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1

Treatment Options for Ewing Sarcoma  

MedlinePLUS

... for Ewing sarcoma that has spread to the lung . Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor . ...

2

Promiscuous Partnerships in Ewing’s Sarcoma  

PubMed Central

Ewing’s sarcoma is a highly aggressive bone and soft tissue tumor of children and young adults. At the molecular genetic level Ewing’s sarcoma is characterized by a balanced reciprocal translocation, t(11;22)(q24;q12), which encodes an oncogenic fusion protein and transcription factor EWS/FLI. This tumor-specific chimeric fusion retains the amino terminus of EWS, a member of the TET (TLS/EWS/TAF15) family of RNA-binding proteins, and the carboxy terminus of FLI, a member of the ETS family of transcription factors. In addition to EWS/FLI, variant translocation fusions belonging to the TET/ETS family have been identified in Ewing’s sarcoma. These studies solidified the importance of TET/ETS fusions in the pathogenesis of Ewing’s sarcoma and have since been used as diagnostic markers for the disease. EWS fusions with non-ETS transcription factor family members have been described in sarcomas that are clearly distinct from Ewing’s sarcoma. However, in recent years there have been reports of rare fusions in “Ewing’s-like tumors” that harbor the amino-terminus of EWS fused to the carboxy-terminal DNA or chromatin-interacting domains contributed by non-ETS proteins. This review aims to summarize the growing list of fusion oncogenes that characterize Ewing’s sarcoma and Ewing’s-like tumors and highlights important questions that need to be answered to further support the existing concept that Ewing’s sarcoma is strictly a “TET/ETS” fusion-driven malignancy. Understanding the molecular mechanisms of action of the various different fusion oncogenes will provide better insights into the biology underlying this rare but important solid tumor. PMID:21872822

Sankar, Savita; Lessnick, Stephen L.

2011-01-01

3

Collecting and Storing Biological Samples From Patients With Ewing Sarcoma  

ClinicalTrials.gov

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

2014-08-26

4

Genetics Home Reference: Ewing sarcoma  

MedlinePLUS

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

5

Targeted therapies in Ewing's sarcoma.  

PubMed

Ewing's sarcoma, the second most common malignant bone tumor, is an extremely aggressive neoplasm, mainly occurring in children and adolescents. Ewing's sarcoma shows a low survival rate despite the adoption of multimodal treatments, including local control of the disease by surgery and/or radiotherapy and multidrug adjuvant chemotherapy. No new effective drugs have been recently described and proposed for sarcomas and, therefore, innovative treatment modalities are very welcome and needed. In this respect, two new entry sites for therapeutic intervention may derive from tailored therapies against the insulin-like growth factor receptor I (IGF-IR) or CD99, a cell surface transmembrane protein highly expressed in Ewing's sarcoma. Neutralizing IGF-IR functions was shown to significantly affect Ewing's sarcoma malignancy. However, it is only recently that new clinically applicable drugs targeting IGF-IR are available and represent a concrete opportunity. Engagement of CD99 induces massive apoptosis of Ewing's sarcoma cells through caspase-independent mechanisms and reduces their malignant potential. Since the apoptotic functions of this molecule are of potential clinical interest, the effects of a tailored therapy triggering CD99 were analyzed against Ewing's sarcoma local tumors and distal (lung and bone) metastases in athymic mice. The effects of targeted therapies against CD99 or IGF-IR were evaluated in combination with conventional chemotherapeutic agents to assess best drug-drug interactions and treatment schedule. Toxic effects of these tailored therapies were also considered to offer the necessary rationale for the application of possible forthcoming clinical trials. PMID:17163152

Scotlandi, Katia

2006-01-01

6

The Biology of Ewing Sarcoma  

PubMed Central

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

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

2013-01-01

7

Treatment Option Overview (Ewing Sarcoma)  

MedlinePLUS

... carry drugs, toxins , or radioactive material directly to cancer cells. Kinase inhibitor therapy is another type of targeted therapy being studied in the treatment of recurrent Ewing sarcoma. Kinase inhibitors are drugs that block a ... needed for cancer cells to divide. Patients may want to think about ...

8

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

ClinicalTrials.gov

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

2015-02-04

9

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. PMID:22690342

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

2012-01-01

10

WT1 regulates angiogenesis in Ewing Sarcoma  

PubMed Central

Angiogenesis is required for tumor growth. WT1, a protein that affects both mRNA transcription and splicing, has recently been shown to regulate expression of vascular endothelial growth factor (VEGF), one of the major mediators of angiogenesis. In the present study, we tested the hypothesis that WT1 is a key regulator of tumor angiogenesis in Ewing sarcoma. We expressed exogenous WT1 in the WT1-null Ewing sarcoma cell line, SK-ES-1, and we suppressed WT1 expression using shRNA in the WT1-positive Ewing sarcoma cell line, MHH-ES. Suppression of WT1 in MHH-ES cells impairs angiogenesis, while expression of WT1 in SK-ES-1 cells causes increased angiogenesis. Different WT1 isoforms result in vessels with distinct morphologies, and this correlates with preferential upregulation of particular VEGF isoforms. WT1-expressing tumors show increased expression of pro-angiogenic molecules such as VEGF, MMP9, Ang-1, and Tie-2, supporting the hypothesis that WT1 is a global regulator of angiogenesis. We also demonstrate that WT1 regulates the expression of a panel of pro-angiogenic molecules in Ewing sarcoma cell lines. Finally, we found that WT1 expression is correlated with VEGF expression, MMP9 expression, and microvessel density in samples of primary Ewing sarcoma. Thus, our results demonstrate that WT1 expression directly regulates tumor angiogenesis by controlling the expression of a panel of pro-angiogenic genes. PMID:24810959

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

2014-01-01

11

Cellular immunotherapy strategies for Ewing sarcoma.  

PubMed

Ewing sarcoma is a rare cancer of bone and soft tissues defined by a specific chromosomal rearrangement. Preclinical development of immunological treatment strategies includes expansion of T cells with native or grafted T-cell receptor specificities for Ewing sarcoma-associated intracellular antigens, and T-cell engineering with chimeric antigen receptors targeting surface antigens. In vitro preactivated NK cells may also have activity in this cancer. Major challenges are the heterogeneity of antigen expression in individual Ewing sarcomas, and the coexpression of most candidate targets on normal cells. Moreover, homing of therapeutic effector cells to both primary and metastatic tumor sites and adequate function within the immunosuppressive tumor microenvironment will have to be ensured to allow for effective immune targeting of this cancer. PMID:24896629

Rossig, Claudia

2014-01-01

12

Novel Combination Chemotherapy for Localized Ewing Sarcoma  

Cancer.gov

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

13

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. PMID:23580819

Jully, Babu; Rajkumar, Thangarajan

2012-01-01

14

Functional results after partial pelvic resection in Ewing’s sarcoma of the ilium  

Microsoft Academic Search

Ewing’s sarcoma of the pelvis has an unfavourable prognosis. The clinical and functional results of 7 patients who had a\\u000a Ewing’s sarcoma of the pelvis stage IIB were reviewed. All patients received multiple-agent chemotherapy pre- and postoperatively\\u000a (modified T6 and T2 protocol according to Rosen) and underwent local resection of the pelvic tumour. According to Enneking,\\u000a five patients had a

M. Porsch; B. Kornhuber; L. Hovy

1999-01-01

15

Ewing Sarcoma of the Posterior Fossa in an Adolescent Girl  

PubMed Central

Medulloblastoma, astrocytoma, and ependymoma represent the most common infratentorial tumors in childhood, while Ewing sarcomas in that localization are extremely rare. A large left infratentorial space-occupying lesion was diagnosed in a 12-year-old girl with signs of increased intracranial pressure. Following total tumor resection, histological and molecular examination revealed Ewing sarcoma with rearranged EWSR-1 gene. The patient achieved complete remission following adjuvant chemotherapy and radiotherapy according to Euro-EWING 2008 treatment protocol. Intracranial Ewing sarcoma, although rare, should be an important differential diagnosis of intracranial tumors in childhood which requires aggressive multimodal treatment. PMID:25614743

Stark, Andreas M.; Leuschner, Ivo; Mehdorn, H. Maximilian; Claviez, Alexander

2014-01-01

16

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

ClinicalTrials.gov

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

2015-03-17

17

Mesenchymal Stem Cells and the Origin of Ewing's Sarcoma  

PubMed Central

The origin of Ewing's sarcoma is a subject of much debate. Once thought to be derived from primitive neuroectodermal cells, many now believe it to arise from a mesenchymal stem cell (MSC). Expression of the EWS-FLI1 fusion gene in MSCs changes cell morphology to resemble Ewing's sarcoma and induces expression of neuroectodermal markers. In murine cells, transformation to sarcomas can occur. In knockdown experiments, Ewing's sarcoma cells develop characteristics of MSCs and the ability to differentiate into mesodermal lineages. However, it cannot be concluded that MSCs are the cell of origin. The concept of an MSC still needs to be rigorously defined, and there may be different subpopulations of mesenchymal pluripotential cells. Furthermore, EWS-FLI1 by itself does not transform human cells, and cooperating mutations appear to be necessary. Therefore, while it is possible that Ewing's sarcoma may originate from a primitive mesenchymal cell, the idea needs to be refined further. PMID:20953407

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

2011-01-01

18

Ewing’s Sarcoma: Overcoming the Therapeutic Plateau  

PubMed Central

The hallmark of Ewing’s sarcoma (EWS) is a translocation -- t(11;22)(q24;q12) -- that most frequently results in the EWS/FLI1 aberrant chimeric gene. Because EWS afflicts young patients, it stands out among the diverse sarcoma subtypes. The frontline, standard-of-care cytotoxic chemotherapy regimens produce minimal benefit in patients with metastases at presentation or those with relapsed disease. While the outcomes of chemorefractory EWS patients are poor, recent developments have led to the promising use of targeted therapy. Specifically, inhibition of insulin-like growth factor 1 receptor (IGF1R) signaling and the mammalian target of rapamycin (mTOR) pathways has emerged as a targeted therapy in EWS, with select patients experiencing dramatic therapeutic responses. However, targeted therapies in general, and these responders in particular, are faced with the ultimate conundrum of eventual resistance. To optimize response, combining IGF1R and mTOR inhibitor-based regimens with chemotherapy in the upfront setting in newly diagnosed high-risk EWS may clarify the true benefit of IGF1R inhibitors in these patients. Another option is to explore novel targeted multikinase inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors, which have experienced a surge in supporting preclinical data. Drugs inhibiting the downstream targets of EWS/FLI1 are also in preclinical development. However, ultimately, the underlying biomarker correlates of resistance and response must be delineated along with ways to overcome them. Novel agents, together with integration of advances in multimodal approaches (including surgery and radiation), as well as offering targeted therapies early in the disease course represent new strategies for confronting the challenges of EWS. PMID:22742646

Subbiah, Vivek; Kurzrock, Razelle

2013-01-01

19

Ewing’s Sarcoma: An Uncommon Breast Tumor  

PubMed Central

Ewing’s sarcoma/primitive neuroectodermal tumors (EWS/PNET) are rare malignant and aggressive tumors, usually seen in the trunk and lower limbs of children and young adults. They are uncommon in the breast. We report a case of a 43-year-old woman who developed a painless breast mass. An initial core needle biopsy concluded to a fibrocystic dystrophy contrasting with a rapidly growing mass; thus a large lumpectomy was done. Diagnosis of primary PNET of the breast was established, based on both histopathological examination and immunohistochemical findings. Surgical margins were positive, therefore, left modified radical mastectomy with axillary lymph nodes dissection was performed. The patient was given 6 cycles of adjuvant chemotherapy containing cyclophosphamide, adriamycin and vincristine. Twenty months later, she is in life without recurrence or metastasis. EWS/PNET may impose a diagnostic challenge. Indeed, mammography and ultrasonography features are non specific. The histopathological pattern is variable depending on the degree of neuroectodermal differentiation. Immuno-phenotyping is necessary and genetic study is the only confirmatory tool of diagnosis showing a characteristic cytogenetic anomaly; t (11; 22) translocation. PMID:25332765

Meddeb, Sawsen; Rhim, Mohamed Salah; Kouira, Mouna; Mestiri, Sarra; Bibi, Mohamed; Yacoubi, Mohamed Tahar

2014-01-01

20

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

PubMed Central

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

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

2014-01-01

21

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

PubMed Central

Cellular mechanisms that account for tumour osteolysis associated with Ewing's sarcoma are uncertain. Osteoclasts are marrow-derived multinucleated cells (MNCs) that effect tumour osteolysis. Osteoclasts are known to form from macrophages by both receptor activator for nuclear factor-?B (RANK) ligand (RANKL)-dependent and -independent mechanisms. In this study, our aim has been to determine whether tumour-associated macrophages (TAMs) isolated from Ewing's sarcoma are capable of differentiating into osteoclasts and to characterise the cellular and humoral mechanisms whereby this occurs. Tumour-associated macrophages were isolated from two Ewing's sarcomas and cultured on both coverslips and dentine slices for up to 21 days with soluble RANKL and macrophage colony stimulating factor (M-CSF). Osteoclast formation from TAMs (CD14+) was evidenced by the formation of tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor (VNR)-positive MNCs, which were capable of carrying out lacunar resorption. This osteoclast formation was inhibited by the addition of bisphosphonates. Both Ewing's sarcoma-derived fibroblasts and some bone stromal cells expressed RANKL and supported osteoclast formation by a contact-dependent mechanism. We also found that osteoclast differentiation occurred when Ewing's TAMs were cultured with tumour necrosis factor (TNF)-? in the presence of M-CSF and that TC71 Ewing's sarcoma cells stimulated osteoclast formation through the release of a soluble factor, the action of which was abolished by an antibody to TNF-?. These results indicate that TAMs in Ewing's sarcoma are capable of osteoclast differentiation by both RANKL-dependent and TNF-?-dependent mechanisms and that Ewing's sarcoma cells produce osteoclastogenic factor(s). Our findings suggest that anti-resorptive and anti-osteoclastogenic therapies may be useful in inhibiting the osteolysis of Ewing's sarcoma. PMID:17533390

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

2007-01-01

22

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

PubMed

Cellular mechanisms that account for tumour osteolysis associated with Ewing's sarcoma are uncertain. Osteoclasts are marrow-derived multinucleated cells (MNCs) that effect tumour osteolysis. Osteoclasts are known to form from macrophages by both receptor activator for nuclear factor-kappaB (RANK) ligand (RANKL)-dependent and -independent mechanisms. In this study, our aim has been to determine whether tumour-associated macrophages (TAMs) isolated from Ewing's sarcoma are capable of differentiating into osteoclasts and to characterise the cellular and humoral mechanisms whereby this occurs. Tumour-associated macrophages were isolated from two Ewing's sarcomas and cultured on both coverslips and dentine slices for up to 21 days with soluble RANKL and macrophage colony stimulating factor (M-CSF). Osteoclast formation from TAMs (CD14+) was evidenced by the formation of tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor (VNR)-positive MNCs, which were capable of carrying out lacunar resorption. This osteoclast formation was inhibited by the addition of bisphosphonates. Both Ewing's sarcoma-derived fibroblasts and some bone stromal cells expressed RANKL and supported osteoclast formation by a contact-dependent mechanism. We also found that osteoclast differentiation occurred when Ewing's TAMs were cultured with tumour necrosis factor (TNF)-alpha in the presence of M-CSF and that TC71 Ewing's sarcoma cells stimulated osteoclast formation through the release of a soluble factor, the action of which was abolished by an antibody to TNF-alpha. These results indicate that TAMs in Ewing's sarcoma are capable of osteoclast differentiation by both RANKL-dependent and TNF-alpha-dependent mechanisms and that Ewing's sarcoma cells produce osteoclastogenic factor(s). Our findings suggest that anti-resorptive and anti-osteoclastogenic therapies may be useful in inhibiting the osteolysis of Ewing's sarcoma. PMID:17533390

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

2007-06-01

23

Primary intracranial Ewing’s sarcoma with unusual features  

PubMed Central

Pediatric primary “small round blue cell” tumors in the CNS represent several entities, some more common than others. Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) is rare and must be distinguished from other tumors such as medulloblastoma [1, 2], atypical rhabdoid/teratoid tumor, ependymomal tumors, metastatic sarcomas, hematologic malignancies, and other mimics. Although therapy for ES/pPNET is effective, it brings severe side effects, including cardiac toxicity, making correct recognition important [3]. As small blue cell tumors look similar, diagnosis often depends on special stains, immunohistochemistry, and molecular techniques. While the combination of membranous immunohistochemical reactivity for CD99 with cytoplasmic glycogen provides effective screening, demonstration of characteristic translocations of EWSR1 (chromosome 22) or FUS (chromosome 16) by fluorescent in situ hybridization (FISH) can confirm the diagnosis. We are reporting three primary ES/pPNET of the CNS, two of which occurred in children. While the adult case demonstrates the classic histopathology, the two pediatric cases have histopathology that significantly deviates from the usual. One is suggestive of a primary sarcoma, and the other mimics an ependymoma, but all three cases are confirmed with FISH. These observations suggest that primary ES in the CNS may have histology different from the classic morphology and a high index of suspicion should be maintained in order to make the correct diagnosis. A search of the literature suggests that these tumors are most frequently seen in children and young adults. Imaging often shows a supratentorial enhancing mass that touches the leptomeninges. Survival over three years is good but long term prognosis is unknown [3, 4]. PMID:25755713

VandenHeuvel, Katherine A; Al-Rohil, Rami N; Stevenson, Michael E; Qian, Jiang; Gross, Naina L; McNall-Knapp, Rene; Li, Shibo; Wartchow, Eric P; Mierau, Gary W; Fung, Kar-Ming

2015-01-01

24

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. PMID:21942527

Lessnick, Stephen L.; Ladanyi, Marc

2013-01-01

25

Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma  

PubMed Central

Purpose of review In 2012, two publications revealed a particular sensitivity of Ewing sarcoma cells to the inhibition of poly(ADP-ribose) polymerase (PARP). This review updates the reader on PARP function, the development of PARP inhibitors (PARPi) and the evidence for targeting PARP in Ewing sarcoma. It concludes with a description of ongoing/emerging PARPi clinical trials in patients with Ewing sarcoma. Recent findings PARP has a major role in DNA repair, and is a transcription regulator. The oncoprotein in Ewing sarcoma, EWS-FLI1, is proposed to interact with PARP-1, driving PARP-1 expression, which further promotes transcriptional activation by EWS-FLI1. Thus, there are two rationales for PARPi in the treatment of Ewing sarcoma: to disrupt the interaction between EWS-FLI1 and PARP, and for chemo-potentiation or radio-potentiation. The first clinical trial with a single agent PARPi failed to show significant responses, but preclinical evidence for combinations of PARPi with chemotherapy or radiotherapy is very promising. Summary Despite initial excitement for the potential of PARPi as single agent therapy in Ewing sarcoma, the emerging preclinical data now strongly support testing PARPi in combination with chemo/radiotherapy clinically. PMID:24840521

Vormoor, Britta; Curtin, Nicola J.

2014-01-01

26

Primary intracranial Ewing's sarcoma with unusual features.  

PubMed

Pediatric primary "small round blue cell" tumors in the CNS represent several entities, some more common than others. Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) is rare and must be distinguished from other tumors such as medulloblastoma [1, 2], atypical rhabdoid/teratoid tumor, ependymomal tumors, metastatic sarcomas, hematologic malignancies, and other mimics. Although therapy for ES/pPNET is effective, it brings severe side effects, including cardiac toxicity, making correct recognition important [3]. As small blue cell tumors look similar, diagnosis often depends on special stains, immunohistochemistry, and molecular techniques. While the combination of membranous immunohistochemical reactivity for CD99 with cytoplasmic glycogen provides effective screening, demonstration of characteristic translocations of EWSR1 (chromosome 22) or FUS (chromosome 16) by fluorescent in situ hybridization (FISH) can confirm the diagnosis. We are reporting three primary ES/pPNET of the CNS, two of which occurred in children. While the adult case demonstrates the classic histopathology, the two pediatric cases have histopathology that significantly deviates from the usual. One is suggestive of a primary sarcoma, and the other mimics an ependymoma, but all three cases are confirmed with FISH. These observations suggest that primary ES in the CNS may have histology different from the classic morphology and a high index of suspicion should be maintained in order to make the correct diagnosis. A search of the literature suggests that these tumors are most frequently seen in children and young adults. Imaging often shows a supratentorial enhancing mass that touches the leptomeninges. Survival over three years is good but long term prognosis is unknown [3, 4]. PMID:25755713

VandenHeuvel, Katherine A; Al-Rohil, Rami N; Stevenson, Michael E; Qian, Jiang; Gross, Naina L; McNall-Knapp, Rene; Li, Shibo; Wartchow, Eric P; Mierau, Gary W; Fung, Kar-Ming

2015-01-01

27

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

2000-01-01

28

Is time of the essence? Delayed diagnosis of Ewing's sarcoma.  

PubMed

Rarely in modern medicine are we able to observe the natural history of a patient with a sarcoma. This unusual case provides that opportunity. A CT scan was performed on the leg of a 15-year-old boy with a tender soft tissue mass on the lateral aspect of his left calf. Despite showing a lesion consistent with a sarcoma, neither the patient nor his family was informed. Almost a year and a half later, the patient returned and was diagnosed with Ewing's sarcoma. A staging work up showed no metastatic disease. After undergoing chemotherapy and a complete surgical resection of the tumour, the patient remains disease-free 10?years later, indicating that the biology of Ewing's sarcoma may be more important than time to diagnosis in determining outcome. PMID:25628326

Edwards, Madeline; Halton, Jacqueline; Ramphal, Raveena; Johnston, Donna

2015-01-01

29

Factors Affecting EWS-FLI1 Activity in Ewing's Sarcoma  

PubMed Central

Ewing's sarcoma family tumors (ESFT) are characterized by specific chromosomal translocations, which give rise to EWS-ETS chimeric proteins. These aberrant transcription factors are the main pathogenic drivers of ESFT. Elucidation of the factors influencing EWS-ETS expression and/or activity will guide the development of novel therapeutic agents against this fatal disease. PMID:22135504

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

2011-01-01

30

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  

ClinicalTrials.gov

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

2015-03-31

31

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. PMID:21804475

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

2011-01-01

32

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

PubMed Central

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-G1 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-G1 cell populations after irradiation. Together, these findings suggest that APLP2 lowers the sensitivity of Ewing sarcoma cells to radiotherapy-induced apoptosis and that APLP2 expression is increased in Ewing sarcoma cells able to survive exposure to cytotoxic immune cells. PMID:23792571

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

2013-01-01

33

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. PMID:20718987

2010-01-01

34

Pseudohemangioma of the Vertebra: An Unusual Radiographic Manifestation of Primary Ewing's Sarcoma  

Microsoft Academic Search

Summary: Primary Ewing's sarcoma (ES) of the spine is uncommon, exhibiting a variety of appearances on plain- film radiographs and cross-sectional images. We report the unusual CT imaging manifestations of a primary ES with a coarse trabecular pattern that mimicked an aggressive hemiangioma of the cervical spine. Ewing's sarcoma (ES) is an aggressive malignant neoplasm accounting for 6% to 8%

Joshua A. Bemporad; Gordon Sze; John C. Chaloupka; Charles Duncan

1999-01-01

35

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

ClinicalTrials.gov

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

2015-01-07

36

Variable Expression of PIK3R3 and PTEN in Ewing Sarcoma Impacts Oncogenic Phenotypes  

PubMed Central

Ewing Sarcoma is an aggressive malignancy of bone and soft tissue affecting children and young adults. Ewing Sarcoma is driven by EWS/Ets fusion oncoproteins, which cause widespread alterations in gene expression in the cell. Dysregulation of receptor tyrosine kinase signaling, particularly involving IGF-1R, also plays an important role in Ewing Sarcoma pathogenesis. However, the basis of this dysregulation, including the relative contribution of EWS/Ets-dependent and independent mechanisms, is not well understood. In the present study, we identify variable expression of two modifiers of PI3K signaling activity, PIK3R3 and PTEN, in Ewing Sarcoma, and examine the consequences of this on PI3K pathway regulation and oncogenic phenotypes. Our findings indicate that PIK3R3 plays a growth-promotional role in Ewing Sarcoma, but suggest that this role is not strictly dependent on regulation of PI3K pathway activity. We further show that expression of PTEN, a well-established, potent tumor suppressor, is lost in a subset of Ewing Sarcomas, and that this loss strongly correlates with high baseline PI3K pathway activity in cell lines. In support of functional importance of PTEN loss in Ewing Sarcoma, we show that re-introduction of PTEN into two different PTEN-negative Ewing Sarcoma cell lines results in downregulation of PI3K pathway activity, and sensitization to the IGF-1R small molecule inhibitor OSI-906. Our findings also suggest that PTEN levels may contribute to sensitivity of Ewing Sarcoma cells to the microtubule inhibitor vincristine, a relevant chemotherapeutic agent in this cancer. Our studies thus identify PIK3R3 and PTEN as modifiers of oncogenic phenotypes in Ewing Sarcoma, with potential clinical implications. PMID:25603314

Niemeyer, Brian F.; Parrish, Janet K.; Spoelstra, Nicole S.; Joyal, Teresa; Richer, Jennifer K.; Jedlicka, Paul

2015-01-01

37

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. PMID:21979944

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

2012-01-01

38

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. PMID:24082883

2013-01-01

39

Retrospective Study on Osteosarcoma and Ewing Sarcoma – Our Experience  

PubMed Central

Introduction: Primary bone tumors are relatively rare types of cancer. Their relative frequency is not yet well established and still there is more information needed regarding the evolution and prognosis of those patients. Objectives: We analyzed several factors (site of lesion, tumor stage, tumor volume, disease related complications, therapy related complications) that influenced the evolution of bone tumor in a lot of patients diagnosed with osteosarcoma or Ewing sarcome. Material and methods: A retrospective review was conducted on hospital-based registry from the Emergency Hospital for Children "Louis Turcanu" Timisoara. Patients with newly diagnosed osteosarcoma and Ewing sarcoma, hospitalised in our clinic during a period of 10 years (1996-2006) were included. Records were analyzed for patient demographics, site of lesion, treatment and outcomes. The study group was composed of 36 patients with bone tumors, with ages betwen 3-23 years, who came from Timis and several counties around it. Results: We found Ewing Sarcoma (ES) in 52.94% of cases and osteosarcoma (OS) in 47.06% of cases analyzed. We found diseases in advanced stages in 33.3% of cases in stage III and in 27.7% in stage IV. Tumoral volume had more than 200 cm3 in 53.3% of OS patients and in 21% of cases of ES. Treatment was accomplished according to the European protocols, COSS 96 in 66.6% of OS cases, EWING 99 in 73.6% of ES cases. Disease related complications were found in 26.6% of OS cases and in 51% of ES patients. Conclusion: In this study, the patients survival rate at 5 years after diagnosis was lower than in other studies. A possible explaination for such a high rate of mortality could be the delayed diagnosis and the advanced stage of the neoplasia, especially for Ewing sarcoma where only 16.66% of the patients were stage I or II. For the short time survival it was found a corelation with the period of time between the simptoms appearance and the moment of diagnosis, tumor stage, metastasis and severity of the complications. PMID:25705270

NEDELCU, Daniela; ANDREESCU, Nicoleta; BOERIU, Estera; STEFANESCU, Radu; ARGHIRESCU, Smaranda; PUIU, Maria

2014-01-01

40

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

Microsoft Academic Search

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

L. M. Smith; S. S. Donaldson

1991-01-01

41

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

SciTech Connect

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

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

2012-03-01

42

Structure-Function Based Molecular Relationships in Ewing's Sarcoma  

PubMed Central

Ewing's Sarcoma Oncogene (ews) on chromosome 22q12 is encoding a ubiquitously expressed RNA-binding protein (EWS) with unknown function that is target of tumor-specific chromosomal translocations in Ewing's sarcoma family of tumors. A model of transcription complex was proposed in which the heterodimer Rpb4/7 binds to EAD, connecting it to Core RNA Pol II. The DNA-binding domain, provided by EFP, is bound to the promoter. Rpb4/7 binds RNA, stabilizing the transcription complex. The complex Rpb4/7 can stabilize the preinitiation complexes by converting the conformation of RNA Pol II. EWS may change its conformation, so that NTD becomes accessible. Two different mechanisms of interaction between EWS and RNA Pol II are proposed: (I) an intermolecular EWS-EWS interaction between two molecules, pushing conformation from “closed” to “open” state, or (II) an intramolecular interaction inside the molecule of EWS, pushing conformation of the molecule from “closed” to “open” state. The modified forms of EWS may interact with Pol II subunits hsRpb5 and hsRpb7. The EWS and EFPs binding partners are described schematically in a model, an attempt to link the transcription with the splicing. The proposed model helps to understand the functional molecular interactions in cancer, to find new partners and ways to treat cancer. PMID:25688366

2015-01-01

43

Extraskeletal Ewing’s sarcoma/primitive neuroectodermal tumor of the mediastinum: Significant response to chemoradiotherapy  

PubMed Central

Primary mediastinal extraskeletal Ewing’s sarcoma (EES) is quite rare. To the best of our knowledge, only five cases have been reported. Given the paucity of data, there is consequently no optimal treatment strategy available. The current study presents the case of a 51-year-old female with unresectable EES of the posterior mediastinum. Chemoradiotherapy achieved near complete remission without severe side-effects. The literature associated with EES is also reviewed. The present case highlights the possibility of the diagnosis of EES for a mediastinal mass. Chemoradiotherapy may be a good option for unresectable cases. In the future, large-scale collaborative clinical trials should be initiated to provide an improved understanding of the characteristics of EES and the best treatment strategy. PMID:25621030

LIU, MIN; LIU, BAILONG; DONG, LIHUA; HAN, TAO; ZHANG, LEI

2015-01-01

44

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

PubMed

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

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

2013-11-01

45

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. PMID:22848594

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

2012-01-01

46

Angiogenesis and Vascular Targeting in Ewing Sarcoma: A Review of Preclinical and Clinical Data  

PubMed Central

Ewing sarcoma is the second most common type of bone cancer in children and young adults. In recent years, the mechanisms by which these tumors develop and maintain their vascular supply have been elucidated. Additional work has demonstrated that inhibition of angiogenic pathways or disruption of established vasculature can attenuate the growth of Ewing sarcoma mouse xenografts. Early clinical data suggest that these results may also extend to patients with Ewing sarcoma treated with anti-angiogenic or anti-vascular therapies. This review summarizes the available data supporting this approach. PMID:20029966

DuBois, Steven G.; Marina, Neyssa; Glade-Bender, Julia

2009-01-01

47

Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma  

ClinicalTrials.gov

Metastatic Ewing Sarcoma; Metastatic Malignant Neoplasm to the Bone; Metastatic Malignant Neoplasm to the Bone Marrow; Metastatic Malignant Neoplasm to the Lung; Metastatic Peripheral Primitive Neuroectodermal Tumor of Bone; Peripheral Primitive Neuroectodermal Tumor of Soft Tissues

2015-03-05

48

Identification of CD56 and CD57 by flow cytometry in Ewing’s sarcoma or primitive neuroectodermal tumor  

Microsoft Academic Search

CD56 and CD57 are commonly considered as natural killer and neuroectodermal markers, but their expression has been identified\\u000a in a wide spectrum of neoplasms including some cases of Ewing’s sarcoma (ES) and primitive neuroectodermal tumor (PNET). We\\u000a report two cases of small, round blue cell tumor (SRBCT), in which flow cytometry immunophenotyping (FCI) detected strong\\u000a expression of CD56 and CD57

L. J. Gardner; J. M. Polski; R. Fallon; C. H. Dunphy

1998-01-01

49

Ewing sarcoma as a second malignant neoplasm after acute lymphoblastic leukemia.  

PubMed

Second malignant neoplasms (SMNs) are being increasingly recognized. This report describes a case of a 7-year-old girl with a history of acute lymphoblastic leukemia (ALL) who presented with a mass in her humerus that was diagnosed as Ewing sarcoma. Second malignant neoplasms are relatively rare in survivors of ALL treated without radiation. Even more unusual is the development of Ewing sarcoma as the SMN. PMID:15700259

Kim, Grace E; Beach, Barbara; Gastier-Foster, Julie M; Murata-Collins, Joyce L; Rowland, Jon M; O'Donnell, Richard J; Goldsby, Robert E

2005-07-01

50

Primitive Neuroectodermal Tumor/Ewing Sarcoma Presenting with Pulmonary Nodular Lesions  

PubMed Central

Primitive neuroectodermal tumors (PNETs) and Ewing sarcoma (EWS) belong to the same family of malignant, small, round cell neoplasms of soft tissue or bone origin. EWS-PNETs that arise in the lung parenchyma involvement are extremely rare in adults. A case of a 32-year-old male presenting with chest pain and diffuse pulmonary nodules on chest X-ray and diagnosed with Ewing sarcoma-PNETs will be presented here. PMID:25705534

Asker, Selvi; Sayir, Fuat; Bulut, Gulay; Sunnetcioglu, Aysel; Ekin, Selami

2015-01-01

51

3D Tissue-Engineered Model of Ewing Sarcoma  

PubMed Central

Despite longstanding reliance upon monolayer culture for studying cancer cells, and numerous advantages from both a practical and experimental standpoint, a growing body of evidence suggests more complex three-dimensional (3D) models are necessary to properly mimic many of the critical hallmarks associated with the oncogenesis, maintenance and spread of Ewing sarcoma (ES), the second most common pediatric bone tumor. And as clinicians increasingly turn to biologically-targeted therapies that exert their effects not only on the tumor cells themselves, but also on the surrounding extracellular matrix, it is especially important that preclinical models evolve in parallel to reliably measure antineoplastic effects and possible mechanisms of de novo and acquired drug resistance. Herein, we highlight a number of innovative methods used to fabricate biomimetic ES tumors, encompassing both the surrounding cellular milieu and extracellular matrix (ECM), and suggest potential applications to advance our understanding of ES biology, preclinical drug testing, and personalized medicine. PMID:25109853

Lamhamedi-Cherradi, Salah-Eddine; Santoro, Marco; Ramammoorthy, Vandhana; Menegaz, Brian A.; Bartholomeusz, Geoffrey; Iles, Lakesla R.; Amin, Hesham M.; Livingston, Andrew J.; Mikos, Antonios G.; Ludwig, Joseph A.

2015-01-01

52

Delta like ligand 4 plays a critical role in pericyte/vascular smooth muscle cell formation during vasculogenesis and tumor vessel expansion in Ewing’s sarcoma  

PubMed Central

Purpose Bone marrow (BM) cells contribute to tumor vessel formation that supports the growth of Ewing’s sarcoma. These BM cells migrate into the tumor and differentiate into endothelial cells and pericytes. We investigated whether Delta like ligand 4 (DLL4) played a role in the formation of BM-derived pericytes/vascular smooth muscle cells (vSMCs) during tumor vessel formation. Experimental Design Using immunohistochemistry, we examined the expression pattern of DLL4 in 14 patient samples and 2 xenograft mouse models of Ewing’s sarcoma. We then used intratumor injections of shRNA to inhibit DLL4 expression in Ewing’s sarcoma tumors in mice, and evaluated the effect on BM-derived pericytes/vSMCs. Results DLL4 was expressed by perivascular cells in 12 of 14 human samples and in BM-derived pericytes/vSMCs in both A4573 and TC71 xenograft tumors. Inhibition of DLL4 expression by shRNA correlated with decreased numbers of BM-derived cells in tumor vessels and decreased numbers of ?-SMA+, desmin+, and NG2+ pericytes/vSMCs, as well as increased tumor hypoxia. Conclusions DLL4 is important for the formation of BM-derived pericytes/vSMCs during vasculogenesis in Ewing’s sarcoma. DLL4 may be a therapeutic target for treatment of Ewing’s sarcoma by inhibition of blood vessel formation. PMID:20103680

Schadler, Keri L.; Zweidler-McKay, Patrick A.; Guan, Hui; Kleinerman, Eugenie S.

2009-01-01

53

[Ewing/PNET sarcoma family of tumors: towards a new paradigm?].  

PubMed

Ewing sarcoma family of tumors are mainly aggressive sarcomas of bone and also arising in soft tissues, which share common features: morphological features of basophilic round cell tumors, immunohistochemical features by expression of membrane CD99 protein, and genetic features with a translocation involving EWS and FLI1 in approximately 90% of cases. The discovery of this translocation has made it possible to unify in a single entity several lesions such as PNET, neuropitheliomas, Askin tumors, Ewing sarcomas… Since then, the extensive use of molecular/genetic methods has helped to identify an increasing number of molecular anomalies in unclassified round cell sarcomas, these sarcomas often harboring an atypical morphology and a less frequent CD99 positivity. Besides the rearrangements between the FET family of genes (EWS or FUS) and the wide ETS family of genes (FLI1, ERG, FEV, ETV…), new partner genes are gradually identified: cases with EWS-non ETS partners are extremely rare, but there are more important groups which are CIC-DUX4 and BCOR-CCNB3 translocation-positive sarcomas. These findings raise the problem of the nosological borders of the Ewing/PNET entity and its links with new "Ewing-like" groups of tumors, and raise the therapeutic problems. The forward-looking identification of new round cell sarcomas should enable studies of wider series to try to answer these questions. PMID:25534668

Renard, Caroline; Ranchère-Vince, Dominique

2015-01-01

54

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. PMID:23443465

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

2013-01-01

55

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. PMID:22523703

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

2012-01-01

56

Huntsman Cancer Institute researchers discover possible new treatment for Ewing sarcoma  

Cancer.gov

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

57

The Ca, Cl, Mg, Na, and P mass fractions in human bone affected by Ewing's sarcoma.  

PubMed

The Ca, Cl, Mg, Na, and P contents and Ca/P, Ca/Mg, Ca/Na, Cl/Ca, and Cl/Na ratios in samples of intact bone, inflamed bone, and Ewing's sarcoma tissue were investigated by neutron activation analysis with high-resolution spectrometry of short-lived radionuclides. In Ewing's sarcoma tissue, the mass fractions of Cl and Na are higher and the mass fractions of Ca and Mg are lower than those of both normal and inflamed bone tissues. It was shown that the levels of Ca and Cl mass fractions and also levels of the Ca/Cl and Cl/Na ratios can be used as an additional test for differential diagnosis between inflamed (or normal) bone and Ewing's sarcoma. PMID:24723217

Zaichick, Vladimir; Zaichick, Sofia

2014-06-01

58

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

PubMed Central

Ewing sarcoma is a tumor of the bone and soft tissue caused by the expression of a translocation-derived oncogenic transcription factor, EWS/FLI. Overt metastases are associated with a poor prognosis in Ewing sarcoma, but patients without overt metastases frequently harbor micrometastatic disease at presentation. This suggests that the metastatic potential of Ewing sarcoma exists at an early stage during tumor development. We have therefore explored whether the inciting oncogenic event in Ewing sarcoma, EWS/FLI, directly modulates tumor cell features that support metastasis, such as cell adhesion, cell migration, and cytoarchitecture. We used an RNAi-based approach in patient-derived Ewing sarcoma cell lines. Although we hypothesized that EWS/FLI might induce classic metastatic features, such as increased cell adhesion, migration, and invasion (similar to the phenotypes observed when epithelial malignancies undergo an epithelial-to-mesenchymal transition during the process of metastasis), surprisingly, we found the opposite. Thus, EWS/FLI expression inhibited the adhesion of isolated cells in culture and prevented adhesion in an in vivo mouse lung assay. Cell migration was similarly inhibited by EWS/FLI expression. Furthermore, EWS/FLI expression caused a striking loss of organized actin stress fibers and focal adhesions and a concomitant loss of cell spreading, suggesting that EWS/FLI disrupts the mesenchymal phenotype of a putative tumor cell-of-origin. These data suggest a new paradigm for the dissemination and metastasis of mesenchymally derived tumors: these tumors may disseminate via a “passive/stochastic” model rather than via an “active” epithelial-to-mesenchymal type transition. In the case of Ewing sarcoma, it appears that the loss of cell adhesion needed to promote tumor cell dissemination might be induced by the EWS/FLI oncogene itself rather than via an accumulation of stepwise mutations. PMID:23050043

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

2012-01-01

59

Peripheral neuroectodermal tumour of the kidney (Ewing’s sarcoma): Restaging with 18F-fluorodeoxyglucose (FDG)-PET/CT  

PubMed Central

Primitive peripheral neuroectodermal tumour and Ewing’s sarcoma (PNET/EWS) were originally described as two distinct pathologic entities, although both share common stem-cell precursor and unique chromosomal abnormality. Although its incidence has increased recently, its share in all sarcomas is 1%. It is usually seen in men and women in their twenties. We present a case of a 38-year-old woman with a left renal mass detected incidentally. Magnetic resonance imaging revealed a centrally located hypervascular renal mass with diameter of 6 cm with non-homogenous contrast enhancement containing necrotic and calcific areas. The patient was diagnosed as having PNET/EWS by histopathological examination following radical nephrectomy. Para-aortic lymph node metastasis was found on imaging by 18F-fluorodeoxyglucose (FDG)-positron-emission tomography/computed tomography (PET/CT). PMID:25624967

Ozturk, Hakan

2015-01-01

60

Giant extraosseous Ewing sarcoma of the lung in a young adolescent female--a case report.  

PubMed

Extraosseous Ewing sarcoma is a rare soft tissue tumour that is histologically indistinguishable from the bone Ewing sarcoma. The translocation involving chromosome 22 along with CD 99 expression is pathognomonic and is useful in differentiating from other small round cell tumours. Primary lung involvement by this malignant tumour is very uncommon and up to this date only ten cases have been reported. We report a further case in a 15 year-old-female who presented with a huge lung mass causing an opaque haemithorax. PMID:21667743

Siddiqui, Mohammed Azfar; Akhtar, Jamal; Shameem, Mohammad; Baneen, Ummul; Zaheer, Samreen; Shahid, Mohammad

2011-04-01

61

ZEB2 Represses the Epithelial Phenotype and Facilitates Metastasis in Ewing Sarcoma  

PubMed Central

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

Wiles, Elizabeth T.; Bell, Russell; Thomas, Dafydd; Beckerle, Mary

2013-01-01

62

Pre-clinical and clinical significance of heparanase in Ewing's sarcoma.  

PubMed

Heparanase is an endoglycosidase that specifically cleaves heparan sulphate side chains of heparan sulphate proteoglycans, activity that is strongly implicated in cell migration and invasion associated with tumour metastasis, angiogenesis and inflammation. Heparanase up-regulation was documented in an increasing number of human carcinomas, correlating with reduced post-operative survival rate and enhanced tumour 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 tumour 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 tumour 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. PMID:21029368

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

2011-09-01

63

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

PubMed

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

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

2013-05-01

64

Ewing sarcoma inhibition by disruption of EWSR1-FLI1 transcriptional activity and reactivation of p53.  

