely absent in bone sarcomas, necessitating different approaches to study progression and metastasis in these diseases. One process that is less well-studied in bone sarcomas is dormancy, which allows micrometastatic disease to remain viable but not growing in distant sites – typically the lungs – for months or years before renewing growth to become overt metastatic disease. By understanding the basic biology of these processes, novel therapeutic strategies may be developed that could improve survival in children with OS or ES.

Zhu, Limin; McManus, Madonna M.; Hughes, Dennis P. M.



Intravaginal sponges to synchronize estrus decrease sexual attractiveness in ewes.  


Vaginal secretions are an important source of chemical signals, which affect ewes' attractiveness. Moreover, alterations of vaginal flora reduce sexual attractiveness of estrous ewes. As intravaginal sponges containing progestagens (widely used for estrous synchronization) affect vaginal flora, our aims were to determine if estrous ewes pretreated with intravaginal sponges were less attractive than ewes displaying spontaneous estrus, and if the addition of antibiotic to the sponge mitigated the decreased sexual attractiveness. Seventy-two estrous ewes were used in experiment 1: in 36, estrus was synchronized with commercial intravaginal sponges (50 mg medroxyprogesterone acetate for 14 days, group MAP1), whereas the other 36 were given a PGF2? analogue 19 to 20 days earlier and displayed spontaneous estrus (group C1). In experiment 2, 72 ewes were treated with intravaginal sponges for 14 days; for 36 ewes, the sponges contained 0.02 mg oxytetracycline (group Ox), whereas there was no antibiotic in the sponges for the remaining 36 ewes (group MAP2). In both experiments, sexual attractiveness was determined in 12 groups of six estrous ewes (three MAP1 vs. three C1, and three MAP2 vs. three Ox for Experiments 1 and 2, respectively) located in a 4 × 4 m pen. Courting and mating time that each ram spent with each ewe was recorded. After 5 min, the ewe with which the ram spent more time (most attractive ewe, ranked one, scale one to six) was taken out from the pen. The procedure was repeated until the ram ranked all six ewes, and repeated in the 12 groups in both experiments. In experiment 1, C1 ewes were more attractive than MAP1 ewes (ranks: 2.9 ± 0.3 vs. 4.1 ± 0.3, mean ± SEM, respectively; P < 0.002). In experiment 2, sexual attractiveness of MAP2 and Ox ewes was similar (3.5 ± 0.3 vs. 3.4 ± 0.3, respectively). We concluded that the use of intravaginal sponges impregnated with medroxyprogesterone acetate negatively affected ewes' sexual attractiveness, but this decrease was not mitigated by inclusion of a local antibiotic. PMID:22925645

Gatti, M; Ungerfeld, R



Sarcoma - Adult Soft Tissue Cancer: Chemotherapy  


... Next Topic Targeted therapy for soft tissue sarcoma Chemotherapy for soft tissue sarcomas Chemotherapy (chemo) is the use of drugs given into ... Depending on the type and stage of sarcoma, chemotherapy may be given as the main treatment or ...


Sarcoma - Adult Soft Tissue Cancer: Radiation Therapy  


... sarcomas Next Topic Chemotherapy for soft tissue sarcomas Radiation therapy for soft tissue sarcomas Radiation therapy uses ... spread. This is called palliative treatment. Types of radiation therapy External beam radiation therapy: For this treatment, ...


The future of sarcoma treatment.  


The last two decades have shown exciting and dramatic improvements in the management of osteogenic sarcoma, while progress in soft tissue sarcomas has lagged behind considerably. Osteogenic sarcoma treatment has been a model of multidisciplinary collaboration. Orthopedic surgeons working together with medical and pediatric oncologists have improved disease-free survival while improving limb salvage rates and limb function. In contrast, the care of soft tissue sarcoma remains fragmented among many disciplines and specialties. Medical and pediatric oncologists, radiation oncologists, and a myriad of surgical specialists are all involved in the care of soft tissue sarcomas, and significant treatment (usually surgical) often occurs before referral to a center. Significant variation in managment leads to considerable difficulty in assessing the effects of treatment on outcome. Improvement in soft tissue sarcoma management will occur only when physicians recognize the need to centralize care to appropriate physicians within referral centers where patients can be treated on standardized cooperative protocols. PMID:9344326

Biermann, J S; Baker, L H



Serum protein pattern in ewe with pregnancy toxemia  

Microsoft Academic Search

Pregnancy toxemia is a metabolic disease of pregnant ewes which causes significant economic losses in sheep industry. The\\u000a pathophysiology and metabolic changes of this disorder remain poorly understood. We conducted this study to describe the serum\\u000a protein pattern associated with the pregnancy toxemia in ewes. In this study, the electrophoretic pattern of serum proteins\\u000a of 15 ewes with naturally occuring

Gul Fatma Yarim; Gulay Ciftci



Influence of maternal experience on fear reactions in ewes  

Microsoft Academic Search

The effects of maternal experience on fearfulness were assessed in ewes by comparing fear reactions of nulliparous (21 months old; N=19), primiparous (21 months old, one lamb reared; N=27) and multiparous (mean age: 4.5±1.2 years; one to four litters reared; N=17) Ile-de-France ewes. All ewes were individually subjected to three fear-eliciting situations in a familiar environment: isolation from conspecifics, surprise

Manon Viérin; Marie-France Bouissou



Recurrent gastrointestinal stromal sarcomas.  


Gastrointestinal stromal sarcomas, formerly categorized as leiomyosarcomas of gastrointestinal origin, have a common pattern of intraperitoneal dissemination. Despite surgical resection with or without adjuvant systemic chemotherapy the vast majority of these patients succumb to intraperitoneal sarcomatosis and/or hepatic metastases. In an attempt to improve upon the morbidity and mortality associated with this disease we and several other centers have begun treating these patients with intraperitoneal chemotherapy. We have found that aggressive surgical resection with postoperative intraperitoneal chemotherapy has significantly lowered the peritoneal recurrence rate in patients with recurrent gastrointestinal stromal sarcomas as compared to those who have undergone surgical resection alone. However, this treatment approach has proven to be ineffective in preventing hepatic metastases, and thus has had little effect upon overall survival. With the treatment of primary rather than recurrent disease we hope to interrupt the disease process at an earlier stage further decreasing peritoneal recurrences and potentially improving survival. PMID:11094326

Eilber, F C; Rosen, G; Forscher, C; Nelson, S D; Dorey, F; Eilber, F R



Biomaterial-Induced Sarcoma  

PubMed Central

In the study of carcinogenesis most interest has focused on carcinomas, as they represent the majority of human cancers. The recognition of the adenoma-carcinoma sequence both in humans and in animal experimental models has given the field of basic oncology the opportunity to elucidate individual mechanisms in the multistep development of carcinoma. The relative scarcity of human sarcomas coupled with the lack of adequate animal models has hampered understanding of the molecular genetic steps involved. We present an experimental model in the rat in which a high incidence of malignant mesenchymal tumors arise around a subcutaneously implanted biomaterial. Nine commercially available biomaterials were implanted in a total of 490 rats of the Fischer strain for 2 years. On average, macroscopic tumors were found in 25.8% of implantation sites over a period from 26 to 110 weeks after implantation. The most frequent tumors were malignant fibrous histiocytomas and pleomorphic sarcomas, although fibrosarcomas, leiomyosarcomas, and angiosarcomas readily developed, the latter especially around polyurethane implants. Of particular interest are the results of a detailed histological study of the capsules around the implanted biomaterials without tumors. Here a spectrum of change from focal proliferative lesions through preneoplastic proliferation to incipient sarcoma could be observed. A parallel immunohistochemical study of peri-implant capsules showed that proliferating cell nuclear antigen was of particular help in identifying these atypical proliferative lesions. To our knowledge this is the first description of a sarcoma model in which preneoplastic lesions can be readily identified and also reproducibly induced. This model provides the molecular biologist with defined stages in the development of mesenchymal malignancy, with which the multistage tumorigenesis hypothesis can be tested, analogous to the well-known adenoma-carcinoma sequence.

Kirkpatrick, C. James; Alves, Antonio; Kohler, Holger; Kriegsmann, Jorg; Bittinger, Fernando; Otto, Mike; Williams, David F.; Eloy, Rosy



Primary Mediastinal Synovial Sarcoma  

PubMed Central

Synovial sarcoma occurs predominantly in the soft tissues of the extremities, but is exceedingly rare in the mediastinum. It has overlapping histological and immunophenotypic features with other tumours in the differential diagnosis. We report a case of a patient who had an incidental finding of such a tumour. Because of the rarity of this tumour in the mediastinum, optimal therapy is unknown and the prognosis remains guarded.

Jeganathan, Reubendra; Davis, Richard; Wilson, Lorraine; McGuigan, James; Sidhu, Pushpinder



[Prostatic stromal sarcoma].  


Prostatic sarcoma is a very rare tumour arising from the specialized stroma of the prostatic parenchyma. The clinical and histological features and biological behaviour of this entity are poorly elucidated at the present time. The authors report a case of prostatic stromal sarcoma in a 47-year-old man presenting with complete bladder retention. The initial diagnosis was that of benign prostatic hyperplasia and the patient was treated by suprapubic prostatectomy with no other complementary treatment. Histological examination demonstrated primary neuroectodermal tumour (PNET). The patient was subsequently lost to follow-up and was only reviewed 22 months later in a context of haematuria. Digital rectal examination revealed a large, soft prostate with an estimated weight of 83 grams on ultrasound. Transurethral resection was performed and histological examination of the resection material and review of the slides of the primary tumour showed identical microscopic and immunohistochemical features, corresponding to stromal sarcoma. The patient was treated by local and regional radiotherapy (60 Grays). With a follow-up of 36 months, he presents urinary symptoms with no signs of local extension or metastasis. PMID:16821358

Rammeh Rommani, Soumaya; Zermani, Rachida; Sfaxi, Mohamed; Farah, Faten; Zouari, Soufiène; Chebil, Mohamed; Ben Jilani, Sarra



Gene Expression Profiling of Human Sarcomas: Insights into Sarcoma Biology  

Microsoft Academic Search

Sarcomas are a biologically complex group of tumors of mesenchymal origin. By using gene expression microarray analysis, we aimed to find clues into the cellular differenti- ation and oncogenic pathways active in these tumors as well as potential biomarkers and therapeutic targets. We exam- ined 181 tumors representing 16 classes of human bone and soft tissue sarcomas on a 12,601-feature

Kristin Baird; Sean Davis; Cristina R. Antonescu; Ursula L. Harper; Robert L. Walker; Yidong Chen; Arthur A. Glatfelter; Paul H. Duray; Paul S. Meltzer



Undifferentiated Small Round Cell Sarcomas with Rare EWS Gene Fusions  

PubMed Central

Ewing family tumors (EFTs) are prototypical primitive small round blue cell sarcomas arising in bone or extraskeletal soft tissues in children or adolescents. EFTs show fusions of EWS with a gene of the ETS family of transcription factors, either EWS-FLI1 (90 to 95%) or EWS-ERG (5 to 10%). Rare cases with fusions of EWS to other ETS family genes, such as ETV1, E1AF, and FEV, have been identified, but their clinicopathological similarity to classic EFTs remains unclear. We report four new cases of EFT-like tumors with rare EWS fusions, including two with EWS-ETV1, one with EWS-FEV, and a fourth case in which we cloned a novel EWS-SP3 fusion, the first known cancer gene fusion involving a gene of the Sp zinc finger family. Analysis of these three new cases along with data on nine previously reported cases with fusions of EWS to ETV1, E1AF, or FEV suggest a strong predilection for extraskeletal primary sites. EFT-like cases with fusions of EWS to non-ETS translocation partners are also uncommon but involve the same amino-terminal portion of EWS, which in our novel EWS-SP3 fusion is joined to the SP3 zinc-finger DNA-binding domain. As these data further support, these types of EWS fusions are associated with primitive extraskeletal small round cell sarcomas of uncertain lineage arising mainly in the pediatric population.

Wang, Lu; Bhargava, Rohit; Zheng, Tao; Wexler, Leonard; Collins, Margaret H.; Roulston, Diane; Ladanyi, Marc



Supranutritional selenium increases mammary gland vascularity in postpartum ewe lambs.  


Objectives were to determine the effects of maternal dietary supranutritional Se and nutritional plane during gestation on capillary surface density, capillary area density, and angiogenic factor expression in the developing mammary gland of primiparous ewes. Selenium treatments were initiated at breeding [adequate Se (ASe; 9.5 ?g/kg of body weight) vs. high Se (HSe; 81.8 ?g/kg of body weight)] and nutritional planes at d 50 of gestation [Low, 60%; moderate (Mod), 100%; and High, 140% of requirements). Mammary glands were collected within 24h postpartum. Vascular development was assessed in the glandular portion of the mammary gland. Vascularity was determined for mammary tissue with the following measurements taken: the cross-sectional capillary area density (total capillary area as a proportion of tissue area) and capillary surface density (CSD; total capillary circumference per unit of tissue area). High-Se ewes had greater capillary surface and area densities compared with ASe ewes. A tendency existed for an Se × plane of nutrition interaction for CSD with maternal diet not affecting CSD in HSe ewes, but Low ewes had a decreased CSD compared with Mod ewes, with High being intermediate in ASe ewes. Moreover, HSe-Low and HSe-High ewes had increased CSD compared with ASe-Low and ASe-High, respectively. Although Se status did not influence angiogenic factor mRNA expression, mammary glands from Low ewes tended to have increased VEGF and FLT1 mRNA expression compared with High ewes, with Mod being intermediate. Maternal plane of nutrition did not affect mammary gland glutathione peroxidase activity, but it was increased in HSe compared with ASe ewes. Increased mammary capillary nutrient exchange area may contribute to previously observed changes in colostrum quality. PMID:21605755

Vonnahme, K A; Wienhold, C M; Borowicz, P P; Neville, T L; Redmer, D A; Reynolds, L P; Caton, J S



DNA methylation profile distinguishes clear cell sarcoma of the kidney from other pediatric renal tumors.  


A number of specific, distinct neoplastic entities occur in the pediatric kidney, including Wilms' tumor, clear cell sarcoma of the kidney (CCSK), congenital mesoblastic nephroma (CMN), rhabdoid tumor of the kidney (RTK), and the Ewing's sarcoma family of tumors (ESFT). By employing DNA methylation profiling using Illumina Infinium HumanMethylation27, we analyzed the epigenetic characteristics of the sarcomas including CCSK, RTK, and ESFT in comparison with those of the non-neoplastic kidney (NK), and these tumors exhibited distinct DNA methylation profiles in a tumor-type-specific manner. CCSK is the most frequently hypermethylated, but least frequently hypomethylated, at CpG sites among these sarcomas, and exhibited 490 hypermethylated and 46 hypomethylated CpG sites in compared with NK. We further validated the results by MassARRAY, and revealed that a combination of four genes was sufficient for the DNA methylation profile-based differentiation of these tumors by clustering analysis. Furthermore, THBS1 CpG sites were found to be specifically hypermethylated in CCSK and, thus, the DNA methylation status of these THBS1 sites alone was sufficient for the distinction of CCSK from other pediatric renal tumors, including Wilms' tumor and CMN. Moreover, combined bisulfite restriction analysis could be applied for the detection of hypermethylation of a THBS1 CpG site. Besides the biological significance in the pathogenesis, the DNA methylation profile should be useful for the differential diagnosis of pediatric renal tumors. PMID:23638012

Ueno, Hitomi; Okita, Hajime; Akimoto, Shingo; Kobayashi, Kenichiro; Nakabayashi, Kazuhiko; Hata, Kenichiro; Fujimoto, Junichiro; Hata, Jun-Ichi; Fukuzawa, Masahiro; Kiyokawa, Nobutaka



Soft tissue sarcoma subtypes exhibit distinct patterns of acquired uniparental disomy  

PubMed Central

Background Soft tissue sarcomas (STS) are heterogeneous mesenchymal tumors with diverse subtypes. STS can be classified into two main categories according to the type of genomic alteration: recurrent translocation driven STS, and non-recurrent translocations. However, little has known about acquired uniparental disomy in STS. Methods In this study, we analyzed SNP microarray data to determine the frequency and distribution patterns of acquired uniparental disomy (aUPD) in major soft tissue sarcoma (STS) subtypes using CNAG and R softwares. Results We identified recurrent aUPD regions specific to alveolar rhabdomyosarcoma with the most frequent at 11p15.4, gastrointestinal stromal tumor at 1p36.11-p35.3, leiomyosarcoma at 17p13.3-p13.1, myxofibrosarcoma at 1p35.1-p34.2 and 16q23.3-q24.1, and pleomorphic liposarcoma at 13q13.2-q13.3 and 13q14.11-q14.2. In contrast, specific recurrent aUPD regions were not identified in dedifferentiated liposarcoma, Ewing sarcoma, myxoid/round cell liposarcoma, and synovial sarcoma. Strikingly total, centromeric and segmental aUPD regions are more frequent in STS that do not exhibit recurrent translocation events. Conclusions Our study yields a detailed map of aUPD across 9 diverse STS subtypes and suggests the potential location of several novel tumor suppressor genes and oncogenes.