PubMed

Translocations involving ETS-transcription factors, most commonly leading to the EWSR1-FLI1 fusion protein, are the hallmark of Ewing sarcoma. Despite knowledge of this driving molecular event, an effective therapeutic strategy is lacking. To test potential treatment regimes, we established a novel Ewing sarcoma zebrafish engraftment model allowing time-effective, dynamic quantification of Ewing sarcoma progression and tumour burden in vivo, applicable for screening of single and combined compounds. In Ewing sarcoma the tumour-suppressor gene TP53 is commonly found to be wild-type, thus providing an attractive target for treatment. Here, we study TP53 wild-type (EW7, CADO-ES1 and TC32) and TP53-deleted (SK-N-MC) Ewing sarcoma cell lines to investigate the potentiating effect of p53 reactivation by Nutlin-3 on treatment with YK-4-279 to block transcriptional activity of EWSR1-FLI1 protein. Blocking EWSR1-FLI1 transcriptional activity reduced Ewing sarcoma tumour cell burden irrespective of TP53 status. We show that simultaneous YK-4-279 treatment with Nutlin-3 to stabilize p53 resulted in an additive inhibition of TP53 wild-type Ewing sarcoma cell burden, whilst not affecting TP53-deleted Ewing sarcoma cells. Improved inhibition of proliferation and migration by combinatorial treatment was confirmed in vivo by zebrafish engraftments. Mechanistically, both compounds together additively induced apoptosis of tumour cells in vivo by engaging distinct pathways. We propose reactivation of the p53 pathway in combination with complementary targeted therapy by EWSR1-FLI1 transcriptional activity disruption as a valuable strategy against p53 wild-type Ewing sarcoma. PMID:24974828

van der Ent, Wietske; Jochemsen, Aart G; Teunisse, Amina F A S; Krens, S F Gabriel; Szuhai, Karoly; Spaink, Herman P; Hogendoorn, Pancras C W; Snaar-Jagalska, B Ewa

2014-08-01

65

Megachemotherapy followed by autologous stem cell transplantation in children with Ewing's sarcoma.  

PubMed

Twenty-one children with high-risk Ewing's tumor received high-dose chemotherapy with a PBSCT. Aim of the study was evaluation of efficiency and safety of this procedure. All but three patients have meta-static disease at presentation. There were 11 females and the median age at diagnosis was 12 yr (range 4.5-18 yr). Megachemotherapy consisted of melphalan 140 mg/m2/busulfan 16 mg/kg in 12 patients, melphalan 140 mg2/treosulfan 10.0 g/m2 in two patients and melphalan with other drugs in seven patients. Eight of 11 patients transplanted in CR survived with a median follow-up 24 month (range 14-60) and probability of 2-year OS is 0.68 and DFS is 0.63. There was no severe regimen-related toxicity in this group. Children transplanted without remission died: Two of them due to transplant related causes and eight had progression of disease in a median time 7 month after PBSCT. Megachemotherapy with PBSCT is a safe procedure in children with Ewing's sarcoma in remission. Autologos transplantation in children with metastatic Ewing's sarcoma seems to improve their outcome. Patients with Ewing's sarcoma, resistant to conventional therapy and with recurrent disease did not benefit from megachemotherapy. New approaches such as anti-tumor vaccination or using of imatinib are reasonable to introduce in patients with relapsed or resistant to therapy Ewing's tumor. PMID:16176419

Drabko, Katarzyna; Zawitkowska-Klaczynska, Joanna; Wojcik, Beata; Choma, Marta; Zaucha-Prazmo, Agnieszka; Kowalczyk, Jerzy; Gorczynska, Ewa; Toporski, Jacek; Ka?wak, Krzysztof; Turkiewicz, Dominik; Chybicka, Alicja

2005-10-01

66

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

Microsoft Academic Search

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

Joel Tepper; Daniel Glaubiger; Allen Lichter; Judith Wackenhut; Eli Glatstein

1980-01-01

67

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

Cancer.gov

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

68

Ewing Sarcoma Eswa Protein Regulates Chondrogenesis of Meckel's Cartilage through Modulation of Sox9 in Zebrafish  

E-print Network

Ewing sarcoma is the second most common skeletal (bone and cartilage) cancer in adolescents, and it is characterized by the expression of the aberrant chimeric fusion gene EWS/FLI1. Wild-type EWS has been proposed to play a role in mitosis, splicing...

Merkes, Chris; Turkalo, Timothy K.; Wilder, Nicole; Park, Hyewon; Wenger, Luke W.; Lewin, Seth J.; Azuma, Mizuki

2015-01-24

69

Long noncoding RNA EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesis  

PubMed Central

Chromosomal translocation that results in fusion of the genes encoding RNA-binding protein EWS and transcription factor FLI1 (EWS-FLI1) is pathognomonic for Ewing sarcoma. EWS-FLI1 alters gene expression through mechanisms that are not completely understood. We performed RNA sequencing (RNAseq) analysis on primary pediatric human mesenchymal progenitor cells (pMPCs) expressing EWS-FLI1 in order to identify gene targets of this oncoprotein. We determined that long noncoding RNA-277 (Ewing sarcoma–associated transcript 1 [EWSAT1]) is upregulated by EWS-FLI1 in pMPCs. Inhibition of EWSAT1 expression diminished the ability of Ewing sarcoma cell lines to proliferate and form colonies in soft agar, whereas EWSAT1 inhibition had no effect on other cell types tested. Expression of EWS-FLI1 and EWSAT1 repressed gene expression, and a substantial fraction of targets that were repressed by EWS-FLI1 were also repressed by EWSAT1. Analysis of RNAseq data from primary human Ewing sarcoma further supported a role for EWSAT1 in mediating gene repression. We identified heterogeneous nuclear ribonucleoprotein (HNRNPK) as an RNA-binding protein that interacts with EWSAT1 and found a marked overlap in HNRNPK-repressed genes and those repressed by EWS-FLI1 and EWSAT1, suggesting that HNRNPK participates in EWSAT1-mediated gene repression. Together, our data reveal that EWSAT1 is a downstream target of EWS-FLI1 that facilitates the development of Ewing sarcoma via the repression of target genes. PMID:25401475

Marques Howarth, Michelle; Simpson, David; Ngok, Siu P.; Nieves, Bethsaida; Chen, Ron; Siprashvili, Zurab; Vaka, Dedeepya; Breese, Marcus R.; Crompton, Brian D.; Alexe, Gabriela; Hawkins, Doug S.; Jacobson, Damon; Brunner, Alayne L.; West, Robert; Mora, Jaume; Stegmaier, Kimberly; Khavari, Paul; Sweet-Cordero, E. Alejandro

2014-01-01

70

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

PubMed

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

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

2014-01-01

71

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

PubMed Central

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

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

2014-01-01

72

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. PMID:20490326

Jedlicka, Paul

2010-01-01

73

Primary subcutaneous spindle cell Ewing sarcoma with strong S100 expression and EWSR1-FLI1 fusion: a case report.  

PubMed

Ewing sarcoma is described classically as a small, round cell tumor of bone and soft tissue in children and young adults. Ewing sarcoma most often is characterized by a fusion of the Ewing sarcoma breakpoint region 1 (EWSR1) and the Friend leukemia virus integration 1 (FLI1) genes, forming an EWSR1-FLI1 fusion transcript. We report an exceptional case of primary subcutaneous Ewing sarcoma in a 16-year-old female composed entirely of spindle cells with focal fascicular growth and exhibiting strong, diffuse immunohistochemical reactivity for S100, unlike classic Ewing sarcoma. However, reverse transcription-polymerase chain reaction (RT-PCR) analysis confirmed the presence of a rare variant of the EWSR1-FLI1 fusion transcript, featuring fusion of EWSR1 exon 10 to FLI1 exon 6. To our knowledge, the combined histologic, molecular, and clinical features have not been reported previously in Ewing sarcoma, and raise a broad differential diagnosis emphasizing the importance of molecular techniques in the diagnosis of this tumor. PMID:24735198

Arnold, Michael A; Ballester, Leomar Y; Pack, Svetlana D; Abdullaev, Ziedulla; Merchant, Melinda; Tsokos, Maria G

2014-01-01

74

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))

1991-05-01

75

A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma.  

PubMed

Differential diagnosis of small round cell sarcomas (SRCSs) grouped under the Ewing sarcoma family of tumors (ESFT) can be a challenging situation for pathologists. Recent studies have revealed that some groups of Ewing-like sarcoma show typical ESFT morphology but lack any EWSR1-ETS gene fusions. Here we identified a novel gene fusion, CIC-FOXO4, in a case of Ewing-like sarcoma with a t(X;19)(q13;q13.3) translocation. The patient was a 63-year-old man who had an asymptomatic, 30-mm, well-demarcated, intramuscular mass in his right posterior neck, and imaging findings suggested a diagnosis of high-grade sarcoma. He was treated with complete resection and subsequent radiotherapy and chemotherapy. He was alive without local recurrence or distant metastasis 6 months after the operation. Histologic examination revealed SRCS with abundant desmoplastic fibrous stroma suggesting a desmoplastic small round cell tumor. Immunohistochemical analysis showed weak to moderate and partial staining for MIC2 (CD99) and WT1, respectively. High-throughput transcriptome sequencing revealed a gene fusion, and the genomic rearrangement between the CIC and FOXO4 genes was identified by fluorescence in situ hybridization. Aside from the desmoplastic stroma, the CIC-FOXO4 fusion sarcoma showed morphologic and immunohistochemical similarity to ESFT and Ewing-like sarcomas, including the recently described CIC-DUX4 fusion sarcoma. Although clinicopathologic analysis with additional cases is necessary, we conclude that CIC-FOXO4 fusion sarcoma is a new type of Ewing-like sarcoma that has a specific genetic signature. These findings have important implications for the differential diagnosis of SRCS. PMID:25007147

Sugita, Shintaro; Arai, Yasuhito; Tonooka, Akiko; Hama, Natsuko; Totoki, Yasushi; Fujii, Tomoki; Aoyama, Tomoyuki; Asanuma, Hiroko; Tsukahara, Tomohide; Kaya, Mitsunori; Shibata, Tatsuhiro; Hasegawa, Tadashi

2014-11-01

76

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

Cancer.gov

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

77

Preoperative evaluation and monitoring chemotherapy in patients with high-grade osteogenic and Ewing’s sarcoma: review of current imaging modalities  

Microsoft Academic Search

Diagnostic imaging is pivotal in the initial detection, characterization, staging and post-treatment follow-up of patients\\u000a with high-grade osteogenic and Ewing’s sarcoma. In the present review article, conventional and new imaging modalities are\\u000a discussed with regard to the monitoring of the effect of neoadjuvant chemotherapy in such patients. Presurgical monitoring\\u000a of response to chemotherapy may have an impact on modification of

Henk-Jan van der Woude; Johan L. Bloem; Pancras C. W. Hogendoorn

1998-01-01

78

Sarcomas.  

PubMed

Malignant bone tumors (osteosarcoma, Ewing sarcoma) and soft-tissue sarcomas (rhabdomyosarcoma, nonrhabdomyosarcoma) account for approximately 14% of childhood malignancies. Successful treatment of patients with sarcoma depends on a multidisciplinary approach to therapy, including oncology, surgery, radiation oncology, radiology, pathology, and physiatry. By combining systemic treatment with chemotherapy and primary tumor control using surgery and/or radiation, survival rates for localized disease range from 70% to 75%. However, children with metastatic or recurrent disease continue to have dismal outcomes. A better understanding of the biology underlying both bone and soft-tissue sarcomas is required to further improve outcomes for children with these tumors. PMID:25435119

HaDuong, Josephine H; Martin, Andrew A; Skapek, Stephen X; Mascarenhas, Leo

2015-02-01

79

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. PMID:24124617

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

2013-01-01

80

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. PMID:18537159

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

2008-01-01

81

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. PMID:21085683

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

2010-01-01

82

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

PubMed

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

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

2014-08-01

83

[Ewing's sarcoma and peripheral neuroectodermal tumors. Report of a case with laterothoracic localization].  

PubMed

The authors report the case of a 20-year old male patient presenting with a lateral thoracic tumour which at pathological examination looked like an extra-osseous Ewing's sarcoma. Strongly positive NSE immunolabeling suggested a recently described variant of this lesion: Askin's tumour. In 1979, F. B. Askin described a tumour made of round small cells, located on the side of the thorax and possibly derived from differentiated neuroectodermal tissue. Since that time, the ever wider use of electron microscopy and immunohistochemical methods has made it possible to demonstrate the existence of peripheral neuroectodermal tumours (PNETs) distinct from neuroblastomas. Askin's tumour being only, as it turned out, one of their clinical forms. Following a brief presentation of the clinical, pathological and therapeutic features of PNETs, the authors underline the great similarity between these tumours and Ewing's sarcoma. Owing to the successive discoveries of a cytogenetic abnormality common to these tumour--t(11;22)(q24;q12)--, of a similar expression of proto-oncogens and of identical neuroenzymatic characteristics, Ewing's syndrome can now be regarded as the most undifferentiated of all PNETs, probably arising from the postganglionic neuron of the parasympathetic system. PMID:2173115

Cuvelier, A; L'Her, P; Schill, H; Jancovici, R; Bassoulet, J; Vauterin, G; Allard, P

1990-01-01

84

Antagonizing Bcl-2 Family Members Sensitizes Neuroblastoma and Ewing’s Sarcoma to an Inhibitor of Glutamine Metabolism  

PubMed Central

Neuroblastomas (NBL) and Ewing’s sarcomas (EWS) together cause 18% of all pediatric cancer deaths. Though there is growing interest in targeting the dysregulated metabolism of cancer as a therapeutic strategy, this approach has not been fully examined in NBL and EWS. In this study, we first tested a panel of metabolic inhibitors and identified the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) as the most potent chemotherapeutic across all NBL and EWS cell lines tested. Myc, a master regulator of metabolism, is commonly overexpressed in both of these pediatric malignancies and recent studies have established that Myc causes cancer cells to become “addicted” to glutamine. We found DON strongly inhibited tumor growth of multiple tumor lines in mouse xenograft models. In vitro, inhibition of caspases partially reversed the effects of DON in high Myc expressing cell lines, but not in low Myc expressing lines. We further showed that induction of apoptosis by DON in Myc-overexpressing cancers is via the pro-apoptotic factor Bax. To relieve inhibition of Bax, we tested DON in combination with the Bcl-2 family antagonist navitoclax (ABT-263). In vitro, this combination caused an increase in DON activity across the entire panel of cell lines tested, with synergistic effects in two of the N-Myc amplified neuroblastoma cell lines. Our study supports targeting glutamine metabolism to treat Myc overexpressing cancers, such as NBL and EWS, particularly in combination with Bcl-2 family antagonists. PMID:25615615

Olsen, Rachelle R.; Mary-Sinclair, Michelle N.; Yin, Zhirong; Freeman, Kevin W.

2015-01-01

85

Ewing’s sarcoma family of tumors of the maxillary sinus: a case report of multidisciplinary examination enabling prompt diagnosis  

PubMed Central

There have been approximately 10 reports in English literature of cases of Ewing’s sarcoma family of tumors (EFT) arising in the maxillary sinus. In this location, some tumors mimic EFT, and are more frequently encountered. Herein, we present an additional case of an EFT originating in the maxillary sinus. The patient was a 15-year-old boy complaining of a non-tender swelling of the left cheek. Laboratory tests showed no abnormalities. Computed tomography and magnetic resonance imaging revealed a mass centered in the maxillary sinus with degeneration of the surrounding bones. Pathological examination along with flow cytometry and G-banding enabled the prompt diagnosis of EFT with the EWS/FLI1 fusion gene. The patient is planned to undergo chemotherapy. An origin in the head and neck and the presence of the typical EWS/FLI1, in conjunction with an opportunity for immediate treatment, may predict a relatively better prognosis for EFT in our case. PMID:25755803

Tajima, Shogo; Ohkubo, Aki; Yoshida, Matsumi; Koda, Kenji; Nameki, Ichirota

2015-01-01

86

Arsenic trioxide inhibits Ewing's sarcoma cell invasiveness by targeting p38(MAPK) and c-Jun N-terminal kinase.  

PubMed

Ewing's sarcoma is the second most frequent primary malignant bone tumor, mainly affecting children and young adults. The notorious metastatic capability of this tumor aggravates patient mortality and remains a problem to be overcome. We investigated the effect of arsenic trioxide (As?O?) on the metastasis capability of Ewing's sarcoma cells. We performed 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazolium bromide assays to choose appropriate concentrations of As?O? for the experiments. Migration, invasion, and adhesion assays were performed to assess the effect of As?O? on the metastasis of Ewing's sarcoma. Immunofluorescent staining was used to observe cytoskeleton reorganization in Ewing's sarcoma cells treated with As?O?. Changes in matrix metalloproteinase-9 expression and the mitogen-activated protein kinase (MAPK) pathway were investigated using western blot. Inhibitors of p38(MAPK) (sb202190) and c-Jun NH?-terminal kinase (JNK, sp600125) were used in invasion assays to determine the effect of p38(MAPK) and JNK. We found that As?O? may markedly inhibit the migration and invasion capacity of Ewing's sarcoma cells with structural rearrangements of the actin cytoskeleton. The expressions of matrix metalloproteinase-9, phosphor-p38(MAPK), and phosphor-JNK were suppressed by As?O? treatment in a dose-dependent manner. The inhibitors of p38(MAPK) (sb202190) and JNK (sp600125) enhanced the inhibition induced by As?O?, which was counteracted by anisomycin, an activating agent of p38(MAPK) and JNK. Taken together, our results demonstrate that As?O? can inhibit the metastasis capability of RD-ES and A-673 cells and may have new therapeutic value for Ewing's sarcoma. PMID:21946058

Zhang, Shuai; Guo, Wei; Ren, Ting-Ting; Lu, Xin-Chang; Tang, Guo-Qing; Zhao, Fu-Long

2012-01-01

87

EWS-FLI1 inhibits TNF{alpha}-induced NF{kappa}B-dependent transcription in Ewing sarcoma cells  

SciTech Connect

Research highlights: {yields} EWS-FLI1 interferes with TNF-induced activation of NF{kappa}B in Ewing sarcoma cells. {yields} EWS-FLI1 knockdown in Ewing sarcoma cells increases TNF-induced NF{kappa}B binding to DNA. {yields} EWS-FLI1 reduces TNF-stimulated NF{kappa}B-dependent transcriptional activation. {yields} Constitutive NF{kappa}B activity is not affected by EWS-FLI1. {yields} EWS-FLI1 physically interacts with NF{kappa}B p65 in vivo. -- Abstract: Ewing sarcoma is primarily caused by a t(11;22) chromosomal translocation encoding the EWS-FLI1 fusion protein. To exert its oncogenic function, EWS-FLI1 acts as an aberrant transcription factor, broadly altering the gene expression profile of tumor cells. Nuclear factor-kappaB (NF{kappa}B) is a tightly regulated transcription factor controlling cell survival, proliferation and differentiation, as well as tumorigenesis. NF{kappa}B activity is very low in unstimulated Ewing sarcoma cells, but can be induced in response to tumor necrosis factor (TNF). We wondered whether NF{kappa}B activity could be modulated by EWS-FLI1 in Ewing sarcoma. Using a knockdown approach in Ewing sarcoma cells, we demonstrated that EWS-FLI1 has no influence on NF{kappa}B basal activity, but impairs TNF-induced NF{kappa}B-driven transcription, at least in part through inhibition of NF{kappa}B binding to DNA. We detected an in vivo physical interaction between the fusion protein and NF{kappa}B p65, which could mediate these effects. Our findings suggest that, besides directly controlling the activity of its primary target promoters, EWS-FLI1 can also indirectly influence gene expression in tumor cells by modulating the activity of key transcription factors such as NF{kappa}B.

Lagirand-Cantaloube, Julie, E-mail: julie.cantaloube@crbm.cnrs.fr [UMR8113 CNRS, LBPA, Ecole Normale Superieure, Cachan (France)] [UMR8113 CNRS, LBPA, Ecole Normale Superieure, Cachan (France); Laud, Karine, E-mail: karine.laud@curie.fr [U830 INSERM, Institut Curie, Paris (France) [U830 INSERM, Institut Curie, Paris (France); Institut Curie, Genetique et biologie des cancers, Paris (France); Lilienbaum, Alain, E-mail: alain.lilienbaum@univ-paris-diderot.fr [EA300 Universite Paris 7, Stress et pathologies du cytosquelette, Paris (France)] [EA300 Universite Paris 7, Stress et pathologies du cytosquelette, Paris (France); Tirode, Franck, E-mail: franck.tirode@curie.fr [U830 INSERM, Institut Curie, Paris (France) [U830 INSERM, Institut Curie, Paris (France); Institut Curie, Genetique et biologie des cancers, Paris (France); Delattre, Olivier, E-mail: olivier.delattre@curie.fr [U830 INSERM, Institut Curie, Paris (France) [U830 INSERM, Institut Curie, Paris (France); Institut Curie, Genetique et biologie des cancers, Paris (France); Auclair, Christian, E-mail: auclair@lbpa.ens-cachan.fr [UMR8113 CNRS, LBPA, Ecole Normale Superieure, Cachan (France)] [UMR8113 CNRS, LBPA, Ecole Normale Superieure, Cachan (France); Kryszke, Marie-Helene, E-mail: kryszke@lbpa.ens-cachan.fr [UMR8113 CNRS, LBPA, Ecole Normale Superieure, Cachan (France)] [UMR8113 CNRS, LBPA, Ecole Normale Superieure, Cachan (France)

2010-09-03

88

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

PubMed Central

The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p?=?0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p?=?0.15) and a modest decrease in overall survival (p?=?0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing. PMID:25010205

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

2014-01-01

89

The role of surgical therapy in patients with nonmetastatic Ewing's sarcoma of the limbs.  

PubMed

Of 131 patients with primary Ewing's sarcoma (ES) with extremity locations, treated between April 1972 and May 1987, 13 had amputation; 56 had a local resection with 31 (55%) requiring radiation therapy (RT) as an adjuvant to local therapy. Sixty-two of 131 patients (47%) had RT only. Local recurrences were reported in 5% of patients treated with surgery alone, 1% of the group treated with surgery and radiation therapy, 24% of patients treated with radiation therapy alone (46% for cesium-radiation therapy, and 12% with cobalt-radiation therapy). PMID:8425351

Toni, A; Neff, J R; Sudanese, A; Ciaroni, D; Bacci, G; Picci, P; Barbieri, E; Campanacci, M; Giunti, A

1993-01-01

90

Establishing a panel of chemo-resistant mesothelioma models for investigating chemo-resistance and identifying new treatments for mesothelioma  

PubMed Central

Mesothelioma is inherently chemo-resistant with only 50% of patients responding to the standard of care treatments, and consequently it has a very grim prognosis. The aim of this study was to establish a panel of chemo-resistant mesothelioma models with clinically relevant levels of resistance as tools for investigating chemo-resistance and identifying new treatments for mesothelioma. Chemo-resistant cell lines were established in vitro and characterized in vivo using syngeneic Fischer rats. Tumors derived from all chemo-resistant cell lines were immunohistochemically classified as mesothelioma. Homozygous deletion of p16INK4A/p14ARF and increased expression of several ATP-binding cassette transporters were demonstrated, consistent with findings in human mesothelioma. Further, the acquisition of chemo-resistance in vitro resulted in changes to tumor morphology and overall survival. In conclusion, these models display many features corresponding with the human disease, and provide the first series of matched parental and chemo-resistant models for in vitro and in vivo mesothelioma studies. PMID:25141917

Hudson, Amanda L.; Weir, Chris; Moon, Elizabeth; Harvie, Rozelle; Klebe, Sonja; Clarke, Stephen J.; Pavlakis, Nick; Howell, Viive M.

2014-01-01

91

APLP2 regulates the expression of MHC class I molecules on irradiated Ewing’s sarcoma cells  

PubMed Central

Ewing’s sarcoma (EWS) is a pediatric cancer that is conventionally treated by surgery, chemotherapy, and radiation therapy. Innovative immunotherapies to treat EWS are currently under development. Unfortunately for EWS patients, when the disease is found to be resistant to current therapeutic approaches, the prognosis is predictably grim. Radiation therapy and immunotherapy could potentially synergize in the eradication of EWS, as some studies have previously shown that irradiation increases the presence of immune receptors, including MHC class I molecules, on the surface of tumor cells. However, EWS cells have been reported to express low levels of MHC class I molecules, a phenotype that would inhibit T-cell mediated lysis. We have previously demonstrated that the transgene-driven overexpression of amyloid ? (A4) precursor-like protein 2 (APLP2) reduces the expression of MHC class I molecules on the surface of human cervical carcinoma HeLa cells. We thus examined whether endogenously expressed APLP2 downregulates MHC class I expression on EWS cells, particularly upon irradiation. We found that irradiation induces the relocalization of APLP2 and MHC class I molecules on the surface of EWS cells, redistributing cells from subpopulations with relatively low APLP2 and high MHC class I into subpopulations with relatively high APLP2 and low MHC class I surface expression. Consistent with these findings, the transfection of an APLP2-targeting siRNA into EWS cells increased MHC class I expression on the cell surface. Furthermore, APLP2 was found by co-immunoprecipitation to bind to MHC class I molecules. Taken together, these findings suggest that APLP2 inhibits MHC class I expression on the surface of irradiated EWS cells by a mechanism that involves APLP2/MHC class I interactions. Thus, therapeutic strategies that limit APLP2 expression may boost the ability of T cells to recognize and eradicate EWS in patients. PMID:24353913

Peters, Haley L; Yan, Ying; Solheim, Joyce C

2013-01-01

92

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

PubMed Central

Background Ewing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties. Methods Invasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 ?g/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology. Results ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and ?9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases. Conclusion These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs. PMID:24612486

2014-01-01

93

Stereotactic Body Radiotherapy for Metastatic and Recurrent Ewing Sarcoma and Osteosarcoma  

PubMed Central

Background. Radiotherapy has been utilized for metastatic and recurrent osteosarcoma and Ewing sarcoma (ES), in order to provide palliation and possibly prolong overall or progression-free survival. Stereotactic body radiotherapy (SBRT) is convenient for patients and offers the possibility of increased efficacy. We report our early institutional experience using SBRT for recurrent and metastatic osteosarcoma and Ewing sarcoma. Methods. We reviewed all cases of osteosarcoma or ES treated with SBRT between 2008 and 2012. Results. We identified 14 patients with a total of 27 lesions from osteosarcoma (n = 19) or ES (n = 8). The median total curative/definitive SBRT dose delivered was 40?Gy in 5 fractions (range, 30–60?Gy in 3–10 fractions). The median total palliative SBRT dose delivered was 40?Gy in 5 fractions (range, 16–50?Gy in 1–10 fractions). Two grade 2 and 1 grade 3 late toxicities occurred, consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy. Toxicity was seen in the settings of concurrent chemotherapy and reirradiation. Conclusions. This descriptive report suggests that SBRT may be a feasible local treatment option for patients with osteosarcoma and ES. However, significant toxicity can result, and thus systematic study is warranted to clarify efficacy and characterize long-term toxicity. PMID:25548538

Brown, Lindsay C.; Lester, Rachael A.; Grams, Michael P.; Haddock, Michael G.; Olivier, Kenneth R.; Arndt, Carola A. S.; Rose, Peter S.; Laack, Nadia N.

2014-01-01

94

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

E-print Network

Ewing sarcoma (ES) is an aggressive malignancy driven by an oncogenic fusion protein, EWS-FLI1. Neuropeptide Y (NPY), and two of its receptors, Y1R and Y5R are up-regulated by EWS-FLI1 and abundantly expressed in ES cells. ...

Lu, Congyi

95

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

PubMed Central

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 the growth inhibition, we examined the changes of signal transducing proteins by immunoblot analysis in Ewing's sarcoma cells stably expressing antisense EWS-Fli-1 transcripts. Western blotting of the cell proteins revealed that expressions of phospholipase C?2 and ?3 (PLC?2, PLC?3), and also protein kinase C ? and ? (PKC?, ?) were significantly reduced by transfecting with antisense EWS-Fli-1. The inositol phosphates production by bradykinin (BK), but not platelet-derived growth factor (PDGF), was suppressed in these cells. These results suggest that the PLC?2 and PLC?3 may play a role in tumour proliferation in Ewing's sarcoma cells. © 2000 Cancer Research Campaign PMID:10638960

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

1999-01-01

96

Extra-osseous Ewing's sarcoma of sciatic nerve masquerading as an infected hemangioma: A rare case report  

PubMed Central

Extra-osseous Ewing's Sarcoma (EES) arising from the peripheral nerve is rarely reported in children. Here, we report an instance of EES arising from the left sciatic nerve mimicking an infected hemangioma. This case highlights the need for a high index of suspicion and early histological diagnosis to avoid diagnostic delay. PMID:25336807

Dhua, Anjan K; Bharathi, Ravindhra; Kiran, Chokka Mahesh; Lingam, Pappu Paramartha; Joshi, Manoj

2014-01-01

97

Targeted imaging of Ewing sarcoma in preclinical models using a 64Cu-labeled anti-CD99 antibody  

PubMed Central

Purpose Ewing sarcoma is a tumor of the bone and soft tissue characterized by diffuse cell membrane expression of CD99 (MIC2). Single-site, surgically resectable disease is associated with an excellent 5-year event-free survival; conversely, patients with distant metastases have a poor prognosis. Non-invasive imaging is the standard approach to identifying sites of metastatic disease. We sought to develop a CD99-targeted imaging agent for staging Ewing sarcoma and other CD99-expressing tumors. Experimental Design We identified a CD99 antibody with highly specific binding in vitro and labeled this antibody with 64Cu. Mice with either subcutaneous Ewing sarcoma xenograft tumors or micrometastases were imaged with the 64Cu-labeled anti-CD99 antibody and these results were compared to conventional MRI and FDG-PET imaging. Results 64Cu-labeled anti-CD99 antibody demonstrated high avidity for the CD99 positive subcutaneous tumors, with a high tumor-to-background ratio, greater than that demonstrated with FDG-PET. Micrometastases, measuring 1-2 mm on MRI, were not detected with FDG-PET but readily visualized with the 64Cu-labeled anti-CD99 antibody. Probe biodistribution studies demonstrated high specificity of the probe for CD99 positive tumors. Conclusions 64Cu-labeled anti-CD99 antibody can detect subcutaneous Ewing sarcoma tumors and metastatic sites with high sensitivity, outperforming FDG-PET in preclinical studies. This targeted radiotracer may have important implications for the diagnosis, surveillance, and treatment of Ewing sarcoma. Similarly, it may impact the management of other CD99 positive tumors. PMID:24218512

O'Neill, Allison F.; Dearling, Jason L.J.; Wang, Yuchuan; Tupper, Tanya; Sun, Yanping; Aster, Jon C.; Calicchio, Monica L.; Perez-Atayde, Antonio R.; Packard, Alan; Kung, Andrew L.

2014-01-01

98

Ewing Sarcoma with Novel Translocation t(2;16) Producing an In-Frame Fusion of FUS and FEV  

PubMed Central

Ewing family tumors are molecularly characterized by expression of chimeric transcripts generated by specific chromosomal translocations, most commonly involving fusion of the EWS gene to a member of the ETS family of transcription factors (including FLI1, ERG, ETV1, E1AF, and FEV). Approximately 85% of reported cases of Ewing sarcoma bear an EWS-FLI1 fusion. In rare cases, FUS can substitute for EWS, with translocation t(16;21)(p11;q24) producing a FUS-ERG fusion with no EWS rearrangement. We report a case of Ewing sarcoma, presenting as a pathological fracture of the distal clavicle in a 33-year-old male, in which cytogenetic analysis revealed a single t(2;16)(q35;p11) balanced translocation. Fluorescence in situ hybridization using a commercially available diagnostic probe was negative for an EWS gene rearrangement; instead, break-apart fluorescence in situ hybridization probes for FUS and FEV were positive for a translocation involving these genes. Cloning and sequencing of the breakpoint region demonstrated an in-frame fusion of FUS to FEV. In conclusion, this represents the first reported case of Ewing family tumors demonstrating a variant translocation involving FUS and FEV and highlights the need to consider alternative permutations of fusion partners for molecular diagnosis of sarcomas. PMID:17620387

Ng, Tony L.; O’Sullivan, Maureen J.; Pallen, Catherine J.; Hayes, Malcolm; Clarkson, Paul W.; Winstanley, Mark; Sorensen, Poul H.B.; Nielsen, Torsten O.; Horsman, Douglas E.

2007-01-01

99

Stable interference of EWS–FLI1 in an Ewing sarcoma cell line impairs IGF-1\\/IGF-1R signalling and reveals TOPK as a new target  

Microsoft Academic Search

BACKGROUND: Ewing sarcoma is a paradigm of solid tumour -bearing chromosomal translocations resulting in fusion proteins that act as deregulated transcription factors. Ewing sarcoma translocations fuse the EWS gene with an ETS transcription factor, mainly FLI1. Most of the EWS–FLI1 target genes still remain unknown and many have been identified in heterologous model systems.METHODS: We have developed a stable RNA

D Herrero-Martín; D Osuna; J L Ordóñez; V Sevillano; A S Martins; C Mackintosh; M Campos; J Madoz-Gúrpide; A P Otero-Motta; G Caballero; A T Amaral; D H Wai; Y Braun; M Eisenacher; K-L Schaefer; C Poremba; E de Alava

2009-01-01

100

Sequential half-body irradiation as systemic treatment of progressive Ewing sarcoma  

SciTech Connect

Sequential half-body irradiation (HBI) to be delivered in two session was used in 18 consecutive patients with metastastic Ewing sarcoma who relapsed after radiotherapy and multidrug chemotherapy. The HIB program to both upper and lower hemi body was completed in 11 patients (61%). The remaining 7 patients received only one single treatment of HBI because of relapse before the completion of the treatment program. In 20 of the 29 sessions HBI was employed to treat overt metastases. The overall objective response rate was 50%. Six of 18 patients (33%) are alive from 4 to 27 months, 3 of them without evidence of disease. No severe toxicity was observed. HBI as systemic treatment was more effective in patients who relapsed while off chemotherapy, with metatases confined to the lungs or to one single bone segment.

Lombardi, F.; Lattuada, A.; Gasparini, M.; Gianni, C.; Marchesini, R.

1982-10-01

101

Sequential half-body irradiation as systemic treatment of progressive Ewing sarcoma  

SciTech Connect

Sequential half-body irradiation (HBI) to be delivered in two sessions was used in 18 consecutive patients with metastatic Ewing sarcoma who relapsed after radiotherapy and multidrug chemotherapy. The HBI program to both upper and lower hemi body was completed in 11 patients (61%). The remaining 7 patients received only one single treatment of HBI because of relapse before the completion of the treatment program. In 20 of the 29 sessions HBI was employed to treat overt metastases. The overall objective response rate was 50%. Six of 18 patients (33%) are alive from 4 to 27 months, 3 of them without evidence of disease. No severe toxicity was observed. HBI as systemic treatment was more effective in patients who relapsed while off chemotherapy, with metastases confined to the lungs or to one single bone segment.

Lombardi, F.; Lattuada, A.; Gasparini, M.; Gianni, C.; Marchesini, R.

1982-10-01

102

Nanodiamond as a vector for siRNA delivery to Ewing sarcoma cells.  

PubMed

The ability of diamond nanoparticles (nanodiamonds, NDs) to deliver small interfering RNA (siRNA) into Ewing sarcoma cells is investigated with a view to the possibility of in-vivo anticancer nucleic-acid drug delivery. siRNA is adsorbed onto NDs that are coated with cationic polymer. Cell uptake of NDs is demonstrated by taking advantage of the NDs' intrinsic fluorescence from embedded color-center defects. Cell toxicity of these coated NDs is shown to be low. Consistent with the internalization efficacy, a specific inhibition of EWS/Fli-1 gene expression is shown at the mRNA and protein level by the ND-vectorized siRNA in a serum-containing medium. PMID:21913326

Alhaddad, Anna; Adam, Marie-Pierre; Botsoa, Jacques; Dantelle, Géraldine; Perruchas, Sandrine; Gacoin, Thierry; Mansuy, Christelle; Lavielle, Solange; Malvy, Claude; Treussart, François; Bertrand, Jean-Rémi

2011-11-01

103

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

PubMed Central

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

2014-01-01

104

Epigenetic reprogramming and re-differentiation of a Ewing sarcoma cell line  

PubMed Central

Developmental reprogramming techniques have been used to generate induced pluripotent stem (iPS) cells from both normal and malignant cells. The derivation of iPS cells from cancer has the potential to provide a unique scientific tool to overcome challenges associated with the establishment of cell lines from primary patient samples and a readily expandable source of cells that may be used to model the initial disease. In the current study we developmentally reprogrammed a metastatic Ewing sarcoma (EWS) cell line to a meta-stable embryonic stem (ES)-like state sharing molecular and phenotypic features with previously established ES and iPS cell lines. EWS-iPS cells exhibited a pronounced drug resistant phenotype despite persistent expression of the oncogenic EWS-FLI1 fusion transcript. This included resistance to compounds that specifically target downstream effector pathways of EWS-FLI1, such as MAPK/ERK and PI3K/AKT, which play an important role in EWS pathogenesis. EWS-iPS cells displayed tumor initiation abilities in vivo and formed tumors exhibiting characteristic Ewing histopathology. In parallel, EWS-iPS cells re-differentiated in vitro recovered sensitivity to molecularly targeted chemotherapeutic agents, which reiterated pathophysiological features of the cells from which they were derived. These data suggest that EWS-iPS cells may provide an expandable disease model that could be used to investigate processes modulating oncogenesis, metastasis, and chemotherapeutic resistance in EWS. PMID:25806369

Moore, Joseph B.; Loeb, David M.; Hong, Kyung U.; Sorensen, Poul H.; Triche, Timothy J.; Lee, David W.; Barbato, Michael I.; Arceci, Robert J.

2015-01-01

105

Pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor, alone and in combination with bortezomib in Ewing sarcoma  

PubMed Central

Ewing sarcoma is characterized by multiple deregulated pathways that mediate cell survival and proliferation. Heat shock protein 90 (HSP90) is a critical component of the multi-chaperone complexes that regulate the disposition and activity of a large number of proteins involved in cell-signaling systems. We tested the efficacy of PU-H71, a novel HSP90 inhibitor in Ewing sarcoma cell lines, primary samples, benign mesenchymal stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis and reverse phase protein array in Ewing cell lines and in vivo experiments in NSG and nude mice using the A673 cell line. We noted a significant therapeutic window in the activity of PU-H71 against Ewing cell lines and benign cells. PU-H71 treatment resulted in G2/M phase arrest. Exposure to PU-H71 resulted in depletion of critical proteins including AKT, pERK, RAF-1, c-MYC, c-KIT, IGF1R, hTERT and EWS-FLI1 in Ewing cell lines. Our results indicated that Ewing sarcoma tumor growth and the metastatic burden were significantly reduced in the mice injected with PU-H71 compared to the control mice. We also investigated the effects of bortezomib, a proteasome inhibitor, alone and in combination with PU-H71 in Ewing sarcoma. Combination index (CI)-Fa plots and normalized isobolograms indicated synergism between PU-H71 and bortezomib. Ewing sarcoma xenografts were significantly inhibited when mice were treated with the combination compared to vehicle or either drug alone. This provides a strong rationale for clinical evaluation of PU-H71 alone and in combination with bortezomib in Ewing sarcoma. PMID:24388362

Ambati, Srikanth R.; Lopes, Eloisi Caldas; Kosugi, Kohji; Mony, Ullas; Zehir, Ahmet; Shah, Smit K.; Taldone, Tony; Moreira, Andre L.; Meyers, Paul A.; Chiosis, Gabriela; Moore, Malcolm A.S.

2014-01-01

106

EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma.  

PubMed

The aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation. PMID:25453903

Riggi, Nicolò; Knoechel, Birgit; Gillespie, Shawn M; Rheinbay, Esther; Boulay, Gaylor; Suvà, Mario L; Rossetti, Nikki E; Boonseng, Wannaporn E; Oksuz, Ozgur; Cook, Edward B; Formey, Aurélie; Patel, Anoop; Gymrek, Melissa; Thapar, Vishal; Deshpande, Vikram; Ting, David T; Hornicek, Francis J; Nielsen, G Petur; Stamenkovic, Ivan; Aryee, Martin J; Bernstein, Bradley E; Rivera, Miguel N

2014-11-10

107

Peripheral primitive neuroectodermal tumour and extra-osseous Ewing's sarcoma; a histological, immunohistochemical and DNA flow cytometric study  

Microsoft Academic Search

Although peripheral primitive neuroectodermal tumour (pPNET) and extra-osseous Ewing's sarcoma (EES) are thought to be closely related neoplasms, their clinical behaviour differs considerably. To determine the clinical relevance of the Schmidt classification scheme for differentiating pPNET and EES, 20 tumour specimens of poorly differentiated round cell tumours were evaluated. In addition, the diagnostic value of several neural markers and the

M. Brinkhuis; L. C. D. Wijnaendts; J. C. Linden; J. P. A. Baak; C. J. L. M. Meijer; A. J. M. Unnik; P. A. Voûte

1995-01-01

108

High risk Ewing's sarcomas. Effectiveness and toxicity of a regimen designed for children and used in adults  

Microsoft Academic Search

Introduction  Ewing's sarcoma is a highly malignant small round-cell tumor arising primarily from bone. Adults with this neoplasm have a\\u000a poorer survival than that of children. The Spanish Society of Paediatric Oncology (SEOP) recommends that high-risk patients\\u000a be treated with a combination of 5 different drugs (EVAIA schedule). The objective of this study is to evaluate response,\\u000a overall survival, dose intensity

Ángel Segura Huerta; José A. Pérez-Fidalgo; Aparicio Urtasun; Pedro López-Tendero; Ángel Guerrero Zotano; Joaquín Montalar Salcedo

2004-01-01

109

Characterization of Human Mesenchymal Stem Cells from Ewing Sarcoma Patients. Pathogenetic Implications  

PubMed Central

Background Ewing Sarcoma (EWS) is a mesenchymal-derived tumor that generally arises in bone and soft tissue. Intensive research regarding the pathogenesis of EWS has been insufficient to pinpoint the early events of Ewing sarcomagenesis. However, the Mesenchymal Stem Cell (MSC) is currently accepted as the most probable cell of origin. Materials and Methods In an initial study regarding a deep characterization of MSC obtained specifically from EWS patients (MSC-P), we compared them with MSC derived from healthy donors (MSC-HD) and EWS cell lines. We evaluated the presence of the EWS-FLI1 gene fusion and EWSR1 gene rearrangements in MSC-P. The presence of the EWS transcript was confirmed by q-RT-PCR. In order to determine early events possibly involved in malignant transformation, we used a multiparameter quantitative strategy that included both MSC immunophenotypic negative/positive markers, and EWS intrinsic phenotypical features. Markers CD105, CD90, CD34 and CD45 were confirmed in EWS samples. Results We determined that MSC-P lack the most prevalent gene fusion, EWSR1-FLI1 as well as EWSR1 gene rearrangements. Our study also revealed that MSC-P are more alike to MSC-HD than to EWS cells. Nonetheless, we also observed that EWS cells had a few overlapping features with MSC. As a relevant example, also MSC showed CD99 expression, hallmark of EWS diagnosis. However, we observed that, in contrast to EWS cells, MSC were not sensitive to the inhibition of CD99. Conclusions In conclusion, our results suggest that MSC from EWS patients behave like MSC-HD and are phenotypically different from EWS cells, thus raising important questions regarding MSC role in sarcomagenesis. PMID:24498265

Amaral, Ana Teresa; Manara, Maria Cristina; Berghuis, Dagmar; Ordóñez, José Luis; Biscuola, Michele; Lopez-García, Maria Angeles; Osuna, Daniel; Lucarelli, Enrico; Alviano, Francesco; Lankester, Arjan; Scotlandi, Katia; de Álava, Enrique

2014-01-01

110

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

SciTech Connect

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

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

2011-09-01

111

Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma.  

PubMed

The developmental receptor NOTCH plays an important role in various human cancers as a consequence of oncogenic mutations. Here we describe a novel mechanism of NOTCH-induced tumor suppression involving modulation of the deacetylase SIRT1, providing a rationale for the use of SIRT1 inhibitors to treat cancers where this mechanism is inactivated because of SIRT1 overexpression. In Ewing sarcoma cells, NOTCH signaling is abrogated by the driver oncogene EWS-FLI1. Restoration of NOTCH signaling caused growth arrest due to activation of the NOTCH effector HEY1, directly suppressing SIRT1 and thereby activating p53. This mechanism of tumor suppression was validated in Ewing sarcoma cells, B-cell tumors, and human keratinocytes where NOTCH dysregulation has been implicated pathogenically. Notably, the SIRT1/2 inhibitor Tenovin-6 killed Ewing sarcoma cells in vitro and prohibited tumor growth and spread in an established xenograft model in zebrafish. Using immunohistochemistry to analyze primary tissue specimens, we found that high SIRT1 expression was associated with Ewing sarcoma metastasis and poor prognosis. Our findings suggest a mechanistic rationale for the use of SIRT1 inhibitors being developed to treat metastatic disease in patients with Ewing sarcoma. PMID:25281719

Ban, Jozef; Aryee, Dave N T; Fourtouna, Argyro; van der Ent, Wietske; Kauer, Max; Niedan, Stephan; Machado, Isidro; Rodriguez-Galindo, Carlos; Tirado, Oscar M; Schwentner, Raphaela; Picci, Piero; Flanagan, Adrienne M; Berg, Verena; Strauss, Sandra J; Scotlandi, Katia; Lawlor, Elizabeth R; Snaar-Jagalska, Ewa; Llombart-Bosch, Antonio; Kovar, Heinrich

2014-11-15

112

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

PubMed Central

Most Ewing's sarcomas harbor chromosomal translocations that encode fusions between EWS and ETS family members. The most common fusion, EWS/FLI, consists of an EWSR1-derived strong transcriptional activation domain fused, in frame, to the DNA binding domain-containing portion of FLI1. EWS/FLI functions as an aberrant transcription factor to regulate genes that mediate the oncogenic phenotype of Ewing's sarcoma. One of these regulated genes, NR0B1, encodes a co-repressor protein, and likely plays a transcriptional role in tumorigenesis. However, the genes that NR0B1 regulates and the transcription factors it interacts with in Ewing's sarcoma are largely unknown. We used transcriptional profiling and chromatin immunoprecipitation to identify genes that are regulated by NR0B1, and compared these data to similar data for EWS/FLI. While the transcriptional profile overlapped as expected, we also found that the genome-wide localization of NR0B1and EWS/FLI overlapped as well, suggesting that they regulate some genes coordinately. Further analysis revealed that NR0B1 and EWS/FLI physically interact. This protein-protein interaction is likely to be relevant for Ewing's sarcoma development because mutations in NR0B1 that disrupt the interaction have transcriptional consequences and also abrogate oncogenic transformation. Taken together, these data suggest that EWS/FLI and NR0B1 physically interact, coordinately modulate gene expression, and mediate the transformed phenotype of Ewing's sarcoma. PMID:19920188

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

2009-01-01

113

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

PubMed Central

Background A wide range of techniques is now available for analyzing regulatory networks. Nonetheless, most of these techniques fail to interpret large-scale transcriptional data at the post-translational level. Results We address the question of using large-scale transcriptomic observation of a system perturbation to analyze a regulatory network which contained several types of interactions - transcriptional and post-translational. Our method consisted of post-processing the outputs of an open-source tool named BioQuali - an automatic constraint-based analysis mimicking biologist's local reasoning on a large scale. The post-processing relied on differences in the behavior of the transcriptional and post-translational levels in the network. As a case study, we analyzed a network representation of the genes and proteins controlled by an oncogene in the context of Ewing's sarcoma. The analysis allowed us to pinpoint active interactions specific to this cancer. We also identified the parts of the network which were incomplete and should be submitted for further investigation. Conclusions The proposed approach is effective for the qualitative analysis of cancer networks. It allows the integrative use of experimental data of various types in order to identify the specific information that should be considered a priority in the initial - and possibly very large - experimental dataset. Iteratively, new dataset can be introduced into the analysis to improve the network representation and make it more specific. PMID:21044309

2010-01-01

114

CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis  

PubMed Central

Ewing sarcoma (EWS) is an aggressive bone tumor of uncertain cellular origin. CD99 is a membrane protein that is expressed in most cases of EWS, although its function in the disease is unknown. Here we have shown that endogenous CD99 expression modulates EWS tumor differentiation and malignancy. We determined that knocking down CD99 expression in human EWS cell lines reduced their ability to form tumors and bone metastases when xenografted into immunodeficient mice and diminished their tumorigenic characteristics in vitro. Further, reduction of CD99 expression resulted in neurite outgrowth and increased expression of ?-III tubulin and markers of neural differentiation. Analysis of a panel of human EWS cells revealed an inverse correlation between CD99 and H-neurofilament expression, as well as an inverse correlation between neural differentiation and oncogenic transformation. As knockdown of CD99 also led to an increase in phosphorylation of ERK1/2, we suggest that the CD99-mediated prevention of neural differentiation of EWS occurs through MAPK pathway modulation. Together, these data indicate a new role for CD99 in preventing neural differentiation of EWS cells and suggest that blockade of CD99 or its downstream molecular pathway may be a new therapeutic approach for EWS. PMID:20197622

Rocchi, Anna; Manara, Maria Cristina; Sciandra, Marika; Zambelli, Diana; Nardi, Filippo; Nicoletti, Giordano; Garofalo, Cecilia; Meschini, Stefania; Astolfi, Annalisa; Colombo, Mario P.; Lessnick, Stephen L.; Picci, Piero; Scotlandi, Katia

2010-01-01

115

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

PubMed Central

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

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

2013-01-01

116

Intercohort Gene Expression Co-analysis Reveals Chemokine Receptors as Prognostic Indicators in Ewing's Sarcoma  

PubMed Central

Purpose We report a novel analytical method, named intercohort co-analysis or Ican, which aids in the discovery of genes with predictive value for the progression or outcome of diseases from small-size cohorts. We tested this premise in Ewing's sarcoma (ES), a highly metastatic cancer of bone and soft tissues that lacks validated molecular metastasis and prognostic indicators. Experimental Design To uncover genes significantly expressed in ES patient subsets, we first determined a non-arbitrary gene expression significance cutoff based on expression levels in validated expressing and non-expressing tissues. We next searched for genes that were consistently significantly expressed in several ES cohort and cell line datasets. Significantly expressed genes were independently validated by quantitative RT-PCR in an additional ES cohort. Results Analysis of ES cohorts revealed marked intercohort gene expression variability. After filtering out the intercohort variability, CXCR4 and CXCR7 were found to be consistently associated with specific ES subsets. Pairwise analyses showed CXCR4 to correlate with ES metastases, and CXCR4 and CXCR7 to patient survival, but not with several other clinicopathological variables. Conclusion Ican is a powerful novel method to identifying genes consistently associated with particular disease states in cancers for which large cohorts are not available, currently the case of most cancers. We report for the first time that high CXCR4 expression preferentially associates with metastatic ES and that of CXCR7 with poor patient survival. PMID:20525755

Bennani-Baiti, Idriss M.; Cooper, Aaron; Lawlor, Elizabeth R.; Kauer, Maximilian; Ban, Jozef; Aryee, Dave N.T.; Kovar, Heinrich

2010-01-01

117

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

SciTech Connect

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

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

2009-12-25

118

RETRA exerts anticancer activity in Ewing's sarcoma cells independent of their TP53 status.  

PubMed

Mutant p53 can exert oncogenic activity by inhibitory interaction with p73. The small-molecule RETRA has been described to disrupt this interaction and to suppress carcinoma cells (Kravchenko et al., 2008). RETRA's anticancer activity was restricted to tumour cells bearing mutant p53; it was not active in p53 negative and in p53 wild-type cells. Here, we explored the responsiveness of Ewing's sarcoma (ES) cells with mutant p53 to RETRA. For comparison, we also tested RETRA in p53 null and in p53 wild-type ES cells. We found RETRA to be effective in the three mutant p53 ES cell lines investigated. Strikingly, however, RETRA was similarly effective in the p53-deficient and in the two p53 wild-type ES cell lines examined. RETRA elicited apoptosis, as assessed by flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation, caspase 3/7 activity assay and PARP-1 cleavage immunodetection, and G2/M cell cycle arrest completely independent of the cellular TP53 status. In contrast, various p53-deficient and -proficient carcinoma, osteosarcoma and leukaemia cells were unresponsive to RETRA. RETRA also induced gene expression of p53 target genes PUMA and p21 in ES cells irrespective of their TP53 status. These in vitro findings provide a rationale for an in vivo exploration of RETRA's potential as an effective therapeutic approach for patients with ES. PMID:25801700

Sonnemann, Jürgen; Grauel, Désirée; Blümel, Lisa; Hentschel, Julia; Marx, Christian; Blumrich, Annelie; Focke, Katharina; Becker, Sabine; Wittig, Susan; Schinkel, Sandra; Krämer, Oliver H; Beck, James F

2015-05-01

119

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

PubMed Central

Background Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma in adolescents and young adults. The hallmark of this disease is a EWS-WT1 translocation resulting from apposition of the Ewing’s sarcoma (EWS) gene with the Wilms’ tumor (WT1) gene. We performed morphoproteomic profiling of DSRCT (EWS-WT1), Ewing’s sarcoma (EWS-FLI1) and Wilms’ tumor (WT1) to better understand the signaling pathways for selecting future targeted therapies. Methodology This pilot study assessed patients with DSRCT, Wilms’ tumor and Ewing’s sarcoma. Morphoproteomics and immunohistochemical probes were applied to detect: p-mTOR (Ser2448); p-Akt (Ser473); p-ERK1/2 (Thr202/Tyr204); p-STAT3 (Tyr 705); and cell cycle-related analytes along with their negative controls. Principal Findings In DSRCT the PI3K/Akt/mTOR pathway is constitutively activated by p-Akt (Ser 473) expression in the nuclear compartment of the tumor cells and p-mTOR phosphorylated on Ser 2448, suggesting mTORC2 (rictor+mTOR) as the dominant form. Ewing’s sarcoma had upregulated p-Akt and p-mTOR, predominantly mTORC2. In Wilm’s tumor, the mTOR pathway is also activated with most tumor cells moderately expressing p-mTOR (Ser 2448) in plasmalemmal and cytoplasmic compartments. This coincides with the constitutive activation of one of the downstream effectors of the mTORC1 signaling pathway, namely p-p70S6K (Thr 389). There was constitutive activation of the Ras/Raf/ERK pathway p-ERK 1/2 (Thr202/Tyr204) expression in the Wilms tumor and metastatic Ewing’s sarcoma, but not in the DSRCT. Conclusion Morphoproteomic tumor analyses revealed constitutive activation of the mTOR pathway as evidenced by: (a) expression of phosphorylated (p)-mTOR, p-p70S6K; (b) mTORC 2 in EWS and DSRCT; (c) ERK signaling was seen in the advanced setting indicating these as resistance pathways to IGF1R related therapies. This is the first morphoproteomic study of such pathways in these rare malignancies and may have potential therapeutic implications. Further study using morphoproteomic assessments of these tumors are warranted. PMID:23922674

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

2013-01-01

120

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. PMID:23935076

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

2013-01-01

121

Comprehensive analysis of published phase I/II clinical trials between 1990-2010 in osteosarcoma and Ewing sarcoma confirms limited outcomes and need for translational investment  

PubMed Central

Background High grade primary bone sarcomas are rare cancers that affect mostly children and young adults. Osteosarcoma and Ewing sarcoma are the most common histological subtypes in this age group, with current multimodality treatment strategies achieving 55-70% overall survival. As there remains an urgent need to develop new therapeutic interventions, we have reviewed published phase I/II trials that have been reported for osteosarcoma and Ewing sarcoma in the last twenty years. Results We conducted a literature search for clinical trials between 1990 and 2010, either for trials enrolling bone sarcoma patients as part of a general sarcoma indication or trials specifically in osteosarcoma and Ewing sarcoma. We identified 42 clinical trials that fulfilled our search criteria for general sarcoma that enrolled these patient groups, and eight and twenty specific trials for Ewing and osteosarcoma patients, respectively. For the phase I trials which enrolled different tumour types our results were incomplete, because the sarcoma patients were not mentioned in the PubMed abstract. A total of 3,736 sarcoma patients were included in these trials over this period, 1,114 for osteosarcoma and 1,263 for Ewing sarcoma. As a proportion of the worldwide disease burden over this period, these numbers reflect a very small percentage of the potential patient recruitment, approximately 0.6% for Ewing sarcoma and 0.2% for osteosarcoma. However, these data show an increase in recent activity overall and suggest there is still much room for improvement in the current trial development structures. Conclusion Lack of resources and commercial investment will inevitably limit opportunity to develop sufficiently rapid improvements in clinical outcomes. International collaboration exists in many well founded co-operative groups for phase III trials, but progress may be more effective if there were also more investment of molecular and translational research into disease focused phase I/II clinical trials. Examples of new models for early translational and early phase trial collaboration include the European based EuroBoNeT network, the Sarcoma Alliance for Research through Collaboration network (SARC) and the new European collaborative translational trial network, EuroSarc. PMID:22587841

2012-01-01

122

Development of a Preclinical Orthotopic Xenograft Model of Ewing Sarcoma and Other Human Malignant Bone Disease Using Advanced In Vivo Imaging  

PubMed Central

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

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

2014-01-01

123

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

PubMed

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

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

2014-01-01

124

Ewing Sarcoma Ewsa Protein Regulates Chondrogenesis of Meckel’s Cartilage through Modulation of Sox9 in Zebrafish  

PubMed Central

Ewing sarcoma is the second most common skeletal (bone and cartilage) cancer in adolescents, and it is characterized by the expression of the aberrant chimeric fusion gene EWS/FLI1. Wild-type EWS has been proposed to play a role in mitosis, splicing and transcription. We have previously shown that EWS/FLI1 interacts with EWS, and it inhibits EWS activity in a dominant manner. Ewing sarcoma is a cancer that specifically develops in skeletal tissues, and although the above data suggests the significance of EWS, its role in chondrogenesis/skeletogenesis is not understood. To elucidate the function of EWS in skeletal development, we generated and analyzed a maternal zygotic (MZ) ewsa/ewsa line because the ewsa/wt and ewsa/ewsa zebrafish appeared to be normal and fertile. Compared with wt/wt, the Meckel’s cartilage of MZ ewsa/ewsa mutants had a higher number of craniofacial prehypertrophic chondrocytes that failed to mature into hypertrophic chondrocytes at 4 days post-fertilization (dpf). Ewsa interacted with Sox9, which is the master transcription factor for chondrogenesis. Sox9 target genes were either upregulated (ctgfa, ctgfb, col2a1a, and col2a1b) or downregulated (sox5, nog1, nog2, and bmp4) in MZ ewsa/ewsa embryos compared with the wt/wt zebrafish embryos. Among these Sox9 target genes, the chromatin immunoprecipitation (ChIP) experiment demonstrated that Ewsa directly binds to ctgfa and ctgfb loci. Consistently, immunohistochemistry showed that the Ctgf protein is upregulated in the Meckel’s cartilage of MZ ewsa/ewsa mutants. Together, we propose that Ewsa promotes the differentiation from prehypertrophic chondrocytes to hypertrophic chondrocytes of Meckel’s cartilage through inhibiting Sox9 binding site of the ctgf gene promoter. Because Ewing sarcoma specifically develops in skeletal tissue that is originating from chondrocytes, this new role of EWS may provide a potential molecular basis of its pathogenesis. PMID:25617839

Merkes, Chris; Turkalo, Timothy K.; Wilder, Nicole; Park, Hyewon; Wenger, Luke W.; Lewin, Seth J.; Azuma, Mizuki

2015-01-01

125

Quantification of the heterogeneity of prognostic cellular biomarkers in ewing sarcoma using automated image and random survival forest analysis.  

PubMed

Driven by genomic somatic variation, tumour tissues are typically heterogeneous, yet unbiased quantitative methods are rarely used to analyse heterogeneity at the protein level. Motivated by this problem, we developed automated image segmentation of images of multiple biomarkers in Ewing sarcoma to generate distributions of biomarkers between and within tumour cells. We further integrate high dimensional data with patient clinical outcomes utilising random survival forest (RSF) machine learning. Using material from cohorts of genetically diagnosed Ewing sarcoma with EWSR1 chromosomal translocations, confocal images of tissue microarrays were segmented with level sets and watershed algorithms. Each cell nucleus and cytoplasm were identified in relation to DAPI and CD99, respectively, and protein biomarkers (e.g. Ki67, pS6, Foxo3a, EGR1, MAPK) localised relative to nuclear and cytoplasmic regions of each cell in order to generate image feature distributions. The image distribution features were analysed with RSF in relation to known overall patient survival from three separate cohorts (185 informative cases). Variation in pre-analytical processing resulted in elimination of a high number of non-informative images that had poor DAPI localisation or biomarker preservation (67 cases, 36%). The distribution of image features for biomarkers in the remaining high quality material (118 cases, 104 features per case) were analysed by RSF with feature selection, and performance assessed using internal cross-validation, rather than a separate validation cohort. A prognostic classifier for Ewing sarcoma with low cross-validation error rates (0.36) was comprised of multiple features, including the Ki67 proliferative marker and a sub-population of cells with low cytoplasmic/nuclear ratio of CD99. Through elimination of bias, the evaluation of high-dimensionality biomarker distribution within cell populations of a tumour using random forest analysis in quality controlled tumour material could be achieved. Such an automated and integrated methodology has potential application in the identification of prognostic classifiers based on tumour cell heterogeneity. PMID:25243408

Bühnemann, Claudia; Li, Simon; Yu, Haiyue; Branford White, Harriet; Schäfer, Karl L; Llombart-Bosch, Antonio; Machado, Isidro; Picci, Piero; Hogendoorn, Pancras C W; Athanasou, Nicholas A; Noble, J Alison; Hassan, A Bassim

2014-01-01

126

Quantification of the Heterogeneity of Prognostic Cellular Biomarkers in Ewing Sarcoma Using Automated Image and Random Survival Forest Analysis  

PubMed Central

Driven by genomic somatic variation, tumour tissues are typically heterogeneous, yet unbiased quantitative methods are rarely used to analyse heterogeneity at the protein level. Motivated by this problem, we developed automated image segmentation of images of multiple biomarkers in Ewing sarcoma to generate distributions of biomarkers between and within tumour cells. We further integrate high dimensional data with patient clinical outcomes utilising random survival forest (RSF) machine learning. Using material from cohorts of genetically diagnosed Ewing sarcoma with EWSR1 chromosomal translocations, confocal images of tissue microarrays were segmented with level sets and watershed algorithms. Each cell nucleus and cytoplasm were identified in relation to DAPI and CD99, respectively, and protein biomarkers (e.g. Ki67, pS6, Foxo3a, EGR1, MAPK) localised relative to nuclear and cytoplasmic regions of each cell in order to generate image feature distributions. The image distribution features were analysed with RSF in relation to known overall patient survival from three separate cohorts (185 informative cases). Variation in pre-analytical processing resulted in elimination of a high number of non-informative images that had poor DAPI localisation or biomarker preservation (67 cases, 36%). The distribution of image features for biomarkers in the remaining high quality material (118 cases, 104 features per case) were analysed by RSF with feature selection, and performance assessed using internal cross-validation, rather than a separate validation cohort. A prognostic classifier for Ewing sarcoma with low cross-validation error rates (0.36) was comprised of multiple features, including the Ki67 proliferative marker and a sub-population of cells with low cytoplasmic/nuclear ratio of CD99. Through elimination of bias, the evaluation of high-dimensionality biomarker distribution within cell populations of a tumour using random forest analysis in quality controlled tumour material could be achieved. Such an automated and integrated methodology has potential application in the identification of prognostic classifiers based on tumour cell heterogeneity. PMID:25243408

Yu, Haiyue; Branford White, Harriet; Schäfer, Karl L.; Llombart-Bosch, Antonio; Machado, Isidro; Picci, Piero; Hogendoorn, Pancras C. W.; Athanasou, Nicholas A.; Noble, J. Alison; Hassan, A. Bassim

2014-01-01

127

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

PubMed

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

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

2014-01-30

128

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

PubMed Central

The genetic hallmark of Ewing's sarcoma family of tumours (ET) is the presence of the translocation t(11;22)(q24;q12), which creates the ET fusion gene, leading to cellular transformation. Five human gamma-glutamyl transpeptidase (gamma-GT) genes are located near the chromosomal translocation in ET. gamma-GT is a major enzyme involved in glutathione homoeostasis. Five human cell lines representative of primary or metastatic tumours were investigated to study whether gamma-GT alterations could occur at the chromosomal breaks and rearrangements in ET. As shown by enzymic assays and FACS analyses, all ET cell lines consistently expressed a functional gamma-GT which however did not discriminate steps of ET progression. As shown previously [Sancéau, Hiscott, Delattre and Wietzerbin (2000) Oncogene 19, 3372-3383], ET cells respond to the antiproliferative effects of interferons (IFNs) type I (alpha and beta) and to a much less degree to IFN type II (gamma). IFN-alpha and -beta arrested cells in the S-phase of the cell cycle. We found an enhancement of gamma-GT mRNA species with IFN-alpha and -beta by reverse transcriptase-PCR analyses. This is reflected by up-regulation of gamma-GT protein, which coincides with the increase in gamma-GT-specific enzymic activity. Similarly, IFNs up-regulate the levels of gamma-GT in another IFN-responsive B cell line. Whether this up-regulation of gamma-GT by IFNs is of physiological relevance to cell behaviour remains to be studied. PMID:12049636

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

2002-01-01

129

Predictors of Acute Chemotherapy-Associated Toxicity in Patients with Ewing Sarcoma  

PubMed Central

Background Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue of children and young adults. Patients with ES are treated with intensive chemotherapy regimens. We describe predictors of acute chemotherapy-associated toxicity in this population. Procedure In this retrospective cohort study, records of ES patients treated at two academic medical centers between 1980 and 2010 were reviewed. Grade 3 and 4 non-hematologic chemotherapy-associated toxicities during frontline therapy were recorded for each patient, along with potential clinical and demographic predictors of toxicity. Bivariate analyses were performed using the Fisher exact test. Multivariate analysis was performed using logistic regression. Results The cohort included 142 patients with ES and toxicity data. In bivariate analyses, age <12 years at diagnosis, Latino ethnicity, low family income, and treatment on a clinical trial were associated with higher incidence of toxicity (p <0.01). Tumor size, site, stage, mode of local control, body mass index, overall chemotherapy exposure and dose-intensity were not associated with toxicity. In multivariate analysis, low income (odds ratio (OR) 4.97, 95% CI 1.9–13.1), clinical trial enrollment (OR 3.67, 95% CI 1.2–10.9), pelvic tumor site (OR 3.88, 95% CI 1.17–12.88), and age <12 years (OR 2.8, 95% CI 1.0–7.5) were independent predictors of toxicity. Conclusion ES patients who are younger, of Latino ethnicity, have pelvic tumors or low income have higher rates of toxicity that may require increased supportive care. Treatment on a clinical trial was also associated with higher rates of toxicity, though this finding may reflect better reporting in these patients. PMID:22180320

Sharib, Jeremy M.; Cyrus, Jobin; Horvai, Andrew; Gray Hazard, Florette K.; Neuhaus, John; Matthay, Katherine K.; Goldsby, Robert; Marina, Neyssa; DuBois, Steven G.

2011-01-01

130

Novel Secondary Somatic Mutations in Ewing's Sarcoma and Desmoplastic Small Round Cell Tumors  

PubMed Central

Background Ewing's sarcoma (ES) and desmoplastic small round cell tumors (DSRCT) are small round blue cell tumors driven by an N-terminal containing EWS translocation. Very few somatic mutations have been reported in ES, and none have been identified in DSRCT. The aim of this study is to explore potential actionable mutations in ES and DSRCT. Methodology Twenty eight patients with ES or DSRCT had tumor tissue available that could be analyzed by one of the following methods: 1) Next-generation exome sequencing platform; 2) Multiplex PCR/Mass Spectroscopy; 3) Polymerase chain reaction (PCR)-based single- gene mutation screening; 4) Sanger sequencing; 5) Morphoproteomics. Principal Findings Novel somatic mutations were identified in four out of 18 patients with advanced ES and two of 10 patients with advanced DSRCT (six out of 28 (21.4%));KRAS (n?=?1), PTPRD (n?=?1), GRB10 (n?=?2), MET (n?=?2) and PIK3CA (n?=?1). One patient with both PTPRD and GRB10 mutations and one with a GRB10 mutation achieved a complete remission (CR) on an Insulin like growth factor 1 receptor (IGF1R) inhibitor based treatment. One patient, who achieved a partial remission (PR) with IGF1R inhibitor treatment, but later developed resistance, demonstrated a KRAS mutation in the post-treatment resistant tumor, but not in the pre-treatment tumor suggesting that the RAF/RAS/MEK pathway was activated with progression. Conclusions We have reported several different mutations in advanced ES and DSRCT that have direct implications for molecularly-directed targeted therapy. Our technology agnostic approach provides an initial mutational roadmap used in the path towards individualized combination therapy. PMID:25119929

Janku, Filip; Ludwig, Joseph A.; Naing, Aung; Benjamin, Robert S.; Brown, Robert E.; Anderson, Pete; Kurzrock, Razelle

2014-01-01

131

Variability in functional p53 reactivation by PRIMA-1Met/APR-246 in Ewing sarcoma  

PubMed Central

Background: Though p53 mutations are rare in ES, there is a strong indication that p53 mutant tumours form a particularly bad prognostic group. As such, novel treatment strategies are warranted that would specifically target and eradicate tumour cells containing mutant p53 in this subset of ES patients. Methods: PRIMA-1Met, also known as APR-246, is a small organic molecule that has been shown to restore tumour-suppressor function primarily to mutant p53 and also to induce cell death in various cancer types. In this study, we interrogated the ability of APR-246 to induce apoptosis and inhibit tumour growth in ES cells with different p53 mutations. Results: APR-246 variably induced apoptosis, associated with Noxa, Puma or p21WAF1 upregulation, in both mutant and wild-type p53 harbouring cells. The apoptosis-inducing capability of APR-246 was markedly reduced in ES cell lines transfected with p53 siRNA. Three ES cell lines established from the same patient at different stages of the disease and two cell lines of different patients with identical p53 mutations all exhibited different sensitivities to APR-246, indicating cellular context dependency. Comparative transcriptome analysis on the three cell lines established from the same patient identified differential expression levels of several TP53 and apoptosis-associated genes such as APOL6, PENK, PCDH7 and MST4 in the APR-246-sensitive cell line relative to the less APR-246-sensitive cell lines. Conclusion: This is the first study reporting the biological response of Ewing sarcoma cells to APR-246 exposure and shows gross variability in responses. Our study also proposes candidate genes whose expression might be associated with ES cells' sensitivity to APR-246. With APR-246 currently in early-phase clinical trials, our findings call for caution in considering it as a potential adjuvant to conventional ES-specific chemotherapeutics. PMID:24129240

Aryee, D N T; Niedan, S; Ban, J; Schwentner, R; Muehlbacher, K; Kauer, M; Kofler, R; Kovar, H

2013-01-01

132

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

SciTech Connect

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

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

2006-02-01

133

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

PubMed Central

Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT. PMID:24312454

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

2013-01-01

134

Comparison of Latino and Non-Latino Patients with Ewing Sarcoma  

PubMed Central

Background Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES. Methods Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing. Results Latino patients were diagnosed at a younger age (p=0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (p=0.001), were less likely to have insurance (p=0.001), and were more likely to present to the emergency room at onset of symptoms (p= 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% p=0.37; OS: 77.6% vs. 68.6% p=0.54). Conclusion Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients. PMID:23970433

Sharib, Jeremy; Horvai, Andrew; Gray Hazard, Florette K.; Daldrup-Link, Heike; Goldsby, Robert; Marina, Neyssa; DuBois, Steven G.

2014-01-01

135

Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing’s Sarcoma Family Tumors  

PubMed Central

SUMMARY Purpose Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R). Experimental Design Patients received cixutumumab, 6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Median follow up was 8.9 months. Results Twenty patients (17 with Ewing’s sarcoma [EWS], 3 with desmoplastic small-round-cell tumor [DSCRT]) were enrolled). Twelve patients (60%) were men; median age, 24 years; median number of prior systemic therapies in metastatic setting, 6. The most frequent toxicities were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%) (mostly grade 1–2). Seven of 20 patients (35%) achieved stable disease (SD) >5 months or complete/partial (CR/PR) responses. Tumor regression of over 20% (23%, 23%, 27%, 100%, 100%) occurred in 5/17 (29%) patients with EWS, and they remained on study for 8 to 27 months. One of six EWS patients who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR. Four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which was controlled while maintaining drug dose. Conclusion Cixutumumab combined with temsirolimus was well tolerated and showed preliminary evidence of durable antitumor activity in heavily-pretreated EWS family tumors. PMID:22465830

Naing, Aung; LoRusso, Patricia; Fu, Siqing; Hong, David S.; Anderson, Pete; Benjamin, Robert S.; Ludwig, Joseph; Chen, Helen X.; Doyle, Laurence A.; Kurzrock, Razelle

2013-01-01

136

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. PMID:22879388

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.

2012-01-01

137

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. PMID:17425403

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

2007-01-01

138

Trial of Dasatinib in Advanced Sarcomas  

ClinicalTrials.gov

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

2014-12-17

139

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. PMID:23596566

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

2013-01-01

140

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

PubMed Central

Ewing sarcoma is the second most common bone malignancy in children and young adults. It is driven by oncogenic fusion proteins (i.e. EWS/FLI1) acting as aberrant transcription factors that upregulate and downregulate target genes, leading to cellular transformation. Thus, identificating these target genes and understanding their contribution to Ewing sarcoma tumorigenesis are key for the development of new therapeutic strategies. In this study we show that lysyl oxidase (LOX), an enzyme involved in maintaining structural integrity of the extracellular matrix, is downregulated by the EWS/FLI1 oncoprotein and in consequence it is not expressed in Ewing sarcoma cells and primary tumors. Using a doxycycline inducible system to restore LOX expression in an Ewing sarcoma derived cell line, we showed that LOX displays tumor suppressor activities. Interestingly, we showed that the tumor suppressor activity resides in the propeptide domain of LOX (LOX-PP), an N-terminal domain produced by proteolytic cleavage during the physiological processing of LOX. Expression of LOX-PP reduced cell proliferation, cell migration, anchorage-independent growth in soft agar and formation of tumors in immunodeficient mice. By contrast, the C-terminal domain of LOX, which contains the enzymatic activity, had the opposite effects, corroborating that the tumor suppressor activity of LOX is mediated exclusively by its propeptide domain. Finally, we showed that LOX-PP inhibits ERK/MAPK signalling pathway, and that many pathways involved in cell cycle progression were significantly deregulated by LOX-PP, providing a mechanistic explanation to the cell proliferation inhibition observed upon LOX-PP expression. In summary, our observations indicate that deregulation of the LOX gene participates in Ewing sarcoma development and identify LOX-PP as a new therapeutic target for one of the most aggressive paediatric malignancies. These findings suggest that therapeutic strategies based on the administration of LOX propeptide or functional analogues could be useful for the treatment of this devastating paediatric cancer. PMID:23750284

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

2013-01-01

141

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

PubMed Central

Background Hypoxia inducible factor-1 ? (HIF-1?) has been identified as an important novel target in apoptosis resistance of pediatric tumors such as Rhabdomyosarcoma (RMS) and Ewing’s sarcoma (ES). Evidence suggests that PI3K/Akt signaling plays a role in regulation of HIF-1? activation as well as apoptosis resistance in various adult tumors. However the relevance of PI3K/Akt signaling in HIF-1b? activation and apoptosis resistance in childhood tumors has not been addressed yet. Thus, this study was to investigate whether PI3K/Akt signaling is involved in hypoxia induced activation of HIF-1? as well as in resistance to hypoxia-induced apoptosis in childhood tumors such as RMS and ES. Methods Constitutive activation of PI3K/Akt signaling was analyzed by Western blotting. Hypoxic activation of HIF-1? was determined by Western Blot analysis and electrophoretic mobility shift assay. Apoptosis was determined by flow cytometric analysis of the propidium iodine stained nuclei of cells treated with PI3K inhibitor LY294002 in combination with either TNF-related apoptosis-inducing ligand (TRAIL) or doxorubicin. Results This study demonstrated that PI3K/Akt signaling was constitutively activated in RMS and ES cell lines, A204 and A673, respectively. Targeting PI3K/Akt signaling by the inhibitor LY294002 (30 ?M) significantly decreased the protein expression as well as DNA binding activity of HIF-1? and restored the apoptosis-inducing ability of cells in hypoxia Additionally, pretreatment with LY294002 sensitized A204 and A673 cells to TRAIL or doxorubicin induced apoptosis under hypoxia. Conclusion These results suggest that the constitutively active PI3K/Akt signaling contributes to hypoxic activation of HIF-1? as well as HIF1?-mediated apoptosis resistance in RMS and ES cells under hypoxia. PMID:23590596

2013-01-01

142

FOXO1 is a direct target of EWS-Fli1 oncogenic fusion protein in Ewing's sarcoma cells  

SciTech Connect

Research highlights: {yields} Inducible and reversible siRNA knockdown of an oncogenic fusion protein such as EWS-Fli1 is feasible and more advantageous than other siRNA methods. {yields} The tumor suppressor gene FOXO1 is a new EWS-Fli1 target. {yields} While trans-activators are known for the FOXO1 gene, there has been no report on negative regulators of FOXO1 transcription. {yields} This study provides first evidence that the EWS-Fli1 oncogenic fusion protein can function as a transcriptional repressor of the FOXO1 gene. -- Abstract: Ewing's family tumors are characterized by a specific t(11;22) chromosomal translocation that results in the formation of EWS-Fli1 oncogenic fusion protein. To investigate the effects of EWS-Fli1 on gene expression, we carried out DNA microarray analysis after specific knockdown of EWS-Fli1 through transfection of synthetic siRNAs. EWS-Fli1 knockdown increased expression of genes such as DKK1 and p57 that are known to be repressed by EWS-Fli1 fusion protein. Among other potential EWS-Fli1 targets identified by our microarray analysis, we have focused on the FOXO1 gene since it encodes a potential tumor suppressor and has not been previously reported in Ewing's cells. To better understand how EWS-Fli1 affects FOXO1 expression, we have established a doxycycline-inducible siRNA system to achieve stable and reversible knockdown of EWS-Fli1 in Ewing's sarcoma cells. Here we show that FOXO1 expression in Ewing's cells has an inverse relationship with EWS-Fli1 protein level, and FOXO1 promoter activity is increased after doxycycline-induced EWS-Fli1 knockdown. In addition, we have found that direct binding of EWS-Fli1 to FOXO1 promoter is attenuated after doxycycline-induced siRNA knockdown of the fusion protein. Together, these results suggest that suppression of FOXO1 function by EWS-Fli1 fusion protein may contribute to cellular transformation in Ewing's family tumors.

Yang, Liu, E-mail: lyang@u.washington.edu [Department of Orthopedics, University of Washington, Seattle, WA 98195 (United States) [Department of Orthopedics, University of Washington, Seattle, WA 98195 (United States); Medical Research Service, VA Puget Sound Health Care System, Seattle, WA 98108 (United States); Hu, Hsien-Ming; Zielinska-Kwiatkowska, Anna; Chansky, Howard A. [Department of Orthopedics, University of Washington, Seattle, WA 98195 (United States) [Department of Orthopedics, University of Washington, Seattle, WA 98195 (United States); Medical Research Service, VA Puget Sound Health Care System, Seattle, WA 98108 (United States)

2010-11-05

143

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

PubMed

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

2012-11-01

144

Ewing's sarcoma family of tumors of the maxillary sinus: a case report of multidisciplinary examination enabling prompt diagnosis.  

PubMed

There have been approximately 10 reports in English literature of cases of Ewing's sarcoma family of tumors (EFT) arising in the maxillary sinus. In this location, some tumors mimic EFT, and are more frequently encountered. Herein, we present an additional case of an EFT originating in the maxillary sinus. The patient was a 15-year-old boy complaining of a non-tender swelling of the left cheek. Laboratory tests showed no abnormalities. Computed tomography and magnetic resonance imaging revealed a mass centered in the maxillary sinus with degeneration of the surrounding bones. Pathological examination along with flow cytometry and G-banding enabled the prompt diagnosis of EFT with the EWS/FLI1 fusion gene. The patient is planned to undergo chemotherapy. An origin in the head and neck and the presence of the typical EWS/FLI1, in conjunction with an opportunity for immediate treatment, may predict a relatively better prognosis for EFT in our case. PMID:25755803

Tajima, Shogo; Ohkubo, Aki; Yoshida, Matsumi; Koda, Kenji; Nameki, Ichirota

2015-01-01

145

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

PubMed Central

Round cell sarcomas harboring CIC-DUX4 fusions have recently been described as highly aggressive soft tissue tumors of children and young adults. Due to partial morphologic and immunohistochemical overlap with Ewing sarcoma (ES), CIC-DUX4-positive tumors have generally been classified as Ewing sarcoma-like and managed similarly, however, a systematic comparison at the molecular and immunohistochemical levels between these two groups has not yet been conducted. Based on an initial observation that CIC-DUX4-positive tumors show nuclear immunoreactivity for WT1 and ETS transcription factors, FLI1 and ERG, we performed a detailed immunohistochemical and molecular analysis including these markers, to further investigate the relationship between CIC-DUX4 tumors and ES. The study group included 21 CIC-DUX4-positive sarcomas and 20 EWSR1-rearranged ES. Immunohistochemically, CIC-DUX4 sarcomas showed membranous CD99 positivity in 18 (86%) cases, but only 5 (24%) with a diffuse pattern, while WT1 and FLI1 were strongly positive in all cases. ERG was positive in 18% of cases. All ES expressed CD99 and FLI1, while ERG positivity was only seen in EWSR1-ERG fusion positive ES. WT1 was negative in all ES. Expression profiling validated by q-PCR revealed a distinct gene signature associated with CIC-DUX4 fusion, with upregulation of ETS transcription factors (ETV4, ETV1 and ETV5) and WT1, among top overexpressed genes compared to ES, other sarcomas and normal tissue. In conclusion, the distinct gene signature and immunoprofile of CIC-DUX4 sarcomas suggest a distinct pathogenesis from ES. The consistent WT1 expression may provide a useful clue in the diagnosis in the context of round cell sarcomas negative for EWSR1-rearrangement. PMID:24723486

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

2014-01-01

146

Redirecting T Cells to Ewing's Sarcoma Family of Tumors by a Chimeric NKG2D Receptor Expressed by Lentiviral Transduction or mRNA Transfection  

Microsoft Academic Search

We explored the possibility to target Ewing's sarcoma family of tumors (ESFT) by redirecting T cells. To this aim, we considered NKG2D-ligands (NKG2D-Ls) as possible target antigens. Detailed analysis of the expression of MICA, MICB, ULBP-1, -2, and -3 in fourteen ESFT cell lines revealed consistent expression of at least one NKG2D-L. Thus, for redirecting T cells, we fused a

Manfred Lehner; Gabriel Götz; Julia Proff; Niels Schaft; Jan Dörrie; Florian Full; Armin Ensser; Yves A. Muller; Adelheid Cerwenka; Hinrich Abken; Ornella Parolini; Peter F. Ambros; Heinrich Kovar; Wolfgang Holter

2012-01-01

147

Clinical and Biochemical Function of Polymorphic NR0B1 GGAA-Microsatellites in Ewing Sarcoma: A Report from the Children's Oncology Group  

PubMed Central

Background The genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood. EWS/FLI and related EWS/ETS chimeras upregulate numerous gene targets via promoter-based GGAA-microsatellite response elements. These microsatellites are highly polymorphic in humans, and preliminary evidence suggests EWS/FLI-mediated gene expression is highly dependent on the number of GGAA motifs within the microsatellite. Objectives Here we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the NR0B1 promoter (a critical EWS/FLI target) in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes. Results A complex, bimodal pattern of EWS/FLI-mediated gene expression was observed across a wide range of GGAA motifs, with maximal expression observed in constructs containing 20–26 GGAA motifs. Relative to white European and African controls, the NR0B1 GGAA-microsatellite in tumor cells demonstrated a strong bias for haplotypes containing 21–25 GGAA motifs suggesting a relationship between microsatellite function and disease susceptibility. This selection bias was not a product of microsatellite instability in tumor samples, nor was there a correlation between NR0B1 GGAA-microsatellite polymorphisms and survival outcomes. Conclusions These data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma. PMID:25093581

Monument, Michael J.; Johnson, Kirsten M.; McIlvaine, Elizabeth; Abegglen, Lisa; Watkins, W. Scott; Jorde, Lynn B.; Womer, Richard B.; Beeler, Natalie; Monovich, Laura; Lawlor, Elizabeth R.; Bridge, Julia A.; Schiffman, Joshua D.; Krailo, Mark D.; Randall, R. Lor; Lessnick, Stephen L.