[Intraosseous highly differentiated osteogenic sarcoma].  


A man of 20 developed well-differentiated intraosseous osteogenic sarcoma of the femur. Clinico-roentgenologic, computed tomography and histological findings revealed a number of features uncommon for the tumor: (1) a torpid course, (2) histological appearance typical for parosteal sarcoma, (3) low malignant potential. PMID:3196181

Petrovichev, N N; Khmelev, O N; Luk'ianchenko, A B; Karapetian, R M



Influence of lamb presence on daily rhythm in lactating ewes  

Microsoft Academic Search

To determine the influence of lamb presence on the dairy ewes circadian system we monitored simultaneously 16 different parameters (insulin, glucose, total protein, urea, cholesterol, triglycerides, total bilirubine, calcium, phosphorus, magnesium, sodium, potassium, chloride, rectal temperature, respiratory rate and heart rate). Sixteen clinically healthy Sarda breed dairy ewes, divided into two groups, group A with their lambs and group B

M. Morgante; C. Stelletta; M. Gianesella; C. Cannizzo; A. Sfefani; C. Giannetto; G. Piccione




Technology Transfer Automated Retrieval System (TEKTRAN)

Providing supplemental protein for ewes grazing dormant rangeland pastures is a common practice. The form of the protein supplement may affect feed intake and animal performance. Thus, an experiment was conducted to determine whether supplement form affected ewe body weight, body condition score, wo...


Composition of ewe, goat and cow milk and of colostrum of ewes and goats  

Microsoft Academic Search

Colostral samples were taken immediately after confinement from 16 Chios ewes and 12 Damascus goats for determination of fat, crude protein (CP), lactose, ash and total solids (TS). Milk samples from sheep (n = 432), goats (n = 721) and cows (n = 861) representative of all stages of lactation were also taken, over the period 1983 to 1988. These

M. Hadjipanayiotou



Immunohistochemical validation of TLE1, a novel marker, for synovial sarcomas  

PubMed Central

Background & objectives: Logistic and financial constraints limit application of several available immunohistochemical (IHC) markers and molecular analysis in every case of synovial sarcoma, diagnosed in our settings. Recently, TLE1 has been recognized as a robust IHC marker for diagnosing a synovial sarcoma. Here, we present IHC features of synovial sarcomas, including TLE1 expression in these cases and in some other tumours. Methods: Conventional sections from 42 synovial sarcomas (30 retrospective & 12 prospectively diagnosed) were subjected to TLE1 IHC staining, including 21 tumours confirmed with molecular testing. TLE1 immunostaining was graded from 0, 1+, 2+, 3+, with 2+ or 3+ grades interpreted as positive staining. Results: Of the 42 tumours, 26 (61.9%) were of monophasic spindle cell type, 13 biphasic type (30.9%), two (4.7%) calcifying type and remaining one (2.3%) was a poorly differentiated synovial sarcoma. On immunohistochemistry (IHC), tumours were positive for epithelial membrane antigen (EMA) (26/34, 76.4%), cytokeratin (CK)7 (6/10, 60%), CK/MNF116 (6/21, 28.6%), B cell lymphoma 2 (BCL2) (36/37, 97.3%), cluster of differentiation molecule 99 (MIC2) (23/31, 74.1%) and transducin-like enhancer of split 1 (TLE1) (40/42, 95.2%), while negative for CD34 in all 21 tumours, wherever performed. TLE1 was also positive in tumour controls, including schwannomas (5/5, 100%), neurofibromas (2/2, 100%), malignant peripheral nerve sheath tumors (2/12, 17%) and Ewing sarcomas (4/10, 40%). TLE1 sensitivity for diagnosis of synovial sarcomas was 95.2 per cent. Its overall specificity was 63.7 per cent, whereas with regards to tumors forming its closest differential diagnoses, its specificity was 72 per cent. Interpretation & conclusions: Although molecular confirmation is the diagnostic gold standard for synovial sarcoma, TLE1, in view of its high sensitivity may be a useful marker within the optimal IHC panel comprising EMA, BCL2, MIC2, CD34 and CK7, especially on small biopsy samples, for substantiating a diagnosis of synovial sarcoma. Awareness of TLE1 expression in other tumours and its correct interpretation are necessary.

Rekhi, Bharat; Basak, Ranjan; Desai, Sangeeta B.; Jambhekar, Nirmala A.



Panel of Monoclonal Antibodies Which Discriminate Neuroblastoma from Ewing's Sarcoma, Rhabdomyosarcoma, Neuroepithelioma, and Hematopoietic Malignancies.  

National Technical Information Service (NTIS)

Neuroblastomas generally displayed strong immunoreactivity with anti-neural antibodies, but showed weak or negative binding with the remaining antibodies of the panel. Particularly striking was very weak or negative binding of antibodies against HLA-ABC, ...

L. Donner T. J. Triche M. A. Israel R. C. Seeger C. P. Reynolds



An integrated analysis of miRNA and gene copy numbers in xenografts of Ewing's sarcoma  

PubMed Central

Background Xenografts have been shown to provide a suitable source of tumor tissue for molecular analysis in the absence of primary tumor material. We utilized ES xenograft series for integrated microarray analyses to identify novel biomarkers. Method Microarray technology (array comparative genomic hybridization (aCGH) and micro RNA arrays) was used to screen and identify copy number changes and differentially expressed miRNAs of 34 and 14 passages, respectively. Incubated cells used for xenografting (Passage 0) were considered to represent the primary tumor. Four important differentially expressed miRNAs (miR-31, miR-31*, miR-145, miR-106) were selected for further validation by real time polymerase chain reaction (RT-PCR). Integrated analysis of aCGH and miRNA data was performed on 14 xenograft passages by bioinformatic methods. Results The most frequent losses and gains of DNA copy number were detected at 9p21.3, 16q and at 8, 15, 17q21.32-qter, 1q21.1-qter, respectively. The presence of these alterations was consistent in all tumor passages. aCGH profiles of xenograft passages of each series resembled their corresponding primary tumors (passage 0). MiR-21, miR-31, miR-31*, miR-106b, miR-145, miR-150*, miR-371-5p, miR-557 and miR-598 showed recurrently altered expression. These miRNAS were predicted to regulate many ES-associated genes, such as genes of the IGF1 pathway, EWSR1, FLI1 and their fusion gene (EWS-FLI1). Twenty differentially expressed miRNAs were pinpointed in regions carrying altered copy numbers. Conclusion In the present study, ES xenografts were successfully applied for integrated microarray analyses. Our findings showed expression changes of miRNAs that were predicted to regulate many ES associated genes, such as IGF1 pathway genes, FLI1, EWSR1, and the EWS-FLI1 fusion genes.



Alisertib in Treating Patients With Advanced or Metastatic Sarcoma

Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Neurofibrosarcoma; Chondrosarcoma; Endometrial Stromal Sarcoma; Mast Cell Sarcoma; Metastatic Adult Malignant Fibrous Histiocytoma of Bone; Ovarian Carcinosarcoma; Ovarian Sarcoma; Recurrent Adult Malignant Fibrous Histiocytoma of Bone; Recurrent Adult Soft Tissue Sarcoma; Small Intestine Leiomyosarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma



Epitheloid Sarcoma of the Penis  

Microsoft Academic Search

We report a case representing the clinical as well as histopathologic features of epitheloid sarcoma. Both a clinical review and the results of definitive treatment together with the follow-up data are presented.

Kemal Sarica; Kemal Bakir; Özcan Özalpat; Canan Korkmaz



Differentiating small round cell sarcomas of the soft parts by an innovative immunogold labeling method: an ultrastructural study.  


A new immunoelectron microscopy procedure was developed by remaking the fixed-frozen tissue specimens into LR White resin blocks suitable for postembedding colloidal gold immunolabeling, and used to examine 16 cases of small round cell soft tissue sarcomas. In rhabdomyosarcoma, ultrastructural double-immunogold staining demonstrated a coexpression of muscle specific actin and desmin in the same tumor cell. In both Ewing's sarcoma and peripheral neuroepithelioma, the heterogeneous expression of MIC2 gene product (p30/32MIC2) in each tumor cell was demonstrated as well. In peripheral neuroepithelioma, the colloidal gold immunolabeling for neurofilament demonstrated the intermediate filaments surrounding microtubules. The procedure for ultrastructural colloidal gold immunolabeling using fixed-frozen tissue is thus considered to be useful not only for tumor diagnosis, but also for investigating various subcellular structures. PMID:8940762

Kawauchi, S; Fukuda, T; Tsuneyoshi, M


The effect of pasture allowance fed to twin- and triplet-bearing ewes in late pregnancy on ewe and lamb behaviour and performance to weaning  

Microsoft Academic Search

This paper investigates whether pasture allowance before and at lambing affects ewe behaviour, lamb behaviour and subsequent twin and triplet lamb performance to weaning. The trial was carried out at Massey University Keeble Farm in New Zealand. At pregnancy scanning, 186 first cycle-mated ewes were identified as carrying twins (n=96) or triplets (n=90). The ewes were randomly divided into four

J. M. Everett-Hincks; H. T. Blair; K. J. Stafford; N. Lopez-Villalobos; P. R. Kenyon; S. T. Morris



Reduced Intensity Allogeneic Stem Cell Transplantation in Children and Young Adults with Ultra-High Risk Pediatric Sarcomas  

PubMed Central

Some subsets of pediatric sarcoma patients have very poor survival rates. We sought to determine the feasibility and efficacy of allogeneic HSCT (alloHSCT) in pediatric sarcoma populations with <25% predicted overall survival. Patients with ultra-high risk Ewing’s sarcoma family of tumors (ESFT), alveolar rhabdomyosarcoma or desmoplastic small round cell tumor received EPOCH-fludarabine induction, a cyclophosphamide/fludarabine/melphalan preparative regimen and HLA matched related peripheral blood stem cells. Thirty patients enrolled; 7 did not undergo alloHSCT due to progressive disease with diminishing performance status during induction. All 23 alloHSCT recipients experienced rapid full donor engraftment, with no peri-transplant mortality. Five of 23 alloHSCT recipients (22%) remain alive (overall survival of 30% by Kaplan-Meier analysis at 3 years), including 3 of 7 (42%) transplanted without overt disease (median survival 14.5 vs. 29.0 months from alloHSCT for patients transplanted with vs. without overt disease, respectively). Among the 28 patients who progressed on the study, the median survival from date of progression was 1.9 months for the 7 who did not receive a transplant compared to 11.4 months for the 21 transplanted (p=0.0003). We found prolonged survival after post-transplant progression with several patients exhibiting indolent tumor growth. We also saw several patients with enhanced anti-tumor effects from post-transplant chemotherapy (objective response to pre-transplant EPOCH-F was 24% vs. 67% to post-transplant EOCH), however this was associated with increased toxicity. This largest reported series of alloHSCT in sarcomas demonstrates that alloHSCT is safe in this population, and that patients undergoing alloHSCT without overt disease show higher survival rates than reported using standard therapies. Enhanced chemo- and radio-sensitivity of tumors and normal tissues was observed post-transplant.

Baird, Kristin; Fry, Terry J.; Steinberg, Seth M.; Bishop, Michael R.; Fowler, Daniel H.; Delbrook, Cynthia P.; Humphrey, Jennifer L.; Rager, Alison; Richards, Kelly; Wayne, Alan S.; Mackall, Crystal L.



Multiple trait genetic evaluation of ewe traits in Icelandic sheep.  


The prolificacy of the ewes was measured as the number of lambs born per ewe mated (NLB) when the ewes were 1-4 years of age. The ewe productivity related to the same age interval was measured by special ewe production indices (EPI). The genetic parameters for these traits were estimated by a series of bivariate REML analyses using animal models. The material used for the genetic analysis contained records on 193,213 ewes. The heritability estimates for NLB were h(2) = 0.17, 0.13, 0.11, 0.10 for the four respective age classes. Corresponding estimates for EPI were h(2) = 0.16, 0.17, 0.17, 0.15. The genetic correlations among NLB at different ages ranged from 0.63 to 0.98 and among EPI from 0.82 to 0.99. The genetic correlations between NLB and EPI were generally low. The material used for estimating the breeding values by the MT-BLUP Animal Model consisted of 1.5 million individuals in the pedigree file. In total 815,782 ewes had records for the NLB and 763,491 ewes had production index (at least 1 year). The records were registered in the years 1990-2006. All possible missing patterns were present in the data. In the iteration process expected values for missing traits were generated and solutions were obtained on canonical transformed scale. The genetic evaluations were run independently for NLB and EPI for computational convenience given the correlations between these traits were negligible. PMID:19134074

Arnason, T; Jónmundsson, J V



Abattoir survey of congenital reproductive abnormalities in ewes  

Microsoft Academic Search

A survey of abnormalities of the reproductive tract of female sheep was undertaken at two abattoirs in the south west of England over a period of 12 months. During the survey, 9970 reproductive tracts from cull ewes and 23,536 tracts from nulliparous sheep (prime lambs and hoggets) were examined. A total of 655 (6.57 per cent) ewes and 459 (1.95

K. C. Smith; S. E. Long; T. J. Parkinson



Pregnancy is associated with low fear reactions in ewes  

Microsoft Academic Search

The aims of the study were: (1) to test the influence of pregnancy on responses of ewes to several fear-eliciting situations, (2) to compare the first and latest stages of pregnancy, and (3) to investigate possible correlations between fear reactions and progesterone levels. Fear reactions of nonpregnant (NP; N=22) and pregnant (P) Ile-de-France ewes (day 40 of pregnancy: N=43; day

Manon Viérin; Marie-France Bouissou



Spindle cell sarcoma of the maxillary antrum.  


Maxillary antral malignancies are mostly squamous cancers. Sarcomas in this region are rare. The head and neck region houses around 8.9% of all sarcomas and spindle cell sarcomas of the maxillary antrum had rarely been reported.The presentation, pathology, clinical findings, management and short term response to treatment of a left maxillary antral spindle cell sarcoma, in a Muslim, male tobacco chewer is reported here. PMID:23741844

Bhaumik, Gautam; Chatterjee, Koushik



Synovial sarcoma of the sellar region  

PubMed Central

Primary sarcomas of the sellar region are uncommon, although a wide variety have been reported. To date, no cases of primary synovial sarcoma have been described as occurring at this site. We report an immunohistochemically and molecular genetically confirmed primary synovial sarcoma involving the sellar/parasellar region and cavernous sinus in an adult male. Subtotal resection and radiosurgery proved to be efficacious. The spectrum of primary sellar region sarcomas is summarized.