2014-01-01

148

A Unique Case of Primary Ewing's Sarcoma of the Cervical Spine in a 53-Year-Old Male: A Case Report and Review of the Literature  

PubMed Central

Extraskeletal Ewing's sarcoma (EES) is a rare presentation, representing only 15% of all primary Ewing's sarcoma cases. Even more uncommon is EES presenting as a primary focus in the spinal canal. These rapidly growing tumors often present with focal neurological symptoms of myelopathy or radiculopathy. There are no classic characteristic imaging findings and thus the physician must keep a high index of clinical suspicion. Diagnosis can only be definitively made by histopathological studies. In this report, we discuss a primary cervical spine EES in a 53-year-old man who presented with a two-month history of left upper extremity pain and acute onset of weakness. Imaging revealed a cervical spinal canal mass. After undergoing cervical decompression, histopathological examination confirmed a diagnosis of Ewing's sarcoma. A literature search revealed fewer than 25 reported cases of primary cervical spine EES published in the past 15 years and only one report demonstrating this pathology in a patient older than 30 years of age (age = 38). Given the low incidence of this pathology presenting in this age group and the lack of treatment guidelines, each patient's plan should be considered on a case-by-case basis until further studies are performed to determine optimal evidence based treatment. PMID:25802527

Holland, Marshall T.; Flouty, Oliver E.; Close, Liesl N.; Reddy, Chandan G.; Howard, Matthew A.

2015-01-01

149

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

ClinicalTrials.gov

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

2014-04-01

150

DNA methylation and gene expression profiling of ewing sarcoma primary tumors reveal genes that are potential targets of epigenetic inactivation.  

PubMed

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. PMID:23024594

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

2012-01-01

151

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. PMID:23024594

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

2012-01-01

152

The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma  

PubMed Central

New targets for Ewing sarcoma (ES) patients are urgently needed. Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA expression was determined by RT-PCR on 29 ES samples. Low, medium and high AXL mRNA expression was observed in 31% (n = 9), 48% (n = 14) and 21% (n = 6) of samples. Gas6 was abundantly present in all specimens. We next tested AXL protein expression immunohistochemically in 36 tumors (primary, post-chemotherapy, metastasized and relapsed samples) from 25 ES patients. Low, medium and high AXL protein expression was observed in 17% (n = 6), 19% (n = 7) and 36% (n = 13) of samples. In primary tumors (n = 15), high AXL expression correlated significantly with a worse overall survival compared to patients with lower expression (61 vs. 194 months, p = 0.026). No genetic aberrations were detected in the AXL RTK domain (n = 29). The AXL-inhibitor BGB324 affected viability (IC50 0.79–2.13 ?mol/L) and migratory potential of all tested ES cell lines in vitro (n = 5–6). BGB324 chemosensitized chemotherapy-resistant ES-4 cells to vincristine and doxorubicin. These data suggest that AXL is a potential novel, druggable therapeutic target in ES. PMID:25528764

Fleuren, Emmy D.G.; Hillebrandt-Roeffen, Melissa H.S.; Flucke, Uta E.; te Loo, D. Maroeska W.M.; Boerman, Otto C.; van der Graaf, Winette T.A.; Versleijen-Jonkers, Yvonne M.H.

2014-01-01

153

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. PMID:23761859

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

2013-01-01

154

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

Microsoft Academic Search

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

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

1996-01-01

155

Combining poly(ADP-ribose) polymerase 1 (PARP-1) inhibition and radiation in Ewing sarcoma results in lethal DNA damage  

PubMed Central

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

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

2013-01-01

156

Potential of herpesvirus saimiri-based vectors to reprogram a somatic Ewing's sarcoma family tumor cell line.  

PubMed

Herpesvirus saimiri (HVS) infects a range of human cell types with high efficiency. Upon infection, the viral genome can persist as high-copy-number, circular, nonintegrated episomes that segregate to progeny cells upon division. This allows HVS-based vectors to stably transduce a dividing cell population and provide sustained transgene expression in vitro and in vivo. Moreover, the HVS episome is able to persist and provide prolonged transgene expression during in vitro differentiation of mouse and human hemopoietic progenitor cells. Together, these properties are advantageous for induced pluripotent stem cell (iPSC) technology, whereby stem cell-like cells are generated from adult somatic cells by exogenous expression of specific reprogramming factors. Here we assess the potential of HVS-based vectors for the generation of induced pluripotent cancer stem-like cells (iPCs). We demonstrate that HVS-based exogenous delivery of Oct4, Nanog, and Lin28 can reprogram the Ewing's sarcoma family tumor cell line A673 to produce stem cell-like colonies that can grow under feeder-free stem cell culture conditions. Further analysis of the HVS-derived putative iPCs showed some degree of reprogramming into a stem cell-like state. Specifically, the putative iPCs had a number of embryonic stem cell characteristics, staining positive for alkaline phosphatase and SSEA4, in addition to expressing elevated levels of pluripotent marker genes involved in proliferation and self-renewal. However, differentiation trials suggest that although the HVS-derived putative iPCs are capable of differentiation toward the ectodermal lineage, they do not exhibit pluripotency. Therefore, they are hereby termed induced multipotent cancer cells. PMID:23596304

Brown, Hannah F; Unger, Christian; Whitehouse, Adrian

2013-06-01

157

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

PubMed Central

Ewing sarcoma (ES) is an aggressive malignancy driven by an oncogenic fusion protein, EWS-FLI1. Neuropeptide Y (NPY), and two of its receptors, Y1R and Y5R are up-regulated by EWS-FLI1 and abundantly expressed in ES cells. Paradoxically, NPY acting via Y1R and Y5R stimulates ES cell death. Here, we demonstrate that these growth-inhibitory actions of NPY are counteracted by hypoxia, which converts the peptide to a growth-promoting factor. In ES cells, hypoxia induces another NPY receptor, Y2R, and increases expression of dipeptidyl peptidase IV (DPPIV), an enzyme that cleaves NPY to a shorter form, NPY3-36. This truncated peptide no longer binds to Y1R and, therefore, does not stimulate ES cell death. Instead, NPY3-36 acts as a selective Y2R/Y5R agonist. The hypoxia-induced increase in DPPIV activity is most evident in a population of ES cells with high aldehyde dehydrogenase (ALDH) activity, rich in cancer stem cells (CSCs). Consequently, NPY, acting via Y2R/Y5Rs, preferentially stimulates proliferation and migration of hypoxic ALDHhigh cells. Hypoxia also enhances the angiogenic potential of ES by inducing Y2Rs in endothelial cells and increasing the release of its ligand, NPY3-36, from ES cells. In summary, hypoxia acts as a molecular switch shifting NPY activity away from Y1R/Y5R-mediated cell death and activating the Y2R/Y5R/DPPIV/NPY3-36 axis, which stimulates ES CSCs and promotes angiogenesis. Hypoxia-driven actions of the peptide such as these may contribute to ES progression. Due to the receptor-specific and multifaceted nature of NPY actions, these findings may inform novel therapeutic approaches to ES. PMID:24318733

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

2013-01-01

158

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

SciTech Connect

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

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

1993-11-01

159

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

PubMed Central

Small interfering RNAs (siRNAs) are powerful tools commonly used for the specific inhibition of gene expression. However, vectorization is required to facilitate cell penetration and to prevent siRNA degradation by nucleases. We have shown that diamond nanocrystals coated with cationic polymer can be used to carry siRNAs into Ewing sarcoma cells, in which they remain traceable over long periods, due to their intrinsic stable fluorescence. We tested two cationic polymers, polyallylamine and polyethylenimine. The release of siRNA, accompanied by Ewing sarcoma EWS-Fli1 oncogene silencing, was observed only with polyethylenimine. We investigated cell penetration and found that the underlying mechanisms accounted for these differences in behavior. Using drugs selectively inhibiting particular pathways and a combination of fluorescence and electronic microscopy, we showed that siRNA gene silencing occurred only if the siRNA:cationic nanodiamond complex followed the macropinocytosis route. These results have potential implications for the design of efficient drug-delivery vectors. PMID:23284935

Alhaddad, Anna; Durieu, Catherine; Dantelle, Géraldine; Le Cam, Eric; Malvy, Claude; Treussart, François; Bertrand, Jean-Rémi

2012-01-01

160

Let-7a Functions as a Tumor Suppressor in Ewing's Sarcoma Cell Lines Partly by Targeting Cyclin-Dependent Kinase 6  

PubMed Central

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

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

2014-01-01

161

Plasma hydrogenated cationic detonation nanodiamonds efficiently deliver to human cells in culture functional siRNA targeting the Ewing sarcoma junction oncogene.  

PubMed

The expression of a defective gene can lead to major cell dysfunctions among which cell proliferation and tumor formation. One promising therapeutic strategy consists in silencing the defective gene using small interfering RNA (siRNA). In previous publications we showed that diamond nanocrystals (ND) of primary size 35 nm, rendered cationic by polyethyleneimine-coating, can efficiently deliver siRNA into cell, which further block the expression of EWS/FLI-1 oncogene in a Ewing sarcoma disease model. However, a therapeutic application of such nanodiamonds requires their elimination by the organism, particularly in urine, which is impossible for 35 nm particles. Here, we report that hydrogenated cationic nanodiamonds of primary size 7 nm (ND-H) have also a high affinity for siRNA and are capable of delivering them in cells. With siRNA/ND-H complexes, we measured a high inhibition efficacy of EWS/FLI-1 gene expression in Ewing sarcoma cell line. Electron microscopy investigations showed ND-H in endocytosis compartments, and especially in macropinosomes from which they can escape before siRNA degradation occurred. In addition, the association of EWS/FLI-1 silencing by the siRNA/ND-H complex with a vincristine treatment yielded a potentiation of the toxic effect of this chemotherapeutic drug. Therefore ND-H appears as a promising delivery agent in anti-tumoral gene therapy. PMID:25662499

Bertrand, Jean-Rémi; Pioche-Durieu, Catherine; Ayala, Juan; Petit, Tristan; Girard, Hugues A; Malvy, Claude P; Le Cam, Eric; Treussart, François; Arnault, Jean-Charles

2015-03-01

162

miR-375 Mediated Acquired Chemo-Resistance in Cervical Cancer by Facilitating EMT  

PubMed Central

Acquired chemo-resistance is one of the key causal factors in cancer death. Emerging evidences suggest that miRNA and epithelial–mesenchymal transition play critical roles in the chemo-resistance in cancers. Here, we showed the association of paclitaxel-resistance with miR-375 over-expression and epithelial–mesenchymal transition inducement in cervical cancer. Using different cervical cancer cell models, we found that paclitaxel transiently induced up-regulation of miR-375 expression, proliferation inhibition, transition from epithelial to mesenchymal phenotype, and consequently impaired paclitaxel sensitivity. Forced over-expression of miR-375 may suppress Ecadherin expression by a directly targeting pathway, which led to paclitaxel resistance. Contrarily, re-expression of Ecadherin partly reversed epithelial–mesenchymal transition phenotype and miR-375 induced paclitaxel-resistance. Our findings suggest that paclitaxel-induced miR-375 over-expression facilitates epithelial–mesenchymal transition process via directly targeting Ecadherin, proliferation inhibition, and consequently results in chemo-resistance in cervical cancer cells. A reversion of miR-375 or Ecadherin expression may be a novel therapeutic approach for overcoming chemo-resistance in cervical cancer. PMID:25330011

Shen, Yuanming; Zhou, Jiansong; Li, Yang; Ye, Feng; Wan, Xiaoyun; Lu, Weiguo; Xie, Xing; Cheng, Xiaodong

2014-01-01

163

In vitro antiproliferative effects of albumin-doxorubicin conjugates against Ewing's sarcoma and peripheral neuroectodermal tumor cells.  

PubMed

The 3-5 year survival rates of patients with disseminated Ewing's sarcoma (ES) or the closely related peripheral primitive neuroectodermal tumors (PNET) remain low, even under aggressive treatment involving highly toxic multidrug chemotherapeutic regimens. ES and PNET are sensitive to doxorubicin, but may escape treatment by expression of the multidrug-resistant phenotype and/or other mechanisms. In this study, we have identified albumin as growth supporting factor for ES and PNET cells in IGF-I-supplemented serum-free tissue culture medium. To investigate the specificity and toxicity of albumin-based drug conjugates, doxorubicin was coupled to bovine serum albumin (BSA) by either a two step glutaraldehyde or carbodiimide-C4-spacer technique, yielding monomeric DOX-albumin conjugates with conjugation numbers ranging from 3-20 moles DOX/mole BSA. Cellular uptake of fluorescein-isothiocyanate-(FITC)-labeled albumin and DOX-albumin conjugates could be demonstrated by flow cytometric measurements of cell-associated fluorescence and confocal microscopy. The cytostatic activity of these conjugates against ES/PNET cell lines, a neuroblastoma (LAN-1) and prostate cancer carcinoma cell line (PC-3) and normal lymphoblasts was tested in short-term proliferation assays (48 h). The results show a high selectivity of the DOX-albumin conjugates for ES/PNET cell lines, with highest growth inhibition by conjugates with low DOX conjugation numbers (n = 3) in serum-supplemented medium (17-32 fold loss of activity compared to free DOX), followed by 20-DOX-C4-albumin in serum-free medium and low activity of the other conjugates. In conclusion, DOX-albumin conjugates inhibit the growth of ES/PNET cell lines selectively, showing low activity against the unrelated carcinoma line PC-3 and sparing normal lymphoblasts. The inverse correlation of activity and conjugation number demonstrates a low cytotoxic activity of DOX in acid-stable binding to monomeric albumin, pointing to a selective cytostatic activity of the modified albumin against ES and PNET cells, even in the presence of a 100 fold excess of unmodified serum albumin. PMID:7847832

Gabor, F; Wollmann, K; Theyer, G; Haberl, I; Hamilton, G

1994-01-01

164

Full-term newborn after repeated ovarian tissue transplants in a patient treated for Ewing sarcoma by sterilizing pelvic irradiation and chemotherapy.  

PubMed

We report the first successful transplantation of cryopreserved ovarian cortical tissue into heavily irradiated tissues in a patient who had received sterilizing pelvic radiotherapy (54 Gy) and 40 weeks of intensive high-dose chemotherapy for the treatment of Ewing's sarcoma 14 years earlier. Repeated transplantation procedures were required to obtain fully functional follicular development. Enlargement of the transplants over time and increase of the size of the uterus were demonstrated on sequential ultrasonographic examinations. Eggs of good quality that could be fertilized in vitro were obtained only after a substantial incremental increase of the amount of ovarian tissue transplanted. Single embryo replacement resulted in a normal pregnancy and the birth of a healthy child by cesarean section at full-term. No neonatal or maternal postoperative complications occurred. Women facing high-dose pelvic radiotherapy should not be systematically excluded from fertility preservation options, as is currently the trend. PMID:25545009

Rodriguez-Wallberg, Kenny A; Karlström, Per-Olof; Rezapour, Masoumeh; Castellanos, Enrique; Hreinsson, Julius; Rasmussen, Carsten; Sheikhi, Mona; Ouvrier, Bettina; Bozóky, Béla; Olofsson, Jan I; Lundqvist, Monalill; Hovatta, Outi

2015-03-01

165

A phase II study to determine the efficacy and safety of oral treosulfan in patients with advanced pre-treated Ewing sarcoma ISRCTN11631773.  

PubMed

We report a prospective Phase II study of efficacy and toxicity for oral treosulfan in advanced Ewing sarcoma. Twenty patients, median age 19 years (range 7-39) from five UK sites, were treated with oral treosulfan 1 g/m(2) daily for 7 days in 28. Primary endpoint was objective response rate. Best response was stable disease in one patient. All patients died of progressive disease, after median 6.41 months. Median progression free survival was 1.8 months. Toxicity was minimal. No activity was demonstrated for treosulfan at this dose. Progression free survival data should be able to be used for comparison when planning future clinical trials. PMID:25284019

Michelagnoli, M; Whelan, J; Forsyth, S

2015-01-01

166

Baylor scientists find that wound response of cancer stem cells may explain chemo-resistance in bladder cancer  

Cancer.gov

A novel mechanism -- similar to how normal tissue stem cells respond to wounding -- might explain why bladder cancer stem cells actively contribute to chemo-resistance after multiple cycles of chemotherapy drug treatment.

167

Stages of Ewing Sarcoma  

MedlinePLUS

... attack specific cancer cells without harming normal cells. Monoclonal antibody therapy is a type of targeted therapy being studied ... to the lungs . A clinical trial of targeted therapy with a monoclonal antibody . Check for U.S. clinical trials from NCI's list ...

168

Cytotoxic effect of the pentacyclic oxindole alkaloid mitraphylline isolated from Uncaria tomentosa bark on human Ewing's sarcoma and breast cancer cell lines.  

PubMed

Preparations from Uncaria tomentosa, a South American Rubiaceae, have been used in the Peruvian traditional medicine for the treatment of infective, inflammatory and tumoral processes. In this study, the pentacyclic oxindole alkaloid mitraphylline was isolated from the dried inner bark of this plant species, and its structure elucidated by analysis of NMR spectroscopic data. Mitraphylline was differentially identified from its stereoisomeric pair isomitraphylline by (15)N-NMR. Its antiproliferative and cytotoxic effects have been tested on human Ewing's sarcoma MHH-ES-1 and breast cancer MT-3 cell lines, using cyclophosphamide and vincristine as reference controls. A Coulter counter was used to determine viable cell numbers, followed by the application of the tetrazolium compound MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium] an inner salt. A colorimetric method was employed to evaluate cell viability in this cytotoxic assay. Micromolar concentrations of mitraphylline (5 microM to 40 microM) inhibited the growth of both cell lines in a dose-dependent manner. The IC (50) +/- SE values were 17.15 +/- 0.82 microM for MHH-ES-1 and 11.80 +/- 1.03 microM for MT-3 for 30 hours, smaller than those obtained for the reference compounds. This action suggests that the pentacyclic oxindole alkaloid mitraphylline might be a new promising agent in the treatment of both human sarcoma and breast cancer. PMID:19724995

García Giménez, Dolores; García Prado, Elena; Sáenz Rodríguez, Teresa; Fernández Arche, Angeles; De la Puerta, Rocío

2010-02-01

169

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. PMID:22025154

Juergens, Heribert; Daw, Najat C.; Geoerger, Birgit; Ferrari, Stefano; Villarroel, Milena; Aerts, Isabelle; Whelan, Jeremy; Dirksen, Uta; Hixon, Mary L.; Yin, Donghua; Wang, Tao; Green, Stephanie; Paccagnella, Luisa; Gualberto, Antonio

2011-01-01

170

Targeted therapy for sarcomas  

PubMed Central

Sarcomas are tumors of mesenchymal origin that make up approximately 1% of human cancers. They may arise as primary tumors in either bone or soft tissue, with approximately 11,280 soft tissue tumors and 2,650 bone tumors diagnosed each year in the United States. There are at least 50 different subtypes of soft tissue sarcoma, with new ones described with ever-increasing frequency. One way to look at sarcomas is to divide them into categories on the basis of their genetic make-up. One group of sarcomas has an identifiable, relatively simple genetic signature, such as the X:18 translocation seen in synovial sarcoma or the 11:22 translocation seen in Ewing’s sarcoma. These specific abnormalities often lead to the presence of fusion proteins, such as EWS-FLI1 in Ewing’s sarcoma, which are helpful as diagnostic tools and may become therapeutic targets in the future. Another group of sarcomas is characterized by complex genetic abnormalities as seen in leiomyosarcoma, osteosarcoma, and undifferentiated sarcoma. It is important to keep these distinctions in mind when contemplating the development of targeted agents for sarcomas. Different abnormalities in sarcoma could be divided by tumor subtype or by the molecular or pathway abnormality. However, some existing drugs or drugs in development may interfere with or alter more than one of the presented pathways. PMID:24669185

Forscher, Charles; Mita, Monica; Figlin, Robert

2014-01-01

171

Is fluoride a risk factor for bone cancer? Small area analysis of osteosarcoma and Ewing sarcoma diagnosed among 0–49-year-olds in Great Britain, 1980–2005  

PubMed Central

Background: Artificial fluoridation of drinking water to improve dental health has long been a topic of controversy. Opponents of this public health measure have cited the possibility of bone cancer induction. The study objective was to examine whether increased risk of primary bone cancer was associated with living in areas with higher concentrations of fluoride in drinking water. Methods: Case data on osteosarcoma and Ewing sarcoma, diagnosed at ages 0–49 years in Great Britain (GB) (defined here as England, Scotland and Wales) during the period 1980–2005, were obtained from population-based cancer registries. Data on fluoride levels in drinking water in England and Wales were accessed through regional water companies and the Drinking Water Inspectorate. Scottish Water provided data for Scotland. Negative binomial regression was used to examine the relationship between incidence rates and level of fluoride in drinking water at small area level. Results: The study analysed 2566 osteosarcoma and 1650 Ewing sarcoma cases. There was no evidence of an association between osteosarcoma risk and fluoride in drinking water [relative risk (RR) per one part per million increase in the level of fluoride = 1·001; 90% confidence interval (CI) 0·871, 1·151] and similarly there was no association for Ewing sarcoma (RR = 0·929; 90% CI 0·773, 1·115). Conclusions: The findings from this study provide no evidence that higher levels of fluoride (whether natural or artificial) in drinking water in GB lead to greater risk of either osteosarcoma or Ewing sarcoma. PMID:24425828

Blakey, Karen; Feltbower, Richard G; Parslow, Roger C; James, Peter W; Gómez Pozo, Basilio; Stiller, Charles; Vincent, Tim J; Norman, Paul; McKinney, Patricia A; Murphy, Michael F; Craft, Alan W; McNally, Richard JQ

2014-01-01

172

Depsipeptide (Romidepsin) in Treating Patients With Metastatic or Unresectable Soft Tissue Sarcoma  

ClinicalTrials.gov

Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Malignant Mesenchymoma; Adult Neurofibrosarcoma; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Gastrointestinal Stromal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

2014-08-26

173

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. PMID:22022506

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

2011-01-01

174

Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma.  

PubMed

Ewing sarcoma is the second-most-common bone cancer in children. Driven by an oncogenic chromosomal translocation that results in the expression of an aberrant transcription factor, EWS/FLI, the disease is typically aggressive and micrometastatic upon presentation. Silencing of EWS/FLI in patient-derived tumor cells results in the altered expression of hundreds to thousands of genes and is accompanied by dramatic morphological changes in cytoarchitecture and adhesion. Genes encoding focal adhesion, extracellular matrix, and actin regulatory proteins are dominant targets of EWS/FLI-mediated transcriptional repression. Reexpression of genes encoding just two of these proteins, zyxin and ?5 integrin, is sufficient to restore cell adhesion and actin cytoskeletal integrity comparable to what is observed when the EWS/FLI oncogene expression is compromised. Using an orthotopic xenograft model, we show that EWS/FLI-induced repression of ?5 integrin and zyxin expression promotes tumor progression by supporting anchorage-independent cell growth. This selective advantage is paired with a tradeoff in which metastatic lung colonization is compromised. PMID:25057021

Chaturvedi, Aashi; Hoffman, Laura M; Jensen, Christopher C; Lin, Yi-Chun; Grossmann, Allie H; Randall, R Lor; Lessnick, Stephen L; Welm, Alana L; Beckerle, Mary C

2014-09-15

175

Suppression of FOXO1 is responsible for a growth regulatory repressive transcriptional sub-signature of EWS-FLI1 in Ewing sarcoma.  

PubMed

The Ewing sarcoma (ES) EWS-FLI1 chimeric oncoprotein is a prototypic aberrant ETS transcription factor with activating and repressive regulatory functions. We report that EWS-FLI1-repressed promoters are enriched in forkhead box (FOX) recognition motifs, and identify FOXO1 as a EWS-FLI1-suppressed regulator orchestrating a major subset of EWS-FLI1-repressed genes. In addition to FOXO1 regulation by direct promoter binding of EWS-FLI1, its subcellular localization and activity is regulated by cyclin-dependent kinase 2- and AKT-mediated phosphorylation downstream of EWS-FLI1. Restoration of nuclear FOXO1 expression in ES cells impaired proliferation and significantly reduced clonogenicity. Gene-expression profiling revealed a significant overlap between EWS-FLI1-repressed and FOXO1-activated genes. As a proof of principle for a potential therapeutic application of our findings, the treatment of ES cell lines with methylseleninic acid (MSA) reactivated endogenous FOXO1 in the presence of EWS-FLI1 in a dose- and time-dependent manner and induced massive cell death dependent on FOXO1. In an orthotopic xenograft mouse model, MSA increased FOXO1 expression in the tumor paralleled by a significant decrease in ES tumor growth. FOXO1 reactivation by small molecules may therefore serve as a promising strategy for a future ES-specific therapy. PMID:23995784

Niedan, S; Kauer, M; Aryee, D N T; Kofler, R; Schwentner, R; Meier, A; Pötschger, U; Kontny, U; Kovar, H

2014-07-24

176

Suppression of FOXO1 is responsible for a growth regulatory repressive transcriptional sub-signature of EWS-FLI1 in Ewing sarcoma  

PubMed Central

The Ewing sarcoma (ES) EWS-FLI1 chimeric oncoprotein is a prototypic aberrant ETS transcription factor with activating and repressive regulatory functions. We report that EWS-FLI1-repressed promoters are enriched in forkhead box (FOX) recognition motifs, and identify FOXO1 as a EWS-FLI1-suppressed regulator orchestrating a major subset of EWS-FLI1-repressed genes. In addition to FOXO1 regulation by direct promoter binding of EWS-FLI1, its subcellular localization and activity is regulated by cyclin-dependent kinase 2- and AKT-mediated phosphorylation downstream of EWS-FLI1. Restoration of nuclear FOXO1 expression in ES cells impaired proliferation and significantly reduced clonogenicity. Gene-expression profiling revealed a significant overlap between EWS-FLI1-repressed and FOXO1-activated genes. As a proof of principle for a potential therapeutic application of our findings, the treatment of ES cell lines with methylseleninic acid (MSA) reactivated endogenous FOXO1 in the presence of EWS-FLI1 in a dose- and time-dependent manner and induced massive cell death dependent on FOXO1. In an orthotopic xenograft mouse model, MSA increased FOXO1 expression in the tumor paralleled by a significant decrease in ES tumor growth. FOXO1 reactivation by small molecules may therefore serve as a promising strategy for a future ES-specific therapy. PMID:23995784

Niedan, S; Kauer, M; Aryee, D N T; Kofler, R; Schwentner, R; Meier, A; Pötschger, U; Kontny, U; Kovar, H

2014-01-01

177

Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma  

PubMed Central

Ewing sarcoma is the second-most-common bone cancer in children. Driven by an oncogenic chromosomal translocation that results in the expression of an aberrant transcription factor, EWS/FLI, the disease is typically aggressive and micrometastatic upon presentation. Silencing of EWS/FLI in patient-derived tumor cells results in the altered expression of hundreds to thousands of genes and is accompanied by dramatic morphological changes in cytoarchitecture and adhesion. Genes encoding focal adhesion, extracellular matrix, and actin regulatory proteins are dominant targets of EWS/FLI-mediated transcriptional repression. Reexpression of genes encoding just two of these proteins, zyxin and ?5 integrin, is sufficient to restore cell adhesion and actin cytoskeletal integrity comparable to what is observed when the EWS/FLI oncogene expression is compromised. Using an orthotopic xenograft model, we show that EWS/FLI-induced repression of ?5 integrin and zyxin expression promotes tumor progression by supporting anchorage-independent cell growth. This selective advantage is paired with a tradeoff in which metastatic lung colonization is compromised. PMID:25057021

Chaturvedi, Aashi; Hoffman, Laura M.; Jensen, Christopher C.; Lin, Yi-Chun; Grossmann, Allie H.; Randall, R. Lor; Lessnick, Stephen L.; Welm, Alana L.; Beckerle, Mary C.

2014-01-01

178

The role of surgical margins in treatment of Ewing's sarcoma family tumors: Experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy  

SciTech Connect

Purpose: To evaluate the importance of surgical margins for local and systemic control of Ewing's sarcoma family tumors (ESFT). Methods and Materials: Between 1979 and 1999, 512 patients with ESFTs entered 4 different adjuvant and neoadjuvant studies performed at a single institution. Of these patients, 335 were treated with surgery alone (196) or surgery followed by radiotherapy at doses of 44.8 Gy (139). We compared their outcome with that of the 177 patients who were locally treated by radiotherapy at 60 Gy. Results: Local control (88.8% vs. 80.2%, p < 0.009) and 5-year disease-free survival (63.8% vs. 47.6%, p < 0.0007) were significantly better in patients treated with surgery and, among them, in those with adequate surgical margins (96.6% vs. 71,7%, p < 0.0008, and 69.6% vs. 46.3%, p < 0.0002). Nonetheless, better results were observed only in extremity tumors. Conclusions: Surgery is better than radiotherapy in cases of extremity ESFT with achievable adequate surgical margins, and in cases of inadequate surgical margins, adjuvant reduced-dose radiotherapy is ineffective. Therefore, when inadequate margins are expected, patients are better treated with full-dose radiotherapy from the start.

Bacci, Gaetano [Section of Chemotherapy, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy)]. E-mail: gaetano.bacci@ior.it; Longhi, Alessandra [Section of Chemotherapy, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy); Briccoli, Antonio [Section of Thoracic Surgery, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy); Bertoni, Franco [Laboratory for Pathology, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy); Versari, Michela [Section of Chemotherapy, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy); Picci, Piero [Laboratory for Oncologic Research, Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna (Italy)

2006-07-01

179

EphA2-induced angiogenesis in ewing sarcoma cells works through bFGF production and is dependent on caveolin-1.  

PubMed

Angiogenesis is the result of the combined activity of the tumor microenvironment and signaling molecules. The angiogenic switch is represented as an imbalance between pro- and anti-angiogenic factors and is a rate-limiting step in the development of tumors. Eph receptor tyrosine kinases and their membrane-anchored ligands, known as ephrins, constitute the largest receptor tyrosine kinase (RTK) subfamily and are considered a major family of pro-angiogenic RTKs. Ewing sarcoma (EWS) is a highly aggressive bone and soft tissue tumor affecting children and young adults. As other solid tumors, EWS are reliant on a functional vascular network for the delivery of nutrients and oxygen and for the removal of waste. Based on the biological roles of EphA2 in promoting angiogenesis, we explored the functional role of this receptor and its relationship with caveolin-1 (CAV1) in EWS angiogenesis. We demonstrated that lack of CAV1 results in a significant reduction in micro vascular density (MVD) on 3 different in vivo models. In vitro, this phenomenon correlated with inactivation of EphA2 receptor, lack of AKT response and downregulation of bFGF. We also demonstrated that secreted bFGF from EWS cells acted as chemoattractant for endothelial cells. Furthermore, interaction between EphA2 and CAV1 was necessary for the right localization and signaling of the receptor to produce bFGF through AKT and promote migration of endothelial cells. Finally, introduction of a dominant-negative form of EphA2 into EWS cells mostly reproduced the effects occurred by CAV1 silencing, strongly suggesting that the axis EphA2-CAV1 participates in the promotion of endothelial cell migration toward the tumors favoring EWS angiogenesis. PMID:23951165

Sáinz-Jaspeado, Miguel; Huertas-Martinez, Juan; Lagares-Tena, Laura; Martin Liberal, Juan; Mateo-Lozano, Silvia; de Alava, Enrique; de Torres, Carmen; Mora, Jaume; Del Muro, Xavier Garcia; Tirado, Oscar M

2013-01-01

180

EphA2-Induced Angiogenesis in Ewing Sarcoma Cells Works through bFGF Production and Is Dependent on Caveolin-1  

PubMed Central

Angiogenesis is the result of the combined activity of the tumor microenvironment and signaling molecules. The angiogenic switch is represented as an imbalance between pro- and anti-angiogenic factors and is a rate-limiting step in the development of tumors. Eph receptor tyrosine kinases and their membrane-anchored ligands, known as ephrins, constitute the largest receptor tyrosine kinase (RTK) subfamily and are considered a major family of pro-angiogenic RTKs. Ewing sarcoma (EWS) is a highly aggressive bone and soft tissue tumor affecting children and young adults. As other solid tumors, EWS are reliant on a functional vascular network for the delivery of nutrients and oxygen and for the removal of waste. Based on the biological roles of EphA2 in promoting angiogenesis, we explored the functional role of this receptor and its relationship with caveolin-1 (CAV1) in EWS angiogenesis. We demonstrated that lack of CAV1 results in a significant reduction in micro vascular density (MVD) on 3 different in vivo models. In vitro, this phenomenon correlated with inactivation of EphA2 receptor, lack of AKT response and downregulation of bFGF. We also demonstrated that secreted bFGF from EWS cells acted as chemoattractant for endothelial cells. Furthermore, interaction between EphA2 and CAV1 was necessary for the right localization and signaling of the receptor to produce bFGF through AKT and promote migration of endothelial cells. Finally, introduction of a dominant-negative form of EphA2 into EWS cells mostly reproduced the effects occurred by CAV1 silencing, strongly suggesting that the axis EphA2-CAV1 participates in the promotion of endothelial cell migration toward the tumors favoring EWS angiogenesis. PMID:23951165

Sáinz-Jaspeado, Miguel; Huertas-Martinez, Juan; Lagares-Tena, Laura; Martin Liberal, Juan; Mateo-Lozano, Silvia; de Alava, Enrique; de Torres, Carmen; Mora, Jaume; del Muro, Xavier Garcia; Tirado, Oscar M.

2013-01-01

181

The combination of CD99 and NKX2.2, a transcriptional target of EWSR1-FLI1, is highly specific for the diagnosis of Ewing sarcoma.  

PubMed

Ewing sarcoma (ES) is a high-grade malignant neoplasm primarily affecting children and young adults. The diagnosis of ES is often difficult because of its broad differential diagnosis comprising a diverse group of small round cell tumors (SRCTs). Although the identification of tumor type-specific fusion genes by molecular testing is the gold standard for the diagnosis of ES, such approaches are not always available in a routine pathology practice. Thus, a reliable immunohistochemical marker is required. A recent study using a limited number of tumor samples has shown that NKX2.2, a putative transcriptional target of EWSR1-FLI1, is a useful marker for the diagnosis of ES. In the present study, the immunohistochemical expression of NKX2.2 was evaluated on 46 genetically confirmed ES and 85 non-ES SRCTs, together with comparative assessment of CD99 and other molecular targets of EWSR1-FLI1, including NR0B1, E2F3, and EZH2. NKX2.2 was expressed in 37 (80 %) of the ES samples with a mostly diffuse and strong staining pattern, and 14 (16 %) of the non-ES SRCTs, including olfactory neuroblastomas, extraskeletal myxoid chondrosarcoma, mesenchymal chondrosarcoma, small cell carcinomas, and Merkel cell carcinoma, also expressed this marker. The sensitivity and specificity of the NKX2.2 expression in this cohort were 80 and 84 %, respectively. The specificity when combined with CD99 was 98 %, with exceptional expression of both markers in only two non-ES SRCTs, including one case each of mesenchymal chondrosarcoma and small cell carcinoma. NR0B1, E2F3, and EZH2 were less sensitive for specific markers for ES when applied singly or in any combination. In conclusion, the study reinforces that NKX2.2 is a useful immunohistochemical marker for ES, and that the combination of CD99 and NKX2.2 is a powerful diagnostic tool that can differentiate ES from other SRCTs. PMID:25031013

Shibuya, Ryo; Matsuyama, Atsuji; Nakamoto, Mitsuhiro; Shiba, Eisuke; Kasai, Takahiko; Hisaoka, Masanori

2014-11-01

182

Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma  

ClinicalTrials.gov

Adult Alveolar Soft Part Sarcoma; Adult Angiosarcoma; Adult Desmoplastic Small Round Cell Tumor; Adult Epithelioid Hemangioendothelioma; Adult Epithelioid Sarcoma; Adult Extraskeletal Myxoid Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Mesenchymoma; Adult Malignant Peripheral Nerve Sheath Tumor; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Adult Unclassified Pleomorphic Sarcoma; Chondrosarcoma; Clear Cell Sarcoma of the Kidney; Conjunctival Kaposi Sarcoma; Dermatofibrosarcoma Protuberans; Gastrointestinal Stromal Tumor; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Metastatic Osteosarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Adult Unclassified Pleomorphic Sarcoma of Bone; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Kaposi Sarcoma; Recurrent Osteosarcoma; Recurrent Uterine Corpus Sarcoma; Small Intestine Leiomyosarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma; Unclassified Pleomorphic Sarcoma of Bone

2015-02-18

183

General Information about Ewing Sarcoma  

MedlinePLUS

... lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken. MRI (magnetic resonance imaging) : A procedure that uses a magnet, radio waves , and a computer to make a series of detailed pictures of ...

184

Insulin-Like Growth Factor 1 Receptor as a Therapeutic Target in Ewing Sarcoma: Lack of Consistent Upregulation or Recurrent Mutation and a Review of the Clinical Trial Literature  

PubMed Central

The insulin-like growth factor 1 receptor (IGF-1R) has been considered an important therapeutic target in Ewing sarcoma (ES), generating a need to identify the subset of patients most likely to respond to IGF-1R inhibitors. We assessed IGF-1R expression in ES cell lines and patient tumors to understand the variable clinical responses to anti-IGF-1R therapy. Using ligand-binding displacement, we measured between 13,000 and 40,000 receptors per cell in ES cell lines. We used ELISA to quantify IGF-1R in patient tumors, which expressed 4.8%??± 3.7 to 20.0%??± 0.2 of the levels in a positive control cell line overexpressing IGF-1R. Flow cytometry showed markedly reduced IGF-1R expression in ES cell lines compared to a standard positive control cell line. The IGF1R gene was sequenced in 47 ES tumor samples and 8 ES cell lines; only one tumor sample showed a nonsynonymous mutation, R1353H, in a region with low functional impact. Finally, we assessed IGF-1R pathway activity in the ES stem cell (ESSC) population, to characterize its potential for resistance to anti-IGF-1R therapy, using Luminex technology. We found no significant differences in IGF-1R pathway activity between ESSCs and the total cell population. Overall, our findings suggest that IGF-1R as a therapeutic target in this sarcoma may require reevaluation. PMID:23431249

O'Neill, Alison; Shah, Nilay; Zitomersky, Naamah; Ladanyi, Marc; Shukla, Neerav; Üren, Aykut; Loeb, David; Toretsky, Jeffrey

2013-01-01

185

Critical contribution of MCL-1 in EMT-associated chemo-resistance in A549 non-small cell lung cancer.  

PubMed

Non-small cell lung cancer (NSCLC) is one of the leading causes of death in all lung cancer patients due to its metastatic spread. Even though cisplatin treatment after surgical resection of the primary tumor has been established as a standard chemotherapy for residual disease including metastatic spread, NSCLC often acquires a resistance against chemotherapy, and metastatic disease is often observed. Amongst many potential mechanisms, epithelial-to-mesenchymal transition (EMT) has been considered as an important process in acquiring both metastatic spread and chemo-resistance of NSCLC. In this study, we identified MCL-1 as a critical molecule for chemo-resistance in A549 cells associated with TGF-?-induced EMT. Importantly, downregulation of MCL-1 by siRNA or inhibition of MCL-1 with pan-BCL2 inhibitor to inhibit MCL-1 was able to overcome the EMT-associated chemo-resistance in A549 cells. Collectively, MCL-1 can be a new therapeutic target for overcoming EMT-associated chemo-resistance in NSCLC patients in the context of post-operative chemotherapies. PMID:25647738

Toge, Masayoshi; Yokoyama, Satoru; Kato, Shinichiro; Sakurai, Hiroaki; Senda, Kazutaka; Doki, Yoshinori; Hayakawa, Yoshihiro; Yoshimura, Naoki; Saiki, Ikuo

2015-04-01

186

Chemo-resistant melanoma sensitized by tamoxifen to low dose curcumin treatment through induction of apoptosis and autophagy.  

PubMed

Melanoma is the deadliest form of skin cancer, which is notoriously aggressive and chemo-resistant, and for which there is little effective treatment available if it goes undetected. Curcumin from the turmeric spice (Curcuma longa) has long been used in Southeast Asian medicine to alleviate ailments and cure an array of diseases and disorders. It possesses anti-inflammatory, anti-oxidant and most importantly anti-carcinogenic activity. There have been contradictory reports discussing the efficacy of curcumin-induced death on melanoma. In this report we show that curcumin does induce apoptosis in A375 and the relatively resistant G361 malignant human melanoma cell lines at higher doses. Tamoxifen is an estrogen receptor (ER) blocker that is used for ER positive breast cancer treatment. Recently, tamoxifen has been shown to directly target the mitochondria. Given that curcumin is a pro oxidant and tamoxifen can act on mitochondria, we ask whether the combinatorial treatment could result in synergistic induction of apoptosis in chemo-resistant melanoma. Our results show a corresponding increase in phosphatidyl serine flipping, mitochondria depolarization and reactive oxygen species (ROS) generation by the combined treatment at lower doses. Interestingly, there was significant induction of autophagy along with apoptosis following the combined treatment. Importantly, non-cancerous cells are unaffected by the combination of these non-toxic compounds. However, once exposed to low doses of this co-treatment, melanoma cells still retain signals to commit suicide even after removal of the drugs. This combination provides a non-toxic option for combinatorial chemotherapy with great potential for future use. PMID:21088500

Chatterjee, Sudipa June; Pandey, Siyaram

2011-01-15

187

The Epidemiology of Sarcoma  

PubMed Central

Sarcomas account for over 20% of all pediatric solid malignant cancers and less than 1% of all adult solid malignant cancers. The vast majority of diagnosed sarcomas will be soft tissue sarcomas, while malignant bone tumors make up just over 10% of sarcomas. The risks for sarcoma are not well-understood. We evaluated the existing literature on the epidemiology and etiology of sarcoma. Risks for sarcoma development can be divided into environmental exposures, genetic susceptibility, and an interaction between the two. HIV-positive individuals are at an increased risk for Kaposi’s sarcoma, even though HHV8 is the causative virus. Radiation exposure from radiotherapy has been strongly associated with secondary sarcoma development in certain cancer patients. In fact, the risk of malignant bone tumors increases as the cumulative dose of radiation to the bone increases (p for trend <0.001). A recent meta-analysis reported that children with a history of hernias have a greater risk of developing Ewing’s sarcoma (adjusted OR 3.2, 95% CI 1.9, 5.7). Bone development during pubertal growth spurts has been associated with osteosarcoma development. Occupational factors such as job type, industry, and exposures to chemicals such as herbicides and chlorophenols have been suggested as risk factors for sarcomas. A case-control study found a significant increase in soft tissue sarcoma risk among gardeners (adjusted OR 4.1, 95% CI 1.00, 14.00), but not among those strictly involved in farming. A European-based study reported an increased risk in bone tumors among blacksmiths, toolmakers, or machine-tool operators (adjusted OR 2.14, 95% CI 1.08, 4.26). Maternal and paternal characteristics such as occupation, age, smoking status, and health conditions experienced during pregnancy also have been suggested as sarcoma risk factors and would be important to assess in future studies. The limited studies we identified demonstrate significant relationships with sarcoma risk, but many of these results now require further validation on larger populations. Furthermore, little is known about the biologic mechanisms behind each epidemiologic association assessed in the literature. Future molecular epidemiology studies may increase our understanding of the genetic versus environmental contributions to tumorigenesis in this often deadly cancer in children and adults. PMID:23036164

2012-01-01

188

Basic fibroblast growth factor in the bone microenvironment enhances cell motility and invasion of Ewing's sarcoma family of tumours by activating the FGFR1–PI3K–Rac1 pathway  

PubMed Central

Background: Ewing's sarcoma family of tumours (ESFT) is a malignant small round-cell tumour of the bone and soft tissues. It is characterised by a strong tendency to invade and form metastases. The microenvironment of the bone marrow is a large repository for many growth factors, including the basic fibroblast growth factor (bFGF). However, the role of bFGF in the invasive and metastatic phenotype of ESFT has not been investigated. Methods: The motility and invasion of ESFT cells were assessed by a wound-healing assay, chemotaxis assay, and invasion assay. The expression and activation of FGF receptors (FGFRs) in ESFT cell lines and clinical samples were detected by RT–PCR, western blotting, and immunohistochemistry. The morphology of ESFT cells was investigated by phase-contrast microscopy and fluorescence staining for actin. Activation of Rac1 was analysed by a pull-down assay. Results: bFGF strongly induced the motility and invasion of ESFT cells. Furthermore, FGFR1 was found to be expressed and activated in clinical samples of ESFT. Basic FGF-induced cell motility was mediated through the FGFR1–phosphatidylinositol 3-kinase (PI3K)–Rac1 pathway. Conditioned medium from bone marrow stromal cells induced the motility of ESFT cells by activating bFGF/FGFR1 signalling. Conclusion: The bFGF–FGFR1–PI3K–Rac1 pathway in the bone microenvironment may have a significant role in the invasion and metastasis of ESFT. PMID:20606682

Kamura, S; Matsumoto, Y; Fukushi, J-i; Fujiwara, T; Iida, K; Okada, Y; Iwamoto, Y

2010-01-01

189

The epidemiology of sarcoma.  