Scheithauer, Bernd W.; Silva, Ana Isabel; Kattner, Keith; Seibly, Jason; Oliveira, Andre M.; Kovacs, Kalman



Sarcoma risk after radiation exposure.  


Sarcomas were one of the first solid cancers to be linked to ionizing radiation exposure. We reviewed the current evidence on this relationship, focusing particularly on the studies that had individual estimates of radiation doses. There is clear evidence of an increased risk of both bone and soft tissue sarcomas after high-dose fractionated radiation exposure (10?+?Gy) in childhood, and the risk increases approximately linearly in dose, at least up to 40?Gy. There are few studies available of sarcoma after radiotherapy in adulthood for cancer, but data from cancer registries and studies of treatment for benign conditions confirm that the risk of sarcoma is also increased in this age-group after fractionated high-dose exposure. New findings from the long-term follow-up of the Japanese atomic bomb survivors suggest, for the first time, that sarcomas can be induced by acute lower-doses of radiation (<5?Gy) at any age, and the magnitude of the risk is similar to that observed for other solid cancers. While there is evidence that individuals with certain rare familial genetic syndromes predisposing to sarcoma, particularly Nijmegen Breakage Syndrome, are particularly sensitive to the effects of high dose radiation, it is unclear whether this is also true in very low-dose settings (<0.1?Gy). The effects of common low-penetrance alleles on radiosensitivity in the general population have not been well-characterized. Some evidence suggests that it may be possible to identify radiation-induced sarcomas by a distinct molecular signature, but this work needs to be replicated in several dose settings, and the potential role of chemotherapy and tumor heterogeneity needs to be examined in more detail. In summary, radiation exposure remains one of the few established risk factors for both bone and soft tissue sarcomas. Similar to many other cancers children have the highest risks of developing a radiation-related sarcoma. Efforts to limit unnecessary high-dose radiation exposure, particularly in children, therefore remain important given the high fatality rates associated with this disease. PMID:23036235

Berrington de Gonzalez, Amy; Kutsenko, Alina; Rajaraman, Preetha



[Primary synovial sarcoma of the esophagus].  


Synovial sarcomas are uncommon malignant mesenchymal tumors occurring mainly near the joints of the extremities of young adults. Synovial sarcomas are exceedingly rare neoplasms of the digestive tract. We report the first diagnosed case of esophageal synovial sarcoma, highlighting its diagnostic features surgical management and follow-up. PMID:23174799

de Alencar, Mário Henrique Leite; Boldrini, Domingos; Costa, Aluysio de Mendonça; Torres de Oliveira, Antônio Talvane; Attab, Cyomara Sanches


The role of the CXCL12-CXCR4/CXCR7 axis in the progression and metastasis of bone sarcomas (Review).  


Bone sarcomas, which comprise less than 1% of all human malignancies, are a group of relatively rare mesenchymal-derived tumors. They are mainly composed of osteosarcoma, chondrosarcoma and Ewing's sarcoma. In spite of advances in adjuvant chemotherapy and wide surgical resection, prognosis remains poor due to the high propensity for lung metastasis, which is the leading cause of mortality in patients with bone sarcomas. Chemokines are a superfamily of small pro-inflammatory chemoattractant cytokines which can bind to specific G protein-coupled seven-span transmembrane receptors. Chemokine 12 (CXCL12), also designated as stromal cell-derived factor-1 (SDF-1), is able to bind to its cognate receptors, chemokine receptor 4 (CXCR4) and chemokine receptor 7 (CXCR7), with high affinity. The binding of CXCL12 to CXCR4/CXCR7 stimulates the activation of several downstream signaling pathways that regulate tumor progression and metastasis. In this review, the structure and function of CXCL12 and its receptors, CXCR4 and CXCR7, as well as many factors affecting their expression are discussed. Phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways are the two most important downstream pathways regulated by the CXCL12-CXCR4/CXCR7 interaction. CXCR4 expression in bone sarcomas, including tumor cells and samples and the correlation between CXCR4/CXCR7 expression and the survival of patients with bone sarcomas are also discussed. In addition, we review the involvement of the CXCL12?CXCR4/CXCR7 axis in the growth and metastasis of bone sarcomas and the targeting of this axis in preclinical studies. PMID:24127013

Liao, Yu-Xin; Zhou, Cheng-Hao; Zeng, Hui; Zuo, Dong-Qing; Wang, Zhuo-Ying; Yin, Fei; Hua, Ying-Qing; Cai, Zheng-Dong



Antibody-dependent cell lysis by NK cells is preserved after sarcoma-induced inhibition of NK cell cytotoxicity.  


Osteosarcoma and Ewing's sarcoma tumor cells are susceptible to IL15-induced or antibody-mediated cytolytic activity of NK cells in short-term cytotoxicity assays. When encountering the tumor environment in vivo, NK cells may be in contact with tumor cells for a prolonged time period. We explored whether a prolonged interaction with sarcoma cells can modulate the activation and cytotoxic activity of NK cells. The 40 h coculture of NK cells with sarcoma cells reversibly interfered with the IL15-induced expression of NKG2D, DNAM-1 and NKp30 and inhibited the cytolytic activity of NK cells. The inhibitory effects on receptor expression required physical contact between NK cells and sarcoma cells and were independent of TGF-?. Five days pre-incubation of NK cells with IL15 prevented the down-regulation of NKG2D and cytolytic activity in subsequent cocultures with sarcoma cells. NK cell Fc?RIIIa/CD16 receptor expression and antibody-mediated cytotoxicity were not affected after the coculture. Inhibition of NK cell cytotoxicity was directly linked to the down-regulation of the respective NK cell-activating receptors. Our data demonstrate that the inhibitory effects of sarcoma cells on the cytolytic activity of NK cells do not affect the antibody-dependent cytotoxicity and can be prevented by pre-activation of NK cells with IL15. Thus, the combination of cytokine-activated NK cells and monoclonal antibody therapy may be required to improve tumor targeting and NK cell functionality in the tumor environment. PMID:23624801

Pahl, Jens H W; Ruslan, S Eriaty N; Kwappenberg, Kitty M C; van Ostaijen-Ten Dam, Monique M; van Tol, Maarten J D; Lankester, Arjan C; Schilham, Marco W



The IGF-1 Receptor Targeting Antibody, CP-751,871, Suppresses Tumor-Derived VEGF and Synergizes with Rapamycin in Models of Childhood Sarcoma  

PubMed Central

Signaling through the type 1 insulin-like growth factor receptor (IGF-1R) occurs in many human cancers, including childhood sarcomas. As a consequence, targeting the IGF-1R has become a focus for cancer drug development. We examined the antitumor activity of CP-751,871, a human antibody that blocks IGF-1R ligand binding, alone and in combination with rapamycin against sarcoma cell lines in vitro and xenograft models in vivo. In Ewing sarcoma (EWS) cell lines CP751,871 inhibited growth poorly (<50%), but prevented rapamycin-induced hyperphosphorylation of AKT(Ser473) and induced greater than additive apoptosis. Rapamycin treatment also increased secretion of IGF-1 resulting in phosphorylation of IGF-1R (Tyr1136) that was blocked by CP751,871. In vivo CP-751,871, rapamycin or the combination waere evaluated against EWS, osteosarcoma and rhabdomyosarcoma xenografts. CP751871 induced significant growth inhibition (EFS(T/C) >2) in four models. Rapamycin induced significant growth inhibition (EFS(T/C) >2) in nine models. Although neither agent given alone caused tumor regressions. in combination these agents had greater than additive activity against 5/13 xenografts and induced complete remissions (CR) in one model each of rhabdomyosarcoma and Ewing sarcoma, and in three of four osteosarcoma models. CP751,871 caused complete IGF-1R downregulation, suppression of AKT phosphorylation and dramatically suppressed tumor-derived VEGF in some sarcoma xenografts. Rapamycin treatment did not markedly suppress VEGF in tumors and synergized only in tumor lines where VEGF was dramatically inhibited by CP751,871. These data suggest a model in which blockade of IGF-1R suppresses tumor-derived VEGF to a level where rapamycin can effectively suppress the response in vascular endothelial cells.

Kurmasheva, Raushan T.; Dudkin, Lorina; Billups, Catherine; Debelenko, Larisa V.; Morton, Christopher L.; Houghton, Peter J.



Abattoir survey of congenital reproductive abnormalities in ewes.  


A survey of abnormalities of the reproductive tract of female sheep was undertaken at two abattoirs in the south west of England over a period of 12 months. During the survey, 9970 reproductive tracts from cull ewes and 23,536 tracts from nulliparous sheep (prime lambs and hoggets) were examined. A total of 655 (6.57 per cent) ewes and 459 (1.95 per cent) nulliparous sheep had abnormalities of the reproductive tract. Of these, congenital abnormalities of the paramesonephric ducts accounted for 2.4 per cent of the ewes and 7.4 per cent of the nulliparous sheep, congenital abnormalities of the ovaries accounted for 2.6 per cent of the ewes and 7.4 per cent of the nulliparous sheep and cystic structures that were considered to have been of congenital origin accounted for 27.2 per cent of the ewes and 52.7 per cent of the nulliparous sheep. The most common lesion was paraovarian cysts (26.6 per cent of ewes and 39.0 per cent of nulliparous sheep), but few of these appeared to have affected the sheep's reproductive function. Several specific conditions were recorded, including some described for the first time in sheep. Uterus unicornis occurred in 20 sheep and other forms of segmental aplasia of parts of the paramesonephric ducts occurred in a further 13 animals. Uterus didelphys occurred in six sheep, and 11 animals were intersex. Intersex sheep had vestigial structures that were derived from the paramesonephric ducts, hypoplastic or masculinised gonads and some had masculinised external genitalia. Ovarian hypoplasia occurred in 34 sheep, and in a further 12 mainly nulliparous animals, the ovaries were fused. Sixty nulliparous animals and two ewes had hydatids of Morgagni. PMID:9921622

Smith, K C; Long, S E; Parkinson, T J


Concurrent metastatic thymic carcinoma and postirradiation sarcoma.  


We present a case of concurrent metastatic thymic carcinoma and postirradiation sarcoma in the same lobe of the lung in a woman who had received partial resection of thymic carcinoma with chemoradiotherapy 11 years ago. One tumor showed similar histology to the previous carcinoma. The other tumor was a pleomorphic sarcoma, suggestive of a postirradiation sarcoma. Irradiation-induced sarcomas are rare and have not been reported in patients with thymic carcinoma. This case may serve as a model in considering the possibility of postirradiation sarcoma for patients encountering recurrent masses with the history of radiotherapy for thymic carcinoma several years ago. PMID:22450080

Chen, Tzu-Ju; Lu, Hung-I; Huang, Cheng-Hua; Hsu, Hsuan-Chih; Chen, Sung-Ting; Chen, Wei-jen; Huang, Chao-Cheng



High-Dose Chemotherapy and Stem Cell Transplant for Ewing Tumors  


... trials for Ewing tumors High-dose chemotherapy and stem cell transplant for Ewing tumors This type of treatment ... a stem cell transplant. What happens in a stem cell transplant The first step in a stem cell ...


Rare sarcoma presented as sinusitis.  


Myxofibrosarcoma (MFS) also known as myxoid variant of malignant fibrous histocytoma is one of the most common soft tissue sarcomas of the extremities in adult and elderly patients with rare occurrences in head and neck region. Low-grade MFS is unusual among low-grade sarcomas because it often recurs relentlessly and multiplies despite wide local resection with gross negative margins. We report a case of extreme rarity and a tumour of aggressive nature in the maxillary sinus, which presented with non-specific sinonasal symptoms and we present a review of the radiological and histopathological characteristics of this rare tumour and recent evidence of management. PMID:22927267

Taghi, Ali S; Ali, Ahmed; Kuchai, Romana; Saleh, Hesham



Antitumor efficacy of the heparanase inhibitor SST0001 alone and in combination with antiangiogenic agents in the treatment of human pediatric sarcoma models.  


The activity of heparanase is responsible for heparan sulfate cleavage, thus resulting in the release of heparan sulfate-bound growth factors. Since heparanase activity is upregulated in several tumor types and is implicated in the malignant behavior, the enzyme is regarded as a promising target for antitumor therapy. Based on previous evidence that the heparanase inhibitor SST0001, a non-anticoagulant N-acetylated glycol split heparin, is effective against an Ewing's sarcoma model, the present study was performed to extend the preclinical evaluation of SST0001 to a panel of pediatric sarcoma models, representative of various tumor histotypes (soft tissue and bone sarcomas) and to further elucidate its mode of action. SST0001 treatment downregulated several angiogenic factors in the conditioned media of sarcoma cells, inhibited the pro-invasive effect of heparin-binding factors (VEGF, bFGF, HGF, PDGF), and abrogated PDGF receptor tyrosine phosphorylation. Subcutaneous administration of SST0001 was very effective, resulting in a significant growth inhibition (range, 64-95%) of all tested tumor xenografts. The efficacy of SST0001 was enhanced in combination with antiangiogenic agents (bevacizumab, sunitinib) as documented by the high rate of complete response. The synergistic effect of SST0001 in combination with antiangiogenic agents is consistent with the heparanase mode of action and with the relevant role of heparin-binding proangiogenic/growth factors in the malignant behavior of sarcoma cells. PMID:23466421

Cassinelli, G; Lanzi, C; Tortoreto, M; Cominetti, D; Petrangolini, G; Favini, E; Zaffaroni, N; Pisano, C; Penco, S; Vlodavsky, I; Zunino, F



Yellow grease as an alternative energy source for nursing Awassi ewes and their suckling lambs  

Microsoft Academic Search

Thirty Awassi ewes with an initial body weight (BW) of 52.0kg (SD=8.4) nursing single lambs with an initial BW of 6.2kg (SD=1.0) were utilized to study yellow grease, by partially replacing barley, as an alternative energy source. The ewes aged 3–7 years and parity ranged from 2 to 6. All ewes gave birth 6–8 days before starting the experiment. Ewes

M. S. Awawdeh; B. S. Obeidat; R. T. Kridli



Gemcitabine Hydrochloride, Docetaxel, and Radiation Therapy in Treating Patients With Uterine Sarcoma That Has Been Removed By Surgery

Stage IA Uterine Sarcoma; Stage IB Uterine Sarcoma; Stage IC Uterine Sarcoma; Stage IIA Uterine Sarcoma; Stage IIB Uterine Sarcoma; Stage IIIA Uterine Sarcoma; Stage IIIB Uterine Sarcoma; Stage IIIC Uterine Sarcoma; Stage IVA Uterine Sarcoma; Stage IVB Uterine Sarcoma; Uterine Leiomyosarcoma



Seasonal Fluctuations of Nematode Populations in Breeding Ewes and Lambs  

PubMed Central

The seasonal changes in nematode populations of a flock of sheep in the Montreal area were determined using serial fecal egg counts, fecal culture of larvae and necropsy worm counts. It was found that Ostertagia spp.,Nematodirus spp., Trichostrongylus agei, Trichostrongylus spp. and Chabertia ovina over-wintered on pasture and could initiate patent infections the following spring. The development of populations of H. contortus was typical of that seen with most of the other species and was characterized by the following series of events. In early winter when the study was started with stabled pregnant ewes, most of the populations were immature and the egg counts were low and remained so throughout the entire winter. However, in the spring, following lambing, large numbers of adult worms were seen with a consequent decrease in immatures and a sudden increase in egg counts. When the ewes and lambs were pastured together, the egg counts in ewes dropped consequent to “self-cure”, the “spring-rise” providing the major source of overwhelming infections for lambs with deaths by the end of July. As the season progressed larvae taken in by both ewes and lambs did not mature, and by early fall, most of the worm population consisted of immature forms. It appeared that H. contortus could not have more than two generations in ewes or lambs in a single grazing season.

Ayalew, L.; Gibbs, H. C.



Individual mineral supplement intake by ewes swath grazing or confinement fed pea-barley forage  

Technology Transfer Automated Retrieval System (TEKTRAN)

Sixty mature ewes (non-pregnant, non-lactating) were used in a completely randomized design to determine if feeding method of pea-barley forage (swath grazing or hay in confinement) had an effect on individual ewe mineral consumption. Thirty ewes were randomly allocated to 3 confinement pens and 30 ...



Microsoft Academic Search

Summary Female reproductive traits were studied in four pure breeds (the Finnsheep, Suffolk, Targhee and Minnesota 100), the F 1 crosses between Finnsheep rams and females of the other three breeds and F2 and backcross ewes. Precocity of sexual development, defined as the percentage of ewe lambs lambing at 12 months of age, was measured in 709 ewe lambs in

E. A. Branford Oltenacu; W. J. Boylan


A study on superovulation using FSH and eCG in Awassi ewes.  


The present study was conducted to evaluate superovulatory treatments in Awassi ewes by eCG and FSH. High number of unovulated follicles (P < 0.05) was observed in ewes treated with eCG in non-breeding season. It could be concluded that using FSH to induce superovulation in Awassi ewes is better than eCG. PMID:19882226

Azawi, Osama Ibrahim; Al-Mola, M K M A



Molecular Diagnosis in Ewing Family Tumors  

PubMed Central

The Ewing's family of tumors (EFTs) are characterized by chimeric transcripts generated by specific chromosomal rearrangements. The most common fusions are between the EWSR1 gene on chromosome 22 and the ETS family of transcription factors; rarely, FUS (on chromosome 16) substitutes for EWSR1. The detection of specific translocations using molecular analysis is now a routine part of the pathological examination of EFT. Here, we report our experience with molecular diagnosis of EFT during the 4 years (2006–2009) at the Rizzoli Institute. We analyzed 222 consecutive tumors with a presumptive diagnosis of EFT using molecular techniques and IHC. We found five distinct types of EWSR1-FLI1 fusion transcripts resulting from translocation t(11;22), three types of EWSR1-ERG transcripts resulting from t(21;22), and one type of t(2;22) resulting in EWSR1-FEV fusion. Molecular investigation validated 92% of cases ultimately diagnosed as EFT; IHC validated 76% of the cases. Thus, despite the difficulties and limitations associated with both molecular and IHC analysis on fresh and formalin-fixed, paraffin-embedded tissue, a combination of these techniques is the best approach to enhancing the accuracy of EFT diagnosis. We also present our method for choosing which molecular techniques to apply. Finally, we collected the most prevalent breakpoints reported in the literature, indicating which exons are involved, the sequence breakpoints, and the NCBI reference sequences.

Gamberi, Gabriella; Cocchi, Stefania; Benini, Stefania; Magagnoli, Giovanna; Morandi, Luca; Kreshak, Jennifer; Gambarotti, Marco; Picci, Piero; Zanella, Licciana; Alberghini, Marco



Yeasts associated with Sardinian ewe's dairy products.  


In the present work, the occurrence of yeasts in different types of typical Sardinian ewe's cheeses (32 samples of pecorino, 32 of caciotta, 40 of feta, 56 of ricotta) was determined. For the strains isolated the following properties were studied: proteolytic and lipolytic activities, the ability to grow at different temperatures, different concentrations of salt, and to assimilate and/or ferment compounds like lactate, citrate, lactose, glucose, galactose, lactic acid. Of 160 samples analysed, 76.2% yielded growth of yeasts. Yeast counts showed a certain variability among the samples. The highest levels were observed in caciotta and feta cheeses. A total of 281 strains belonging to 16 genera and 25 species were identified. In general, Debaryomyces hansenii was the dominant species, representing 28.8% of the total isolates. Other frequently appearing species were Geotrichum candidum, Kluyveromyces lactis and K. marxianus. Other genera encountered were Pichia, Candida, Dekkera, Yarrowia and Rhodotorula. With regard to the biochemical and technological properties of the yeasts, only K. lactis, K. marxianus and Dek. anomala assimilated and fermented lactose, whereas the majority of the species assimilated lactic acid. The assimilation of citrate was a characteristic of D. hansenii, R. rubra and Y. lipolytica. On the whole, the yeasts were weakly proteolytic while lipolytic activity was present in several species. A high percentage of strains showed a certain tolerance to low temperatures while only some strains of D. hansenii and K. lactis were able to grow at a 10% NaCl concentration. PMID:11589560

Cosentino, S; Fadda, M E; Deplano, M; Mulargia, A F; Palmas, F



Maurice Ewing Medalist: Xavier Le Pichon  

NASA Astrophysics Data System (ADS)

Mr. President, fellow members of the American Geophysical Union, and members of the U.S. Navy, it gives me great pleasure to present the citation for the 1984 AGU/USN Maurice Ewing Medal, to be awarded to Dr. Xavier Le Pichon.After receiving diplomas in several disciplines of geology, physics, and geophysics from the University of Strasbourg during the 1950s, Xavier came to the Lamont-Doherty Geological Observatory as a visiting scientist where he put his knowledge to practice until 1968. In 1966 he received the Doctor of Sciences degree from the University of Strasbourg. Returning to France in 1968, Xavier spent the next five years at the Centre Océanologique de Bretagne in Brest where he founded the Research Group. From Brest he moved to the headquarters of CNEXO in Paris for 5 years and then to the University of Paris to found the new Laboratoire de Géodynamique. From his present position of professor at the university he will move next year to become director of the Geology Laboratory in the Ecole Normale Supérieure, one of the French Grandes Ecoles.

Ewing, John I.; Le Pichon, Xavier



Irradiation for Conjunctival Granulocytic Sarcoma  

Microsoft Academic Search

Case History and Findings: A 73-year-old woman with a history of myeloproliferative syndrome (MPS) presented with bilateral chemosis, redness and burning of the eyes. The ocular motility was severely impaired. Ophthalmological examination revealed markedly distended conjunctivas on both sides. Biopsy disclosed conjunctival granulocytic sarcoma as an initial symptom of acute myelogenous leukemia (AML). Diagnosis was confirmed by peripheral blood smear

Katharina Fleckenstein; Hans Geinitz; Anca Grosu; Katharina Goetze; Martin Werner; Michael Molls



Epithelioid sarcoma of the tongue  

Microsoft Academic Search

A case of epithelioid sarcoma in the tongue is reported. The patient, a 35 year old woman, presented with a non-ulcerated painful lesion of the tongue. Microscopically, the tumour was characterised by multiple coalescent nodules with central geographic necrosis infiltrating the lingual muscle. The tumour cells were epithelioid with abundant eosinophilic cytoplasm and atypical nuclei. Immunohistochemically, the tumour cells stained

X Leroy; A Delobelle; J L Lefebvre; V Cabaret; F Bloget; M O Vilain



Molecular Approaches to Sarcoma Therapy  

PubMed Central

Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed.

Olsen, R. J.; Tarantolo, S. R.



Periparturient transmission of Cryptosporidium xiaoi from ewes to lambs.  


The mechanism for the maintenance of Cryptosporidium infection in sheep between yearly lambing periods is not clear. Previously, periparturient shedding of oocysts as the result of stress from lambing was suspected to be a mechanism for the initiation of Cryptosporidium infection in lambs, but this has never been verified by genotyping studies. In this study, fecal specimens from four age groups of sheep in Inner Mongolia, China were examined for Cryptosporidium spp. by PCR-restricted fragment length polymorphism and sequence analyses of the small subunit (SSU) rRNA gene, including 59 ewes 1 week before parturition, 154 ewes at parturition, 87 lambs of 3-4 weeks, and 75 lambs of 15-16 weeks. The Cryptosporidium infection rate in ewes at parturition (7.8%) was significantly higher than at 1 week before parturition (1.7%). Higher infection rates were found in lambs (18.4% and 26.7% for 3-4-week-old and 15-16-week-old lambs, respectively). Most (10/13) Cryptosporidium-positive ewes were shedding Cryptosporidium xiaoi, which was also the dominant species (15/16) in neonatal lambs of 3-4 weeks in age (15/16). The less common species in ewes, Cryptosporidium ubiquitum, was not found in lambs of 3-4 weeks but was the dominant species (14/20) in lambs of 15-16 weeks. The major zoonotic Cryptosporidium species, C. parvum (of the IIaA15G2R1 subtype), was only found in one lamb. These data support the occurrence of periparturient transmission of Cryptosporidium spp., especially C. xiaoi, from ewes to lambs. PMID:23953146

Ye, Jianbin; Xiao, Lihua; Wang, Yuanfei; Wang, Lin; Amer, Said; Roellig, Dawn M; Guo, Yaqiong; Feng, Yaoyu



What's New in Soft Tissue Sarcomas Research and Treatment?  


... Topic Additional resources for soft tissue sarcoma What`s new in soft tissue sarcoma research and treatment? Research ... develop. This information is already being applied to new tests to diagnose and classify sarcomas. This is ...


Angiogenesis, Kaposi's Sarcoma and Kaposi's Sarcoma-Associated Herpesvirus*  

PubMed Central

Tumor angiogenesis is the uncontrolled growth of blood vessels in tumors, serving to supply nutrients and oxygen, and remove metabolic wastes. Kaposi’s sarcoma (KS), a multifocal angioproliferative disorder characterized by spindle cell proliferation, neo-angiogenesis, inflammation, and edema, is associated with infection by Kaposi’s sarcoma-associated herpesvirus (KSHV). Recent studies indicate that KSHV infection directly promotes angiogenesis and inflammation through an autocrine and paracrine mechanism by inducing pro-angiogenic and pro-inflammatory cytokines. Many of these cytokines are also expressed in KS lesions, implicating a direct role of KSHV in the pathogenesis of this malignancy. Several KSHV genes are involved in KSHV-induced angiogenesis. These studies have provided insights into the pathogenesis of KS, and identified potential therapeutic targets for this malignancy.

Kang, Tao; Ye, Feng-Chun; Gao, Shou-Jiang; Wang, Lin-Ding



High-grade pelvic sarcoma after radiation therapy for low-grade endometrial stromal sarcoma  

SciTech Connect

A high-grade heterologous pelvic sarcoma arose in a 60-year-old woman 15 years after she received whole-pelvic radiation for a low-grade endometrial stromal sarcoma. This complication must be considered in determining therapy for low-grade endometrial sarcomas, which are usually inherently of indolent biological behavior.

Chumas, J.C.; Patsner, B.; Mann, W.J. (State Univ. of New York, Stony Brook (USA))



Soft tissue sarcomas with complex genomic profiles  

Microsoft Academic Search

Soft tissue sarcomas (STS) with complex genomic profiles (50% of all STS) are predominantly composed of spindle cell\\/pleomorphic\\u000a sarcomas, including leiomyosarcoma, myxofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, malignant peripheral\\u000a nerve sheath tumor, angiosarcoma, extraskeletal osteosarcoma, and spindle cell\\/pleomorphic unclassified sarcoma (previously\\u000a called spindle cell\\/pleomorphic malignant fibrous histiocytoma). These neoplasms show, characteristically, gains and losses\\u000a of numerous chromosomes or chromosome regions, as

Louis Guillou; Alain Aurias



Behavioral and endocrine responses of hair sheep ewes exposed to different mating stimuli around estrus.  


Hair sheep ewes were used to evaluate the influence of various levels of mating stimuli on the duration and timing of estrus and LH concentrations around estrus. Ewes were treated with PGF2alpha (15 mg, im) 10 d apart. At the time of the second PGF2alpha treatment (Day 0) ewes were placed in groups and exposed to different types of mating stimuli. One group of ewes (n = 16) was exposed to an epididymectomized ram (RAM), a second group of ewes (n = 16) was exposed to an epididymectomized ram wearing an apron to prevent intromission (APRON) and a third group of ewes (n = 17) was exposed to an androgenized ovariectomized ewe (T-EWE). Jugular blood samples were collected from ewes at 6-h intervals through Day 5. Plasma was harvested and LH concentration was determined by RIA. The ewes were observed at 6-h intervals to detect estrus. A ewe was considered to be out of estrus when she no longer stood to be mounted by the teaser animal. There was no difference (P > 0.10) in the proportion of ewes expressing estrus (79.6%) or having an LH surge (85.7%) among the treatments. Neither the time to estrus nor the duration of estrus were different (P > 0.10) among APRON, RAM or T-EWE groups (41.6+/-3.8 vs 43.6+/-3.6 vs 46.1+/-3.6 h, respectively, and 26.5+/-2.2 vs 24.8+/-2.3 vs 30.5+/-2.2 h, respectively). The time to LH surge was similar (P > 0.10) among APRON, RAM and T-EWE groups (51.2+/-4.5 vs 51.2+/-4.7 vs 52.7+/-4.5 h, respectively). The magnitude of the LH surge was similar (P > 0.10) in the T-EWE, APRON and RAM ewes (99.7+/-4.9 vs 87.2+/-4.9 vs 85.8+/-5.0 ng/mL, respectively). The time from estrus to the LH surge was not different (P > 0.10) among APRON, RAM or T-EWE ewes (10.1+/-2.2 vs 9.8+/-2.3 vs 11.6+/-2.3 h, respectively). These results show that the expression and duration of estrus are not influenced by different types of mating stimuli in hair sheep ewes. In addition, the timing and the magnitude of LH release does not appear to be influenced by mating stimuli around the time of estrus. PMID:11291911

Godfrey, R W; Collins, J R; Hensley, E L



Infarct-associated Bone Sarcomas  

Microsoft Academic Search

Sarcoma associated with bone infarct is a rare condition sparsely reported in the literature. Sixty percent of cases arise\\u000a about the knee and most are malignant fibrous histiocytomas. We report 15 patients; 12 of 15 presented with a tumor around\\u000a the knee. Treatment was limb salvage in seven patients, amputation in six, and biopsy alone in two. For patients without

Gregory F. Domson; Amir Shahlaee; John D. Reith; Charles H. Bush; C. Parker Gibbs



Extraosseous osteogenic sarcoma: case report.  


Extraosseous osteogenic sarcoma is a highly malignant tumor, and in order to improve the chances of survival of those who have it, aggressive surgical treatment, including major amputations, should be performed. Based on the results obtained in the treatment of its osseous counterpart, the use of adjuvant chemotherapy is strongly recommended. Evaluation should not be done because it is usually followed by local recurrence. PMID:289878

Lopez, R; Karakousis, C P; Rao, U; Berjian, R A; Bakamjian, V



Low-grade fibromyxoid sarcoma.  