PubMed

Sarcomas account for over 20% of all pediatric solid malignant cancers and less than 1% of all adult solid malignant cancers. The vast majority of diagnosed sarcomas will be soft tissue sarcomas, while malignant bone tumors make up just over 10% of sarcomas. The risks for sarcoma are not well-understood. We evaluated the existing literature on the epidemiology and etiology of sarcoma. Risks for sarcoma development can be divided into environmental exposures, genetic susceptibility, and an interaction between the two. HIV-positive individuals are at an increased risk for Kaposi's sarcoma, even though HHV8 is the causative virus. Radiation exposure from radiotherapy has been strongly associated with secondary sarcoma development in certain cancer patients. In fact, the risk of malignant bone tumors increases as the cumulative dose of radiation to the bone increases (p for trend <0.001). A recent meta-analysis reported that children with a history of hernias have a greater risk of developing Ewing's sarcoma (adjusted OR 3.2, 95% CI 1.9, 5.7). Bone development during pubertal growth spurts has been associated with osteosarcoma development. Occupational factors such as job type, industry, and exposures to chemicals such as herbicides and chlorophenols have been suggested as risk factors for sarcomas. A case-control study found a significant increase in soft tissue sarcoma risk among gardeners (adjusted OR 4.1, 95% CI 1.00, 14.00), but not among those strictly involved in farming. A European-based study reported an increased risk in bone tumors among blacksmiths, toolmakers, or machine-tool operators (adjusted OR 2.14, 95% CI 1.08, 4.26). Maternal and paternal characteristics such as occupation, age, smoking status, and health conditions experienced during pregnancy also have been suggested as sarcoma risk factors and would be important to assess in future studies. The limited studies we identified demonstrate significant relationships with sarcoma risk, but many of these results now require further validation on larger populations. Furthermore, little is known about the biologic mechanisms behind each epidemiologic association assessed in the literature. Future molecular epidemiology studies may increase our understanding of the genetic versus environmental contributions to tumorigenesis in this often deadly cancer in children and adults. PMID:23036164

Burningham, Zachary; Hashibe, Mia; Spector, Logan; Schiffman, Joshua D

2012-01-01

190

Targeted therapies for bone sarcomas  

PubMed Central

Bone sarcomas include a very large number of tumour subtypes, which originate form bone and more particularly from mesenchymal stem cell lineage. Osteosarcoma, Ewing's sarcoma and chondrosarcoma, the three main bone sarcoma entities develop in a favourable microenvironment composed by bone cells, blood vessels, immune cells, based on the ‘seed and soil theory'. Current therapy associates surgery and chemotherapy, however, bone sarcomas remain diseases with high morbidity and mortality especially in children and adolescents. In the past decade, various new therapeutic approaches emerged and target the tumour niche or/and directly the tumour cells by acting on signalling/metabolic pathways involved in cell proliferation, apoptosis or drug resistance. The present review gives a brief overview from basic to clinical assessment of the main targeted therapies of bone sarcoma cells. PMID:24422100

Heymann, Dominique; Rédini, Françoise

2013-01-01

191

Targeted therapies for bone sarcomas.  

PubMed

Bone sarcomas include a very large number of tumour subtypes, which originate form bone and more particularly from mesenchymal stem cell lineage. Osteosarcoma, Ewing's sarcoma and chondrosarcoma, the three main bone sarcoma entities develop in a favourable microenvironment composed by bone cells, blood vessels, immune cells, based on the 'seed and soil theory'. Current therapy associates surgery and chemotherapy, however, bone sarcomas remain diseases with high morbidity and mortality especially in children and adolescents. In the past decade, various new therapeutic approaches emerged and target the tumour niche or/and directly the tumour cells by acting on signalling/metabolic pathways involved in cell proliferation, apoptosis or drug resistance. The present review gives a brief overview from basic to clinical assessment of the main targeted therapies of bone sarcoma cells. PMID:24422100

Heymann, Dominique; Rédini, Françoise

2013-01-01

192

Mir-34a Mimics Are Potential Therapeutic Agents for p53-Mutated and Chemo-Resistant Brain Tumour Cells  

PubMed Central

Chemotherapeutic drug resistance and relapse remains a major challenge for paediatric (medulloblastoma) and adult (glioblastoma) brain tumour treatment. Medulloblastoma tumours and cell lines with mutations in the p53 signalling pathway have been shown to be specifically insensitive to DNA damaging agents. The aim of this study was to investigate the potential of triggering cell death in p53 mutated medulloblastoma cells by a direct activation of pro-death signalling downstream of p53 activation. Since non-coding microRNAs (miRNAs) have the ability to fine tune the expression of a variety of target genes, orchestrating multiple downstream effects, we hypothesised that triggering the expression of a p53 target miRNA could induce cell death in chemo-resistant cells. Treatment with etoposide, increased miR-34a levels in a p53-dependent fashion and the level of miR-34a transcription was correlated with the cell sensitivity to etoposide. miR-34a activity was validated by measuring the expression levels of one of its well described target: the NADH dependent sirtuin1 (SIRT1). Whilst drugs directly targeting SIRT1, were potent to trigger cell death at high concentrations only, introduction of synthetic miR-34a mimics was able to induce cell death in p53 mutated medulloblastoma and glioblastoma cell lines. Our results show that the need of a functional p53 signaling pathway can be bypassed by direct activation of miR-34a in brain tumour cells. PMID:25250818

Fan, Yuen Ngan; Meley, Daniel; Pizer, Barry; Sée, Violaine

2014-01-01

193

Searching for molecular targets in sarcoma.  

PubMed

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

2012-07-01

194

Epidemiology and therapies for metastatic sarcoma  

PubMed Central

Sarcomas are cancers arising from the mesenchymal layer that affect children, adolescents, young adults, and adults. Although most sarcomas are localized, many display a remarkable predilection for metastasis to the lungs, liver, bones, subcutaneous tissue, and lymph nodes. Additionally, many sarcoma patients presenting initially with localized disease may relapse at metastatic sites. While localized sarcomas can often be cured through surgery and often radiation, controversies exist over optimal management of patients with metastatic sarcoma. Combinations of chemotherapy are the most effective in many settings, and many promising new agents are under active investigation or are being explored in preclinical models. Metastatic sarcomas are excellent candidates for novel approaches with additional agents as they have demonstrated chemosensitivity and affect a portion of the population that is motivated toward curative therapy. In this paper, we provide an overview on the common sarcomas of childhood (rhabdomyosarcoma), adolescence, and young adults (osteosarcoma, Ewing sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor) and older adults (leiomyosarcoma, liposarcoma, and undifferentiated high grade sarcoma) in terms of the epidemiology, current therapy, promising therapeutic directions and outcome with a focus on metastatic disease. Potential advances in terms of promising therapy and biologic insights may lead to more effective and safer therapies; however, more clinical trials and research are needed for patients with metastatic sarcoma. PMID:23700373

Amankwah, Ernest K; Conley, Anthony P; Reed, Damon R

2013-01-01

195

Extremity preservation by combined modality therapy in sarcomas of the hand and foot: an analysis of local control, disease free survival and functional result  

Microsoft Academic Search

A primary tumor arising in the hand or foot represents an uncommon presentation for patients with Ewing's sarcoma (ES) or soft tissue sarcoma (STS). While there exists considerable literature on the treatment of extremity sarcomas, very little deals specifically with lesions of the hand or foot. It remains controversial whether these lesions can be successfully treated with combined modality therapy

Timothy J. Kinsella; Jay S. Loeffler; Benedick A. Fraass; Joel Tepper

1983-01-01

196

Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas  

ClinicalTrials.gov

Childhood Solid Neoplasm; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Neuroblastoma; Recurrent Osteosarcoma; Refractory Childhood Hodgkin Lymphoma; Refractory Non-Hodgkin Lymphoma

2015-03-18

197

Retroperitoneal Sarcomas  

Microsoft Academic Search

\\u000a Retroperitoneal sarcomas are rare, accounting for approximately 10–15% of all soft-tissue sarcomas with an estimated 1,500\\u000a cases occurring annually in USA [1, 2]. The most common histologic subtypes include liposarcoma, leiomyosarcoma, and malignant\\u000a fibrohistiocytoma [3]. Approximately 33–50% of retroperitoneal sarcomas are low grade, in contrast to 19–26% of extremity\\u000a and truncal sarcomas [4, 5], possibly explaining the lower incidence or

Brian Czito; John Donohue; Christopher G. Willett; Douglas Tyler; Ivy A. Petersen; Robert Krempien; Kenneth S. Hu; Felipe A. Calvo; Matthew D. Callister; Kaled M. Alektiar; Michael Eble; Ana Alvarez

198

Bone Sarcomas: From Biology to Targeted Therapies  

PubMed Central

Primary malignant bone tumours, osteosarcomas, and Ewing sarcomas are rare diseases which occur mainly in adolescents and young adults. With the current therapies, some patients remain very difficult to treat, such as tumour with poor histological response to preoperative CT (or large initial tumour volume for Ewing sarcomas not operated), patients with multiple metastases at or those who relapsed. In order to develop new therapies against these rare tumours, we need to unveil the key driving factors and molecular abnormalities behind the malignant characteristics and to broaden our understanding of the phenomena sustaining the metastatic phenotype and treatment resistance in these tumours. In this paper, starting with the biology of these tumours, we will discuss potential therapeutic targets aimed at increasing local tumour control, limiting metastatic spread, and finally improving patient survival. PMID:23226965

Gaspar, Nathalie; Di Giannatale, Angela; Geoerger, Birgit; Redini, Françoise; Corradini, Nadège; Enz-Werle, Natacha; Tirode, Franck; Marec-Berard, Perrine; Gentet, Jean-Claude; Laurence, Valérie; Piperno-Neumann, Sophie; Oberlin, Odile; Brugieres, Laurence

2012-01-01

199

Effect of Indirect Nonequilibrium Atmospheric Pressure Plasma on Anti-Proliferative Activity against Chronic Chemo-Resistant Ovarian Cancer Cells In Vitro and In Vivo  

PubMed Central

Purpose Nonequilibrium atmospheric pressure plasma (NEAPP) therapy has recently been focused on as a novel medical practice. Using cells with acquired paclitaxel/cisplatin resistance, we elucidated effects of indirect NEAPP-activated medium (NEAPP-AM) exposure on cell viability and tumor growth in vitro and in vivo. Methods Using chronic paclitaxel/cisplatin-resistant ovarian cancer cells, we applied indirect NEAPP-exposed medium to cells and xenografted tumors in a mouse model. Furthermore, we examined the role of reactive oxygen species (ROS) or their scavengers in the above-mentioned EOC cells. Results We assessed the viability of NOS2 and NOS3 cells exposed to NEAPP-AM, which was prepared beforehand by irradiation with NEAPP for the indicated time. In NOS2 cells, viability decreased by approximately 30% after NEAPP-AM 120-sec treatment (P<0.01). The growth-inhibitory effects of NEAPP-AM were completely inhibited by N-acetyl cysteine treatment, while L-buthionine-[S, R]-sulfoximine, an inhibitor of the ROS scavenger used with NEAPP-AM, decreased cell viability by 85% after NEAPP-AM 60-sec treatment(P<0.05) and by 52% after 120 sec, compared to the control (P<0.01). In the murine subcutaneous tumor-formation model, NEAPP-AM injection resulted in an average inhibition of the NOS2 cell-inoculated tumor by 66% (P<0.05) and NOS2TR cell-inoculated tumor by 52% (P<0.05), as compared with the control. Conclusion We demonstrated that plasma-activated medium also had an anti-tumor effect on chemo-resistant cells in vitro and in vivo. Indirect plasma therapy is a promising treatment option for EOC and may contribute to a better patient prognosis in the future. PMID:24367486

Utsumi, Fumi; Kajiyama, Hiroaki; Nakamura, Kae; Tanaka, Hiromasa; Mizuno, Masaaki; Ishikawa, Kenji; Kondo, Hiroki; Kano, Hiroyuki; Hori, Masaru; Kikkawa, Fumitaka

2013-01-01

200

Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways  

SciTech Connect

5-Fluorouracil (5-FU) is one of the widely used chemotherapeutic drugs targeting various cancers, but its chemo-resistance remains as a major obstacle in clinical settings. In the present study, HT-29 colon cancer cells were markedly sensitized to apoptosis by both 5-FU and genistein compared to the 5-FU treatment alone. There is an emerging evidence that genistein, soy-derived phytoestrogen, may have potential as a chemotherapeutic agent capable of inducing apoptosis or suppressing tumor promoting proteins such as cyclooxygenase-2 (COX-2). However, the precise mechanism of cellular cytotoxicity of genistein is not known. The present study focused on the correlation of AMPK and COX-2 in combined cytotoxicity of 5-FU and genistein, since AMPK is known as a primary cellular homeostasis regulator and a possible target molecule of cancer treatment, and COX-2 as cell proliferation and anti-apoptotic molecule. Our results demonstrated that the combination of 5-FU and genistein abolished the up-regulated state of COX-2 and prostaglandin secretion caused by 5-FU treatment in HT-29 colon cancer cells. These appear to be followed by the specific activation of AMPK and the up-regulation of p53, p21, and Bax by genistein. Under same conditions, the induction of Glut-1 by 5-FU was diminished by the combination treatment with 5-FU and genistein. Furthermore, the reactive oxygen species (ROS) was found as an upstream signal for AMPK activation by genistein. These results suggested that the combination of 5-FU and genistein exert a novel chemotherapeutic effect in colon cancers, and AMPK may be a novel regulatory molecule of COX-2 expression, further implying its involvement in cytotoxicity caused by genistein.

Hwang, Jin-Taek [Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University College of Medicine, Seoul 130-701 (Korea, Republic of); Ha, Joohun [Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University College of Medicine, Seoul 130-701 (Korea, Republic of); Park, Ock Jin [Department of Food and Nutrition, Hannam University, 133 Ojeong-dong Daedeok-gu, Daejeon 306-791 (Korea, Republic of)]. E-mail: ojpark@hannam.ac.kr

2005-07-01

201

Circulating tumor cells in sarcomas: a brief review.  

PubMed

Although rare, sarcomas represent a source of significant morbidity and mortality with nearly one reported death for every two new diagnoses. The detection and surveillance of circulating tumor cells (or CTCs) has been found to have significant clinical utility in epithelial malignancies, such as carcinoma of the colon, breast and prostate. Here, we summarize what is known regarding CTCs in sarcomas. Although still in its relative infancy, the detection of CTCs in sarcoma patients may help to diagnose and predict recurrence or metastasis as well as improve the overall management of sarcoma patients. CTCs are most often detected via reverse transcriptase polymerase chain reaction or antibody-based detection of cell surface proteins, including flow cytometry. Samples may be obtained from either peripheral blood or bone marrow. CTC detection in translocation sarcomas is perhaps most promising, as a recurrent abnormal gene fusion product can be detected in involved individuals but not in the normal patient. Studies in Ewing's sarcoma/peripheral neuroectodermal tumor, synovial sarcoma and alveolar soft part sarcoma have confirmed the feasibility of this approach. Other investigators have turned toward detection of more universal markers of sarcomas, such as the pan-mesenchymal marker Vimentin. In the case of osteosarcoma, more specific markers of osteogenic differentiation (Type I Collagen) have been utilized. In summary, although in its relative nascency, the use of CTC detection for the management of sarcoma patients shows initial promise. PMID:25491143

Chang, Le; Asatrian, Greg; Dry, Sarah M; James, Aaron W

2015-01-01

202

[Molecular biology of sarcoma and therapeutic choices].  

PubMed

Soft tissue sarcomas (STS) are a set of very heterogeneous tumors with numerous histological categories. The development of the molecular biology allowed identifying recurring molecular anomalies in certain subgroups of sarcomas, being able to represent diagnostic, prognosis and therapeutic tools. The molecular classification of STS includes until today 5 main groups of abnormalities: sarcomas with "simple genomic profile" showing reciprocal (1) chromosomal translocations, (2) activating mutation, (3) inhibitive mutation or (4) simple amplification; (5) sarcomas with "complex genomic profile" can include several tens of molecular abnormalities. The development of new-targeted therapies is based on the identification of a target, specific of a tumors subgroup and involved in carcinogenesis mechanisms and/or tumoral growth. Then, the aim of clinical research is to establish the proof of the concept through clinical trials, demonstrating the benefit brought to the patient and ending in the marketing of the drug. This proof of the concept was clearly established for imatinib, sunitinib and regorafenib in gastrointestinal stromal tumors, for imatinib in dermatofibrosarcoma protuberans and pigmented vilo-nodular synovitis, for denosumab in giant cell tumors of the bone, ending in the authorization to use these new therapies in these indications. It is in progress and promising for anti-IGF-1R in Ewing sarcomas, for crizotinib in myofibroblastic inflammatory tumors, for mTOR inhibitor in PEComas... The role of molecular abnormalities identified in the mechanisms of tumoral progress for sarcomas and their potential therapeutic impact will be detailed. PMID:25609490

Dufresne, Armelle; Cassier, Philippe; Heudel, Pierre; Pissaloux, Daniel; Wang, Qing; Blay, Jean-Yves; Ray-Coquard, Isabelle

2015-01-01

203

Mesenchymal Stromal Cell Dependent Regression of Pulmonary Metastasis from Ewing’s  

PubMed Central

Introduction: Ewing’s sarcoma (ES) is the second most common bone tumor in children. Survival has not improved over the last decade and once pulmonary metastatic disease is present, survival is dismal. Mesenchymal stromal cell (MSC) therapy has shown potential benefit for Kaposi’s sarcoma; however, the role of progenitor cell therapies for cancer remains controversial. MSC treatment of ES or pulmonary metastatic disease has not been demonstrated. We have developed an orthotopic xenograft model of ES in which animals develop spontaneous pulmonary metastases. Within this model, we demonstrate the use of MSCs to target ES lung metastasis. Materials and Methods: Human ES cells were transfected with luciferase and injected into the rib of nude mice. Development of pulmonary metastases was confirmed by imaging. After flow cytometry based characterization, MSCs were injected into the tail vein of nude mice with established local ES tumor or pulmonary metastasis. Mice were treated with intravenous MSCs weekly followed by bioluminescent imaging. Results: The intravenous injection of MSCs in an ES model decreases the volume of pulmonary metastatic lesions; however, no effect on primary chest wall tumor size is observed. Thus verifying the MSC preferential homing to the lung. MSCs are found to “home to” the pulmonary parenchyma and remain engrafted up to 5?days after delivery. Discussion: MSC treatment of ES slows growth of pulmonary metastasis. MSCs have more affinity for pulmonary metastasis and can effect a greater decrease in tumor growth in the lungs compared to the primary tumor site. PMID:24910847

Hayes-Jordan, Andrea; Wang, Yong Xin; Walker, Peter; Cox, Charles S.

2014-01-01

204

Do pathological fractures influence survival and local recurrence rate in bony sarcomas?  

PubMed

The influence of pathological fracture on surgical management, local recurrence and survival was established in patients with high grade, localised, extremity osteosarcoma (n=484), chondrosarcoma (n=130) and Ewing's sarcoma (n=156). Limb salvage was possible in 79% of patients with a fracture compared to 84% of patients without a fracture (p=0.17). No difference in local recurrence was found between fracture and control groups. In univariate analysis, survival in the fracture group was lower than in the control group for osteosarcoma (34% versus 58%, p<0.01) and chondrosarcoma (35% versus 63%, p=0.04), but not for Ewing's sarcoma (75% versus 64%, p=0.80). In multivariate analysis, fracture remained a significant predictor of survival for osteosarcoma, but not for chondrosarcoma, where dedifferentiated subtype appeared to be decisive. Pathological fracture independently predicts worse survival in osteosarcoma, but not chondrosarcoma and Ewing's sarcoma. Limb saving surgery seems safe, if adequate resection margins are achieved. PMID:17698347

Bramer, J A M; Abudu, A A; Grimer, R J; Carter, S R; Tillman, R M

2007-09-01

205

Kaposi Sarcoma  

Cancer.gov

DCEG researchers conduct studies on Kaposi sarcoma (KS). Infection with KS-associated herpesvirus (KSHV, also known as human herpesvirus-8 [HHV-8]) is necessary for KS to occur, but other factors, such as HIV infection, greatly increase the risk of the disease.

206

Microsatellite instability in sarcoma: fact or fiction?  

PubMed

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. PMID:23401795

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

2012-01-01

207

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. PMID:23401795

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

2012-01-01

208

Uterine sarcoma  

PubMed Central

Objectives: To investigate the clinical and histopathological characteristics, with the prognostic factors, treatment outcome, pattern of relapse, and survival analysis of uterine sarcoma patient Methods: All patients with histologically proven uterine sarcoma were identified using the database at King Abdulaziz University Hospital, Jeddah, Saudi Arabia between January 2000 and December 2012. Results: A total of 36 patients with uterine sarcoma were reviewed. The median age of all patients was 57 years, and the mean age was 57.72±13.17 years. Carcinosarcoma was reported in 21 patients (58%), leiomyosarcoma in 7 (19%), undifferentiated endometrial sarcoma in 6 (17%), and rhabdomyosarcoma in 2 (6%). Approximately half of the patients were stages III and IV (28% and 25%), while 15 patients (41%) were stage I; only 2 patients (6%) were stage II. The surgical treatment was hysterectomy and bilateral salpingoophorectomy (H+BSO) plus staging in 18 patients (50%), while in 4 patients (19%), H+BSO plus debulking was performed. Adjuvant chemotherapy was given in 24 (69%) and adjuvant radiotherapy in 5 (14%) cases, At a median follow-up period of 13.5 months, 8 patients (22%) relapsed. The 2-year disease-free survival (DFS) rate was 22% and the 5-year was 14%. In the multivariate analysis, the advanced stages (p=0.015) and lymph vascular invasion (p=0.0001) were associated with poor DFS, while the use of chemotherapy significantly improved the DFS (p=0.027). Conclusions: The poor outcome of high-grade uterine sarcoma patients was identified, and only one third of patients (30%) survived for 2 years. This finding necessitates the need for more aggressive tools to fight this disease. PMID:25316466

Sait, Hesham K.; Anfinan, Nisrin M.; Sayed, Mohamed E. El; Alkhayyat, Shadi S.; Ghanem, Ahmed T.; Abayazid, Reem M.; Sait, Khalid H.

2014-01-01

209

Preclinical evaluation of nanoparticle albumin-bound paclitaxel for treatment of pediatric bone sarcoma.  

PubMed

The combination of docetaxel and gemcitabine is frequently used to treat recurrent bone sarcoma. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is less toxic and more active than docetaxel or paclitaxel for breast cancer patients. The combination of nab-paclitaxel and gemcitabine has preclinical synergy and is approved to treat pancreatic cancer. We observed growth inhibition and improved survival with nab-paclitaxel in a Ewing sarcoma xenograft, and activity was additive with gemcitabine in an osteosarcoma model. Primary Ewing sarcoma tumors expressed the transport protein SPARC, previously associated with nab-paclitaxel activity. These findings provide rationale for further evaluation of nab-paclitaxel with gemcitabine for bone sarcoma. PMID:24753077

Wagner, Lars M; Yin, Hong; Eaves, David; Currier, Mark; Cripe, Timothy P

2014-11-01

210

Sarcoma Foundation of America  

MedlinePLUS

... Mission The mission of the Sarcoma Foundation of America (SFA) is to advocate for sarcoma patients by ... SARC has leveraged a gener... Sarcoma Foundation of America 9899 Main Street, Suite 204 Damascus, MD 20872 ...

211

Novel therapeutic approaches in pediatric and young adult sarcomas.  

PubMed

Novel therapy as part of sarcoma treatment schemas can enhance quality of life and is important in improving outcomes of high-risk sarcomas. Additional chemotherapy and biotherapy options to reduce tumor burden and prevent metastases include intra-arterial chemotherapy in osteosarcoma; intrapleural chemotherapy, aerosol 9-nitrocamptothecin, or protracted irinotecan and temozolomide in Ewing's sarcoma; continuous hyperthermic peritoneal perfusion for malignancy involving the peritoneum, such as desmoplastic small round cell tumor; and ifosfamide with muramyl tripeptide phosphatidyl ethanolamine liposomes in osteosarcoma. These treatments bring improved control of symptoms, including reduction in nausea, mucositis, cardiotoxicity, and central nervous system toxicity. Portable infusion devices have facilitated introduction of outpatient doxorubicin, ifosfamide, and methotrexate regimens and home-infusion irinotecan. Physical approaches to eliminate sarcoma tumors and metastases are critical for durable responses. Novel local control measures include embolization before surgery, radiosensitization, anti-vascular endothelial growth factor therapy during chemo-radiotherapy, proton therapy, samarium, thermal ablation (radiofrequency ablation), and cryoablation. PMID:17254532

Anderson, Peter M; Pearson, Margaret

2006-07-01

212

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

213

EXTREMITY SARCOMA SURGERY IN YOUNGER CHILDREN: TEN YEARS OF PATIENTS TEN YEARS AND UNDER  

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. PMID:22096434

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

2011-01-01

214

Pediatric Sarcoma in Central America: Outcomes, Challenges and Plans for Improvement  

PubMed Central

Background Children with cancer in middle-income countries have inferior outcomes to those in high-income countries. The magnitude and drivers for this survival gap are not well understood. We sought to describe patterns of clinical presentation, magnitude of treatment abandonment, and survival in children with sarcoma in Central America. Methods Retrospective review of hospital-based registries from national pediatric oncology referral centers. Patients with newly diagnosed osteosarcoma, Ewing sarcoma (Ewing), rhabdomyosarcoma (RMS), and soft tissue sarcomas (STS) between 1/1/00-12/31/09 were included. Survival analysis was performed using standard definitions of overall and event-free survival (OS and EFS) and with abandonment included as an event (AOS and AEFS). Results A total of 785 new cases of pediatric sarcoma were reported (264 osteosarcoma, 175 Ewing, 240 RMS, and 106 STS). Metastatic disease at presentation was high (osteosarcoma 38%, Ewing 39%, RMS 29% and STS 21%). Treatment abandonment rate was high, particularly among patients with extremity bone sarcomas (osteosarcoma 30%, Ewing 15%, RMS 25% and STS 15%). Of 559 patients experiencing a first event, 59% had either relapse or progressive disease. The 4-year OS was 40% (SE±3%) and EFS was 30% (SE±2%), but further decreased to 31% (SE±2%) and 24% (SE±2%), when abandonment was taken into account. Conclusion High rate of metastases and treatment abandonment, and difficulty with upfront treatment effectiveness are important contributors to poor survival of children with pediatric sarcomas in Central America. Initiatives for early diagnosis, psychosocial support, quality improvement, and multidisciplinary care are warranted to improve outcomes. PMID:22972687

Friedrich, Paola; Ortiz, Roberta; Strait, Kelly; Fuentes, Soad; Gamboa, Yéssica; Arambú, Ingrid; Ah-Chu-Sanchez, María; London, Wendy; Rodríguez-Galindo, Carlos; Antillón-Klussmann, Federico; Báez, Fulgencio

2012-01-01

215

Histologic Variability and Diverse Oncologic Outcomes of Prostate Sarcomas  

PubMed Central

Purpose Primary prostate sarcomas are a rare type of prostate cancer that account for less than 0.1% of primary prostate malignancies. We analyzed the experience of a single institution with prostate sarcoma over 20 years. Materials and Methods In this case series, the medical records of 20 patients with prostate sarcoma were reviewed from June 1990 to December 2013 to identify symptoms at presentation, diagnostic procedures, metastasis presence and development, histologic subtype, French Fédération Nationale des Centres de Lutte Contre le Cancer grade, primary tumor grade and size, and treatment sequence, including surgery and preoperative and postoperative therapies. The average follow-up period was 23.6 months (range, 1.4-83.3 months). Results The average patient age was 46.3±16.7 years. Most patients presented with lower urinary tract symptoms (55%). The histologic subtype was spindle cell sarcoma in five patients (25%), rhabdomyosarcoma in three patients (15%), synovial sarcoma in three patients (15%), liposarcoma in three patients (15%), stromal sarcoma in three patients (15%), and Ewing sarcoma, nerve sheath tumor, and adenocarcinoma with sarcomatoid component (5% each). For liposarcoma, two patients were alive after complete surgical resection and had a good prognosis. At last follow-up, 15 patients had died of sarcoma. The 2- and 5-year actuarial survival rates for all 20 patients were 53% and 12%, respectively (medial survival, 20 months). Conclusions The disease-specific survival rate of prostate sarcoma is poor. However, sarcoma that is detected early shows a better result with proper management including surgical intervention with radio-chemotherapy than with no treatment. Early diagnosis and complete surgical resection offer patients the best curative chance. PMID:25512813

Sohn, Mooyoung; Kwon, Taekmin; Jeong, In Gab; Hong, Sungwoo; You, Dalsan; Hong, Jun Hyuk; Ahn, Hanjong

2014-01-01

216

Sarcoma chemotherapy.  

PubMed

Sarcomas are a rare, heterogeneous group of malignant tumors of the bone or soft tissue. Although historically intended for the pharmaceutical treatment of microbes, today chemotherapy is used in orthopaedic oncology and is arguably the primary reason for improved survivorship. Agents such as anthracyclines (eg, doxorubicin), alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate), topoisomerase inhibitors (eg, etoposide [VP-16]), vinca alkaloids (eg, vincristine), and cytotoxic antibiotics (eg, actinomycin D) are used in various combinations to manage different types of tumors. Side effects are common and range from mild to severe. The effectiveness of the chemotherapy regimen correlates with the extent of tumor necrosis. PMID:23908254

Walczak, Brian E; Irwin, Ronald B

2013-08-01

217

Detection of EWS/FLI-1 fusion in non-Ewing soft tissue tumors  

PubMed Central

Objectives: EWS/FLI-1 fusion mainly appears in Ewing’s sarcoma or the primitive neuroectodermal tumors and represents a genomic marker for these tumors. However, it can appear with lower frequency in other soft tissue tumors. The paper investigates the presence of EWS/FLI-1 fusion in clinically diagnosed sarcoma belonging to different non-Ewing connective tissue tumors in order to search for a possible new biomarker valuable for investigators. Methodology: 20 patients with soft tissue tumors, who underwent surgery, were tested. Intra-operative samples of normal and tumor tissue were collected for histopathological diagnosis and genetics determinations. The patients’ RNA from tumor and normal peritumoral tissue was extracted and EWS/FLI-1 fusion screened by quantitative real-time PCR. The relative expression of the fusion in the tumor sample was compared to the similar expression in normal tissue. Results: The amplification in the threshold zone was shown by 5 samples (25%): 2 clear cell sarcoma, 1 fibrosarcoma, 1 malignant tumor of nerve sheath, 1 metastatic adenocarcinoma. We differentiated between the unspecific amplification and concluded that these are weak positive results. Conclusions: Genomic investigation may establish the tumor malignancy and its possible affiliation earlier than histopathology. It can support the screening of EWS/FLI-1 fusion in a larger variety of clinically diagnosed soft tissue tumors.

Tranc?u, IO; Huic?, R; Surcel, M; Munteanu, A; Ursaciuc, C

2014-01-01

218

Optimal Learning for Drug Discovery in Ewing's Sarcoma Diana Negoescu  

E-print Network

usually consists of chemotherapy followed by surgery or radiation therapy, often causing damaging side for research that might lead to better treatments more quickly. A medical research group led by Professor Research and Financial Engineering Graduate student, Princeton University, Department of Operations

Powell, Warren B.

219

What Is Uterine Sarcoma?  

MedlinePLUS

... sarcomas used to be considered a type of endometrial stromal sarcoma, but since they are more aggressive and are treated differently from low-grade tumors, they are now considered separately. These ... (Uterine) Cancer . Benign uterine tumors Several types of ...

220

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.

221

NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis.  

PubMed

A promising targeted therapy against NY-ESO-1 (CTAG 1B) using genetically modified T-cells in synovial sarcomas was recently demonstrated in a clinical trial at the NCI. To investigate the role of NY-ESO-1 immunohistochemistry in patient selection and gain better insight into the incidence of NY-ESO-1 expression in synovial sarcomas and other mesenchymal tumors, we evaluated NY-ESO-1 expression by immunohistochemistry in 417 tumors. This collection of samples included: 50 SS18/SSX1/2 fusion positive synovial sarcomas, 155 gastrointestinal stromal tumors (GIST), 135 other spindle cell sarcomas as well as 77 other sarcomas (chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, rhabdomyosarcoma, angiosarcoma, malignant mesothelioma, and Ewing's sarcoma). We report that 76% of synovial sarcomas expressed NY-ESO-1 in a strong and diffuse pattern (2-3+, >50-70% of tumor cells). In contrast, only rare cases of other spindle cell mesenchymal tumor expressed NY-ESO-1 (GIST (2/155), malignant peripheral nerve sheath tumors (1/34), and dermatofibrosarcoma protuberans (2/20)). Individual cases of other sarcomas (angiosarcoma, malignant mesothelioma, chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, and Ewing's sarcoma) were positive for NY-ESO-1. However, no positive cases were identified amongst our cohort of leiomyosarcomas (0/24), hemangiopericytoma/solitary fibrous tumors (0/40), and cellular schwannomas (0/17). In summary, we find that NY-ESO-1 is strongly and diffusely expressed in a majority of synovial sarcomas, but only rarely in other mesenchymal lesions. Beyond its role in patient selection for targeted therapy, immunohistochemistry for NY-ESO-1 may be diagnostically useful for the distinction of synovial sarcoma from other spindle cell neoplasms. PMID:22388761

Lai, Jin-Ping; Robbins, Paul F; Raffeld, Mark; Aung, Phyu Phyu; Tsokos, Maria; Rosenberg, Steven A; Miettinen, Markku M; Lee, Chyi-Chia Richard

2012-06-01

222

ALDH Activity Correlates with Metastatic Potential in Primary Sarcomas of Bone  

PubMed Central

Osteosarcoma (OS), chondrosarcoma (CSA), and Ewings sarcoma (ES) are the most common primary malignancies of bone, and are rare diseases. As with all sarcomas, the prognosis of these diseases ultimately depends on the presence of metastatic disease. Survival is therefore closely linked with the biology and metastatic potential of a particular bone tumor’s cells. Here we describe a significant correlation of aldehyde dehydrogenase (ALDH) activity and the presence/absence of distant metastases in ten consecutive cases of human bone sarcomas. Additionally, cultured human CSA cells, which are historically chemo- and radio-resistant, may be sensitive to the ALDH inhibitor, disulfiram. While it is premature to draw broad conclusions from such a small series, the importance of ALDH activity and inhibition in the metastatic potential of primary bone sarcomas should be investigated further. PMID:25328803

Greco, Nicholas; Schott, Trevor; Mu, Xiaodong; Rothenberg, Adam; Voigt, Clifford; McGough, Richard L.; Goodman, Mark; Huard, Johnny; Weiss, Kurt R.

2014-01-01

223

SYMPOSIUM: MOLECULAR GENETICS IN SARCOMA Synovial Sarcoma  

E-print Network

protein in effectively all cases of synovial sarcoma suggests a role in the etiology. Other nonspecific, tumor size smaller than 5 cm, and location in the distal extremity [57, 74, 75]. In a prospective series

Capecchi, Mario R.

224

MEDI-573, alone or in combination with mammalian target of rapamycin inhibitors, targets the insulin-like growth factor pathway in sarcomas.  

PubMed

MEDI-573 is a human antibody that neutralizes insulin-like growth factor (IGF) I and IGFII. IGFs are overexpressed in multiple types of cancer; their overexpression is a potential mechanism for resistance to IGFI receptor (IGFIR)-targeting therapy. Effects of IGF on cell proliferation, differentiation, and survival are mediated through its binding to and activation of IGFIR or insulin receptor A (IR-A). In this study, we measured the mRNA levels of IGFI, IGFII, and IGFIR in human pediatric sarcoma xenografts, and protein levels in sarcoma cell lines. MEDI-573 potently inhibited in vitro proliferation of sarcoma cell lines, with Ewing sarcoma cell lines being the most sensitive. In addition, MEDI-573 inhibited IGFI- and IGFII-induced sarcoma cell proliferation in vitro. The effect of MEDI-573 on IGF signaling was also examined. Treatment with MEDI-573 markedly reduced levels of pIGFIR, pIR-A, and pAKT and significantly blocked IGFI- and IGFII-induced activation of the IGFIR and AKT pathways. MEDI-573 inhibited the growth of sarcoma xenografts in vivo and inhibition correlated with neutralization of IGFI and IGFII. Combination of MEDI-573 with either rapamycin or AZD2014, another mTOR inhibitor (mTORi), significantly enhanced the antitumor activity of MEDI-573, and this response correlated with modulation of AKT and mTOR signaling. In summary, sarcoma cells respond to autocrine or paracrine growth stimulation by IGFI and IGFII, and inhibition of IGFI and IGFII by MEDI-573 results in significant slowing of tumor growth rate in sarcoma models, particularly in Ewing sarcoma. These data provide evidence for the potential benefits of MEDI-573 and mTORi combinations in patients with Ewing sarcoma. PMID:25193511

Zhong, Haihong; Fazenbaker, Christine; Breen, Shannon; Chen, Cui; Huang, Jiaqi; Morehouse, Christopher; Yao, Yihong; Hollingsworth, Robert E

2014-11-01

225

Ovarian granulocytic sarcoma.  

PubMed

Granulocytic sarcoma (GS) or chloroma is a neoplasia of immature myeloid cells. Bones, skins, soft tissues and lymph nodes are the most frequently involved organs with this entity and not infrequently it is diagnosed histopathologically as non-Hodgkin's lymphoma (NHL). Ovarian granulocytic sarcoma is a rare entity in daily practice. Here we report an ovarian granulocytic sarcoma, initially diagnosed as NHL, and review the literature. PMID:15061218

Yavuz, Sinan; Paydas, Semra; Disel, Umut; Erdogan, Seyda

2004-01-01

226

Metformin as an Adjuvant Drug against Pediatric Sarcomas: Hypoxia Limits Therapeutic Effects of the Drug  

PubMed Central

Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts anti-mitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas. PMID:24391834

Garofalo, Cecilia; Capristo, Mariantonietta; Manara, Maria Cristina; Mancarella, Caterina; Landuzzi, Lorena; Belfiore, Antonino; Lollini, Pier-Luigi; Picci, Piero; Scotlandi, Katia

2013-01-01

227

Metformin as an adjuvant drug against pediatric sarcomas: hypoxia limits therapeutic effects of the drug.  

PubMed

Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts anti-mitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas. PMID:24391834

Garofalo, Cecilia; Capristo, Mariantonietta; Manara, Maria Cristina; Mancarella, Caterina; Landuzzi, Lorena; Belfiore, Antonino; Lollini, Pier-Luigi; Picci, Piero; Scotlandi, Katia

2013-01-01

228

Kaposi’s sarcoma  

MedlinePLUS

... between HIV, a weakened immune system, and the human herpesvirus-8 (HHV-8). Kaposi's sarcoma has been linked to the spread of HIV and HHV-8 through sexual activity. People who have kidney or other organ transplants are also at risk for Kaposi's sarcoma. ...

229

Classic Kaposi Sarcoma  

MedlinePLUS

... attack specific cancer cells without harming normal cells. Monoclonal antibody therapy is one type of targeted therapy being studied in the treatment of Kaposi sarcoma. Monoclonal antibody therapy is a cancer treatment that uses antibodies made ...

230

Radiation-induced sarcoma  

Microsoft Academic Search

Opinion statement  Radiation-induced sarcomas can originate in either the irradiated bone or soft tissues. Most of these tumors are high-grade.\\u000a The most common histologic subtypes are malignant fibrous histiocytoma (MFH) and osteosarcoma, although other histologies\\u000a (eg, angiosarcoma, rhabdomyosarcoma) can occur. Tumor size and grade are the two most important prognostic factors for soft tissue\\u000a sarcomas, including those associated with radiation therapy.

Shreyaskumar R. Patel

2000-01-01

231

The indications and efficacy of conventional chemotherapy in primary and recurrent sarcoma.  

PubMed

Conventional chemotherapy can have a favorable impact on the natural history of disease for selected patients with primary high-risk bone and soft-tissue sarcomas. In particular, multidrug regimens are integral to the care of patients with the most aggressive histologies, including Ewing sarcoma, osteosarcoma, and non-pleomorphic rhabdomyosarcoma. Appropriately selected patients with high-risk, clinically localized soft-tissue sarcomas may also benefit from histology-tailored adjuvant or neoadjuvant therapy. For patients with recurrent disease, conventional chemotherapy is frequently the most appropriate first-line therapy; active drugs are discussed at length. Several new promising cytotoxic chemotherapeutic agents are currently under development, including aldoxorubicin, TH-302, and trabectedin. J. Surg. Oncol. 2015 111:622-631. © 2015 Wiley Periodicals, Inc. PMID:25581912

Liebner, David A

2015-04-01

232

Treatment Option Overview (Kaposi Sarcoma)  

MedlinePLUS

... may be needed. There are different types of treatment for patients with Kaposi sarcoma. Different types of ... only to patients who have not started treatment. Treatment of epidemic Kaposi sarcoma combines treatment for Kaposi ...