Described is a low-grade fibromyxoid sarcoma (LGFMS) of the abdominal wall muscles in a 38-year-old black woman. There was no evidence of metastatic disease. A 5.2-kg LGFMS - the largest case ever reported - was resected. One year after surgery, the patient is alive without any sign of local recurrence or distant metastasis. Follow-up comprises abdominal and thoracic CT scans at 6-month intervals. PMID:10765121

van den Bossche, M R; Van Mieghem, H



Low-Grade Fibromyxoid Sarcoma  

Microsoft Academic Search

Described is a low-grade fibromyxoid sarcoma (LGFMS) of the abdominal wall muscles in a 38-year-old black woman. There was no evidence of metastatic disease. A 5.2-kg LGFMS – the largest case ever reported – was resected. One year after surgery, the patient is alive without any sign of local recurrence or distant metastasis. Follow-up comprises abdominal and thoracic CT scans

M. R. P. Van den Bossche; H. Van Mieghem



The composition of Karadi ewe's and goat's milk.  


The composition of bulk milk of 18 herds of ewes and 14 herds of goats and the milk of 10 individual animals of each ewes and goats during a 12 weeks lactation period was studied. The average percentage of acidity of bulk ewe's milk (0.22), fat (6.4), lactose (4.3), total nitrogen (0.9) calcium (0.169), ash (0.940) and total solids (18.6) were higher than 0.17, 4.0, 3.9, 0.62, 0.130, 0.81 and 12.8 of bulk goat's milk. Phosphorus (0.074) was almost similar to (0.077), while non-protein nitrogen (0.0022) was about thirteen times lower than 0.028 of goat's milk. Determined parameters increased, whereas lactose and non-protein nitrogen decreased with progression of the lactation period. Individual ewe's milk occasionally contained 1.4% fat and 0.56% total nitrogen closely resembling individual goat's milk. PMID:3990786

Abo-Elnaga, I G; el-Dahan, A S; Ridah, S H



Fate of the theca interna following ovulation in the ewe  

Microsoft Academic Search

The fate of the theca interna after ovulation was studied in ewes, using light and electron microscopic histology and histochemistry. At the time of ovulation the theca interna was incorporated, apparently completely, into the margin of the developing corpus luteum and into the centres of many infoldings of the follicular wall. There was no evidence of degeneration of the more

J. D. O'Shea; D. G. Cran; Mary F. Hay



Prions in Milk from Ewes Incubating Natural Scrapie  

Microsoft Academic Search

Since prion infectivity had never been reported in milk, dairy products originating from transmissible spongiform encephalopathy (TSE)-affected ruminant flocks currently enter unrestricted into the animal and human food chain. However, a recently published study brought the first evidence of the presence of prions in mammary secretions from scrapie-affected ewes. Here we report the detection of consistent levels of infectivity in

Caroline Lacroux; Stéphanie Simon; Sylvie L. Benestad; Séverine Maillet; Jacinthe Mathey; Séverine Lugan; Fabien Corbière; Hervé Cassard; Pierrette Costes; Dominique Bergonier; Jean-Louis Weisbecker; Torffin Moldal; Hugh Simmons; Frederic Lantier; Cécile Feraudet-Tarisse; Nathalie Morel; François Schelcher; Jacques Grassi; Olivier Andréoletti



William J. Jenkins Receives 2010 Maurice Ewing Medal  

NASA Astrophysics Data System (ADS)

William J. Jenkins was awarded the 2010 Maurice Ewing Medal at the AGU Fall Meeting Honors Ceremony, held on 15 December 2010 in San Francisco, Calif. The medal is for “significant original contributions to the scientific understanding of the processes in the ocean; for the advancement of oceanographic engineering, technology, and instrumentation; and for outstanding service to the marine sciences.”

Doney, Scott C.; Kurz, Mark; Jenkins, William J.



[Sarcomas associated with Paget's disease].  


The authors report 12 cases of Paget's disease with sarcomatous degeneration that were observed among 311 patients with Paget's disease hospitalized in the Montpellier Rheumatology Clinic. They compare their experience with information they were able to extract from the literature in French and English. The frequency of such degeneration in cases of Paget's disease is difficult to determine but did not appear to exceed 1%. Degeneration rarely occurred before the age of 50 years, affected men twice as frequently as women, and occurred particularly in cases of diffuse Paget's disease, mainly in the femur or the humerus; the rachis was rarely affected. Pain was the main symptom, was practically constant, was remarkable because of its permanence and its intensity. Tumefaction was frequently seen. Pathological fractures were seen in almost a third of the patients with sarcomas of the long bones. Radiculo-medullary compression characterized the rare cases with involvement of the vertebral column or the sacrum. Radiography showed rupture of cortical layers with invasion of the soft parts without any periostal reaction. Histological investigation confirmed the diagnosis by demonstrating one of the three types of osteogenic sarcoma: osteosarcomas were the most frequent. Less frequently giant-cell sarcomas or reticulosarcomas were found. The affected patients nearly always died, survival at five years being rare. Treatment, amputation or radiotherapy, was disappointing. PMID:1224155

Morlock, G; Sanvy, J; Serre, H



Prognostic factors in localized Ewing's tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study)  

PubMed Central

Purpose: (1) To improve survival rates in patients with Ewing's sarcoma (ES) or peripheral neuroectodermal tumours (PNET) using semi-continuous chemotherapy and aiming to peform surgery in all; (2) To identify early prognostic factors to tailor therapy for future studies. Patients and methods One hundred and forty-one patients were entered onto the trial between January 1988 and December 1991. Induction therapy consisted of five courses of Cytoxan, 150?mg/m2 × 7 days, followed by Doxorubicin, 35?mg/m2 i.v on day 8 given at short intervals. Surgery was recommended whenever possible. The delivery of radiation therapy was based on the quality of resection and the histological response to CT. Maintenance chemotherapy consisted of vincristine + actinomycin and cytoxan + doxorubicin. The total duration of therapy was 10 months. Results After a median follow-up of 8.5 years, the projected overall survival at 5 years was 66% and disease-free survival (DFS) was 58%. In patients treated by surgery, only the histological response to CT had an influence on survival: 75% DFS for patients with a good histological response (less than 5% of cells), 48% for intermediate responders and only 20% for poor responders (? 30% of cells), P < 0.0001. The initial tumor volume by itself had no influence on DFS in these patients. In contrast, the tumour volume had a strong impact on DFS in patients treated by radiation therapy alone. Age had no impact on outcome. Conclusion Therapeutic trials for localized Ewing's sarcoma should be based on the histological response to chemotherapy or on the tumour volume according to the modality used for local therapy. © 2001 Cancer Research Campaign

Oberlin, O; Deley, M C Le; Bui, B N'Guyen; Gentet, J C; Philip, T; Terrier, P; Carrie, C; Mechinaud, F; Schmitt, C; Babin-Boillettot, A; Michon, J



ESF-EMBO Symposium "Molecular Biology and Innovative Therapies in Sarcomas of Childhood and Adolescence" Sept 29-Oct 4, Polonia Castle Pultusk, Poland.  


Rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) are among the most common pediatric sarcomas (Arndt et al., 2012). Despite sarcomas representing a highly heterogeneous group of tumors, ES and alveolar RMS (ARMS) typically share one common genetic characteristic, namely a specific chromosomal translocation (Helman and Meltzer, 2003; Lessnick and Ladanyi, 2012). These translocations generate fusion proteins, which are composed of two transcription factors (TF). Typically, one TF is a developmentally regulated factor that is essential for proper specification of a given lineage and provides the DNA-binding domain, while the partner TF contributes a transactivation domain that drives aberrant expression of target genes. Based on these common genetic characteristics, the first ESF-EMBO research conference entitled "Molecular Biology and Innovative Therapies in Sarcomas of Childhood and Adolescence" with special focus on RMS and ES was held at the Polonia Castle in Pultusk, Poland. The conference gathered 70 participants from more than 15 countries and several continents representing most research groups that are active in this field. PMID:23761860

Schäfer, Beat W; Koscielniak, Ewa; Kovar, Heinrich; Fulda, Simone



The prognostic value of the serum level of C-reactive protein for the survival of patients with a primary sarcoma of bone.  


The aim of this study was to determine whether the level of circulating C-reactive protein (CRP) before treatment predicted overall disease-specific survival and local tumour control in patients with a sarcoma of bone. We retrospectively reviewed 318 patients who presented with a primary sarcoma of bone between 2003 and 2010. Those who presented with metastases and/or local recurrence were excluded. Elevated CRP levels were seen in 84 patients before treatment; these patients had a poorer disease-specific survival (57% at five years) than patients with a normal CRP (79% at five years) (p < 0.0001). They were also less likely to be free of recurrence (71% at five years) than patients with a normal CRP (79% at five years) (p = 0.04). Multivariate analysis showed the pre-operative CRP level to be an independent predictor of survival and local control. Patients with a Ewing's sarcoma or chondrosarcoma who had an elevated CRP before their treatment started had a significantly poorer disease-specific survival than patients with a normal CRP (p = 0.02 and p < 0.0001, respectively). Patients with a conventional osteosarcoma and a raised CRP were at an increased risk of poorer local control. We recommend that CRP levels are measured routinely in patients with a suspected sarcoma of bone as a further prognostic indicator of survival. PMID:23450030

Nakamura, T; Grimer, R J; Gaston, C L; Watanuki, M; Sudo, A; Jeys, L




Microsoft Academic Search

SUMMARY OBJECTIVES: To evaluate the prognoses factors that affect the survival of the patients with head and neck soft parts sarcomas. METHODS: We evaluate retrospectively 24 patients treated at the Head and Neck Surgical Service of the Hospital Oncológico Padre Machado, between January of 1980 and December of 2000, with diagnosis of head and neck soft parts sarcomas. RESULTS: The



Unusual postirradiation sarcoma of chest wall  

Microsoft Academic Search

A sarcoma of the chest wall following postoperative radiation therapy for breast carcinoma is reported. A total of 9346 rads was delivered at a 2-cm tissue depth from two treatment courses separated by a five-year interval. The sarcoma appeared 16 years following the initial radiation course. The existence of two mesenchymal elements in the lesion led to the final diagnosis

Elizabeth L. Travis; Albert Kreuther; Thomas Young; William L. Gerald



Targeting epigenetic misregulation in synovial sarcoma.  


Like many sarcomas, synovial sarcoma is driven by a characteristic oncogenic transcription factor fusion, SS18-SSX. In this issue of Cancer Cell, Su et al. elucidate the protein partners necessary for target gene misregulation and demonstrate a direct effect of histone deacetylase inhibitors on the SS18-SSX complex composition, expression misregulation, and apoptosis. PMID:22439927

Waterfall, Joshua J; Meltzer, Paul S



Proximal-type epithelioid sarcoma - Case report*  

PubMed Central

Epithelioid sarcoma, first described by Enzinger in 1970, is a rare soft-tissue sarcoma typically presenting as a subcutaneous or deep dermal mass in distal portions of the extremities of adolescents and young adults. In 1997, Guillou et al. described a different type of epithelioid sarcoma, called proximal-type epithelioid sarcoma, which is found mostly in the pelvic and perineal regions and genital tracts of young to middle-aged adults. It is characterized by a proliferation of epithelioid-like cells with rhabdoid features and the absence of a granuloma-like pattern. In this paper we present a case of proximal-type epithelioid sarcoma with an aggressive clinical course, including distant metastasis and death nine months after diagnosis.

dos Santos, Luciana Mendes; Nogueira, Lisiane; Matsuo, Christiane Yuri; Talhari, Carolina; Santos, Monica



Sarcomas other than Kaposi sarcoma occurring in immunodeficiency: interpretations from a systematic literature review  

PubMed Central

Purpose of review In immunodeficiency, an increased sarcoma risk is confirmed for Kaposi’s sarcoma. Whether rates of other sarcoma subtypes are elevated in the setting of immunodeficiency is not known. We therefore reviewed published case reports on HIV/AIDS patients and organ transplant recipients with sarcomas. For comparison, we assessed sarcomas in the U.S. general population using Surveillance Epidemiology End Results (SEER) data. Findings One hundred seventy-six non-KS sarcomas were identified, 75 in people with HIV/AIDS and 101 in transplant recipients. Leiomyosarcomas (n=101) were the most frequently reported sarcomas, followed by angiosarcomas (n=23) and fibrohistiocytic tumors (n=17). Leiomyosarcomas were reported with two age peaks, in children and young adults. Epstein-Barr virus (EBV) was detected in the tumor cells in 85% and 88% of leiomyosarcomas in HIV-infected people and transplant recipients, respectively. Angiosaromas and fibrohistiocytic tumors were most frequently reported in males. Among kidney transplant recipients, 20% of sarcomas arose at the site of an arteriovenous fistula. In comparison, leiomyoscarcomas, angiosarcomas, and fibrohistiocytic tumors comprised 16.9%, 3.8%, and 18.7% of sarcomas in the U.S. general population. Summary Leiomyosarcoma and angiosarcoma may occur disproportionately in immunodeficiency. Leiomyosarcomas appear etiologically linked to EBV while angiosarcomas might be correlated with an arteriovenous fistula. Additional studies are necessary to understand the contribution of immunodeficiency to the etiology of these sarcomas.

Bhatia, Kishor; Shiels, Meredith. S.; Berg, Alexandra; Engels, Eric. A.



Kaposi sarcoma in unusual locations  

PubMed Central

Kaposi sarcoma (KS) is a multifocal, vascular lesion of low-grade malignant potential that presents most frequently in mucocutaneous sites. KS also commonly involves lymph nodes and visceral organs. This article deals with the manifestation of KS in unusual anatomic regions. Unusual locations of KS involvement include the musculoskeletal system, central and peripheral nervous system, larynx, eye, major salivary glands, endocrine organs, heart, thoracic duct, urinary system and breast. The development of KS within wounds and blood clots is also presented. KS in these atypical sites may prove difficult to diagnose, resulting in patient mismanagement. Theories to explain the rarity and development of KS in these unusual sites are discussed.

Pantanowitz, Liron; Dezube, Bruce J



Tocopherol induced angiogenesis in placental vascular network in late pregnant ewes  

Microsoft Academic Search

BACKGROUND: Tocopherols have biphasic, proangiogenic and antiangiogenic therapeutic effects. The objective of this clinical trial was to clarify tocopherol's placental angiogenic potential in late pregnant ewes following oral supplementation. METHODS: Eighteen pregnant ewes during late gestation were selected for this study. Ewes were given oral supplementation of 500 mg of alpha-tocopherol (aT; N = 6) or 1000 mg of gamma-tocopherol

Ramanathan K Kasimanickam; Vanmathy R Kasimanickam; Jacobo S Rodriguez; Kevin D Pelzer; Philip D Sponenberg; Craig D Thatcher



Phase II Study of High-Dose Photon/Proton Radiotherapy in the Management of Spine Sarcomas  

SciTech Connect

Purpose: Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of {>=}66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas. Methods and Materials: Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewing's sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to gross disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque. Results: A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE. Conclusions: Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.

DeLaney, Thomas F. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States)], E-mail:; Liebsch, Norbert J. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Pedlow, Francis X. [Department of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Adams, Judith; Dean, Susan [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Yeap, Beow Y. [Department of Biostatistics, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); McManus, Patricia [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Rosenberg, Andrew E.; Nielsen, G. Petur [Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Harmon, David C. [Department of Medicine, Division of Hematology Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Spiro, Ira J. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Raskin, Kevin A. [Department of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Suit, Herman D. [Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Yoon, Sam S. [Department of Surgery (Section of Surgical Oncology), Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States); Hornicek, Francis J. [Department of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States)



Circulatory Changes in the Reproductive Tissues of Ewes during Pregnancy  

Microsoft Academic Search

The blood flows to reproductive organs were measured by means of radionuclide-labeled microspheres in 24 pregnant ewes with gestational ages ranging from 38 to 141 days. The microspheres were injected in the left ventricle of the non-anesthetized animal 4–7 days after surgery and while uterine blood flow was recorded continously by means of electromagnetic probes on both uterine arteries. The

Charles R. Rosenfeld; Edgar L. Makowski; Giacomo Meschia; Frederick C. Battaglia



Prions in milk from ewes incubating natural scrapie.  


Since prion infectivity had never been reported in milk, dairy products originating from transmissible spongiform encephalopathy (TSE)-affected ruminant flocks currently enter unrestricted into the animal and human food chain. However, a recently published study brought the first evidence of the presence of prions in mammary secretions from scrapie-affected ewes. Here we report the detection of consistent levels of infectivity in colostrum and milk from sheep incubating natural scrapie, several months prior to clinical onset. Additionally, abnormal PrP was detected, by immunohistochemistry and PET blot, in lacteal ducts and mammary acini. This PrP(Sc) accumulation was detected only in ewes harbouring mammary ectopic lymphoid follicles that developed consequent to Maedi lentivirus infection. However, bioassay revealed that prion infectivity was present in milk and colostrum, not only from ewes with such lympho-proliferative chronic mastitis, but also from those displaying lesion-free mammary glands. In milk and colostrum, infectivity could be recovered in the cellular, cream, and casein-whey fractions. In our samples, using a Tg 338 mouse model, the highest per ml infectious titre measured was found to be equivalent to that contained in 6 microg of a posterior brain stem from a terminally scrapie-affected ewe. These findings indicate that both colostrum and milk from small ruminants incubating TSE could contribute to the animal TSE transmission process, either directly or through the presence of milk-derived material in animal feedstuffs. It also raises some concern with regard to the risk to humans of TSE exposure associated with milk products from ovine and other TSE-susceptible dairy species. PMID:19079578

Lacroux, Caroline; Simon, Stéphanie; Benestad, Sylvie L; Maillet, Séverine; Mathey, Jacinthe; Lugan, Séverine; Corbière, Fabien; Cassard, Hervé; Costes, Pierrette; Bergonier, Dominique; Weisbecker, Jean-Louis; Moldal, Torffin; Simmons, Hugh; Lantier, Frederic; Feraudet-Tarisse, Cécile; Morel, Nathalie; Schelcher, François; Grassi, Jacques; Andréoletti, Olivier



Prions in Milk from Ewes Incubating Natural Scrapie  

PubMed Central

Since prion infectivity had never been reported in milk, dairy products originating from transmissible spongiform encephalopathy (TSE)-affected ruminant flocks currently enter unrestricted into the animal and human food chain. However, a recently published study brought the first evidence of the presence of prions in mammary secretions from scrapie-affected ewes. Here we report the detection of consistent levels of infectivity in colostrum and milk from sheep incubating natural scrapie, several months prior to clinical onset. Additionally, abnormal PrP was detected, by immunohistochemistry and PET blot, in lacteal ducts and mammary acini. This PrPSc accumulation was detected only in ewes harbouring mammary ectopic lymphoid follicles that developed consequent to Maedi lentivirus infection. However, bioassay revealed that prion infectivity was present in milk and colostrum, not only from ewes with such lympho-proliferative chronic mastitis, but also from those displaying lesion-free mammary glands. In milk and colostrum, infectivity could be recovered in the cellular, cream, and casein-whey fractions. In our samples, using a Tg 338 mouse model, the highest per ml infectious titre measured was found to be equivalent to that contained in 6 µg of a posterior brain stem from a terminally scrapie-affected ewe. These findings indicate that both colostrum and milk from small ruminants incubating TSE could contribute to the animal TSE transmission process, either directly or through the presence of milk-derived material in animal feedstuffs. It also raises some concern with regard to the risk to humans of TSE exposure associated with milk products from ovine and other TSE-susceptible dairy species.

Lacroux, Caroline; Simon, Stephanie; Benestad, Sylvie L.; Maillet, Severine; Mathey, Jacinthe; Lugan, Severine; Corbiere, Fabien; Cassard, Herve; Costes, Pierrette; Bergonier, Dominique; Weisbecker, Jean-Louis; Moldal, Torffin; Simmons, Hugh; Lantier, Frederic; Feraudet-Tarisse, Cecile; Morel, Nathalie; Schelcher, Francois; Grassi, Jacques; Andreoletti, Olivier



Kaposi's sarcoma associated with AIDS.  


In 1872, Moritz Kaposi, first described "Idiopathisches multiples Pigmentsarkom der Haut", which has become known as Kaposi sarcoma (KS). In the present KS is considerate an opportunistic neoplasm rather than a genuine cancer. It is a disease with clinical aspects extremely different, associate with some immunological deficits. The discovering in 1994 of a new type of human herpes virus called human herpes virus type 8 (HHV8) in the KS lesions sustains also a viral etiology. Four forms of Kaposi's sarcoma are recognized: classical, endemic (associated with AIDS), epidemic and iatrogenic (usually after transplant). All these forms have the same histopathologic aspects and are associated with HHV. However, these differ in prognosis and treatment. The authors present a KS case associated with AIDS occurring at a patient in the childhood. The particularities of the case are the presence of only two cutaneous lesions, from which one giant tumor, and the other nodular in aspect and the appearance of an infection HIV in the childhood with involvement of others risk factors except homosexuality. It is important, on one side the importance of the histopathologic exam of an angiomatous tumor for the establishing the diagnosis of KS even when is solitaire and appear in the child, and the other side the absolute necessity to search an eventual concomitant infection with HIV in the presence of a KS. PMID:17641807

St?nescu, Ligia; Foarf?, Camelia; Georgescu, Ana Claudia; Georgescu, Iuliana



Myeloid sarcoma of the maxillary bone.  


Myeloid sarcoma (MS) is a malignant tumour of myeloblasts rarely occurring in the maxillary bone. The tumour may precede or be concurrent with leukaemic infiltration of the bone marrow or herald blastic transformation of a myelodysplastic syndrome or a chronic myeloproliferative disorder. Myeloid sarcoma is uncommon in the oral cavity, but it can involve the palate, gingiva, extraction socket, and cheek. Recognition and diagnosis of myeloid sarcoma involving the soft tissues of the oral cavity in an otherwise asymptomatic patient is important and mandates an appropriate haematological diagnostic workup. We herein report on a new case without any evidence of haematological disorders. We discuss the pathological diagnosis and the therapeutical approaches. PMID:16519776

Goteri, G; Ascani, G; Messi, M; Filosa, A; Segura-Egea, J J; Rubini, C; Bullon, P



Angiosarcomas and other sarcomas of endothelial origin.  


Although benign hemangiomas are among the most common diagnoses among connective tissue tumors, angiosarcomas and other sarcomas arising from blood vessels are rare, even among sarcomas. Because endothelial tumors have unique embryonal derivation compared with other sarcomas, it is not surprising they have unique characteristics. Herein are reviewed some of these unique characteristics and therapeutic options for patients with some of these diagnoses, highlighting the potential of new agents for these tumors, which will in all likelihood also impact treatment on more common cancers. PMID:24093171

Cioffi, Angela; Reichert, Sonia; Antonescu, Cristina R; Maki, Robert G



CD31 staining in epithelioid sarcoma.  


We report an unusual case of epithelioid sarcoma. The tumour occurred in the finger of a 27-year-old female. The clinical history, histology and the electron microscopy of the lesion were typical for epithelioid sarcoma. However, immunohistochemical analysis showed strong membranous CD31 staining, a finding hitherto not described. All other robust vascular markers, including factor-VIII-related antigen (FVIIIrag) were negative. The findings were compared with the available literature data, leading us to conclude that there is insufficient evidence for endothelial derivation of epithelioid sarcoma, but in the differential diagnosis with vascular tumours CD31 may stain and to rule out angiosarcoma FVIIIrag is a useful antibody. PMID:12743818

den Bakker, M A; Flood, S J; Kliffen, M



Primary Undifferentiated Penile Sarcoma in Adolescence  

PubMed Central

We report a case of primary penile undifferentiated sarcoma. A 16-year-old adolescent man visited Pusan National University Hospital complaining of a painless mass on his penis that was increasing in size. Magnetic resonance images revealed a 5×5-cm mass and pathological examinations revealed small round cell sarcomas with neuroendocrine differentiation. The tumor, which had metastatic pulmonary nodules, was treated by tumorectomy and systemic chemotherapy. Thirty-four months after the initial diagnosis, the patient was still alive without evidence of local recurrence or metastatic disease. This is our second case of an undifferentiated penile sarcoma.

Choi, Young Hoon; Kim, Hyeon Woo; Ahn, Jae Hyun; Hwang, Dae Sung; Lee, Jung Woo; Lee, Byung Ki; Jun, So Eun; Lim, Young Tak; Lee, Sang Don



Mid infrared attenuated total reflection spectroscopy as a rapid tool to assess the quality of Sicilo-Sarde ewe’s milk during the lactation period after replacing soybean meal with scotch bean in the feed ration  

Microsoft Academic Search

This study investigates the potential of attenuated total reflection spectroscopy in the mid infrared (MIR) for monitoring changes in the quality of ewe’s milk as a function of lactation period and feeding systems. Twelve 5-year-old lactating Sicilo-Sarde ewes (third lambing) were kept in environmentally controlled sheepfolds and were divided into two homogenous weight matched groups (n=6). Ewes were fed ad

Omar Maâmouri; Hamadi Rouissi; Sami Dridi; Mounir Kammoun; Josse De Baerdemaeker; Romdhane Karoui



Ziv-aflibercept in Treating Patients With Locally Advanced, Unresectable, or Metastatic Gynecologic Soft Tissue Sarcoma

Fallopian Tube Cancer; Female Reproductive Cancer; Ovarian Carcinosarcoma; Ovarian Sarcoma; Recurrent Ovarian Epithelial Cancer; Recurrent Uterine Sarcoma; Stage III Ovarian Epithelial Cancer; Stage III Uterine Sarcoma; Stage IV Ovarian Epithelial Cancer; Stage IV Uterine Sarcoma; Uterine Carcinosarcoma; Uterine Leiomyosarcoma



Composition and sensory profiling of probiotic Scamorza ewe milk cheese.  


The present study aimed to assess the effect of the addition of different usually recognized as probiotic bacterial strains on chemical composition and sensory properties of Scamorza cheese manufactured from ewe milk. To define the sensory profile of Scamorza cheese, a qualitative and quantitative reference frame specific for a pasta filata cheese was constructed. According to the presence of probiotic bacteria, cheeses were denoted S-BB for Scamorza cheese made using a mix of Bifidobacterium longum 46 and Bifidobacterium lactis BB-12, and S-LA for Scamorza cheese made using Lactobacillus acidophilus LA-5. The designation for control Scamorza cheese was S-CO. Analyses were performed at 15d of ripening. The moisture content of Scamorza ewe milk cheese ranged between 44.61 and 47.16% (wt/wt), showing higher values in S-CO and S-BB cheeses than in S-LA cheese; the fat percentage ranged between 25.43 and 28.68% (wt/wt), showing higher value in S-LA cheese. The NaCl percentage in Scamorza cheese from ewe milk was 1.75 ± 0.04% (wt/wt). Protein and casein percentages were the highest in Scamorza cheese containing a mix of bifidobacteria; also, the percentage of the proteose-peptone fraction showed the highest value in S-BB, highlighting the major proteolysis carried out by enzymes associated with B. longum and B. lactis strains. Texture and appearance attributes were able to differentiate probiotic bacteria-added cheeses from the untreated control product. In particular, S-BB and S-LA Scamorza cheeses showed higher color uniformity compared with S-CO cheese. Furthermore, the control cheese showed higher yellowness and lower structure uniformity than S-BB. The control product was less creamy and grainy than S-BB; conversely, the inclusion of probiotics into the cheese determined lower adhesivity and friability in S-BB and S-LA than in S-CO. This study allowed the definition of the principal composition and sensory properties of Scamorza ewe milk cheese. The specific quantitative vocabulary for sensory analysis and reference frame for assessor training also established in this study should be implemented to systematically monitor the quality of this new typology of ewe milk cheese. PMID:23522674

Albenzio, M; Santillo, A; Caroprese, M; Braghieri, A; Sevi, A; Napolitano, F



Effect of protein degradability on milk production of dairy ewes.  


The objective of this experiment was to determine the effect of protein degradability of dairy sheep diets on milk yield and protein utilization across 2 levels of milk production. Three diets were formulated to provide similar energy concentrations and varying concentrations of rumen-degradable protein (RDP) and rumen-undegradable protein (RUP): 12% RDP and 4% RUP (12-4) included basal levels of RDP and RUP, 12% RDP and 6% RUP (12-6) included additional RUP, and 14% RDP and 4% RUP (14-4) included additional RDP. Diets were composed of alfalfa-timothy cubes, whole and ground corn, whole oats, dehulled soybean meal, and expeller soybean meal (SoyPlus, West Central, Ralston, IA). Estimates of RDP and RUP were based on the Small Ruminant Nutrition System model (2008) and feed and orts were analyzed for Cornell N fractions. Eighteen multiparous dairy ewes in midlactation were divided by milk yield (low and high) into 2 blocks of 9 ewes each and were randomly assigned within block (low and high) to 3 pens of 3 ewes each. Dietary treatments were arranged in a 3 x 3 Latin square within each block and applied to pens for 14-d periods. We hypothesized that pens consuming high-RUP diets (12-6) would produce more milk and milk protein than the basal diet (12-4) and pens consuming high-RDP diets (14-4) would not produce more milk than the basal diet (12-4). Ewes in the high-milk-yield square consumed more dry matter and produced more milk, milk fat, and milk protein than ewes in the low-milk-yield square. There was no effect of dietary treatment on dry matter intake. Across both levels of milk production, the 12-6 diet increased milk yield by 14%, increased milk fat yield by 14%, and increased milk protein yield by 13% compared with the 14-4 and 12-4 diets. Gross N efficiency (milk protein N/intake protein N) was 11 and 15% greater in the 12-6 and 12-4 diets, respectively, compared with the 14-4 diet. Milk urea N concentration was greater in the 12-6 diet and tended to be greater in the 14-4 diet compared with the 12-4 diet, indicating that the excretion of urea N in this study was more closely related to dietary crude protein concentration than to protein degradability. PMID:19700712

Mikolayunas-Sandrock, C; Armentano, L E; Thomas, D L; Berger, Y M



Postirradiation sarcomas of the head and neck  

SciTech Connect

We discuss four cases of postirradiation sarcomas of the head and neck. Two cases were metachronous sarcomas that appeared after operation and irradiation for primary sarcomas, 1 case was a mandibular malignant fibrous histiocytoma that developed on the opposite side of the jaw from a malignant histiocytic neoplasm that was irradiated 8 years previously, and 1 case was a laryngeal tumor that appeared 5 years after combined operative and radiation therapy for a laryngeal squamous carcinoma. Immunohistochemical studies more precisely defined and classified these tumors, and assisted in determining a therapeutic protocol. The therapy for postirradiation sarcomas includes extirpative operation when possible, but the role of chemotherapy is uncertain. The aggressive behavior of these neoplasms was attested to by the death of three patients within 18 months of their operations.

Maisel, R.H.; Manivel, J.C.; Porto, D.P.; Stanley, M.



Monophasic synovial sarcoma of the nasopharynx.  


Synovial sarcomas are rare, aggressive malignant neoplasms, and less than 10% of cases involve the head and neck. Cases that involve the nasopharynx are even more exceptional and little information is available concerning their diagnosis and management. We report the third case of synovial sarcoma of the nasopharynx, which was diagnosed as a monophasic type and was successfully treated with a complete surgical excision followed by irradiation. The present case indicates that appropriate immunohistochemical and cytogenetic analysis are essential for accurate diagnosis of monophasic synovial sarcoma in unusual locations. A review of the literature indicates that synovial sarcoma of the nasopharynx exhibits an improved prognosis following tumor resection and postoperative adjuvant radiation unless it invades adjacent bones, even though the tumor is larger than 4 cm. PMID:22867523

Nakahira, Mitsuhiko; Sugasawa, Masashi; Morita, Kei



Primary clear cell sarcoma of the tongue.  