233

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

ClinicalTrials.gov

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

2014-08-11

234

Recombinant Interferon Gamma in Treating Patients With Soft Tissue Sarcoma  

ClinicalTrials.gov

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

2014-11-17

235

Temporal Bone Myeloid Sarcoma  

PubMed Central

Myeloid sarcoma is a rare condition that's caused by the aggregation of immature myeloid cells in leukemic patients. Myeloid sarcoma occurring in the temporal bone more frequently involves the mastoid bone than is the case for metastatic lesions arising from non-systemic malignancies. The disease is difficult to diagnose when it presents with symptoms that mimic otomastoiditis. However, an early diagnosis is important in order to achieve complete remission of the disease. Magnetic resonance imaging of the temporal bone is useful for making the diagnosis of myeloid sarcoma, and especially to evaluate the extent of disease. High-dose radio- or chemotherapies are the first-line approaches and possibly the only approaches to achieve complete remission and to cure the disease. With the aim of improving our understanding of myeloid sarcoma in the temporal bone, the present report describes our experience with 5 such cases and we compare the clinical features of these 5 patients with those clinical features of patients who have metastatic lesions. PMID:20072695

Kim, Dong-Kee; Jun, Beom-Cho; Park, Yong-Soo

2009-01-01

236

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...

237

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 ...

238

Allograft Reconstruction After Sarcoma Resection in Children Younger Than 10 Years Old  

PubMed Central

Preservation of limb function in pediatric oncology patients is challenging with the ongoing growth of limbs contralateral to reconstructed limbs. We analyzed 22 patients younger than 10 years old who received an allograft after resection of a bone sarcoma with a minimum followup of 2 years (mean, 4 years; range, 2–14 years). The mean age was 7 years (range, 2–10 years). There were 16 boys and six girls with 17 osteosarcomas and five Ewing’s sarcomas. Thirteen reconstructions were performed with an intercalary allograft and nine with an osteoarticular allograft. Physes were uninvolved in five patients and one physis in 17. We documented outcomes using the Musculoskeletal Tumor Society functional and the International Society of Limb Salvage radiographic scoring systems. At last followup, three of the 22 patients died of their tumor, one was alive but with an amputation, and 18 retained their limbs. These 18 patients had an average functional score of 27 points and a mean radiographic score of 94%. Eight complications required a second surgery; in four, the allograft was removed (one infection, one local recurrence, two fractures) and in four, the allograft was preserved (two local recurrences, one fracture, one nonunion). We consider biologic reconstruction with allografts after sarcoma resection an appropriate reconstructive procedure in young children. Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID:18506559

Ayerza, Miguel A.; Aponte-Tinao, Luis; Farfalli, German

2008-01-01

239

Vascularized Fibula Grafts for Reconstruction of Bone Defects after Resection of Bone Sarcomas  

PubMed Central

We evaluated the results of limb-sparing surgery and reconstruction of bone defects with vascularized fibula grafts in 8 consecutive patients (mean age at operation 13.6 years (range 4.1–24.2 years), female/male = 6/2) with bone sarcomas (BS) (osteosarcoma/Ewing's sarcoma/chondrosarcoma= 4/3/1) operated on form 2000 to 2006. The bone defects reconstructed were proximal femoral diaphysis and epiphysis (n = 2), humeral diaphysis (n = 2), humeral proximal diaphysis and epiphysis (n = 1), femoral diaphysis (n = 1), ulnar diaphysis (n = 1), and tibial diaphysis (n = 1). One patient with Ewing's sarcoma had an early hip disarticulation, developed multiple metastases, and died 9 months after the operation. The remaining patients (n = 7) are all alive 50 months (range 26–75 months) after surgery. During the follow-up the following major complications were seen: 1-2 fractures (n = 4), pseudarthrosis (n = 2), and hip dislocation (n = 1). Limb-sparing surgery with reconstruction of bone defects using vascularized fibular grafts in BS cases is feasible with acceptable clinical results, but fractures should be expected in many patients. PMID:20490263

Petersen, Michael Mørk; Hovgaard, Dorrit; Elberg, Jens Jørgen; Rechnitzer, Catherine; Daugaard, Søren; Muhic, Aida

2010-01-01

240

Treatment Options for Adult Soft Tissue Sarcoma  

MedlinePLUS

... Soft Tissue Sarcoma That Has Not Spread to Lymph Nodes Treatment of stage II adult soft tissue sarcoma ... Adult Soft Tissue Sarcoma That Has Spread to Lymph Nodes (Advanced) Treatment of stage III adult soft tissue ...

241

Stages of Childhood Soft Tissue Sarcoma  

MedlinePLUS

... metastatic soft tissue sarcoma, not lung cancer. One method used to stage childhood soft tissue sarcoma is ... started to other parts of the body). Another method used to stage childhood soft tissue sarcoma is ...

242

Can Uterine Sarcoma Be Found Early?  

MedlinePLUS

... Sarcoma + - Text Size Download Printable Version [PDF] » Early Detection, Diagnosis, and Staging TOPICS Document Topics GO » SEE ... Uterine Sarcoma? Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treating Uterine Sarcoma Talking With ...

243

Artificial Neural Network Inference (ANNI): A Study on Gene-Gene Interaction for Biomarkers in Childhood Sarcomas  

PubMed Central

Objective To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI). Method To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model. Results Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing’s sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen. Conclusions The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas. PMID:25025207

Tong, Dong Ling; Boocock, David J.; R. Dhondalay, Gopal Krishna; Lemetre, Christophe; Ball, Graham R.

2014-01-01

244

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. PMID:24062983

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

2013-01-01

245

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

2005-01-01

246

COMPARATIVE BIOAVAILABILITY OF LEVAMISOLE IN NON LACTATING EWES AND GOATS  

E-print Network

COMPARATIVE BIOAVAILABILITY OF LEVAMISOLE IN NON LACTATING EWES AND GOATS P. GALTIER, L. ESCOULA, R in non lactating adult goats and ewes. In each case, the recommended veterinary therapeutic forms pregnant females (four Romanov ewes and four Alpine goats) were used during a three week-period. Body

Boyer, Edmond

247

Targeted polytherapy in small cell sarcoma and its association with doxorubicin.  

PubMed

A paradigm shift has occurred in the last decade from chemotherapy to targeted therapy for the management of many patients with advanced sarcoma. This work identifies a combination of targeted agents and doxorubicin that are effective against small cell sarcoma cell lines. Three small cell sarcoma cell lines were studied: RD18 (rhabdomyosarcoma), A204 (undifferentiated sarcoma) and TC 71 (Ewing's sarcoma). Each cell line was exposed to increasing concentrations of vorinostat (HDAC inhibitor), 17-DMAG (HSP90 inhibitor), abacavir (anti-telomerase) or sorafenib (tyrosine kinase inhibitor) alone, combined with one another, or combined with doxorubicin. Cell viability, cell cycle analysis and apoptosis were assessed by MTS assay, propidium iodide-Annexin V staining, and caspase 3/7 activity, respectively. The Chou and Talalay combination index (CI) was used to determine whether the effects were additive (CI = 1), synergistic (CI < 1) or antagonistic (CI > 1). In monotherapy, targeted agents achieved 30-90% reductions in viability, with the exception of abacavir. Dual-targeted combination therapies with vorinostat, sorafenib and 17-DMAG demonstrated synergy. Abacavir was antagonistic with every other drug and was not further studied. Both vorinostat and 17-DMAG synergized with doxorubicin, achieving 60% cell killing compared to 12% with doxorubicin alone. No synergy was observed for sorafenib with doxorubicin. The triple therapy vorinostat, 17-DMAG and doxorubicin did not show synergy, but increased the subG1 population at 24H, from 30% to 70% compared to monotherapies with an increase in apoptosis. This work provides evidence of synergy of combinations of vorinostat, 17-DMAG and sorafenib in small cell sarcoma. In addition to doxorubicin, these combinations enhance doxorubicin cytotoxicity at therapeutically relevant concentrations. PMID:24998445

Dumont, S N; Yang, D; Dumont, A G; Reynoso, D; Blay, J-Y; Trent, J C

2014-12-01

248

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.

2007-01-01

249

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...

250

Original article Conjunctival vaccination of pregnant ewes  

E-print Network

Original article Conjunctival vaccination of pregnant ewes and goats with Brucella melitensis Rev 1 vaccine: safety and serological responses E Zundel JM Verger M Grayon R Michel 1 Institut National de la Brucella melitensis strain Rev 1 vaccine (Rev 1) is administered by the standard method (1-2 x 109 viable

Paris-Sud XI, Université de

251

What Should You Ask Your Doctor about Uterine Sarcoma?  

MedlinePLUS

... for uterine sarcoma? What should you ask your doctor about uterine sarcoma? It is important for you ... and Staging Treating Uterine Sarcoma Talking With Your Doctor After Treatment What`s New in Uterine Sarcoma Research? ...

252

Alisertib in Treating Patients With Advanced or Metastatic Sarcoma  

ClinicalTrials.gov

Myxofibrosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Leiomyosarcoma; Recurrent Liposarcoma; Recurrent Malignant Peripheral Nerve Sheath Tumor; Recurrent Unclassified Pleomorphic Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

2015-02-11

253

Surgical management of soft tissue sarcomas: Extremity sarcomas.  

PubMed

Wide surgical resection is the recommended treatment for extremity soft tissue sarcomas. Chemotherapy and/or radiotherapy may improve local control, but with marginal effect on overall survival. Advanced reconstructive techniques and multidisciplinary care, including plastic surgery, may allow a higher rate of limb salvage. This report focuses on surgical and reconstructive aspects in the multimodality care of extremity sarcomas. J. Surg. Oncol. 2015 111:540-545. © 2014 Wiley Periodicals, Inc. PMID:25335973

Chao, Albert H; Mayerson, Joel L; Chandawarkar, Rajiv; Scharschmidt, Thomas J

2015-04-01

254

General Information about Kaposi Sarcoma  

MedlinePLUS

... cancer) can form in the skin, mucous membranes, lymph nodes, and other organs. Kaposi sarcoma is a cancer ... mucous membranes lining the mouth, nose, and throat ; lymph nodes ; or other organs . The lesions are usually purple ...

255

Instantánea del sarcoma de Kaposi  

Cancer.gov

Información sobre las tendencias de incidencia, mortalidad y financiamiento del NCI sobre el sarcoma de Kaposi; así como ejemplos de actividades del NCI y adelantos en la investigación de este tipo de cáncer.

256

Drugs Approved for Kaposi Sarcoma  

Cancer.gov

This page lists cancer drugs approved by the Food and Drug Administration (FDA) for Kaposi sarcoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

257

Conditioning ewes and lambs to increase consumption of spotted knapweed  

Microsoft Academic Search

Spotted knapweed (Centaurea maculosa Lam.) is an invasive plant that alters species composition and grazing value of rangelands in the northwestern United States. The spread of invasive plants may be reduced by using livestock as a biological control. We determined if mature ewes and their lambs (n=34ewe\\/lamb pairs) consume more spotted knapweed when ewes and\\/or lambs are conditioned to fresh-cut

Travis Raymond Whitney; Bret Eugene Olson

2006-01-01

258

BCOR-CCNB3 fusions are frequent in undifferentiated sarcomas of male children.  

PubMed

The BCOR-CCNB3 fusion gene, resulting from a chromosome X paracentric inversion, was recently described in translocation-negative 'Ewing-like' sarcomas arising in bone and soft tissue. Genetic subclassification of undifferentiated unclassified sarcomas may potentially offer markers for reproducible diagnosis and substrates for therapy. Using whole transcriptome paired-end RNA sequencing (RNA-seq) we unexpectedly identified BCOR-CCNB3 fusion transcripts in an undifferentiated spindle-cell sarcoma. RNA-seq results were confirmed through direct RT-PCR of tumor RNA and cloning of the genomic breakpoints from tumor DNA. Five additional undifferentiated sarcomas with BCOR-CCNB3 fusions were identified in a series of 42 pediatric and adult unclassified sarcomas. Genomic breakpoint analysis demonstrated unique breakpoint locations in each case at the DNA level even though the resulting fusion mRNA was identical in all cases. All patients with BCOR-CCNB3 sarcoma were males diagnosed in mid childhood (7-13 years of age). Tumors were equally distributed between axial and extra-axial locations. Five of the six tumors were soft-tissue lesions with either predominant spindle-cell morphology or spindle-cell areas interspersed with ovoid to round cells. CCNB3 immunohistochemistry showed strong nuclear positivity in five tumors before oncologic therapy, but was patchy to negative in post-treatment tumor samples. An RT-PCR assay developed to detect the fusion transcript in archival formalin-fixed tissue was positive in all six cases, with high sensitivity and specificity in both pre- and post-treated samples. This study adds to recent reports on the clinicopathologic spectrum of BCOR-CCNB3 fusion-positive sarcomas, a newly emerging entity within the undifferentiated unclassified sarcoma category and describes a simple RT-PCR assay that in conjunction with CCNB3 immunohistochemistry can be useful in diagnosing these tumors.Modern Pathology advance online publication, 31 October 2014; doi:10.1038/modpathol.2014.139. PMID:25360585

Peters, Tricia L; Kumar, Vijetha; Polikepahad, Sumanth; Lin, Frank Y; Sarabia, Stephen F; Liang, Yu; Wang, Wei-Lien; Lazar, Alexander J; Doddapaneni, HarshaVardhan; Chao, Hsu; Muzny, Donna M; Wheeler, David A; Okcu, M Fatih; Plon, Sharon E; Hicks, M John; López-Terrada, Dolores; Parsons, D Williams; Roy, Angshumoy

2014-10-31

259

Sorafenib in Treating Patients With Metastatic, Locally Advanced, or Recurrent Sarcoma  

ClinicalTrials.gov

Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Leiomyosarcoma; Adult Malignant Fibrous Histiocytoma; Adult Neurofibrosarcoma; Adult Synovial Sarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma; Uterine Carcinosarcoma; Uterine Leiomyosarcoma

2014-05-07

260

Soft Tissue Sarcomas and Agent Orange  

MedlinePLUS

... ZIP code here Soft Tissue Sarcomas and Agent Orange VA presumes some soft tissue sarcomas in Veterans are related to their exposure to Agent Orange or other herbicides during military service. The soft ...

261

Radiation Therapy for Soft Tissue Sarcomas  

MedlinePLUS

... Clinical trials for soft tissue sarcomas Complementary and alternative therapies for soft tissue ... for soft tissue sarcomas Radiation therapy uses high-energy rays (such as x-rays) or particles to ...

262

Benign Mesenchymal Stromal Cells in Human Sarcomas  

PubMed Central

Purpose Recent evidence suggests that at least some sarcomas arise through aberrant differentiation of mesenchymal stromal cells (MSCs), but MSCs have never been isolated directly from human sarcoma specimens. Experimental Design We examined human sarcoma cell lines and primary adherent cultures derived from human sarcoma surgical samples for features of MSCs. We further characterized primary cultures as either benign or malignant by the presence of tumor-defining genetic lesions and tumor formation in immunocompromised mice. Results We show that a dedifferentiated liposarcoma cell line DDLS8817 demonstrates fat, bone and cartilage trilineage differentiation potential characteristic of MSCs. Primary sarcoma cultures have the morphology, surface immunophenotype and differentiation potential characteristic of MSCs. Surprisingly, many of these cultures are benign as they do not form tumors in mice and lack sarcoma-defining genetic lesions. Consistent with the recently proposed pericyte origin of MSCs in normal human tissues, sarcoma-derived benign MSCs express markers of pericytes and cooperate with endothelial cells in tube formation assays. In human sarcoma specimens, a subset of CD146-positive microvascular pericytes express CD105, an MSC marker, while malignant cells largely do not. In an in vitro co-culture model, sarcoma-derived benign MSCs as well as normal human pericytes markedly stimulate the growth of sarcoma cell lines. Conclusions Sarcoma-derived benign MSCs/pericytes represent a previously undescribed stromal cell type in sarcoma which may contribute to tumor formation. PMID:21138865

Morozov, Alexei; Downey, Robert J.; Healey, John; Moreira, Andre L.; Lou, Emil; Leung, Roland; Edgar, Mark; Singer, Samuel; LaQuaglia, Michael; Maki, Robert G.; Moore, Malcolm A.S.

2010-01-01

263

Operative and Conservative Treatment of Uterine Sarcomas  

PubMed Central

Uterine sarcomas are rare, aggressive mesenchymal tumours with a relatively poor prognosis. The term comprises various histological subtypes, such as leiomyosarcoma, endometrial stromal sarcomas as well as undifferentiated uterine sarcomas, which require different operative and systemic/radiation therapy strategies accordingly. The evidence on operative, adjuvant and palliative treatment currently available is presented here. PMID:24882876

Harter, P.; El-Khalfaoui, K.; Heitz, F.; du Bois, A.

2014-01-01

264

Sarcoma risk after radiation exposure  

PubMed Central

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

2012-01-01

265

Trabectedin in Soft Tissue Sarcomas  

PubMed Central

Soft tissue sarcomas are a group of rare tumors derived from mesenchymal tissue, accounting for about 1% of adult cancers. There are over 60 different histological subtypes, each with their own unique biological behavior and response to systemic therapy. The outcome for patients with metastatic soft tissue sarcoma is poor with few available systemic treatment options. For decades, the mainstay of management has consisted of doxorubicin with or without ifosfamide. Trabectedin is a synthetic agent derived from the Caribbean tunicate, Ecteinascidia turbinata. This drug has a number of potential mechanisms of action, including binding the DNA minor groove, interfering with DNA repair pathways and the cell cycle, as well as interacting with transcription factors. Several phase II trials have shown that trabectedin has activity in anthracycline and alkylating agent-resistant soft tissue sarcoma and suggest use in the second- and third-line setting. More recently, trabectedin has shown similar progression-free survival to doxorubicin in the first-line setting and significant activity in liposarcoma and leiomyosarcoma subtypes. Trabectedin has shown a favorable toxicity profile and has been approved in over 70 countries for the treatment of metastatic soft tissue sarcoma. This manuscript will review the development of trabectedin in soft tissue sarcomas. PMID:25686274

Petek, Bradley J.; Loggers, Elizabeth T.; Pollack, Seth M.; Jones, Robin L.

2015-01-01

266

Chromosomal translocations highlighted in Primitive Neuroectodermal Tumors (PNET) and Ewing sarcoma  

PubMed Central

Almost 200 molecular markers in oncology, very important in the diagnosis, prognostic and treatment were identified. The cell and tissue markers and also the circulating (sanguine) ones are genetic markers of the hereditary and non-hereditary tumors. Also extremely important are the regulatory ways of cell growth and differentiation, of the cell “senescence” and cell death (apoptosis). The term of “tumor marker” concerns a variety of molecules or processes that are different in the normal cell compared with the malign cell. The tumor markers may include modifications to the genetic level (mutations, deletions or genes amplifications) to the transcription level (super expression or sub-expression), to the translation level (high or low quantities of proteins, abnormal glycosylation of proteins) and/or to the functional level (the level of cell differentiation or presence of neo-vascularisation). Cancer is a genetic disease. There is a deregulation at the genes level that controls the cell division and withdrawal from the cell cycle or there is a genetic susceptibility. In other words, cancer is an end point for several phases in which the oncogenes and stimulatory signals and inhibitors produced and controlled by the products of these oncogenes are involved.

Tranc?u, IO

2014-01-01

267

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

E-print Network

of zash1a. (i–l) Lateral views of the trunk in 24hpf embryos stained with acetylated tubulin (aAT) antibody. Arrowhead identifies disorganized axonal projections in ewsr1 MO injected embryos. Asterisk (*) marks motorneurons. doi:10.1371/journal... embryonic development, morpholinos (MO) directed against the two ewsr1 mRNAs were injected into zebrafish embryos at the one Figure 1. Sequence Analysis of Zebrafish ewsr1 Genes Indicates Homology in Putative Functional Domains. A. Schematic drawing...

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

2007-10-03

268

FREE AMINO ACID CONTENT OF EWE UTERINE FLUID  

E-print Network

FREE AMINO ACID CONTENT OF EWE UTERINE FLUID UNDER VARIOUS HORMONAL TREATMENTS DURING EARLY Recherches zootechniques, I. N. R. A., i'8350 Jouy en Josas SUMMARY Free amino acids are dosed in ewe uterine secretions are very rich in free amino acids, especially glutamic acid + glutamine and glycine. However

Paris-Sud XI, Université de

269

Primary Synovial Sarcoma of Lung  

PubMed Central

Synovial sarcoma (SS) is a highly malignant tumor that accounts for 10% of all soft-tissue sarcomas. Primary SS arising from the lung is extremely rare, and the prognosis is poor. We report a case of pulmonary SS presenting with a mass lesion invading the right upper and middle lobes, extending to the mediastinum and the chest wall. After tru-cut biopsy, surgical resection was performed. The final diagnosis was SS (biphasic type) based on histological and immunohistochemical findings. There are no guidelines for optimal treatment due to the rarity of these tumors. Current treatment includes surgery and adjuvant chemotherapy and/or radiotherapy. PMID:25207234

Cabuk, Devrim; Ustuner, Berna; Akgul, Asli Gul; Acikgoz, Ozgur; Yaprak, Busra; Uygun, Kazim; Topcu, Salih; Muezzinoglu, Bahar

2014-01-01

270

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

ClinicalTrials.gov

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 Corpus Leiomyosarcoma

2015-01-16

271

MATERNAL INGESTION OF LOCOWEED. I. EFFECTS ON EWE-LAMB BONDING AND BEHAVIOUR  

Technology Transfer Automated Retrieval System (TEKTRAN)

This study investigated whether exposure of ewes to locoweed (Oxytropis sericea Nutt. In T. & G.; Leguminosae) during gestation would affect ewe behavior during parturition, ewe-lamb bonding and related behaviors post partum, and maternal responsiveness of ewes to alien and own lambs. Twenty-nine n...

272

Prognostic features of renal sarcomas (Review)  

PubMed Central

The aim of the present review was to evaluate the prognostic features of primary sarcomas of the kidney. A literature review was conducted using a number of databases, including Medline (PubMed) and Scopus, for studies published between January 1992 and December 2013. Of the studies published in English, those describing the prognostic features of primary sarcomas of the kidney were recorded. The electronic search was limited to the following keywords: Sarcoma, renal sarcoma, prognosis, diagnosis, immunohistochemistry, genetic and survey. Subsequent to the search, no review articles and/or meta-analyses associated with the prognosis of primary sarcomas of the kidney were identified. In total, 31 studies, which consisted of case studies, case series and studies concerned with the overall prognosis of urological soft-tissue sarcomas, were reviewed. Primary sarcoma of the kidney has a poor prognosis compared with other sarcomas of the urogenital system. In addition to the surgical excision of renal sarcomas, pathological, molecular and genetic prognostic factors are also considered. Due to the small number of cases, previous studies have not randomized the prognostic features of primary sarcomas of the kidney. The elucidation of the so-called ‘chaotic’ genetic and molecular basis of renal sarcomas will help to predict patient prognoses. Surgical excision is the most significant parameter for determining the prognosis of sarcomas of the kidney. However, sarcomas also exhibit prognostic features that are based upon pathological, genetic and molecular factors. The present review suggests that additional factors may be important in predicting the prognosis of patients with renal sarcomas, and that clinicians should plan treatment and follow-up regimens according to these factors. PMID:25663853

ÖZTÜRK, HAKAN

2015-01-01

273

High-Dose Chemotherapy Followed by Peripheral and/or Bone Marrow Stem Cell Transplant in Patients With Advanced Sarcoma: Experience of a Canadian Centre  

PubMed Central

Purpose: Few reports have been published on the evaluation of stem cell auto transplantation for chemosensitive sarcomas. Some suggest benefit, others do not. We present results of 24 patients with sarcoma undergoing autotransplantation at a Canadian institution. Patients and Methods: Twenty-four patients were treated between 1988 and 1998: 23 were ?18 years (median 27; range 12–56); genders were equal; 12 patients had Ewing's sarcoma. At diagnosis, 12 (50%) had metastatic disease. Prior to autotransplant, all had ?1 chemotherapy regimen. Fourteen (58%) were in complete remission (CR) and seven (29%) had minimal residual disease. All received etoposide 60 mg/kg (Day –4), melphalan 140 mg/m?2 on (Day –3) and a stem cell reinfusion (Day 0). Results: Three patients (12.5%) were alive and disease-free with median follow-up of 92 months (80–142); one was alive with disease 32 months post-autotransplant. Twenty had died (disease, 17; transplant-related, 2; unknown, 1). Of the four alive, three had Ewing's sarcoma, one alveolar rhabdomyosarcoma, and all were in CR at transplant. Median time to relapse was 6 months (2–59). Sixteen of 18 (89%) relapsed within 1 year. Median overall survival was 10 months (0–137). A trend towards improved survival (P=0.07) was evident for patients in CR prior to autotransplant. Conclusions: Stem cell autotransplantation does not benefit most patients with sarcoma. A subgroup of high-risk patients in CR may fare better and warrant further study. PMID:18521397

Smith, Anne M.; Bramwell, Vivien H.C.; Howson-Jan, Kang

2004-01-01

274

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

PubMed

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

2013-05-15

275

CCI-779 in Treating Patients With Soft Tissue Sarcoma or Gastrointestinal Stromal Tumor  

ClinicalTrials.gov

Gastrointestinal Stromal Tumor; Recurrent Adult Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

2013-06-03

276

E-Cadherin Cell-Cell Adhesion in Ewing Tumor Cells Mediates Suppression of Anoikis through Activation of the ErbB4 Tyrosine Kinase  

PubMed Central

Ability to grow under anchorage-independent conditions is one of the major hallmarks of transformed cells. Key to this is the capacity of cells to suppress anoikis, or programmed cell death induced by detachment from the extracellular matrix. To model this phenomenon in vitro, we plated Ewing tumor cells under anchorage-independent conditions by transferring them to dishes coated with agar to prevent attachment to underlying plastic. This resulted in marked up-regulation of E-cadherin and rapid formation of multicellular spheroids in suspension. Addition of calcium chelators, antibodies to E-cadherin (but not to other cadherins or ?1-integrin), or expression of dominant negative E-cadherin led to massive apoptosis of spheroid cultures whereas adherent cultures were unaffected. This correlated with reduced activation of the phosphatidylinositol 3-kinase-Akt pathway but not the Ras-extracellular signal–regulated kinase 1/2 cascade. Furthermore, spheroid cultures showed profound chemoresistance to multiple cytotoxic agents compared with adherent cultures, which could be reversed by ?-E-cadherin antibodies or dominant negative E-cadherin. In a screen for potential downstream effectors of spheroid cell survival, we detected E-cadherin–dependent activation of the ErbB4 receptor tyrosine kinase but not of other ErbB family members. Reduction of ErbB4 levels by RNA interference blocked Akt activation and spheroid cell survival and restored chemosensitivity to Ewing sarcoma spheroids. Our results indicate that anchorage-independent Ewing sarcoma cells suppress anoikis through a pathway involving E-cadherin cell-cell adhesion, which leads to ErbB4 activation of the phosphatidylinositol 3-kinase-Akt pathway, and that this is associated with increased resistance of cells to cytotoxic agents. PMID:17409416

Kang, Hyung-Gyoo; Jenabi, Jasmine M.; Zhang, Jingsong; Keshelava, Nino; Shimada, Hiroyuki; May, William A.; Ng, Tony; Reynolds, C. Patrick; Triche, Timothy J.; Sorensen, Poul H.B.

2014-01-01

277

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

MedlinePLUS

... 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 ...

278

Current concepts in the imaging of uterine sarcoma.  

PubMed

Recent advances in genetics and pathology have improved our understanding of diagnosis and staging of uterine sarcomas. The major types of uterine sarcomas include leiomyosarcoma, low-grade endometrial stromal sarcoma, undifferentiated endometrial sarcoma, adenosarcoma and carcinosarcoma. The distinctive biological behavior and poor overall survival of uterine sarcoma create challenges in the management of these tumors. We herein present a comprehensive review of taxonomy, epidemiology, pathology, imaging findings and natural history of a wide spectrum of uterine sarcomas. PMID:22699695

Tirumani, Sree Harsha; Ojili, Vijayanadh; Shanbhogue, Alampady Krishna Prasad; Fasih, Najla; Ryan, John G; Reinhold, Caroline

2013-04-01

279

Erythroblastic sarcoma, an extremely rare variant of myeloid sarcoma.  

PubMed

A 79-year-old man was admitted to the hospital because of a 20-lb weight loss, low back pain, and leg weakness. He had a 1-year history of fibrotic myelodysplasia, possibly therapy related, with a highly complex chromosome karyotype. Radiologic evaluation showed extensive destructive bone lesions, retroperitoneal lymphadenopathy, and evidence for thoracic spinal cord compression. Core biopsies of a retroperitoneal lymph node showed groups of large, immature-appearing mononuclear cells which, on Wright-stained touch preparation, appeared similar to dysplastic erythroid precursors noted on recent marrow aspirate smears. Immunohistochemical staining showed negativity of neoplastic cells to an extensive panel of nonhematopoietic and myeloid markers, and positivity for CD117, glycophorin A, and CD71, consistent with a diagnosis of erythroblastic sarcoma. This lesion is a very unusual variant of myeloid sarcoma and has been described only rarely in the medical literature. PMID:22795354

Cornfield, Dennis B

2012-11-01

280

Radiation-induced sarcoma of the thyroid  

SciTech Connect

A 23-year-old white man presented with a thyroid mass 12 years after receiving high-dose radiotherapy for a T2 and N1 lymphoepithelioma of the nasopharynx. Following subtotal thyroidectomy, a histopathologic examination revealed liposarcoma of the thyroid gland. The relationship between sarcomas and irradiation is described and Cahan and colleagues' criteria for radiation-induced sarcomas are reviewed. To our knowledge, we are presenting the first such case of a radiation-induced sarcoma of the thyroid gland.

Griem, K.L.; Robb, P.K.; Caldarelli, D.D.; Templeton, A.C. (Rush-Presbyterian-St Luke's Medical Center, Chicago, IL (USA))

1989-08-01

281

NY-ESO-1-specific T Cells in Treating Patients With Advanced NY-ESO-1-Expressing Sarcomas Receiving Palliative Radiation Therapy  

ClinicalTrials.gov

Mast Cell Sarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IIIA Uterine Sarcoma; Stage IIIB Uterine Sarcoma; Stage IIIC Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IVA Uterine Sarcoma; Stage IVB Uterine Sarcoma

2015-01-20

282

Proton Radiotherapy for Pediatric Sarcoma  

PubMed Central

Pediatric sarcomas represent a distinct group of pathologies, with approximately 900 new cases per year in the United States alone. Radiotherapy plays an integral role in the local control of these tumors, which often arise adjacent to critical structures and growing organs. The physical properties of proton beam radiotherapy provide a distinct advantage over standard photon radiation by eliminating excess dose deposited beyond the target volume, thereby reducing both the dose of radiation delivered to non-target structures as well as the total radiation dose delivered to a patient. Dosimetric studies comparing proton plans to IMRT and 3D conformal radiation have demonstrated the superiority of protons in numerous pediatric malignancies and data on long-term clinical outcomes and toxicity is emerging. In this article, we review the existing clinical and dosimetric data regarding the use of proton beam radiation in malignant bone and soft tissue sarcomas. PMID:24424260

Ladra, Matthew M.; Yock, Torunn I.

2014-01-01

283

Undernutrition affects embryo quality of superovulated ewes.  

PubMed

To determine the effect of undernutrition on embryo production and quality in superovulated sheep, 45 ewes were allocated into two groups to be fed diets that provided 1.5 (control, C; n = 20) or 0.5 (low nutrition, L; n = 25) times daily requirements for maintenance, from oestrous synchronization with intravaginal sponges to embryo collection. Embryos were collected 7 days after the onset of oestrus (day 0). Low nutrition resulted in lower live weight and body condition at embryo collection (P < 0.05). Diet (P < 0.01) and day of sampling (P < 0.001) significantly affected plasma non-esterified fatty acid (NEFA) and insulin concentrations. Plasma leptin concentrations decreased on day 7 only in L ewes. A significant effect of dietary treatment (P < 0.05) and day (P < 0.0001) was observed on plasma insulin-like growth factor (IGF)-I concentrations. The number of recovered oocytes and embryos did not differ between the groups (L: 15.4 ± 0.4; C: 12.4 ± 0.4). Recovery rate was lower (P < 0.05) in the L (60%) than in the C group (73%). The total number of embryos and number of viable-transferable embryos (5.0 ± 0.3 and 3.4 ± 0.3 embryos, respectively) of the L group were lower (P < 0.1) when compared with controls (8.4 ± 0.4 and 6.2 ± 0.4 embryos, respectively). Undernutrition during the period of superovulation and early embryonic development reduced total and viable number of embryos. These effects might be mediated by disruption of endocrine homeostasis, oviduct environment and/or oocyte quality. PMID:24103562

Abecia, J A; Forcada, F; Palacín, I; Sánchez-Prieto, L; Sosa, C; Fernández-Foren, A; Meikle, A

2015-02-01

284

Evaluating Dactinomycin and Vincristine in Young Patients With Cancer  

ClinicalTrials.gov

Childhood Acute Lymphoblastic Leukemia; Childhood Rhabdomyosarcoma; Childhood Soft Tissue Sarcoma; Ewing Sarcoma; Ewing Sarcoma of Bone; Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor (PNET); Unspecified Childhood Solid Tumor, Protocol Specific; Wilms Tumor and Other Childhood Kidney Tumors

2014-08-06

285

Murine Sarcoma Virus: The Question of Defectiveness  

Microsoft Academic Search

Infection of mouse and rat cells by the murine sarcoma virus (Moloney isolate) showed two-hit kinetics for focus production in mouse cells but one-hit kinetics in rat cells. Antiserum added to cultures after infection suppressed focus formation in mouse cells but not in rat cells. These studies suggest that, in rat cells infected with murine sarcoma virus, leukemia virus is

Robertson Parkman; Jay A. Levy; Robert C. Ting

1970-01-01

286

Surgical treatment of pulmonary artery sarcoma  

Microsoft Academic Search

Objective: Pulmonary artery sarcomas are rare and usually fatal tumors. The diagnosis is difficult and delayed in most cases. Newer imaging techniques could allow early diagnosis in patients with symptoms of pulmonary vascular obstruction. Surgical resection improves clinical symptoms and offers the only chance of cure. We report the case histories of 7 patients with primary pulmonary artery sarcomas treated

Eckhard Mayer; Jörg Kriegsmann; Andreas Gaumann; Hans Ulrich Kauczor; Manfred Dahm; Ulrich Hake; Franz Xaver Schmid; Hellmut Oelert

2001-01-01

287

Expression of the CD34 antigen distinguishes Kaposi's sarcoma from pseudo-Kaposi's sarcoma (acroangiodermatitis).  

PubMed

The differential diagnosis between Kaposi's sarcoma and the so-called 'pseudo-Kaposi's sarcoma' or acroangiodermatitis of the feet is often fraught with difficulty, not only on clinical but also on histological grounds. The aim of this study was to assess whether immunolabelling for the CD34 antigen, a marker of Kaposi's sarcoma cells, could be of value in the distinction between these two angioproliferative disorders. We comparatively examined 16 biopsy specimens from cases of Kaposi's sarcoma and seven biopsies from patients with pseudo-Kaposi's sarcoma, by a streptavidin-biotin-peroxidase method, using a monoclonal antibody to the CD34 antigen. All cases of Kaposi's sarcoma showed CD34 labelling both on endothelial cells and on the characteristic spindle-shaped, perivascular cells. Biopsies of pseudo-Kaposi's sarcoma showed a strong labelling of endothelial cells of hyperplastic vessels. However, in sharp contrast with Kaposi's sarcoma, a complete absence of perivascular CD34 expression was noted. It seems therefore that immunolabelling for the CD34 antigen appears to be a valuable tool in the differential diagnosis between Kaposi's sarcoma and pseudo-Kaposi's sarcoma. PMID:8745885

Kanitakis, J; Narvaez, D; Claudy, A

1996-01-01

288

Durable remissions are rare following high dose therapy with autologous stem cell transplantation for adults with "paediatric" bone and soft tissue sarcomas  

PubMed Central

Background The role of high dose therapy (HDT) with autologous stem cell transplantation (AuSCT) for the treatment of bone and soft tissue sarcomas remains investigational. There are few reports examining this strategy focusing on the adult population. Methods We retrospectively reviewed our experience of adult patients undergoing HDT and AuSCT for 'paediatric' sarcomas. Results A total of 17 patients (14 male, 3 female) with median age at transplant of 24 years (range 20 – 41) were identified. The diagnosis was Ewings sarcoma/PNET (10), osteosarcoma (5) and rhabdomyosarcoma (2). Status prior to HDT, following conventional-dose chemotherapy +/- surgery +/- radiotherapy, was complete remission (CR) (6), partial remission (PR) (6), stable disease (1) and progressive disease (4). There was no transplant-related mortality. Two patients remain disease free beyond four years and both received HDT as part of their primary therapy (CR1 and PR1) however, the median progression free survival and overall survival following AuSCT for the entire cohort was only 7 months (range: 2–92 months) and 13 months (range: 2 – 92 months), respectively. Conclusion HDT and AuSCT infrequently achieves prolonged remissions in adult patients and should only be considered in patients who are in a PR or CR following conventional-dose therapy. Further studies are required to define the role of HDT with AuSCT for adult patients with sarcoma. PMID:15927067

Nath, Shriram V; Prince, H Miles; Choong, Peter FM; Toner, Guy C

2005-01-01

289

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

PubMed Central

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

2013-01-01

290

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. PMID:18605999

Pantanowitz, Liron; Dezube, Bruce J

2008-01-01

291

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

2009-01-01

292

Escalating topotecan in combination with treosulfan has acceptable toxicity in advanced pediatric sarcomas.  

PubMed

Patients with advanced pediatric sarcomas have a poor prognosis and novel combination therapies are needed to improve the response rates. Hematological and organ related toxicities have been observed when administering topotecan in combination with, e.g., high dose thiotepa. This study evaluates the toxicity of escalating doses of topotecan alone or in combination with thiotepa or treosulfan. We compared the toxicity including death of complication (DOC) of topotecan alone or in combination with thiotepa or treosulfan in advanced pediatric sarcomas (n = 12). Ten of 12 patients (0.83) suffered from advanced tumors of the Ewing family (i.e., bone or marrow metastases or relapse <24 month after diagnosis, including one neuroepithelial tumor of the kidney) and two from alveolar rhabdomyosarcoma stage IV (0.17). Median age was 15 years (range 5-28). Ratio of female to male was 1:1. Two patients received topotecan alone (1.25 mg/m(2) q 5d and 1.5 mg/m(2) q 5d), three patients received four courses of topotecan (2 mg/m(2) q d 1-5) in combination with thiotepa (100 mg/m(2) q d 1-5), and seven patients received topotecan (2 mg/m(2) q d 1-5) in combination with treosulfan (10g/m(2) q d 3-5). Overall toxicity was not different between all three groups; mean scores were 1.6, 1.8, and 1.7 according to WHO grading (Scale 0-4). Organ related toxicity ranged between 0 and 4 and was not different as well. DOC was 0/2, 1/3, and 0/7 patients respectively. Escalating therapy with topotecan in combination with treosulfan has acceptable toxicity and warrants further investigation in advanced pediatric sarcomas. PMID:23509879

Bauer, F; Filipiak-Pittroff, B; Wawer, A; von Luettichau, I; Burdach, S

2013-05-01

293

Usefulness of subjective ovine milk scores: I. Associations with range ewe characteristics and lamb production  

Microsoft Academic Search

Range ewes are commonly evaluated for milking ability by producers to determine the ewe's ability to rear lamb(s). The U.S. Sheep Experiment Sta- tion has subjectively scored (low, average, high) a ewe's milking ability within 24 h of lambing for many years. The relationship of subjective milk scores with lamb production was investigated using lambing records of Columbia (n =

G. D. Snowder; A. D. Knight; L. D. Van Vleck; C. M. Bromley; T. R. Kellom

294

Safety and efficacy of low-dose, subacute exposure of mature ewes to sodium chlorate  

Technology Transfer Automated Retrieval System (TEKTRAN)

The objective was to determine the safety and efficacy of low-dose, subacute exposure of mature ewes to NaClO3 in the drinking water. Twenty-five ewes (BW = 62.5 ± 7.3 kg) were placed indoors in individual pens with ad libitum access to water and feed. After 7 d of adaptation, ewes were assigned ran...

295

Original article Iodine nutrition in ewes. 2. Effects of low to high iodine  

E-print Network

Original article Iodine nutrition in ewes. 2. Effects of low to high iodine intake by ewes on the iodine (I) levels. Dietary I contents (mg/kg dry matter [DM]) in pregnancy and lactation, respectively inorganic iodine (PII) of lambs from birth to d42 of life was affected by ewe I intake, except for groups

Boyer, Edmond

296

The effect of milking frequency on the milk production of Chios ewes and Damascus goats  

E-print Network

The effect of milking frequency on the milk production of Chios ewes and Damascus goats C milking caused a significant reduction (21.6 p. 100) in the milk production of Chios ewes during the first of the ewes milked twice daily were switched to one daily milking. The total reduction in the milk yield

Paris-Sud XI, Université de

297

Yeasts associated with Sardinian ewe's dairy products.  

PubMed

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

2001-09-19

298

Primary osteogenic sarcoma of the breast  

PubMed Central

Background Primary extra-osseous osteogenic sarcomas have been reported in many tissues of the body but their occurrence in the breast is extremely rare. It can arise as a result of osseous metaplasia in a pre-existing benign or malignant neoplasm of the breast or as non-phylloides sarcoma from the soft tissue of a previously normal breast. Case presentation A 40 year-old Nigerian woman was clinically diagnosed to have carcinoma of the left breast. The histology report of core-needle biopsy of the mass showed a malignant neoplasm comprising islands of chondroblastic and osteoblastic stromal cells. This report changed the diagnosis from carcinoma to osteogenic sarcoma of the breast. She had a left modified radical mastectomy, however there was significant post surgery skin deficit. A latissimus dorsi musculocutaneous flap was used to cover the anterior chest wall defect. Sections from the mastectomy specimen confirmed the diagnosis of osteogenic sarcoma. She died six months after mastectomy. Conclusion A diagnosis of osteogenic sarcoma of the breast was made based on histology report and after excluding an osteogenic sarcoma arising from underlying ribs and sternum. This is the second documented case of primary osteogenic sarcoma of the breast coming from Nigeria PMID:17156481

Ogundiran, Temidayo O; Ademola, Samuel A; Oluwatosin, Odunayo M; Akang, Effiong E; Adebamowo, Clement A

2006-01-01

299

Uterine sarcomas: clinical presentation and MRI features.  