Clear cell sarcoma shares features with melanoma, but frequently shows EWSR1 rearrangements. It is an aggressive tumor typically occurring in the soft tissues of the extremities, with a gastrointestinal variant with less consistent melanocytic differentiation. It is extremely rare in the head and neck region, with no reported cases in the oral cavity. We report a case of an 82-year-old woman with a clear cell sarcoma arising in the tongue, with cervical lymph node metastases. Histologically, the tumor showed some features of gastrointestinal clear cell sarcoma. No osteoclast-type giant cells were present. The tumor cells were positive for S100 protein and negative for other melanocytic markers. Fluorescence in situ hybridization showed rearrangements of EWSR1 and ATF1. This case expands the spectrum of clear cell sarcoma with a gastrointestinal-like variant in a novel site, emphasizing the need to consider it as a differential diagnosis to melanoma in mucosal sites. PMID:24168510

Kraft, Stefan; Antonescu, Cristina R; Rosenberg, Andrew E; Deschler, Daniel G; Nielsen, G Petur



[Sarcomas in irradiated fields: Recent data].  


We reviewed the literature data on sarcomas in irradiated fields: incidence, risk factors, prognosis and therapeutic strategy. We discuss more specifically the key-role of p53 mutations and the potential consequences of new radiotherapy techniques. PMID:19963424

Vautravers, C; Dewas, S; Truc, G; Penel, N




Technology Transfer Automated Retrieval System (TEKTRAN)

Objectives were to estimate effects of sire breed (Dorset, Finnsheep, Romanov, Texel, and Montadale), dam breed (Composite III and northwestern whiteface), mating season (March and May), ewe age (4, 5, and 6 yr) and their interactions on reproductive traits of F1 ewes. A total of 1,099 F1 ewes prod...


Repeated transport and isolation during pregnancy in ewes: Effects on the reactivity to humans and to their offspring after lambing  

Microsoft Academic Search

The aim of this study was to determine if repeated exposure to stressors of a different nature and intensity during the last 6 weeks of pregnancy modifies the reactivity of ewes to their lambs and to humans after lambing. Multiparous ewes were either subjected to 10 sessions of transport in isolation twice a week for 1h (TRAN, n=20 ewes), 10

Sabine Roussel; Paul Hamilton Hemsworth; Hélène Leruste; Chris White; Christine Duvaux-Ponter; Raymond Nowak; Alain Boissy



Effect of supplementation of grazing dairy ewes with a cereal concentrate on animal performance and milk fatty acid profile1  

Microsoft Academic Search

This work was conducted to investigate the effect of supplementing grazing ewes on pasture with a cereal concentrate on the milk fatty acid (FA) profile. Ninety Assaf ewes in mid lactation were distributed in 9 lots of 10 animals each and allocated to 3 feeding regimens: 1) pasture—ewes were only allowed to graze pasture (an irrigated sward of Lolium perenne,

P. Gómez-Cortés; P. Frutos; A. R. Mantecón; M. Juárez; M. A. de la Fuente; G. Hervás



Head and Neck Sarcomas and Lymphomas  

Microsoft Academic Search

Sarcoma and lymphoma are tumors of mesenchymal origin that comprise a contrasting subset of uncommon head and neck (HN) neoplasms.\\u000a Lymphomas enjoy excellent response to chemotherapy and radiotherapy (RT) and almost never require surgery. In contrast, sarcomas\\u000a almost always require surgery to achieve local control, and rarely develop regional metastases other than for some uncommon\\u000a histo-logical subtypes so that elective

Brian O'Sullivan; Jonathan Irish; Richard Tsang


Biphasic synovial sarcoma of the abdominal wall  

Microsoft Academic Search

Synovial sarcoma arising in the abdominal wall is a rare tumor. We report a case of a 38-year-old man who complained of abdominal\\u000a pain. Physical examination revealed a firm mobile mass, 25 cm in diameter, in the left lower abdominal wall. The tumor was\\u000a first thought to be a sarcoma arising from the omentum or mesentery. During surgery, a large tumor

Jesús Vera; María-Dolores García; Miguel Marigil; Manuel Abascal; Jose-Ignacio Lopez; Luis Ligorred



NY-ESO-1 expression in sarcomas  

PubMed Central

NY-ESO-1 (CTAG 1B) is highly expressed in the majority of synovial sarcomas and myxoid/round cell liposarcomas as well as in a subset of melanomas, but only rarely in other mesenchymal tumors. This points to a potential for using NY-ESO-1 in the differential diagnosis of these lesions. Furthermore, promising results have been obtained in clinical trials testing NY-ESO-1-targeted immunotherapy in subsets of melanoma and synovial sarcoma patients.

Lai, Jin-Ping; Rosenberg, Avi Z.; Miettinen, Markku M.; Lee, Chyi-Chia R.



Synovial sarcoma of the mandible  

PubMed Central

Synovial sarcoma (SS) is a relatively common soft tissue tumor but only 6%-7% of cases are diagnosed in the head and neck region. It typically occurs in young adults and is slightly more common in males. The most common sites in the head and neck region are hypopharynx and parapharyngeal spaces. However, SS can also occur in tonsils, tongue, and orofacial soft tissues. It is not difficult to diagnose SS microscopically with its classic biphasic appearance, but the diagnosis of monophasic forms is more challenging especially in unusual locations. In this article, we report a rare case of monophasic SS of the mandible. The clinical, histopathological, and immunohistochemical features are discussed and compared with previously reported cases in the literature. To our knowledge, only six primary involvements have been reported in the jaws. Therefore, our case represents the seventh reported case of SS in the area.

Khalili, Maryam; Eshghyar, Nosratollah; Ensani, Fereshteh; Shakib, Pouyan Amini



Fibromyxoid sarcoma of the leg  

PubMed Central

A 48-year-old female with an atypical plaque-like lesion of the lower leg is presented in this article. Histologic investigation revealed a rare low-grade fibromyxoid sarcoma (pT1a cN0 cM0; stage Ia) of suprafascial localization. Staging of the patient did not reveal metastatic spread. The tumor was surgically removed with wide safety margins. The defect was closed using a mesh graft transplant and vacuum-assisted closure. Healing was complete. Regular follow-up for at least 5 years is recommended. Besides the rareness of this tumor, this case is also remarkable because of the localization on the lower leg and the suprafascial soft tissue.

Wollina, Uwe; Runge, Juliane; Schonlebe, Jaqueline



Thromboembolism in pulmonary artery sarcoma.  


Pulmonary artery sarcoma, although rare, must be considered in the differential diagnosis of pulmonary thromboembolism. Clinically and radiologically, it may imitate pulmonary embolism, making diagnosis difficult and delaying treatment. Patients often have no symptom resolution despite therapeutic anticoagulation. Visualization of filling defects within a pulmonary artery on contrast-enhanced CT cannot reliably differentiate between pulmonary thromboembolism and malignant lesions like leiomyosarcoma. FDG PET-CT offers the potential for identification of malignant lesions. The authors report a case with pulmonary artery thromboembolism due to thrombi formed on a pulmonary artery leiomyosarcoma. Integrated FDG PET-CT showed no FDG-uptake along the major part of the filling defect within the right main pulmonary artery suggesting blood clot and increased uptake along the posterior wall of the right main pulmonary artery and the left lower lobar artery suggesting malignancy. PMID:19300057

Farsad, Mohsen; Pernter, Patrizia; Triani, Antonio; Osele, Luzian; Wiedermann, Christian J



Synthetic lethality screens reveal RPS6 and MST1R as modifiers of insulin-like growth factor-1 receptor inhibitor activity in childhood sarcomas.  


The insulin-like growth factor-1 receptor (IGF1R) is emerging as a promising therapeutic target in human cancers. In the high-risk childhood sarcomas Ewing family tumor and rhabdomyosarcoma, IGF1R-blocking antibodies show impressive antitumor activity in some but not all patients, and acquired resistance is observed. Because tumor IGF1R mutations are not described, the basis of IGF1R inhibitor resistance remains unknown. We hypothesized that compensatory signaling cascades bypassing targeted IGF1R inhibition might be involved. To test this systematically, we performed small interfering RNA (siRNA) screens in sarcoma cell lines to identify IGF1R pathway components or related protein tyrosine kinase (PTK) networks that modulate the antitumor efficacy of the BMS-536924 IGF1R kinase inhibitor. This strategy revealed (a) that sarcoma cells are exquisitely sensitive to loss of distal rather than proximal IGF1R signaling components, such as ribosomal protein S6 (RPS6); (b) that BMS-536924 fails to block RPS6 activation in resistant sarcoma cell lines; and (c) that siRNA knockdown of the macrophage-stimulating 1 receptor tyrosine kinase (MST1R; also known as RON) restores BMS-536924 efficacy, even in highly drug-resistant cell lines. We confirmed MST1R expression across a broad panel of childhood sarcomas, and found that loss of MST1R by RNA interference blocks downstream RPS6 activation when combined with BMS-536924 in vitro. These findings underscore the importance of fully understanding PTK networks for successful clinical implementation of kinase inhibitor strategies. PMID:20959493

Potratz, Jenny C; Saunders, Darren N; Wai, Daniel H; Ng, Tony L; McKinney, Steven E; Carboni, Joan M; Gottardis, Marco M; Triche, Timothy J; Jürgens, Heribert; Pollak, Michael N; Aparicio, Samuel A; Sorensen, Poul H B



High Prevalence of CIC Fusion with Double-Homeobox (DUX4) Transcription Factors in EWSR1-Negative Undifferentiated Small Blue Round Cell Sarcomas  

PubMed Central

Primitive round cell sarcomas of childhood and young adults have been problematic to diagnose and classify. Our goal was to investigate the pathologic and molecular characteristics of small blue round cell tumors (SBRCT) that remained unclassified after exhaustive immunohistochemistry and molecular screening to exclude known sarcoma-related translocations. As rare examples of EWSR1-negative SBRCT have been shown to carry rearrangements for FUS and CIC genes, we undertook a systematic screening for these two genes. CIC rearrangements by FISH were detected in 15/22 (68%), while none showed FUS abnormalities. RACE, RT-PCR and/or long range DNA PCR performed in two cases with frozen material showed that CIC was fused to copies of the DUX4 gene on either 4q35 or 10q26.3. Subsequent FISH analysis confirmed fused signals of CIC with either 4q35 or 10q26.3 region in six cases each. Tumors positive for CIC-DUX4 fusion occurred mainly in male young adult patients (median age: 29 years), with the extremities being the most frequent location. Microscopically, tumors displayed a primitive, round to oval cell morphology with prominent nucleoli, high mitotic count and areas of necrosis. O13 expression was variable, being either diffuse or patchy and tumors mostly lacked other markers of differentiation. Although CIC-DUX4 resulting in a t(4;19) translocation has been previously described in primitive sarcomas, this is the first report implicating the related DUX4 on 10q26 in oncogenesis. These results suggest the possibility of a newly defined subgroup of primitive round cell sarcomas characterized by CIC rearrangements, distinct from Ewing sarcoma family of tumors.

Italiano, Antoine; Sung, Yun Shao; Zhang, Lei; Singer, Samuel; Maki, Robert G.; Coindre, Jean-Michel; Antonescu, Cristina R.



Salmonella Indiana as a cause of abortion in ewes: Genetic diversity and resistance patterns  

Microsoft Academic Search

Salmonella enterica subspecies enterica Indiana, a food-borne serovar uncommon in most countries, was responsible for an outbreak of abortion in a flock of Lacaune dairy ewes in southern Spain. Drinking water and feedstuff samples were analysed in an attempt to determine the source of the infection. Pigeons (Columba livia) and turtledoves (Streptopelia turtur) in close contact with the ewes were

I. Luque; A. Echeita; J. León; S. Herrera-León; C. Tarradas; R. González-Sanz; B. Huerta; R. J. Astorga



Improved Methods for the Production of Embryos in Seasonally Anestrous Ewes  

Microsoft Academic Search

In a recent study from our laboratory, a combination of melatonin implants and controlled internal drug release devices increased the number of developing follicles in follicle stimulating hormone-treated anestrous ewes; however, CIDR treatment decreased the rate of in vitro fertilization (IVF). In the current study, effects of alternative CIDR treatments on follicular development and rate of IVF in anestrous ewes

J. S. Luther; D. A. Redmer; L. P. Reynolds; J. T. Choi; D. Pant; C. Navanukraw; P. Borowicz; J. D. Kirsch; R. Weigl; K. C. Kraft; A. T. Grazul-Bilska


Effects of shearing on milk yields and milk composition in machine-milked Dorset ewes  

Microsoft Academic Search

Four experiments were conducted to determine the effects of shearing before lambing or during lactation on the yield and composition of milk from machine-milked Dorset ewes. In Experiments 1 and 2, ewes were shorn in early lactation and although no effects on milk yield were recorded, there were significant increases (8–24%) in the concentrations of fat and protein in the

T. W. Knight; R. Bencini; N. A. Haack; A. F. Death



Ovarian response to gonadotropin treatment initiated relative to wave emergence in ultrasonographically monitored ewes  

Microsoft Academic Search

Follicular recruitment and luteal response to superovulatory treatment initiated relative to the status of the first wave of the ovine estrous cycle (Wave 1) were studied. All ewes (n = 25) received an intravaginal progestagen sponge to synchronize estrous cycles, and ewes were monitored daily by transrectal ultrasonography. Multiple-dose FSH treatment (total dose = 100 mg NIH-FSH-P1) was initiated on

E. Rubianes; R. Ungerfeld; C. Viñoles; A. Rivero; G. P. Adams



Ewe (for Togo). Special Skills Handbook. Peace Corps Language Handbook Series.  

ERIC Educational Resources Information Center

|A book of language and cultural material for teachers and students of Ewe presents vocabulary lists and samples of Ewe language in various contexts, including letters, essays, and newspaper articles. Although not presented in lesson format, the material can be adapted by teachers or used by students for independent study. It is divided into two…

Kozelka, Paul R., Comp.; Agbovi, Yao Ete, Comp.


Steroid secretion rates and plasma binding activity in androstenedione-immune ewes with an autotransplanted ovary  

Microsoft Academic Search

Summary. Mature Merino ewes in which the left ovary and its vascular pedicle had been autotransplanted to the neck were divided into control (N = 5) and immunized groups (N = 6). The immunized ewes were treated (2 ml s.c.) with Fecundin\\\\s=r\\\\1 and 4 weeks before the start of blood sampling. Ovarian and jugular venous blood was collected every 10

B. K. Campbell; R. J. Scaramuzzi; J. A. Downing; G. Evans



Do ewe size and nutrition during pregnancy affect foetus and foetal organ weight in twins?  