PubMed

Uterine sarcomas are a rare heterogeneous group of tumors of mesenchymal origin, accounting for approximately 8% of uterine malignancies. They comprise leiomyosarcoma, endometrial stromal sarcoma, undifferentiated endometrial sarcoma, and adenosarcoma. Compared with the more common endometrial carcinomas, uterine sarcomas behave more aggressively and are associated with a poorer prognosis. Due to their distinct clinical and biological behavior, the International Federation of Gynecology and Obstetrics introduced a new staging system for uterine sarcomas in 2009, categorizing uterine carcinosarcoma as a variant of endometrial carcinoma, rather than a pure sarcoma. Magnetic resonance imaging (MRI) has a developing role in the assessment of these malignancies. Features such as tumor localization, irregular or nodular margins, necrosis, rapid growth, intense contrast enhancement, and restriction at diffusion-weighted imaging can suggest the diagnosis and help differentiate from more common leiomyomas and endometrial carcinoma. MRI is therefore extremely useful in preoperative detection and staging and, consequently, in determination of appropriate management. This pictorial review aims to discuss the clinical features of uterine sarcomas, as well as their most common appearances and distinct characteristics in MRI. PMID:25347940

Santos, Pedro; Cunha, Teresa Margarida

2015-01-01

300

Mesenchymal stem cell transformation and sarcoma genesis  

PubMed Central

MSCs are hypothesized to potentially give rise to sarcomas after transformation and therefore serve as a good model to study sarcomagenesis. Both spontaneous and induced transformation of MSCs have been reported, however, spontaneous transformation has only been convincingly shown in mouse MSCs while induced transformation has been demonstrated in both mouse and human MSCs. Transformed MSCs of both species can give rise to pleomorphic sarcomas after transplantation into mice, indicating the potential MSC origin of so-called non-translocation induced sarcomas. Comparison of expression profiles and differentiation capacities between MSCs and sarcoma cells further supports this. Deregulation of P53- Retinoblastoma-, PI3K-AKT-and MAPK pathways has been implicated in transformation of MSCs. MSCs have also been indicated as cell of origin in several types of chromosomal translocation associated sarcomas. In mouse models the generated sarcoma type depends on amongst others the tissue origin of the MSCs, the targeted pathways and genes and the differentiation commitment status of MSCs. While some insights are glowing, it is clear that more studies are needed to thoroughly understand the molecular mechanism of sarcomagenesis from MSCs and mechanisms determining the sarcoma type, which will potentially give directions for targeted therapies. PMID:23880362

2013-01-01

301

Pazopanib in sarcomas: expanding the PALETTE  

PubMed Central

Purpose of review After failure of standard therapy, few effective treatment options exist for adult patients with metastatic sarcomas, and median survival remains dismal at approximately 1 year. Pazopanib, a multitargeted tyrosine kinase inhibitor, has recently been approved for nonadipocytic soft tissue sarcomas refractory to chemotherapy. In this review, we will revisit the efficacy of pazopanib in sarcomas, and present a patient case that illustrates two of many unanswered questions: which sarcoma patients are most likely to benefit from pazopanib therapy, and what criteria are best suited to accurately detect benefit in clinical trials? Recent findings Pazopanib has been tested in sarcoma patients in a phase II and phase III study, and was shown to prolong progression-free survival by 3 months relative to placebo. Although histology has been the primary stratification variable for subgroup analysis in large sarcoma trials, the PALETTE study did not demonstrate superior response within histologic cohorts. Ongoing trials seek to explore efficacy of pazopanib in previously excluded histologies, as well as include correlative studies to identify histologic and molecular biomarkers to predict patients likely to benefit. Summary Pazopanib has been proven to provide modest benefit overall to nonadipocytic soft tissue sarcoma patients, but we have yet to identify the molecular basis for those patients who derive exceptional benefit. PMID:23666473

Wilky, Breelyn A.; Meyer, Christian F.; Trent, Jonathan C.

2014-01-01

302

Therapeutic Angiotensin-(1-7) in Treating Patients With Metastatic Sarcoma That Cannot Be Removed By Surgery  

ClinicalTrials.gov

Bone Cancer; Chondrosarcoma; Clear Cell Sarcoma of the Kidney; Metastatic Osteosarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; 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

2013-12-10

303

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: tdelaney@partners.org; 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)

2009-07-01

304

Drugs Approved for Soft Tissue Sarcoma  

Cancer.gov

This page lists cancer drugs approved by the Food and Drug Administration (FDA) for soft tissue sarcoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

305

Primary clear cell sarcoma of the tongue.  

PubMed

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

2013-11-01

306

Treatment Options for Childhood Soft Tissue Sarcoma  

MedlinePLUS

... followed by adjuvant chemotherapy . Blood Vessel Tumors Angiosarcoma (deep) Treatment of angiosarcoma may include the following: Surgery ... about clinical trials is available from the NCI Web site . Recurrent and Progressive Childhood Soft Tissue Sarcoma ...

307

Activated T Cells Armed With GD2 Bispecific Antibody in Children and Young Adults With Neuroblastoma and Osteosarcoma  

ClinicalTrials.gov

Desmoplastic Small Round Cell Tumor; Disseminated Neuroblastoma; Metastatic Childhood Soft Tissue Sarcoma; Metastatic Ewing Sarcoma/PNET; Metastatic Osteosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/PNET; Recurrent Melanoma; Recurrent Neuroblastoma; Recurrent Osteosarcoma

2015-03-25

308

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

ClinicalTrials.gov

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

2012-03-14

309

Acroangiodermatitis (Pseudo-Kaposi sarcoma)  

PubMed Central

Acroangiodermatitis or Pseudo-Kaposi sarcoma is a rare angioproliferative entity, related to chronic venous insufficiency or certain other vascular anomalies. It is often associated with chronic venous insufficiency, arteriovenous malformation of the legs, chronic renal failure treated with dialysis, paralyzed legs and amputation stumps. We hereby describe a case of 45 year old female presenting with pitting pedal edema, multiple ulcers over bilateral lower limbs with irregular margins with erythema and hyperpigmentation of the surrounding skin. Color Doppler study of bilateral lower limbs was normal. Histopathological examination from one of the lesions showed hyperplastic epidermis, proliferation of capillaries in dermis, hemosiderin deposits and lymphocytic infiltrate. These features thus confirmed the diagnosis of Acroangiodermatitis. PMID:25165656

Singh, Satyendra Kumar; Manchanda, Kajal

2014-01-01

310

Acroangiodermatitis (Pseudo-Kaposi sarcoma).  

PubMed

Acroangiodermatitis or Pseudo-Kaposi sarcoma is a rare angioproliferative entity, related to chronic venous insufficiency or certain other vascular anomalies. It is often associated with chronic venous insufficiency, arteriovenous malformation of the legs, chronic renal failure treated with dialysis, paralyzed legs and amputation stumps. We hereby describe a case of 45 year old female presenting with pitting pedal edema, multiple ulcers over bilateral lower limbs with irregular margins with erythema and hyperpigmentation of the surrounding skin. Color Doppler study of bilateral lower limbs was normal. Histopathological examination from one of the lesions showed hyperplastic epidermis, proliferation of capillaries in dermis, hemosiderin deposits and lymphocytic infiltrate. These features thus confirmed the diagnosis of Acroangiodermatitis. PMID:25165656

Singh, Satyendra Kumar; Manchanda, Kajal

2014-07-01

311

Technetium scanning in Kaposi's sarcoma and its simulators.  

PubMed

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

1982-04-01

312

Application of Proteomics to Soft Tissue Sarcomas  

PubMed Central

Soft tissue sarcomas are rare and account for less than 1% of all malignant cancers. Other than development of intensive therapies, the clinical outcome of patients with soft tissue sarcoma remains very poor, particularly when diagnosed at a late stage. Unique mutations have been associated with certain soft tissue sarcomas, but their etiologies remain unknown. The proteome is a functional translation of a genome, which directly regulates the malignant features of tumors. Thus, proteomics is a promising approach for investigating soft tissue sarcomas. Various proteomic approaches and clinical materials have been used to address clinical and biological issues, including biomarker development, molecular target identification, and study of disease mechanisms. Several cancer-associated proteins have been identified using conventional technologies such as 2D-PAGE, mass spectrometry, and array technology. The functional backgrounds of proteins identified were assessed extensively using in vitro experiments, thus supporting expression analysis. These observations demonstrate the applicability of proteomics to soft tissue sarcoma studies. However, the sample size in each study was insufficient to allow conclusive results. Given the low frequency of soft tissue sarcomas, multi-institutional collaborations are required to validate the results of proteomic approaches. PMID:22778956

Kondo, Tadashi; Kubota, Daisuke; Kawai, Akira

2012-01-01

313

Genetic analysis of milking ability in Lacaune dairy ewes  

PubMed Central

The milking ability of Lacaune ewes was characterised by derived traits of milk flow patterns, in an INRA experimental farm, from a divergent selection experiment in order to estimate the correlated effects of selection for protein and fat yields. The analysis of selected divergent line effects (involving 34 616 data and 1204 ewes) indicated an indirect improvement of milking traits (+17% for maximum milk flow and -10% for latency time) with a 25% increase in milk yield. Genetic parameters were estimated by multi-trait analysis with an animal model, on 751 primiparous ewes. The heritabilities of the traits expressed on an annual basis were high, especially for maximum flow (0.54) and for latency time (0.55). The heritabilities were intermediate for average flow (0.30), time at maximum flow (0.42) and phase of increasing flow (0.43), and low for the phase of decreasing flow (0.16) and the plateau of high flow (0.07). When considering test-day data, the heritabilities of maximum flow and latency time remained intermediate and stable throughout the lactation. Genetic correlations between milk yield and milking traits were all favourable, but latency time was less milk yield dependent (-0.22) than maximum flow (+0.46). It is concluded that the current dairy ewe selection based on milk solid yield is not antagonistic to milking ability. PMID:16492374

Marie-Etancelin, Christel; Manfredi, Eduardo; Aurel, Marie-Rose; Pailler, François; Arhainx, Jean; Ricard, Edmond; Lagriffoul, Gilles; Guillouet, Philippe; Bibé, Bernard; Barillet, Francis

2006-01-01

314

Influence of supplemental monensin on gestating and lactating ewes  

E-print Network

were grouped into singles and twins by sonogram results, allotted to pens in pairs and assigned to either an ionophore (diet I with 70 mg daily) or non-ionophore (diet 2) treatment groups in a 2 x 2 factorial arrangement. All ewes were fed according...

Peel, Richard Kraig

1997-01-01

315

UTERINE RESPONSE TO INFECTIOUS BACTERIA IN ESTROUS CYCLIC EWES  

Technology Transfer Automated Retrieval System (TEKTRAN)

Luteal-phase uteri are susceptible to infections, and PGE2 and exogenous progesterone can down-regulate, whereas PGF2a can up-regulate, uterine immune functions. To study this phenomenon, uteri of follicular- or luteal-phase ewes were inoculated with either saline or bacteria (Arcanobacterium pyogen...

316

Induction of cervical dilation for transcervical embryo transfer in ewes  

PubMed Central

Background A major limitation in the application of assisted reproductive technologies in sheep arises from the inability to easily traverse the uterine cervix. The cervix of the non-pregnant ewe is a narrow and rigid structure, with 5–7 spiral folds and crypts that block its lumen. The first two folds closest to the vagina appear to be the greatest obstacle for the instrument insertion into the sheep cervix. Therefore, the dilation of the distal part of the cervix could provide the conformational change necessary to perform non-invasive transcervical procedures. The present study set out to assess the efficacy of Cervidil®, a patented dinoprostone (PgE2)-containing vaginal insert with a controlled-release mechanism, to safely induce sufficient cervical dilation for the purpose of transcervical embryo transfer (TCET) in cyclic ewes. Methods The transfer of frozen-thawed ovine embryos was attempted in 22 cross-bred Rideau Arcott x Polled Dorset ewes, with or without the pre-treatment with Cervidil® for 12 or 24 h prior to TCET. Results Cervical penetration rate was significantly improved after Cervidil® pre-treatment, with 55% (6/11) of treated versus 9% (1/11) of control animals successfully penetrated (?2-test, p?ewes that were penetrated, 67% (4/6) had been exposed to Cervidil(R) for 24 h and 33% (2/6) had had a 12-h exposure (p?>?0.05). Variations in the age, weight, genotype, parity, lifetime lamb production (LLP) and post-partum interval (PPI) between penetrated and non-penetrated ewes were not significant (p?>?0.05). The time taken to traverse the uterine cervix was negatively correlated (p?ewes, but no fetuses were detected ultrasonographically 55 days post-TCET. Conclusions The present results indicate a significant benefit of using Cervidil® for inducing cervical dilation during the mid-luteal phase in ewes but the reason(s) for impaired fertility after the transfer of frozen-thawed ovine embryos remains to be elucidated. PMID:24467737

2014-01-01

317

What Should You Ask Your Doctor about Kaposi Sarcoma?  

MedlinePLUS

... for Kaposi sarcoma? What should you ask your doctor about Kaposi sarcoma? As you cope with Kaposi ... need to have honest, open discussions with your doctor. You should ask any question on your mind ...

318

What Should You Ask Your Doctor about Soft Tissue Sarcomas?  

MedlinePLUS

... soft tissue sarcomas? What should you ask your doctor about soft tissue sarcomas? As you cope with ... need to have honest, open discussions with your doctor. You should feel comfortable asking any question no ...

319

What's New in Kaposi Sarcoma Research and Treatment?  

MedlinePLUS

... Next Topic Additional resources for Kaposi sarcoma What’s new in Kaposi sarcoma research and treatment? A great ... once it has developed. Treatment Researchers are studying new and different ways to treat KS. Imiquimod (Aldara) ...

320

What's New in Uterine Sarcoma Research and Treatment?  

MedlinePLUS

... 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 help ...

321

What Are the Key Statistics about Soft Tissue Sarcoma?  

MedlinePLUS

... for soft tissue sarcomas? What are the key statistics about soft tissue sarcomas? The American Cancer Society's ... in the United States for 2015 are (these statistics include both adults and children): About 11,930 ...

322

What Are the Key Statistics about Uterine Sarcoma?  

MedlinePLUS

... factors for uterine sarcoma? What are the key statistics about uterine sarcoma? The American Cancer Society's estimates ... Symptoms of Cancer Treatments & Side Effects Cancer Facts & Statistics News About Cancer Expert Voices Blog Programs & Services ...

323

What Are the Key Statistics about Kaposi Sarcoma?  

MedlinePLUS

... what causes Kaposi sarcoma? What are the key statistics about Kaposi sarcoma? Before the AIDS epidemic, Kaposi ... develop. In areas of the world (such as Africa) where KSHV and HIV infection rates are high, ...

324

Progesterone administration reduces the behavioural and physiological responses of ewes to abrupt weaning of lambs.  

PubMed

Abrupt weaning, a usual management in sheep productive systems, may provoke behavioural and physiological responses indicative of stress in ewes and lambs. Progesterone (P4) has anxiolytic and sedative effects through the union of its metabolites that contain 3?-hydroxyl group to the ?-aminobutyricacidA receptor. Our first aim was to determine whether P4 administration reduces the behavioural and physiological responses of ewes to abrupt weaning of lambs. A complementary aim was to determine whether P4 treatment affects the milk yield and composition of ewes, and the BW of their lambs. In experiment 1, seven ewes received P4 treatment for 32 days (group E1-P4), and eight ewes remained as an untreated control group (group E1-C). BW of the lambs was recorded during P4 treatment. Lambs were weaned at 59 days (Day 0 = weaning). The main behaviours of the ewes before and after weaning were recorded using 10 min scan sampling. The ewes' serum total protein, albumin and globulin concentrations were measured before and after weaning of the lambs. In experiment 2, milk yield and composition were determined in two different groups of six ewes treated with P4 (group E2-P4) for 16 days and in five untreated controls (group E2-C). The BW of lambs increased with time (P = 0.001) in both groups and did not differ. The percentage of observations in which the ewes were seen pacing on Day 0 was greater in the E1-C group than in the E1-P4 group (P = 0.0007). Similarly, the percentage of observations in which the ewes were recorded vocalizing on Day 0 was greater in the E1-C group than in the E1-P4 group (P = 0.04). The percentage of observations in which E1-C ewes were recorded lying did not change from Days 0 to 1; however, it increased in E1-P4 ewes. Total serum protein concentration did not change in E1-P4 ewes from Days 0 to 3, although a decrease was seen in E1-C ewes (P = 0.04). Serum globulin concentration was greater in E1-P4 ewes on Day 3 than in E1-C ewes (P = 0.0008). In experiment 2, there were no differences between E2-P4 and E2-C ewes in terms of milk yield, protein, fat and lactose content. Progesterone administration reduced the behavioural and physiological responses of ewes to abrupt weaning of lambs, and this effect was not mediated by changes in milk yield and composition, or by lambs' BW. PMID:23597263

Freitas-de-Melo, A; Banchero, G; Hötzel, M J; Damián, J P; Ungerfeld, R

2013-08-01

325

Gonadotropin stimulation using P.G. 600® on reproductive success of non-lactating anestrous ewes.  

PubMed

The effect of stimulation with a gonadotropin preparation with combined follicle stimulating and luteininzing hormone like activity on reproductive success in anestrous ewes was evaluated. In Experiment 1, ewes of mixed breeding were treated with CIDR inserts (0.3g progesterone) for 5 days and were assigned randomly to receive either gonadotropin stimulation (3mL i.m. injection of P.G. 600®, 240IU eCG and 120IU hCG) at CIDR removal or no further treatment. Intact raddled rams were joined at insert removal for 30-35 days, and ewes were observed for indications of estrus after 4 days of ram exposure. Pregnancy diagnosis was conducted via transrectal ultrasonography at the time of ram removal and again 20-25 days. The second experiment was similar to Experiment 1, except treated ewes received the gonadotropin 1 day prior to insert removal. In Experiment 1, incidence of estrus was greater for treated ewes (P=0.01), and prolificacy tended to be greater in treated ewes (P=0.06). In Experiment 2, treated ewes had greater conception rates (P=0.01), pregnancy rates to first service (P=0.0007), and tended to have greater overall pregnancy rates than control ewes (P=0.07). A greater percentage of ewes lambed in the gonadotropin treated ewes than in ewes in the control group (P<0.0001), and overall lambing rates in treated ewes were greater than non-treated controls (P<0.0001). In conclusion, gonadotropin treatment 1 day prior to CIDR removal increased reproductive success in progesterone-treated anestrous ewes. PMID:24950998

D'Souza, K N; Rastle-Simpson, S L; Redhead, A K; Baptiste, Q S; Smith, B; Knights, M

2014-08-01

326

A Pilot Study of Consolidative Immunotherapy in Patients with High-Risk Pediatric Sarcomas  

PubMed Central

Purpose Patients with metastatic or recurrent Ewing’s sarcoma (ESFT) and alveolar rhabdomyosarcoma (AR) have <25% 5-yr. survival in most studies. This study administered a novel immunotherapy regimen aimed at consolidating remission in these patients. Experimental Design 52 patients with translocation positive, recurrent or metastatic ESFT or AR underwent pre-chemotherapy cell harvest via apheresis for potential receipt of immunotherapy. Following completion of standard multimodal therapy, 30 patients ultimately initiated immunotherapy and were sequentially assigned to three cohorts. All cohorts received autologous T cells, influenza vaccinations and dendritic cells (DCs) pulsed with peptides derived from tumor specific translocation breakpoints and E7, a peptide known to bind HLA-A2. Cohort 1 received moderate dose rhIL-2, cohort 2 received low dose rhIL-2 and cohort 3 did not receive rhIL-2. Results All immunotherapy recipients generated influenza specific immune responses, whereas immune responses to the translocation breakpoint peptides occurred in 39%, and only 25% of HLA-A2+ patients developed E7 specific responses. Toxicity was minimal. Intention-to-treat analysis revealed a 31% 5-year OS for all patients apheresed (median potential follow-up 7.3 yrs) with a 43% 5-year OS for patients initiating immunotherapy. Conclusions Consolidative immunotherapy is a scientifically based and clinically practical approach for integrating immunotherapy into a multimodal regimen for chemoresponsive cancer. Patients receiving immunotherapy experienced minimal toxicity and favorable survival. The robust influenza immune responses observed suggest that post-chemotherapy immune incompetence will not fundamentally limit this approach. Future studies will seek to increase efficacy by using more immunogenic antigens and more potent DCs. PMID:18676758

Mackall, Crystal L.; Rhee, Eunice H.; Read, Elizabeth J.; Khuu, Hanh M.; Leitman, Susan F.; Bernstein, Donna; Tesso, Merertu; Long, Lauren M.; Grindler, David; Merino, Margret; Kopp, William; Tsokos, Maria; Berzofsky, Jay A.; Helman, Lee J.

2008-01-01

327

Prognostic factors in soft tissue sarcomas: The Aarhus experience  

Microsoft Academic Search

In the present study, the outcome, patterns of local recurrence and survival, as well as prognostic factors, were evaluated in patients surgically treated for soft tissue sarcomas. Between January 1979 and July 1993, 316 consecutive patients were referred to the Sarcoma Centre in Aarhus with localised malignant soft tissue sarcoma of the extremities or trunk. If possible, the patients were

S Vraa; J Keller; O. S Nielsen; O Sneppen; A. G Jurik; O. M Jensen

1998-01-01

328

Gastric myeloid sarcoma without acute myeloblastic leukemia.  

PubMed

Myeloid sarcomas (MS) involve extramedullary blast proliferation from one or more myeloid lineages that replace the original tissue architecture, and these neoplasias are called granulocytic sarcomas, chloromas or extramedullary myeloid tumors. Such tumors develop in lymphoid organs, bones (e.g., skulls and orbits), skin, soft tissue, various mucosae, organs, and the central nervous system. Gastrointestinal (GI) involvement is rare, while the occurrence of myeloid sarcomas in patients without leukemia is even rare. Here, we report a case of a 38-year-old man who presented with epigastric pain and progressive jaundice. An upper GI endoscopy had shown extensive multifocal hyperemic fold thickening and the spread of nodular lesions in the body of the stomach. Biopsies from the gastric lesions indicated myeloid sarcoma of the stomach. However, concurrent peripheral blood and bone marrow examinations showed no evidence of acute myeloid leukemia. For diagnosis, the immunohistochemical markers must be checked when evaluating a suspected myeloid sarcoma case. Accurate MS diagnosis determines the appropriate therapy and prognosis. PMID:25717265

Huang, Xiao-Li; Tao, Jin; Li, Jian-Zhong; Chen, Xiao-Liang; Chen, Jian-Ning; Shao, Chun-Kui; Wu, Bin

2015-02-21

329

Gastric myeloid sarcoma without acute myeloblastic leukemia  

PubMed Central

Myeloid sarcomas (MS) involve extramedullary blast proliferation from one or more myeloid lineages that replace the original tissue architecture, and these neoplasias are called granulocytic sarcomas, chloromas or extramedullary myeloid tumors. Such tumors develop in lymphoid organs, bones (e.g., skulls and orbits), skin, soft tissue, various mucosae, organs, and the central nervous system. Gastrointestinal (GI) involvement is rare, while the occurrence of myeloid sarcomas in patients without leukemia is even rare. Here, we report a case of a 38-year-old man who presented with epigastric pain and progressive jaundice. An upper GI endoscopy had shown extensive multifocal hyperemic fold thickening and the spread of nodular lesions in the body of the stomach. Biopsies from the gastric lesions indicated myeloid sarcoma of the stomach. However, concurrent peripheral blood and bone marrow examinations showed no evidence of acute myeloid leukemia. For diagnosis, the immunohistochemical markers must be checked when evaluating a suspected myeloid sarcoma case. Accurate MS diagnosis determines the appropriate therapy and prognosis. PMID:25717265

Huang, Xiao-Li; Tao, Jin; Li, Jian-Zhong; Chen, Xiao-Liang; Chen, Jian-Ning; Shao, Chun-Kui; Wu, Bin

2015-01-01

330

High expression of the evolutionarily conserved alpha/beta hydrolase domain containing 6 (ABHD6) in Ewing tumors.  

PubMed

Despite improvements in the treatment of patients with Ewing family tumors (EFT), the prognosis for patients with advanced disease is still unsatisfactory. Recently, we identified lipase I as an EFT-associated gene that might be interesting for the development of new immunological or pharmacological treatment strategies. Lipase I is a member of the large protein superfamilies of alpha/beta hydrolases and serine hydrolases. In the present paper we describe high expression of another member of these superfamilies in EFT. By DNA microarray data base mining we found exceptional high expression of alpha/beta hydrolase domain containing 6 (ABHD6) in EFT but not in other sarcomas. Expression of ABHD6 in EFT correlated with expression of another EFT-associated gene, aristaless. Analysis of ABHD6-associated GGAA microsatellites revealed shorter microsatellites in EFT with lack of ABHD6 expression. ABHD6 homologues were found in varying chordata but not in other animal species. Based on homology modeling we predicted the 3D-structure of ABHD6, which shows high similarity with bacterial homoserine transacetylases. High expression of ABHD6 in EFT in comparison to normal tissues and other tumors suggests that ABHD6 might be an interesting new diagnostic or therapeutic target for EFT. However, knock down of ABHD6 in EFT cells did not inhibit tumor cell growth. PMID:19793082

Max, Daniela; Hesse, Manuela; Volkmer, Ines; Staege, Martin S

2009-12-01

331

Pregnancy and genital sarcoma: a systematic review of the literature.  

PubMed

We conducted a literature review to determine the clinical characteristics of genital sarcoma during pregnancy. The systematic literature search was conducted using the search engines PubMed and MEDLINE with keywords "sarcoma" and "pregnancy" and was limited to female genital organs such as ovary, uterus, cervix, vagina, vulva, and retroperitoneal sarcoma. Kaposi's sarcoma, metastatic sarcoma, history of sarcoma, bone sarcoma located in pelvis, and fetal sarcoma were excluded in this study. There were 40 cases of genital sarcoma during pregnancy between 1955 and 2007. The majority of the cases were uterine sarcoma (37.5%), followed by retroperitoneal sarcoma (27.5%), vulvar sarcoma (22.5%), and vaginal sarcoma (12.5%). Mean age of the patient was 27.8 +/- 7.0. The distribution in the onset of symptoms had two peaks: first trimester (27.5%) and third trimester (50.0%). Growing mass (42.5%), abdominal pain (30.0%), and vaginal bleeding (22.5%) were the three most common symptoms. Incidental diagnosis was made in 22.5% and included during cesarean section (12.5%) and routine pelvic exam (7.5%). The cases initially not suspicious for malignancy were 42.5%. Thirty-three (82.5%) cases had live-born infants with term delivery in 55.2%. Mean birth weight was 2843 +/- 791 g, and male infants were more common (66.7%). Intrauterine growth retardation was seen in 12.5% of cases. Preterm labor was a common complication. Median survival period was 2.5 years (95% confidence, 1.9 to 3.1). The 2-, 3-, and 5-year cumulative survival rates were 60%, 38%, and 17%, respectively. Genital sarcomas in pregnancy are rare. There is a delay in diagnosis due to low index of suspicion. A majority had live births, and the 5-year survival is similar to that of advanced-stage sarcoma in nonpregnant women. PMID:19288396

Matsuo, Koji; Eno, Michele L; Im, Dwight D; Rosenshein, Neil B

2009-08-01

332

Myofibroblastic sarcoma in liver: a case report  

PubMed Central

We recently encountered a giant Myofibroblastic sarcoma (MS) exceeding 23 cm in diameter which had developed in the liver in a 27-year-old female, and which was surgically resected with gratifying results. On surveillance imaging, a giant mass was detected in the right lobe of the liver. One the basis of morphology and immunohistochemistry features, the diagnosis of intermediate-grade myofibroblastic sarcoma (MS) was established. MS is extremely rarely found in the abdominal cavity. It is almost impossible to make a definite diagnosis before operation. However, the possibility of sarcoma should be taken into account for liver mass according to multimodal imaging features of the mass, especially when the diagnosis of common hepatic tumor was not supported by signs on imaging. Relative characteristic features on multimodal images maybe helpful to considerate the possibility of MS. This is the first reported case to date. PMID:25755822

Yi, Xiaoping; Xiao, Desheng; Long, Xueying

2015-01-01

333

Primary cardiac sarcoma after breast cancer  

PubMed Central

Primary cardiac sarcomas are rare tumours carrying poor prognosis. Postradiation sarcoma has been reported in patients with breast, cervical and head and neck cancers. We report a case of a 56-year-old woman with stage IIA breast cancer diagnosed in 1997, submitted to mastectomy, adjuvant chemotherapy, radiotherapy and hormonotherapy. Pulmonary metastasis were detected in 2008 and treated with chemotherapy and hormonotherapy, being in complete remission since August 2009. She was admitted in December 2009 with a 3-week history of fever, dyspnoea, polyarthralgias and leg oedema. An echocardiography showed a mass in the left atrium. She was submitted to a surgical tumour resection and the histology revealed a sarcoma of intermediate degree of differentiation. Chemoradiation therapy was started and she remains alive after 3?years, without tumour regrowth or metastasis. This case is a therapeutic challenge, because the previous therapies for breast cancer hampered the options for extra chemoradiation therapy. PMID:23608855

Ramalho, Joana; Nunes, Sandra; Marques, Irene; Marques, Franklim

2013-01-01

334

Giant subcutaneous synovial sarcoma: an interesting case.  

PubMed

A 45-year-old lady presented to us with a large subcutaneous swelling on her left side of back of 1 year duration. Local examination revealed a 13×12 cm spherical swelling on the left lower paraspinal region. Magnetic resonance imaging of lumbosacral spine revealed a 13×12 cm mass having solid and cystic components with internal septations in the subcutaneous tissue of left posterior paraspinal area. The mass was hetrogenously hyperintense on T 2 weighted images suggestive of synovial sarcoma. Wide local excision of the lump was carried out followed by closure of the defect with a lateral intercostal artery based rotational flap. The histopathology of the excised tumor revealed synovial sarcoma that stained positive for cytokeratin and epithelial membrane antigen. This case highlights an unusually large subcutaneous synovial sarcoma present in para-spinal area. PMID:24551714

Garg, Pankaj Kumar; Mohnaty, Debajyoti; Jain, Bhupendra Kumar; Goel, Sunny; Singh, Bharat

2013-12-01

335

Observation, Radiation Therapy, Combination Chemotherapy, and/or Surgery in Treating Young Patients With Soft Tissue Sarcoma  

ClinicalTrials.gov

Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Malignant Mesenchymoma; Adult Neurofibrosarcoma; Adult Synovial Sarcoma; Childhood Alveolar Soft-part Sarcoma; Childhood Angiosarcoma; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Mesenchymoma; Childhood Neurofibrosarcoma; Childhood Synovial Sarcoma; Dermatofibrosarcoma Protuberans; Metastatic Childhood Soft Tissue Sarcoma; Nonmetastatic Childhood Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

2014-09-08

336

Paratesticular sarcomas: A report of seven cases  

PubMed Central

Primary tumors of the paratesticular region are rare, with paratesticular sarcomas constituting a major proportion of these tumors, particularly in the elderly. The paratesticular region consists of mesothelial, various epithelial and mesenchymal cells and may therefore give rise to a number of tumors with various behaviors. Defining the association between the paratesticular mass and the testicle, and differentiation between benign and malignant masses using radiology is challenging, therefore the mass is usually considered to be malignant and radical orchiectomy with high ligation is performed. The present study reports the cases of seven patients with tumors of the paratesticular region and presents the clinical and significant histological features of the tumors. In total, two patients suffered from dedifferentiated liposarcoma (DDLS), two exhibited leiomyosarcoma, two exhibited low-grade fibromyxoid sarcoma and one case of undifferentiated pleomorphic sarcoma was identified. Radical orchiectomy with high ligation was performed in five cases; simple orchiectomy was performed in one case and excisional biopsy was performed in the remaining case. A leiomyosarcomatous and epithelial membrane antigen (EMA) positive whorl pattern was observed during microscopy in the two DDLS cases. Additionally, one of the low-grade fibromyxoid sarcoma patients exhibited pleomorphism and mitosis in focal areas. To the best of our knowledge, the present study is the second time low-grade fibromyxoid sarcoma cases with paratesticular localization have been reported in the literature. Of the seven cases, four patients succumbed to the disease, one patient is living with the disorder and the two cases of DDLS are living without the disease. Paratesticular sarcomas are often aggressive and a multidisciplinary approach is required for the diagnosis and treatment of these tumors. PMID:25435981

ÜNLÜ, YA?AR; HUQ, GÜLBEN ERDEM; ÖZYALVAÇLI, GÜLZADE; ZENGIN, MEHMET; KOCA, SEVIM BAYKAL; YÜCETAS, U?UR; BOZKURT, EROL RÜ?TÜ; BEHZATO?LU, KEMAL

2015-01-01

337

Paratesticular sarcomas: A report of seven cases.  

PubMed

Primary tumors of the paratesticular region are rare, with paratesticular sarcomas constituting a major proportion of these tumors, particularly in the elderly. The paratesticular region consists of mesothelial, various epithelial and mesenchymal cells and may therefore give rise to a number of tumors with various behaviors. Defining the association between the paratesticular mass and the testicle, and differentiation between benign and malignant masses using radiology is challenging, therefore the mass is usually considered to be malignant and radical orchiectomy with high ligation is performed. The present study reports the cases of seven patients with tumors of the paratesticular region and presents the clinical and significant histological features of the tumors. In total, two patients suffered from dedifferentiated liposarcoma (DDLS), two exhibited leiomyosarcoma, two exhibited low-grade fibromyxoid sarcoma and one case of undifferentiated pleomorphic sarcoma was identified. Radical orchiectomy with high ligation was performed in five cases; simple orchiectomy was performed in one case and excisional biopsy was performed in the remaining case. A leiomyosarcomatous and epithelial membrane antigen (EMA) positive whorl pattern was observed during microscopy in the two DDLS cases. Additionally, one of the low-grade fibromyxoid sarcoma patients exhibited pleomorphism and mitosis in focal areas. To the best of our knowledge, the present study is the second time low-grade fibromyxoid sarcoma cases with paratesticular localization have been reported in the literature. Of the seven cases, four patients succumbed to the disease, one patient is living with the disorder and the two cases of DDLS are living without the disease. Paratesticular sarcomas are often aggressive and a multidisciplinary approach is required for the diagnosis and treatment of these tumors. PMID:25435981

Unlü, Ya?ar; Huq, Gülben Erdem; Ozyalvaçli, Gülzade; Zengin, Mehmet; Koca, Sevim Baykal; Yücetas, U?ur; Bozkurt, Erol Rü?tü; Behzato?lu, Kemal

2015-01-01

338

Chordoid sarcoma of the hand. A case report.  

PubMed

Chordoid sarcoma is a rare, distinctive neoplasm that usually occurs in the soft tissue of the extremities. Despite its striking histological resemblance to chordoma at light microscopic level, both clinical and ultrastructural differences exist and chordoid sarcoma may in fact be related to tendosynovial sarcoma. Previous reports of extraskeletal myxoid chondrosarcoma, however, show that this tumour bears a striking light microscopic and ultrastructural similarity to chordoid sarcoma, which suggests that the latter may be a variant of extraskeletal myxoid chondrosarcoma. In this report a further case of chordoid sarcoma is presented; clinical, radiological, histological and ultramicroscopic features support a tendosynovial origin. PMID:7079855

Jacobs, G H; Berson, S D; Skikne, M I; Rippey, J J; Jacobson, J N

1982-04-24

339

The induction of breeding activity in lactating ewes during anestrus by the use of hormones  

E-print Network

changes of ovaries in the untreated ewes which did not exhibit estrus. CHAPTER II REVIEW OF LITERATURE Phillips et al. (1947) reported the seasonal nature of breeding in many breeds of sheep. Most ewes exhibited estrus in late summer or early fall... of these breeds continuing to cycle throughout the year. The seasonal nature was also observed by , Schott, Phillips and Spencer (1939) and Phillips, Fraps and Frank (1945). Hafez (1952) studied the breeding season and reproduction of the ewe. He investigated...

Ahmed, Shams Uddin

1963-01-01

340

Radionuclide scanning in pseudo-Kaposi's sarcoma.  

PubMed

Sodium pertechnetate Tc 99m radionuclide scanning is considered to be a sensitive indicator in detecting lesions of Kaposi's sarcoma, including occult infiltrations. This report describes a "false-positive" scan in a patient with acroanglodermatitis (pseudo-Kaposi's sarcoma); therefore, this technique may not be useful in the differential diagnosis of these two clinically and histologically similar diseases. We suggest, instead that the technetium scan may be helpful in deciding on the course of therapy in acroangiodermatitis by demonstrating the nature of the underlying vascular anomalies. PMID:453882

Rosen, T; Martin, S; Stern, J K

1979-06-01

341

Cellular immunotherapy for soft tissue sarcomas.  

PubMed

Soft tissue sarcomas are rare neoplasms, with approximately 9000 new cases in the USA every year. Unfortunately, during the past two decades, there has been little progress in the treatment of metastatic soft tissue sarcomas beyond the standard approaches of surgery, chemotherapy and radiation. Immunotherapy is a modality complementary to conventional therapy. It is appealing because functional antitumor activity could affect both local-regional and systemic disease, and act over a prolonged period of time. In this report, we review immunotherapeutic investigative strategies that are being developed, including several tumor vaccine, antigen vaccine and dendritic cell vaccine strategies. PMID:22401634

Finkelstein, Steven Eric; Fishman, Mayer; Conley, Anthony P; Gabrilovich, Dmitry; Antonia, Scott; Chiappori, Alberto

2012-03-01

342

Ovarian Follicular Atresia of Ewes during Spring Puerperium  

PubMed Central

The distribution of healthy and atretic follicles on the ovarian surface of improved Valachian ewes 17, 24, and 32 days postpartum is reported in this study. The number of healthy follicles was higher on day 24 postpartum and their mean diameter tended to increase to day 32 (P < 0.05) with the greatest diameter of 5?mm. 78–81% of atretic follicles ?3?mm in diameter was observed where apoptosis began in the follicular cells situated at the follicular cavity. The early atretic follicles are characterized by the presence of mitotic pictures. In one ewe 24 days postpartum, small regressive follicular cysts were observed. Contracting atresia is characterized by thickening of the theca interna even to 190??m. Progesterone and oestradiol-17? concentrations were maintained at relatively low levels, but with no significant difference between the days postpartum. PMID:22567543

Vl?ková, Radoslava; Sopková, Drahomíra; Pošivák, Ján; Valocký, Igor

2012-01-01

343

Trabectedin in soft tissue sarcomas.  

PubMed

Trabectedin (Yondelis®; PharmaMar, Madrid, Spain), a synthetic anticancer agent originally isolated from the Caribbean tunicate, Ecteinascidia turbinata, is currently approved in more than 70 countries worldwide for the treatment of soft tissue sarcoma (STS). Trabectedin is an isoquinoline alkylating agent that, unlike other alkylating agents, binds in the DNA minor groove to initiate cytotoxic activity. Other multitarget mechanisms of action of trabectedin include important effects within the tumor microenvironment; in particular, trabectedin possesses indirect anti-inflammatory and anti-angiogenic activity via tumor-associated macrophages and high-specificity modulation of various transcription factors. The clinical efficacy of trabectedin, administered intravenously over 24 h every 3 weeks, has been demonstrated in several studies in patients with STS. In the Phase II STS-201 trial, 270 patients with liposarcoma or leiomyosarcoma were randomized to receive trabectedin 1.5 mg/m(2) given as a 24-h intravenous (iv.) infusion every 3 weeks or as a weekly regimen (0.58 mg/m(2); 3-h iv. infusion for three consecutive weeks in a 4-week cycle). There was a statistically significant and clinically relevant 27% reduction in the risk of disease progression (primary end point) with trabectedin given as a 24-h infusion q3w (p = 0.0302) with an overall survival rate at 12 months of 60%. Trabectedin was generally well tolerated; the most frequently reported severe adverse events were neutropenia (47% of patients) and elevated transaminases (47%). Overall, the majority of adverse events were mild to moderate and, despite a long duration of exposure to trabectedin in some patients, no cumulative toxicities were experienced. PMID:25048043

Brodowicz, Thomas

2014-06-01

344

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. 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

2008-01-01

345

TCGA Benchmark 4: Evaluating SV and SNV Calls Using Cell Line Genomes - Adam Ewing, TCGA Scientific Symposium 2012  

Cancer.gov

Home News and Events Multimedia Library Videos TCGA Benchmark 4: Evaluating SV and SNV Calls Using Cell Line Genomes - Adam Ewing TCGA Benchmark 4: Evaluating SV and SNV Calls Using Cell Line Genomes - Adam Ewing, TCGA Scientific Symposium 2012 You

346

Combination Therapy for Advanced Kaposi Sarcoma  

Cancer.gov

In this clinical trial, adult patients with any form of advanced Kaposi sarcoma will be treated with liposomal doxorubicin and bevacizumab every 3 weeks for a maximum of six treatments.  Patients who respond to this therapy or have stable disease will receive bevacizumab alone every 3 weeks for a maximum of 11 treatments.

347

Radiation therapy of retroperitoneal soft tissue sarcomas  

Microsoft Academic Search

Between 1971 and 1982, 23 patients have been treated with radiation therpy at the Massachusetts General Hospital(MGH) for retroperitoneal soft tissue sarcomas. Seventeen patients were treated with curative intent and six with palliative intent. Of the patients treated with curative intent, the 5 year actuarial survivial rate was 54% and the 5 year actuarial local control rate was also 54%.

Joel E Tepper; Herman D Suit; William C Wood; Karl H Proppe; David Harmon; Pat McNulty

1984-01-01

348

The Value of Surgery for Retroperitoneal Sarcoma  

PubMed Central

Introduction. Retroperitoneal sarcomas are uncommon large malignant tumors. Methods. Forty-one consecutive patients with localized retroperitoneal sarcoma were retrospectively studied. Results. Median age was 58 years (range 20–91 years). Median tumor size was 17.5 cm (range 4–41 cm). Only 2 tumors were <5 cm. Most were liposarcoma (44%) and high-grade (59%). 59% were stage 3 and the rest was stage 1. Median followup was 10 months (range 1–106 months). Thirty-eight patients had an initial complete resection; 15 (37%) developed recurrent sarcoma and 12 (80%) had a second complete resection. Patients with an initial complete resection had a 5-year survival of 46%. For all patients, tumor grade affected overall survival (P = .006). Complete surgical resection improved overall survival for high-grade tumors (P = .03). Conclusions. Tumor grade/stage and complete surgical resection for high-grade tumors are important prognostic variables. Radiation therapy or chemotherapy had no significant impact on overall or recurrence-free survival. Complete surgical resection is the treatment of choice for patients with initial and locally recurrent retroperitoneal sarcoma. PMID:19826633

Gholami, Sepideh; Jacobs, Charlotte D.; Kapp, Daniel S.; Parast, Layla M.; Norton, Jeffrey A.