Microsoft Academic Search

This study set out to investigate the effects of ewe size and nutrition during pregnancy on the development of twin-foetuses and was part of a large study investigating life-time effect of maternal size and nutrition on the offspring. Heavy (H) and light (L) Romney ewes were allocated to ad libitum (A) or maintenance (M) nutritional regimens from day 21 to

H. T. Blair; D. S. van der Linden; C. M. C. Jenkinson; S. T. Morris; D. D. S. Mackenzie; S. W. Peterson; E. C. Firth; P. R. Kenyon



The effect of ewe maternal behaviour score on lamb and litter survival  

Microsoft Academic Search

The study was carried out on a commercial New Zealand sheep farm with high ewe reproductive rates and lamb survival produced through intensive selection in its Coopworth flock for maternal ability.Heritability and repeatability estimates were derived for ewe maternal behaviour score (MBS) and litter survival (LIS). Heritability estimates were derived for lamb survival as a trait of the lamb (LAS)

J. M. Everett-Hincks; N. Lopez-Villalobos; H. T. Blair; K. J. Stafford



Effects on ewe reproduction of grazing willow fodder blocks during drought  

Microsoft Academic Search

A grazing experiment was conducted in the summer\\/autumn of 2003 to determine the effect of grazing on willow fodder blocks at 6000 stems\\/ha during mating, relative to control ewes grazed on drought pasture, upon ewe production and reproduction. The fodder blocks contained a mixture of herbage and small trees. Grazing occurred over 10 weeks, from 19 February including three cycles

D. W. Pitta; T. N. Barry; N. Lopez-Villalobos; P. D. Kemp



Isolated Limb Perfusion of Melphalan With or Without Tumor Necrosis Factor in Treating Patients With Soft Tissue Sarcoma of the Arm or Leg

Stage IVB Adult Soft Tissue Sarcoma; Stage IIB Adult Soft Tissue Sarcoma; Stage IIC Adult Soft Tissue Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Stage IVA Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma



Technetium scanning in Kaposi's sarcoma and its simulators  

SciTech Connect

The clinical picture of ulcerated purple plaques on the legs often suggests several diagnoses: Kaposi's sarcoma, stasis dermatitis, atrophie blanche (livedoid vasculitis), and a poorly understood condition called acroangiodermatitis of Favre-Chaix (pseudo-Kaposi's sarcoma). Even the skin biopsy may not always be conclusive. We describe our experience with three patients with pseudo-Kaposi's sarcoma, one with true Kaposi's sarcoma and two with atrophie blanche. Clinical and histopathologic similarities among these three conditions pointed up the need for additional confirmatory studies, i.e., isotope scanning. The technetium scan was positive in both Kaposi's sarcoma and pseudo-Kaposi's sarcoma but negative in atrophie blanche.

Gunnoe, R.; Kalivas, J.



Technetium scanning in Kaposi's sarcoma and its simulators.  


The clinical picture of ulcerated purple plaques on the legs often suggests several diagnoses: Kaposi's sarcoma, stasis dermatitis, atrophie blanche (livedoid vasculitis), and a poorly understood condition called acroangiodermatitis of Favre-Chaix (pseudo-Kaposi's sarcoma). Even the skin biopsy may not always be conclusive. We describe our experience with three patients with pseudo-Kaposi's sarcoma, one with "true" Kaposi's sarcoma and two with atrophie blanche. Clinical and histopathologic similarities among these three conditions pointed up the need for additional confirmatory studies, i.e., isotope scanning. The technetium scan was positive in both Kaposi's sarcoma and pseudo-Kaposi's sarcoma but negative in atrophie blanche. PMID:6281316

Gunnoe, R; Kalivas, J



New Therapeutic Targets in Soft Tissue Sarcoma  

PubMed Central

Soft tissue sarcomas are an uncommon and diverse group of more than 50 mesenchymal malignancies. The pathogenesis of many of these is poorly understood, but others have begun to reveal the secrets of their inner workings. With considerable effort over recent years, soft tissue sarcomas have increasingly been classified on the basis of underlying molecular alterations. In turn, this has allowed the development and application of targeted agents in several specific, molecularly defined, sarcoma subtypes. This review will focus the rationale for targeted therapy in sarcoma, with emphasis on the relevance of specific molecular factors and pathways in both translocation-associated sarcomas and in genetically complex tumors. In addition, we will address some of the early successes in sarcoma targeted therapy as well as a few challenges and disappointments in this field. Finally we will discuss several possible opportunities represented by poorly understood, but potentially promising new therapeutic targets, as well as several novel biologic agents currently in preclinical and early phase I/II trials. This will provide the reader with context for understanding the current state this field and a sense of where it may be headed in the coming years.

Demicco, Elizabeth G; Maki, Robert G; Lev, Dina C.; Lazar, Alexander J



[Soft tissue sarcomas: update on molecular data].  


Soft tissue sarcomas are rare and may be a source of problems for diagnosis and treatment. Four types of genetic disorders can be distinguished: translocations, gene amplifications, mutations and complex genetic imbalances. Detection of these disorders may help in diagnosis and in determining prognosis. Detection of specific translocation is recommended in synovial sarcoma, alveolar rhabdomyosarcoma or PNET diagnosis because of therapeutic consequences; in case of rarer histologic type (low grade fibromyxoid sarcoma, clear cell sarcoma, infantile fibrosarcoma...), it may confirm the diagnosis. In some cases, some translocations have a prognostic value (alveolar rhabdomyosarcoma) whereas it is discussed in others (synovial sarcoma). The techniques used to detect these translocations are very sensitive so it may be used to detect microscopical metastasis (bone marrow metastasis of alveolar rhabdomyosarcoma for example). Detection of MDM2 and CDK4 genes amplifications (FISH or quantitative PCR) may be sometimes useful in well differentiated and dedifferentiated liposarcomas diagnosis. Mutation detection of KIT or PDGFRA may help in GIST diagnosis and type of mutation is predictive of response to treatment. Study of complex genomic imbalances in sarcomas is not used in routine practice but remains useful in research. PMID:16442827

Bui Nguyen Binh, M; Collin, F; Coindre, J-M



Lambing rates and litter size following carazolol administration prior to insemination in Kivircik ewes.  


The effect of carazolol on the ease of penetrating the cervix during artificial insemination, lambing rate and litter size was studied using 1.5-4.0-year old Kivircik ewes in an incomplete 3 x 2 x 2 experimental design. All of the ewes in this study were synchronized for oestrus by insertion of a progesterone impregnated vaginal sponge for 12 days and administration of 400 IU PMSG at sponge withdrawal. Three methods of service were compared: natural service, artificial insemination (AI) with fresh semen, or AI with frozen semen. Two times of insemination (fixed time AI versus AI at observed oestrus) were compared on the fresh and frozen AI treatments. The absence (control) or use of carazolol (carazolol; 0.5mg/ewe i.m. 30 min before mating) was the third factor in the design and penetration of the cervix by the insemination pipette was assessed as shallow (<10mm), middle (10-20mm) or deep (>20mm). Natural service ewes were only mated at observed oestrus. Consequently, the factorial design was incomplete and there were a total of 10 treatments each represented by 30 ewes. Natural service resulted in a significantly (P<0.05) higher lambing rate and litter size (86%; 2.0+/-0.05 lambs/ewe) than AI using fresh (65%; 1.6+/-0.1 lambs/ewe) or frozen (40%; 1.4+/-0.14 lambs/ewe) semen. For AI animals the lambing rate and litter size were not significantly different when service was at a fixed time (50%; 1.5+/-0.12 lambs/ewe) or at observed oestrus (56%; 1.5+/-0.12 lambs/ewe). Carazolol did not permit complete cervical penetration in any ewe. Deep penetration of the cervix at AI was achieved in 33% of untreated (control) and 48% of carazolol treated ewes (P<0.05). However, the proportion of ewes in which penetration of the cervix and semen deposition was greater than shallow was similar for control (82%) and carazolol (85%), and lambing rate and litter size were similar for both treatments. Over the three service methods, the lambing rate was 56% for control and 63% for carazolol (NS) and litter size was similar for both treatments. It was concluded that the carazolol treatment used prior to natural mating or AI in this experiment did not improve lambing rate or litter size in Kivircik ewes. PMID:19586730

Gündüz, Mehmet Can; Turna, Ozge; Cirit, Umüt; Uçmak, Melih; Tek, Ca?atay; Sabuncu, Ahmet; Bacino?lu, Süleyman



Relative resistance of Dorper crossbred ewes to gastrointestinal nematode infection compared with St. Croix and Katahdin ewes in the southeastern United States  

Microsoft Academic Search

A study was conducted to evaluate relative resistance of Dorper crossbred (DO), Katahdin (KA), St. Croix (SC), and Hampshire (HA) ewes to natural and experimental gastro-intestinal (GI) nematode infection over a 20-month period. The objective of Experiment 1 was to evaluate breeds for resistance to infection acquired naturally from mixed grass pastures. In Year 1 (May–December 2000) de-worming of ewes

J. M. Burke; J. E. Miller



Possible Differential Diagnosis of Neuroblastoma from Rhabdomyosarcoma and Ewing's Sarcoma by Using a Panel of Monoclonal Antibodies.  

National Technical Information Service (NTIS)

The accurate diagnosis of malignant tumor type is essential to enable the correct therapeutic regimen to be followed and to predict a patient's prognosis. However, the differential diagnosis of small-round-cell tumors, represented by neuroblastoma, rhabdo...

T. Sugimoto T. Sawada S. Arakawa T. Matsumura I. Sakamoto



A Ewing Symposium on the Contemporary Carbon Cycle  

NASA Astrophysics Data System (ADS)

On October 27 and 28, 2000, a Ewing Symposium dealing with the contemporary carbon cycle was held at Lamont-Doherty Earth Observatory of Columbia University. The central theme was understanding the now well-documented large net uptake of CO2 by the terrestrial biosphere with focus on "why and where." As emphasized by Martin Heimann, any deconvolution of the E-W zonal components of terrestrial uptake from atmospheric CO2 distributions is subject to very large uncertainties. Hence additional information is required from other sources.

Broecker, Wallace S.



Treatment of early uterine sarcomas: disentangling adjuvant modalities  

Microsoft Academic Search

Uterine sarcomas are a rare group of neoplasms with aggressive clinical course and poor prognosis. They are classified into four main histological subtypes in order of decreasing incidence: carcinosarcomas, leiomyosarcomas, endometrial stromal sarcomas and \\

Flora Zagouri; Athanasios-Meletios Dimopoulos; Stelios Fotiou; Vassilios Kouloulias; Christos A Papadimitriou



What's New in Kaposi Sarcoma Research and Treatment?  


... Next Topic Additional resources for Kaposi sarcoma What’s new in Kaposi sarcoma research and treatment? A great ... on AIDS-related KS. KSHV also offers a new target for KS drugs and biologic therapy. Clinical ...


What's New in Uterine Sarcoma Research and Treatment?  


... Next Topic Additional resources for uterine sarcoma What`s new in uterine sarcoma research and treatment? Molecular pathology ... the chromosomes leads to the formation of a new gene, called JAZF1/JJAZ. This gene may cause ...


Rapid improvement of immunity to Teladorsagia circumcincta is achieved through a reduction in the demand for protein in lactating ewes.  


Protein supplementation can improve the resistance to parasites of periparturient ewes, as indicated by reduced nematode egg excretion and worm burdens. However, the rate at which this improvement can occur is largely unknown. We investigated the rate of improvement by assessing temporal changes in faecal egg counts after we experimentally reduced nutrient demand. Three groups of nine pregnant ewes each were trickle infected with Teladorsagia circumcincta from day(-70) to day(16) (parturition is day0). Two groups of twin-rearing ewes were fed at 0.8 (L22) or 1.2 (H22) times their assumed metabolizable protein requirements, and a third group was fed the same daily food allowances as L22 ewes, but one of their lambs was removed on day10 (L21). Ewes were slaughtered on day21 to assess worm burdens, in vitro larval establishment on abomasal explants, and mucosal inflammatory cells. Faecal egg counts of L22 ewes were higher than H22 ewes throughout lactation. After the removal of one lamb, faecal egg counts of L21 ewes decreased within 5 days to levels similar to H22 ewes. Relative to L22 ewes, L21 and H22 ewes had lower worm burdens, parasite per capita fecundity and in vitro establishment rates of both T. circumcincta and Haemonchus contortus. Mucosal mast cell and eosinophil counts were similar for all ewes, but H22 ewes had higher globule leukocyte counts than L22 and L21 ewes. The data suggest that a reduction in protein demand can rapidly improve periparturient immunity to T. circumcincta. This may be associated with increased parasite expulsion, reduced fecundity and non-parasite specific reduction of in vitro larval establishment. PMID:16337633

Houdijk, J G M; Jackson, F; Coop, R L; Kyriazakis, I



Lambing date and lamb production of spring-mated Rambouillet, Dorset and Finnsheep ewes and their F1 crosses.  


The reproductive performance of 255 Rambouillet (R), Dorset (D), Finnsheep (F) and F1 ewes born in 1978-1979 (group I) and 1979-1980 (group II) and managed in a semiconfinement fall/winter lambing system was evaluated through 4 yr of age of all ewes and through 5 yr for a portion of group I ewes. Ewes were with rams from approximately May 1 to late September each year, with a 2-wk break late in July/early August. Traits considered were fertility (ewes lambed/ewes exposed), lambing date, litter size, lamb survivial and 70-d lamb weights. Breeds and crossbred groups differed significantly in lambing date, with DR crossbred ewes earliest and F ewes latest. Repeatabilities for groups I and II were .31 and .22, .24 and .24 and .11 and .07 for lambing date, fertility and litter size, respectively. There was no significant heterosis in lambing date, although DR ewes in both groups I and II were superior to (D + R)/2, by about 1 wk on average. There was significant positive heterosis for fertility and traits of which fertility is a component in FR ewes in group I, but none in group II. The FD ewes showed negative heterosis for litter size, -.23 (P less than .05) for group I and -.09 for group II. The results indicate: F and FD ewes are not well adapted to the Mediterranean climate where this experiment was conducted; there is little, if any, useful heterosis in crosses among these three breeds for lambing date or other reproduction traits and RD and R ewes are most suitable of the groups tested, while late onset of the breeding season limits the usefulness of even 50% Finnsheep ewes for an autumn lambing system in this environment. PMID:3759701

Iniguez, L C; Bradford, G E; Mwai, O A



Identification of prognostic markers in bone sarcomas using proton-decoupled phosphorus magnetic resonance spectroscopy.  


It has been hypothesized that the (31)Phosphorus ((31)P) nuclear magnetic resonance spectrum from certain tumors may provide prognostic information. The goal of the present study was to identify prognostic metabolic markers by using proton-decoupled phosphorus magnetic resonance spectroscopic imaging ((31)P MRSI). Twenty patients with bone [osteogenic (OS) and Ewing's (ES) and/or primitive neuroectodermal tumor (PNET)] sarcoma, treated with chemotherapy and surgery or with chemotherapy alone, underwent (31)P MRSI studies pre- and post-therapy. The studies were performed on a 1.5 Tesla General Electric (GE) clinical scanner equipped with a stand-alone proton decoupler and a dual (1)H/(31)P surface coil pair. The limited sensitivity of the (31)P nucleus required that a large soft tissue component of the disease be located within 10 cm (maximum distance) of the body surface and the use of a highly sensitive coil placed near the skin surface. Proton decoupling and nuclear Overhauser enhancement were used to improve the spectral resolution and signal:noise ratio. Baseline (31)P spectral features and metabolic changes with treatment were compared with treatment outcome. The patients were categorized depending on survival as event-free survivors or those who died. The pretreatment nucleoside triphosphate:inorganic phosphate (NTP:P(i)) ratio, an index of tumor bioenergetic status, was significant (P = 0.003) in differentiating event-free survivors versus those who died. The pretreatment NTP:P(i) was higher in patients who were destined to undergo a durable event-free survival compared with those who died. The results are promising, although a prospective study is necessary for confirmation. (31)P MRSI appears to be a useful tool for the prediction of survival before therapy in bone sarcomas. PMID:14695223

Zakian, Kristen L; Shukla-Dave, Amita; Meyers, Paul; Gorlick, Richard; Healey, John; Thaler, Howard T; Huvos, Andrew G; Panicek, David M; Koutcher, Jason A