2009-01-01

349

Soft tissue sarcoma and occupational exposures  

Microsoft Academic Search

The associations between soft tissue sarcoma (STS) and occupational exposures were studied in a case-referent study in the southeast of Sweden. Exposure information was obtained through mailed questionnaires to 96 cases, 450 randomly selected population referents, and 200 cancer referents. Odds ratios (OR), were calculated for various occupational groups, and particularly, for occupations with potential exposure to chlorinated phenoxy herbicides

G. Wingren; M. Fredrikson; H. Noorlind Brage; B. A. Nordenskjoeld; O. Axelson

1990-01-01

350

CENTER FOR SARCOMA AND BONE ONCOLOGY ANGIOSARCOMAS  

E-print Network

CENTER FOR SARCOMA AND BONE ONCOLOGY ANGIOSARCOMAS RESEARCH DESCRIPTION An effective method benefit from chemotherapy. Pazopanib originally received FDA approval as a treatment for advanced renal undergone chemotherapy. With this approval, pazopanib has become the first new drug approved in the United

Liu, Xiaole Shirley

351

Molecular characterization of interdigitating dendritic cell sarcoma.  

PubMed

Interdigitating dendritic cell sarcoma is an extremely rare cancer that lacks a standard treatment approach. We report on a patient who was surgically resected and remains disease- free. The tumor was assessed for druggable targets using immunohistochemical staining to identify potential agents that could be used in the event of disease recurrence. PMID:21139965

Weiss, Glen J; Alarcon, Arlet; Halepota, Maqbool; Penny, Robert J; Von Hoff, Daniel D

2010-01-01

352

Composition and sensory profiling of probiotic Scamorza ewe milk cheese.  

PubMed

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

2013-05-01

353

Effects of service sire on prenatal mortality and prolificacy in ewes.  

PubMed

Ability to select service sires that minimize partial or complete losses of pregnancy could have major economic impacts in sheep production systems. This study tested the null hypothesis that survival of potential progeny did not vary with breed type of service sire or among individual rams. Data included 980 ewes on 10 farms; each ewe was pregnant to 1 of 67 rams of 12 breeds. Number of conceptuses was estimated once during pregnancy by ultrasonography, either transrectal (embryos) or transabdominal (fetuses), and was compared with number of lambs born to estimate losses. Data were examined first for number of lambs born and second for documented losses. Individual service sires affected number born (P < 0.001), which varied from 0.70 to 2.45 lambs per pregnant ewe. The main effects of breed type on lambs born were not significant, but breed types of both service sires (P < 0.0002) and ewes (P < 0.001) interacted with diagnosed number of conceptuses. Lambs born varied with ewe age (P < 0.0001) and among farms (P < 0.0001), and statistically, farms interacted with number of diagnosed conceptuses (P < 0.0001); season had no effect. In documented losses, there were both main effects of individual service sire and a service sire × number of diagnosed embryos interaction (P < 0.005). Thus, ewes bred to some rams were more apt to lose single pregnancies, whereas ewes bred to other rams were more apt to lose 1 or more embryos or fetuses from multiple pregnancies. Breed type of service sire affected (P < 0.05) prenatal death. Complete losses of single conceptuses tended to be greater in ewes bred to black-faced or hair-type rams (service sire breed type × number of diagnosed conceptuses; P < 0.09). Breed type of ewes also varied in incidence of complete losses (P < 0.05); hair-type ewes (46%) lost more (P < 0.02) documented conceptuses from examination to birth than black-faced (27%), white-faced (20%), or dairy-type (25%) ewes. Greater losses of singles than of multiples occurred in black-faced (37% vs. 18%) and hair-type (64% vs. 27%) ewes than in other breeds (ewe breed type × number of conceptuses; P < 0.03) per ewe. Surprisingly, purebred conceptuses were lost less often (24%) than crossbreds (36.4%; P < 0.002). Selection of rams based on records of prenatal losses in ewes they serviced may be a method to decrease embryonic and fetal wastage. However, further study to determine repeatability of differences among service sires from year to year will be required. PMID:24778333

Holler, T L; Dean, M; Taylor, T; Poole, D H; Thonney, M L; Thomas, D L; Pate, J L; Whitley, N; Dailey, R A; Inskeep, E K

2014-07-01

354

Pathogenesis of reproductive failure induced by Trypanosoma vivax in experimentally infected pregnant ewes.  

PubMed

The present study was aimed at investigating the effect of experimental infection by Trypanosoma vivax in different stages of pregnancy, determining the pathogenesis of reproductive failure, and confirming transplacental transmission. We used 12 pregnant ewes distributed into four experimental groups: G1, was formed by three ewes infected with T. vivax in the first third of pregnancy (30 days); G2 comprised three infected ewes in the final third of pregnancy (100 days); G3 and G4 were composed of three non-infected ewes with the same gestational period, respectively. Each ewe of G1 and G2 was inoculated with 1.25×10(5) tripomastigotes. Clinical examination, determination of parasitemia, serum biochemistry (albumin, total protein, glucose, cholesterol, and urea), packed cell volume (PCV), serum progesterone, and pathological examination were performed. Placenta, amniotic fluid, blood and tissues from the fetuses and stillbirths were submitted to PCR. Two ewes of G1 (Ewe 1 and 3) presented severe infection and died in the 34th and 35th days post-infection (dpi), respectively; but both fetuses were recovered during necropsy. In G2, Ewe 5 aborted two fetuses on the 130th day (30 dpi) of pregnancy; and Ewe 6 aborted one fetus in the 140th day (40 dpi) of gestation. Ewes 2 and 4 delivered two weak lambs that died five days after birth. Factors possibly involved with the reproductive failure included high parasitemia, fever, low PCV, body score, serum glucose, total protein, cholesterol, and progesterone. Hepatitis, pericarditis, and encephalitis were observed in the aborted fetuses. The presence of T. vivax DNA in the placenta, amniotic fluid, blood, and tissues from the fetuses confirms the transplacental transmission of the parasite. Histological lesion in the fetuses and placenta also suggest the involvement of the parasite in the etiopathogenesis of reproductive failure in ewes. PMID:23289625

Silva, Taciana M F; Olinda, Roberio G; Rodrigues, Carla M F; Câmara, Antônio C L; Lopes, Francisco C; Coelho, Wesley A C; Ribeiro, Múcio F B; Freitas, Carlos I A; Teixeira, Marta M G; Batista, Jael S

2013-01-01

355

Endometrial stromal sarcoma involving the urinary bladder: a study of 6 cases.  

PubMed

Endometrial stromal sarcoma (ESS) involving the urinary bladder is very rare, with no prior series reported. We identified 6 cases of low-grade ESS involving the bladder at our institution (1998 to 2013), 5 of them consults. The median age at bladder involvement was 60 years (range, 44 to 77 y). One patient presented with bladder involvement at initial diagnosis of ESS. The remaining 5 cases with bladder involvement presented 7 to 30 years (mean 18 y) after a known diagnosis of ESS (n=2) or after a remote history of hysterectomy with an uncertain diagnosis (n=3). The location of bladder involvement included dome (n=1), trigone (n=2), diffuse (n=1), and unknown (n=2). Two cases demonstrated worm-like infiltrating tumor nests classic of low-grade ESS with little stromal reaction with retraction artifact mimicking vascular invasion. One case originating from the ovary showed focal glandular differentiation in the bladder, resembling endometriosis. Two cases had abundant keloidal collagen formation, arranged haphazardly or in a sunburst pattern. One case showed primitive cells infiltrating entirely hyalinized stroma, after chemotherapy given for a misdiagnosis of urothelial carcinoma. CD31 was negative in all cases, except for 1 case with obvious large vessel invasion. The differential diagnosis included a large nested variant of urothelial carcinoma, carcinoid tumor, synovial sarcoma, solitary fibrous tumor, Ewing sarcoma/primitive neuroectodermal tumors, and endometriosis. CD10 was strongly positive in 5 cases, and 1 case had very focal, moderate staining. Estrogen receptor showed strong and diffuse staining in all 6 cases. Progesterone receptor showed moderate to strong staining in 5 cases and focal staining in 1 case. One case showed PAX8 expression, and 2 cases showed p16 nuclear and cytoplasmic expression. CD56 showed weak to strong staining in 4 cases. Two cases had diffuse synaptophysin, and 1 case had focal p63 positivity. GATA-3, CD34, and CD99 were negative in all cases. The Ki-67 index was 1% to 10% (mean 4%). The mitotic count was 0 to 3/10 HPF (mean <1/10 HPF). Two patients had metastases to pelvic lymph nodes, and 1 had possible lung metastasis. Three patients were treated with Megace and 1 with Arimidex after surgery. Follow-up averaged 19 years (0 to 33 y) after the initial diagnosis of ESS or hysterectomy and 3.5 years (0 to 11 y) after bladder surgery. ESS involving the bladder is extremely rare with a very long interval from onset to bladder involvement. In female patients, low-grade spindle cell lesions involving the bladder should include ESS in the differential diagnosis. PMID:24705317

Tian, Wei; Latour, Mathieu; Epstein, Jonathan I

2014-07-01

356

Evaluation of Dorper, Dorset, Katahdin, and Rambouillet crossbred ewes in high- and low-input production systems  

Technology Transfer Automated Retrieval System (TEKTRAN)

The primary objective was to evaluate wool (Dorset, Rambouillet) and hair (Dorper, Katahdin) dam breeds for their ability to complement Romanov germplasm as crossbred ewes managed in distinct production systems. Romanov ewes were mated with 18 rams of each dam breed to produce crossbred ewes for ev...

357

Collecting and Storing Tissue, Blood, and Bone Marrow Samples From Patients With Rhabdomyosarcoma or Other Soft Tissue Sarcoma  

ClinicalTrials.gov

Adult Rhabdomyosarcoma; Childhood Desmoplastic Small Round Cell Tumor; Chordoma; Desmoid Tumor; Metastatic Childhood Soft Tissue Sarcoma; Nonmetastatic Childhood Soft Tissue Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Previously Untreated Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Stage I Adult Soft Tissue Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

2015-03-03

358

Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma  

ClinicalTrials.gov

Adult Alveolar Soft-part Sarcoma; Adult Angiosarcoma; Adult Desmoplastic Small Round Cell Tumor; Adult Epithelioid Hemangioendothelioma; Adult Epithelioid Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Malignant Mesenchymoma; Adult Neurofibrosarcoma; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Childhood Alveolar Soft-part Sarcoma; Childhood Angiosarcoma; Childhood Desmoplastic Small Round Cell Tumor; Childhood Epithelioid Hemangioendothelioma; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Hemangiopericytoma; Childhood Malignant Mesenchymoma; Childhood Neurofibrosarcoma; Childhood Synovial Sarcoma; Dermatofibrosarcoma Protuberans; Metastatic Childhood Soft Tissue Sarcoma; Nonmetastatic Childhood Soft Tissue Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma

2015-01-05

359

LOW FERTILITY IN NURSING EWES DURING THE NON-BREEDING SEASON  

E-print Network

LOW FERTILITY IN NURSING EWES DURING THE NON-BREEDING SEASON Y. COGNIE, M. HERNANDEZ-BARRETO J, regardless of the month of the year. However, the fertility after artificial insemination at the induced a ewes is nursing two lambs, this fertility at the induced oestrus is lower than if only one lamb

Paris-Sud XI, Université de

360

Melatonin and light treatment of ewes for autumn lambing H. WILLIAMS Sandra WARD  

E-print Network

Melatonin and light treatment of ewes for autumn lambing H. WILLIAMS Sandra WARD Kim CAIRNS Jackie II and III were group fed a diet containing melatonin and providing 3 mg/ewe at 16.00 hrs daily practised over several years in some large flocks. In assessing the role of melatonin as a replacement

Paris-Sud XI, Université de

361

Melatonin patterns in ewes maintained under skeleton or resonance photoperiodic regimens  

E-print Network

Melatonin patterns in ewes maintained under skeleton or resonance photoperiodic regimens J. P to that of a third group of 8 females under simulated natural conditions of lighting. Plasma prolactin and melatonin melatonin was high during darkness in ewes under 8L : 16D or 16L : 8D. So, the duration of melatonin

Paris-Sud XI, Université de

362

Naturally occurring scrapie is associated with a lower CBG binding capacity in ewes  

Microsoft Academic Search

Naturally scrapie-affected ewes present a syndrome of hypercortisolism as evaluated by measuring total plasma cortisol concentrations. The objective of this study was to investigate the plasma protein binding of cortisol and to evaluate the concentration of the biologically active free fraction of cortisol in scrapie-affected ewes. Corticosteroid binding globulin (CBG) binding parameters were evalu- ated by equilibrium dialysis in 13

N Picard-Hagen; V Gayrard; M Alvinerie; V Laroute; C Touron; O Andreoletti; P L Toutain

2000-01-01

363

The effect of exogenous oxytocin on estrous cycle length and corpus luteum lysis in ewes  

E-print Network

The effect of exogenous oxytocin on estrous cycle length and corpus luteum lysis in ewes I, University of Thessaloniki, Greece. Summary. The effect of exogenous oxytocin on estrous cycle length of experiment 1 showed no significant reduction of estrous cycle length of oxytocin-treated ewes ; however, 2

Boyer, Edmond

364

Effect of vitamin E on the immune system of ewes during late pregnancy and lactation  

Technology Transfer Automated Retrieval System (TEKTRAN)

The present experiment was designed to determine the effects of a regimen of repeated, intramuscular (i.m.) injections of vitamin E (VE) on innate and humoral components of the immune response of pregnant and lactating ewes. Pregnant ewes were randomly assigned to two treatments consisting of i.m. i...

365

Responses of dairy ewes before and after parturition to different nutritional regimes during pregnancy.  

E-print Network

pregnancy. III. — The concentration of some metabolites in the blood during pregnancy D. STERN, J. H of several metabolites in the blood of ewes in late pregnancy are described. The ewes were included in a 3 x during late pregnancy was positively correlated with glucose and negatively correlated with FFA

Paris-Sud XI, Université de

366

PGF2?-induced milk ejection in ewes having cyclic or pregnant corpora lutea  

E-print Network

Rennes Cedex, France. Summary. The production of luteal oxytocin in ewes, resulting from the intrajugular species, and in particular in ewes, the corpus luteum contains and produces large amounts of oxytocin be due to this liberation of luteal oxytocin (and not to neuro- hypophysial oxytocin) because

Paris-Sud XI, Université de

367

Original article Iodine nutrition in ewes : effects of low to high iodine  

E-print Network

Original article Iodine nutrition in ewes : effects of low to high iodine intake on iodine content; In a first experiment, 2 groups of 46 and 47 multiparous ewes received diets which provided an iodine intake inorganic iodine (Pit) was less affected by the I intake during lactation than during preg- nancy

Boyer, Edmond

368

Udder support as a means for improving milk fractionation in dairy ewes  

E-print Network

Udder support as a means for improving milk fractionation in dairy ewes R. SAGI Faculty supporting arm as a means for increasing the machine milk fraction in dairy ewes was tested. Four groups. The supporting arm showed a profound effect on the machine milk and machine stripping fractions. A significant

Paris-Sud XI, Université de

369

Mutual recognition between ewes and lambs Elizabeth SHILLITO WALSER, G. ALEXANDER  

E-print Network

stay close to their dam at least for the first three days of life and then spend most of the time, and alien lambs are butted away. This behaviour pattern demands that the ewe and lamb recognise each other it as an alien. Secondly, when lambs are given a choice of ewes they will run to their own dam and stay very near

Boyer, Edmond

370

RELATIONSHIP BETWEEN AGING AND NUTRITIONAL CONTROLLED GROWTH RATE ON HEAT PRODUCTION OF EWE LAMBS  

Technology Transfer Automated Retrieval System (TEKTRAN)

The objective of this study was to determine how reducing growth rate nutritionally alters the relationship between heat production per unit body weight and aging. Fasting heat production of 12 Dorset ewe lambs at 114 ± 2 d of age was determined, and ewes were assigned to treatments. Treatments co...

371

Study of male effect on feeding and estrus behavior of Afshari ewes.  

PubMed

This study was conducted to evaluate the male effect on the manifestation of estrus and feeding behavior of Afshari ewes during their breeding season. The study consists of 48 Afshari ewes, 3 years old, 67?±?2 kg live weight, body condition score 3, along with 10 Afshari rams. The study was for a period of 6 weeks in a complementary randomized design. Ewes were equally divided into three treatments (T?, T?, and T?) along with a control (T?) with six animals in each group. Variable factors of treatments was the distance of the ram box (from the ewes), which was determined to be the T?(0-5 m), T?(10-15 m), and T?(25-30 m). Exposure of the ewes to the rams resulted in an earlier manifestation of estrus signs (p?ewes due to the distance from the rams (p?ewes from the rams significantly affected feed intake of the Afshari ewes. PMID:25315371

Asgari Safdar, Amir Hossein; Sadeghi, Ali Asghar

2015-01-01

372

Effect of melatonin on daily LH secretion in intact and ovariectomized ewes during the breeding season.  

PubMed

This study was conducted to find out whether daily LH secretion in ewes may be modulated by melatonin during the breeding season, when the secretion of both hormones is raised. Patterns of plasma LH were determined in luteal-phase ewes infused intracerebroventricularly (icv.) with Ringer-Locke solution (control) and with melatonin (100 microg/100 microl/h). Response in LH secretion to melatonin was also defined in ovariectomized (OVX) ewes without and after estradiol treatment (OVX+E2). Basal LH concentrations by themselves did not differ significantly before, during and after both control and melatonin infusions in intact, luteal-phase ewes. However, single significant (P<0.05) increases in LH concentration were noted during the early dark phase in the control and 1h after start of infusion in melatonin treated ewes. In both OVX and OVX+E2 ewes, melatonin decreased significantly (P<0.01, P<0.05, respectively) mean plasma LH concentrations as compared to the levels noted before the infusions. In OVX+E2 ewes, a single significant (P<0.05) increase in LH occurred 1h after start of melatonin treatment, similarly as in luteal-phase ewes. No significant differences in the frequencies of LH pulses before, during and after melatonin infusion were found in all treatments groups. In conclusion, melatonin may exert a modulatory effect on daily LH secretion in ewes during the breeding season, stimulating the release of this gonadotropin in the presence of estradiol feedback and inhibiting it during steroid deprivation. Thus, estradiol seems to be positively linked with the action of melatonin on reproductive activity in ewes. PMID:11812629

Misztal, Tomasz; Romanowicz, Katarzyna; Barcikowski, Bernard

2002-02-15

373

Breast sarcoma in a pregnant patient A case report.  

PubMed

Sarcoma of the breast is a rare and heterogeneous lesion. We describe a case of a patient surgically treated for a breast lesion during pregnancy. The lesion resulted in a concentric neoplasia with the histological features of high grade sarcoma growing in a phyllodes tumor which was at the time grown in a fibroadenoma. Key words: Breast sarcoma, Non-epithelial breast tumour, Phillode, Pregnancy. PMID:23070281

Pasta, Vittorio; Amabile, Maria Ida; Bizzarri, Mariano; Monti, Massimo

2012-01-01

374

Post-treatment sarcoma in breast cancer patients  

Microsoft Academic Search

Background: Many patients treated for breast cancer with radiotherapy will survive their disease and be at risk for treatment-related sarcoma for many years.\\u000aMethods: In order to identify patients with post-treatment sarcoma and define this disease, we examined the records of 99 patients treated for sarcoma with a history of antecedent breast carcinoma. Of these patients, 51 were felt to

Mary S. Brady; Carol F. Garfein; Jeanne A. Petrek; Murray F. Brennan

1994-01-01

375

Effects of vitamin E and selenium injections on reproduction and preweaning lamb survival in ewes consuming diets marginally deficient in selenium.  

PubMed

Medium wool ewes were injected with vitamin E and(or) Se over a 2-yr period to evaluate the influence of these treatments on reproduction. Ewes were divided randomly into four groups, consisting of a control, plus groups receiving monthly sc injections of either 272 iu vitamin E, 4 mg Se or 272 IU vitamin E plus 4 mg Se during pregnancy. Selenium administration increased (P less than .05) ewe blood Se concentrations, but had no effect (P greater than .10) on fertility (number of ewes lambing of ewes bred), prolificacy (number of lambs born/ewe lambing) or lamb sex ratio. Preweaning survival of lambs was increased (P less than .05) by ewe treatments with either Se or vitamin E and thus, treated ewes weaned approximately 20% more lambs/ewe mated than did control ewes. PMID:6630092

Kott, R W; Ruttle, J L; Southward, G M

1983-09-01

376

Chemotherapy for soft-tissue sarcomas.  

PubMed

Cytotoxic chemotherapy with doxorubicin in combination with ifosfamide or dacarbazine, or gemcitabine in combination with docetaxel, continues to be the mainstay of treatment of metastatic soft-tissue sarcomas. A goal-oriented approach that includes careful consideration of histology, performance status, sites of disease, patient goals, and intent of treatment is vital to the formulation of an effective treatment plan. Both single-agent and combination chemotherapy regimens are available and should be chosen carefully to fit the clinical situation and patient goals. In patients with localized soft-tissue sarcoma who have a high likelihood of recurrent disease, systemic therapy should be strongly considered. The ability to demonstrate efficacy in the neoadjuvant setting may help avoid unnecessary treatment-related toxicity in patients with poor response and maximize recurrence-free survival in patients who do demonstrate an excellent response to therapy. PMID:25592207

Ravi, Vinod; Patel, Shreyaskumar; Benjamin, Robert S

2015-01-01

377

Endometrial stromal sarcoma: a rare entity.  

PubMed

Endometrial Stromal Sarcoma (ESS) is a hormone sensitive tumor. It is a rare gynecological tumor and is considered to occur more often in pre-menopausal women. A proper pre-operative diagnosis is difficult and confirmed in most cases after hysterectomy for a presumed benign disease. Endometrial sampling, ultrasound, and magnetic resonance imaging can provide diagnostic clues. For early disease complete surgical cure is possible, however, adjuvant therapy is available for recurrence. This case of Low Grade Endometrial Stromal Sarcoma (LGESS) in a 21 years old woman was presented as irregular vaginal bleeding. Clinical diagnosis of fibroid was made but analysis of endometrium showed ESS confirmed on hysterectomy specimen. One should consider it in any case with rapid fibroid enlargement. PMID:25772965

Jabeen, Salma; Anwar, Shahnaz; Fatima, Naheed

2015-03-01

378

Soft Tissue Sarcomas, CSR 1975-2008  

Cancer.gov

Percents may not sum to 100 due to rounding. a Sarcomas include histologies 8680, 8700-8711, 8800-8805, 8810-8814, 8830, 8832-8833, 8840-8841, 8850-8860, 8890-8931, 8935-8936, 8964, 8990-8991, 9040-9054, 9120-9124, 9130-9150, 9161-9221, 9231-9260, 9330, 9370-9372, 9490-9506, 9540, 9560-9561, 9580-9581. b Epidermoid Carcinoma includes histologies 8051-8131. c Adenocarcinoma includes histologies 8050, 8140-8147, 8160-8162, 8180-8221, 8250-8507, 8514, 8520-8560, 8570-8574, 8576, 8940-8941. d Other Specified Types includes all histologies not included in Sarcomas, Epidermoid Carcinoma and Adenocarcinoma.

379

Metastatic pleomorphic sarcoma to left atrium  

PubMed Central

Although several thousand patients are diagnosed with sarcoma annually in the United States, metastases to the heart are very uncommon. In this case report, an overall low frequency cancer presents masquerading with common cardiac symptomology. This case illustrates the importance for detailed diagnostic cardiac evaluations and heightened suspicion by physicians to consider metastatic disease to the heart in cancer patients with cardiovascular complications. Also discussed is a review of surgical and chemotherapeutic options for this problem. PMID:21139880

Hawasli, Ammar H; Cayce, Rachael; Luong, Trung; Taiwo, Evelyn; Feliciano, Michael N; Reimold, Sharon C; DiMaio, John M; Haley, Barbara B

2009-01-01

380

Metastatic pleomorphic sarcoma to left atrium.  

PubMed

Although several thousand patients are diagnosed with sarcoma annually in the United States, metastases to the heart are very uncommon. In this case report, an overall low frequency cancer presents masquerading with common cardiac symptomology. This case illustrates the importance for detailed diagnostic cardiac evaluations and heightened suspicion by physicians to consider metastatic disease to the heart in cancer patients with cardiovascular complications. Also discussed is a review of surgical and chemotherapeutic options for this problem. PMID:21139880

Hawasli, Ammar H; Cayce, Rachael; Luong, Trung; Taiwo, Evelyn; Feliciano, Michael N; Reimold, Sharon C; Dimaio, John M; Haley, Barbara B

2009-01-01

381

Multimodality Local Therapy for Retroperitoneal Sarcoma  

SciTech Connect

Purpose: Soft-tissue sarcomas of the retroperitoneum are rare tumors comprising less than 1% of all malignancies. Although surgery continues as the mainstay of treatment, the large size of these tumors coupled with their proximity to critical structures make resection with wide margins difficult to achieve. The role and timing of radiotherapy are controversial. This study updates our institutional experience using multimodality local therapy for resectable retroperitoneal sarcoma and identifies prognostic factors impacting disease control and survival. Methods and Materials: Between 1974 and 2007, 58 patients with nonmetastatic retroperitoneal sarcoma were treated with surgery and radiation at University of Florida. The median age at radiotherapy was 57 years old (range, 18-80 years). Forty-two patients received preoperative radiotherapy and 16 received postoperative radiotherapy. Nineteen patients received 1.8 Gy once daily and 39 patients received 1.2 Gy twice daily. Variables analyzed for prognostic value included age, grade, kidney involvement, histology, de novo versus recurrent presentation, tumor diameter, margin status, radiotherapy sequencing (preoperative vs. postoperative), total radiation dose, fractionation scheme, and treatment era. Results: The 5-year overall survival, cause-specific survival, and local control rates were 49%, 58%, and 62%, respectively. Nearly two-thirds of disease failures involved a component of local progression. On multivariate analysis, only margin status was significantly associated with improved 5-year local control (85%, negative margins; 63%, microscopic positive margins; 0%, gross positive margins; p < 0.0001) and 5-year overall survival (64%, negative margins; 56%, microscopic positive margins; 13%, gross positive margins; p = 0.0012). Thirty-one Grade 3 or greater toxicities were observed in 22 patients, including two treatment-related deaths (3%). Conclusion: For retroperitoneal sarcoma, local control remains a challenge and combined-modality therapy may be associated with significant acute and late morbidity. Our patterns of failure data suggest that improvements in local control may translate into a survival benefit.

Paryani, Nitesh N.; Zlotecki, Robert A.; Swanson, Erika L.; Morris, Christopher G. [Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL (United States); Grobmyer, Stephen R.; Hochwald, Steven N. [Department of General Surgery, 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); Indelicato, Daniel J., E-mail: dindelicato@floridaproton.org [Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL (United States); University of Florida Proton Therapy Institute, Jacksonville, FL (United States)

2012-03-01

382

Treating soft tissue sarcomas with adjuvant chemotherapy  

Microsoft Academic Search

Opinion statement  Surgery remains the cornerstone of treatment and the only curative loco-regional approach of localized resectable soft tissue\\u000a sarcoma (STS) in 2011: the usual first-line treatment is wide margin surgery plus radiotherapy, especially in the case of\\u000a primary tumors arising in the limbs. An optimal initial R0 resection is one of the most reproducible and reliable prognostic\\u000a factors for survival

Anna Patrikidou; Julien Domont; Angela Cioffi; Axel Le Cesne

2011-01-01

383

Management of soft tissue and bone sarcomas  

SciTech Connect

This book contains 32 papers. Some of the titles are: Adjuvant Treatment for Osteosarcoma of the Limbs; Trial 20781 of the SIOP and the EORTC Radiotherapy/Chemotherapy; Application of Magnetic Resonance Imaging (MRI) in Diagnosis and Follow-up During Treatment of Bone Tumors; Radiological Assessment of Local Involvement in Bone Sarcomas; and Prevention of Lung Metastases by Irradiation Alone or Combined with Chemotherapy in an Animal Model.

Van Oosterom, A.T.; Van Unnik, J.A.M.

1986-01-01

384

Sarcoma Immunotherapy: Past Approaches and Future Directions  

PubMed Central

Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25–50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease. PMID:24778572

D'Angelo, S. P.; Tap, W. D.; Schwartz, G. K.; Carvajal, R. D.

2014-01-01

385

The role of Kaposi sarcoma-associated herpesvirus in the pathogenesis of Kaposi sarcoma.  

PubMed

Kaposi sarcoma (KS) is an unusual vascular tumour caused by an oncogenic-herpesvirus, Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV 8). KS lesions are characterized by an abundant inflammatory infiltrate, the presence of KSHV-infected endothelial cells that show signs of aberrant differentiation, as well as faulty angiogenesis/ vascularization. Here we discuss the molecular mechanisms that lead to the development of these histological features of KS, with an emphasis on the viral proteins that are responsible for their development. PMID:25212381

Gramolelli, Silvia; Schulz, Thomas F

2015-01-01

386

Vaginal histological changes after using intravaginal sponges for oestrous synchronization in anoestrous ewes.  

PubMed

To characterize the histological and cytological vaginal changes generated by the use of intravaginal sponge (IS) applied in oestrous synchronization treatments in ewes during mid-non-breeding season. Thirty-five multiparous ewes were allocated to three experimental groups according to the moment in which the samples were taken: (i) ewes treated with IS containing 60 mg of medroxyprogesterone acetate for 14 days, sampled the day of IS removal (group ISR; n = 10), (ii) or after sponge removal at time of oestrus or 72 h after removal (group AR; n = 14) and (iii) ewes without sponge treatment that were sampled at the day of IS removal of the other groups (group CG; n = 11). Vaginal biopsies and cytological samples were taken from the anterior vaginal fornix area. The vagina of the CG group had a stratified squamous epithelium with a moderate degree of cellular infiltration with lymphocytes and plasma cells in the lamina propia. Treated ewes (ISR and AR) had epithelial hyperplasia and hypertrophy. ISR ewes had haemorrhage and perivascular infiltrate and an increased number of epithelial cells, neutrophils, macrophages and erythrocytes at IS removal. The use of IS generated histological and cytological alterations in the vaginal wall when used for oestrous synchronization in anoestrous ewes. PMID:25604995

Manes, J; Campero, C; Hozbor, F; Alberio, R; Ungerfeld, R

2015-04-01

387

Plasma gonadotropin and progesterone concentrations during the estrous cycle of Finn, Suffolk and Targhee ewes.  

PubMed

Hormonal profiles during the estrous cycle of Finn, Suffolk and Targhee ewes were compared in six ewes of each breed. Blood samples were drawn by venipuncture at 8-h intervals from onset to onset of consecutive estrous periods. Number of corpora lutea (CL) and ovarian follicles >/=3 mm in diameter on Day 10 (estrus = Day 0) were observed using endoscopy. Estrous cycle length was 14.9, 15.6 and 16.4 d (P<0.01) in Finn, Suffolk and Targhee ewes, respectively. Finns had more (P<0.001) CL (3.5) than Suffolks (2.0) and Targhees (1.8), but luteal phase progesterone concentrations were similar among breeds in peak level and area under the curve. In Finn ewes, the amplitude of the preovulatory LH surge was lower (P<0.01) and tended to occur later in estrus; otherwise LH levels and patterns were similar among breeds. A coincident follicle stimulating hormone (FSH) preovulatory surge occurred in most ewes, the amplitude of which was related to that of luteinizing hormone (LH); r = 0.67, P<0.01. Plasma FSH levels and patterns were similar in Finn, Suffolk and Targhee ewes and most ewes had three to four secretory episodes. Follicles >/=3 mm averaged 1.8, 1.0 and 1.2 (P>0.1) in Finn, Suffolk and Targhee ewes, respectively. Results indicate that the higher ovulation rate of the Finn ewe is not elicited by increased FSH levels at any stage of the estrous cycle. PMID:16726453

Wheaton, J E; Marchek, J M; Hamra, H A; Al-Raheem, S N

1988-07-01

388

Successful induction of oestrus, ovulation and pregnancy in adult ewes and ewe lambs out of the breeding season using a GnRH+progesterone oestrus synchronisation protocol.  

PubMed

A series of experiments was designed to assess the effect of a treatment protocol (U-synch) for inducing oestrus and ovulation out of the breeding season in adult ewes and ewe lambs. The protocol consisted of a 7-day treatment with an intravaginal progesterone-releasing device (IPRD), administration of GnRH at IPRD insertion on Day 0, and equine chorionic gonadotropin (eCG) and prostaglandin F2? at IPRD removal on Day 7. In Experiment 1, 50 or 100?g GnRH were sufficient to induce ovulation at the beginning of the protocol in 3/9 and 4/9 ewes, respectively; while the resulting proportion of sheep ovulating after the treatment protocol was 88.9% and 77.8% in ewes initially treated with 50 or 100?g GnRH, respectively. In Experiment 2, the proportion of Romney-cross ewe lambs ovulating was greater (P<0.0001) in the U-synch group (95.4%) than in the untreated Control group (3.2%). In Experiment 3, pregnancy rates of Dorset-cross sheep in the U-synch (60.7%) and Standard (12-day IPRD and eCG treatment; 56.5%) groups were greater (P=0.01) than in the untreated Control group (43.4%). The incidence of twin pregnancies was greater (P=0.005) in the U-synch group than in the Control group. A 7-day IPRD treatment including GnRH treatment at device insertion and eCG treatment at device removal induced oestrus and ovulation during the non-breeding season in a high proportion of mature ewes and ewe lambs. High pregnancy rates to natural mating, with a low rate of triplet pregnancies, were also observed. PMID:25708125

Martinez, M F; McLeod, B; Tattersfield, G; Smaill, B; Quirke, L D; Juengel, J L

2015-04-01

389

A typical case of hydrallantois accompanied by fetal monstrosity in a local ewe of Kashmir  

PubMed Central

A full termed local ewe with the history of continuous straining with labored breathing for last 24 hours was presented. The animal was disinclined to move with tense and round abdomen which developed rapidly during last two weeks. Caesarean section revealed hydrallantois accompanied by multiple fetal congenital abnormalities. The ewe was under observation for four weeks. Metritis developed 12 days post-operation and was treated successfully. The ewe was found active on 25 days post-surgery with gain of extra 3 kg bodyweight. PMID:25610574

Bhattacharyya, Hiranya Kumar; Hussain Dar, Shahid; Fazili, Mujeeb-ur-Rehman; Hafiz, Abdul

2012-01-01

390

Association of lameness with milk yield and lactation curves in Chios dairy ewes.  

PubMed

The objective of the study was twofold: (i) to quantify the differences in daily milk yield (DMY) and total milk yield (TMY) between lame and non-lame dairy ewes and (ii) to determine the shape of lactation curves around the lameness incident. The overall study was a prospective study of lameness for the surveyed sheep population, with a nested study including the selection of matching controls for each lame ewe separately. Two intensively reared flocks of purebred Chios ewes and a total of 283 ewes were used. Data, including gait assessment and DMY records, were collected on a weekly basis during on-farm visits across the milking period. A general linear model was developed for the calculation of lactation curves of lame and non-lame ewes, whereas one-way ANOVA was used for the comparisons between lame ewes and their controls. Lameness incidence was 12·4 and 16·8% on Farms A and B, respectively. Average DMY in lame ewes was significantly lower (213·8 g, P < 0·001) compared with the rest of the flock, where DMY averaged 1·340 g. The highest DMY reduction in lame ewes was observed during the week 16 of the milking period (P < 0·001), whereas the reduction of DMY, for lame ewes, remained significant at P < 0·001 level from week 8 to week 28 of milking. Comparisons between lame and controls revealed that at the week of lameness diagnosis a significant DMY reduction (P ? 0·001) was observed in lame ewes (about 32·5%), which was maximised 1 week later (35·8%, P ? 0·001) and continued for several weeks after recovery, resulting in 19·3% lower TMY for lame ewes for the first 210 d of the milking period (P < 0·01). Moreover, at flock level, TMY for non-lame and lame ewes, as calculated by the general linear model, was 318·9 and 268·0 kg, respectively. The results of this study demonstrate evidence of significant financial losses in dairy sheep due to lameness which, however, need to be accurately estimated in further, more detailed, analyses. PMID:25650132

Gelasakis, Athanasios I; Arsenos, Georgios; Valergakis, Georgios E; Banos, Georgios

2015-05-01

391

What Are the Risk Factors for Uterine Sarcoma?  

MedlinePLUS

... know what causes uterine sarcoma? What are the risk factors for uterine sarcoma? A risk factor is anything that affects your chance of getting ... disease such as cancer. Different cancers have different risk factors. For example, exposing skin to strong sunlight is ...

392

What Are the Risk Factors for Soft Tissue Sarcoma?  

MedlinePLUS

... what causes soft tissue sarcomas? What are the risk factors for soft tissue sarcomas? A risk factor is anything that changes your chance of getting a disease like cancer. Different cancers have different risk factors. For example, unprotected exposure to strong sunlight is ...

393

Sirolimus for Kaposi's Sarcoma in Renal-Transplant Recipients  

Microsoft Academic Search

background Recipients of organ transplants are susceptible to Kaposi's sarcoma as a result of treat- ment with immunosuppressive drugs. Sirolimus (rapamycin), an immunosuppressive drug, may also have antitumor effects. methods We stopped cyclosporine therapy in 15 kidney-transplant recipients who had biopsy- proven Kaposi's sarcoma and began sirolimus therapy. All patients underwent an exci- sional biopsy of the lesion and one

Giovanni Stallone; Antonio Schena; Barbara Infante; Salvatore Di Paolo; Antonella Loverre; Giulio Maggio; Elena Ranieri; Loreto Gesualdo; Francesco Paolo Schena; Giuseppe Grandaliano

2005-01-01

394

An unusual pleomorphic sarcoma in a hybrid mallard  

USGS Publications Warehouse

An unusual pleomorphic sarcoma from a hybrid mallard (Anas platyrhynchos) is described. Rhabdomyosarcoma was considered in the original differential diagnoses but rejected due to lack of specific characteristics generally seen in these tumors. The histologic characteristics described are consistent with mammalian sarcomas recorded in the literature as malignant fibrous histiocytoma.

Roffe, T.J.

1987-01-01

395

Current concepts in the treatment of soft tissue sarcomas.  

PubMed

Soft tissue sarcomas encompass a wide variety of lesions and continue to pose a different treatment problem. However the outlook is improving. Recent advances in pre-treatment assessment and pathological assessment of soft tissue sarcomas have resulted in more accurate clinical staging. In addition, recent advances in surgical adjuvant treatment programmes hold promise for better results. PMID:1519901

Sim, F H

1992-03-01

396

Optimal management of primary retroperitoneal sarcoma: an update.  

PubMed

Soft tissue sarcomas are a group of heterogeneous neoplasms with more than 50 histological subtypes exhibiting major differences in terms of pathogenesis, genetic alterations and clinical behavior. Sarcomas represent approximately 1% of malignancies with retroperitoneal sarcomas representing 10-15% of all soft tissue sarcomas. Surgery is currently the only modality which offers the chance of cure. Surgery for retroperitoneal sarcomas presents specific challenges due their location in a complex space surrounded by vital structures and visceral organs often prohibiting resection with wide margins. Furthermore, even after complete resection local recurrence is common and the leading cause of death. In this article the authors describe the initial investigations, prognostic factors and optimal surgical management. The evidence and current research as regards the role of multimodality treatment is reviewed and discussed. PMID:24524274

Miah, Aisha B; Hannay, Jonathan; Benson, Charlotte; Thway, Khin; Messiou, Christina; Hayes, Andrew J; Strauss, Dirk C

2014-05-01

397

Recent advances in the treatment of sarcomas in gynecology.  

PubMed

Uterine sarcomas are a heterologous group of rare malignancies accounting for 8-10% of all uterine malignancies, but are significantly more aggressive and have worse prognoses. Management of uterine sarcomas including leiomyosarcoma and endometrial stromal sarcoma are reviewed here, with additional discussions regarding high-grade undifferentiated sarcoma and adenosarcoma. Uterine carcinosarcomas are currently staged and treated similar to high-grade epithelial endometrial carcinomas, thus will not be discussed in this review. Gemcitabine/docetaxel with adriamycin holds promise for the treatment of leiomyosarcoma, but currently, limited advancements have been made in discovering targeted therapies to these tumors. Continued translational research in both medical oncology and gynecologic oncology is necessary to forward the development of novel and targeted therapeutic agents in the treatment of sarcoma. Enrollment of these patients in clinical trials is encouraged, and will allow for the development of safer and more effective therapies. PMID:25227754

Lange, Sara S; Novetsky, Akiva P; Powell, Matthew A

2014-09-01

398

Spindle cell sarcoma of thyroid: a case report.  

PubMed

Spindle cell sarcoma of thyroid represents a rare entity that may arise primarily from thyroid gland as a variant of thyroid cancer or as metastatic. We report a case of 60 year old man who presented with 2 months history of rapidly growing thyroid enlargement with no obstructive features and preliminary diagnosis of spindle cell lesion of thyroid was made with cytological examination. He underwent total thyroidectomy and histological examination revealed spindle cell sarcoma of thyroid confirmed by immunohistochemical reactions. He was subjected to adjuvant chemoradiotherapy and is on follow up. Sarcoma of thyroid is rarely encountered in routine practice and is diagnosed by microscopic evaluation and immunohistochemical staining which determines the cellular origin and histologic type of tumor . Sarcoma thyroid is best managed with surgery and adjuvant chemoradiotherapy according to the grade of the lesion. In addition overall prognosis in thyroid sarcoma is poor due to late presentation and aggressive nature of the tumour. PMID:25767348

Siyad, A K Abdul; Gopi, Praveen; Jayan, N P; Augustine, Joy

2014-12-01

399

Temporal concentrations of cortisol and LH in virgin ewes acutely exposed to rams during the transition into the breeding season.  

PubMed

The objectives of this study were to determine if exposing seasonally anovular ewes to rams would alter patterns of cortisol concentrations, and if these changes are associated with changes in characteristics of LH concentrations. Seasonally anestrous ewes were assigned to be exposed to rams (RE; n=11) or wethers (NE; n=12). Blood samples were collected at 15-min intervals beginning 120min before introduction of males (time=0min), and continued for 360min after male exposure. Characteristics of cortisol and LH concentrations included: mean and baseline concentrations, pulse amplitude, duration, frequency, and time to first pulse. Mean and baseline cortisol concentrations, and cortisol pulse amplitude, frequency, and time to first pulse after male exposure did not differ between RE and NE ewes. Cortisol pulse duration was longer (P<0.05) in RE ewes than in NE ewes. Mean LH and LH pulse amplitude, duration, and time to first pulse after male exposure did not differ between RE and NE ewes. Baseline LH concentrations and LH pulse frequency were greater (P<0.05) in RE than in NE ewes. In RE ewes, but not NE ewes, LH pulse frequency tended to increase (P=0.06) as pulse frequency of cortisol decreased. In conclusion, exposing ewes to mature rams during the transition into the breeding season increased LH pulse frequency which hastened ovulatory activity. However, the results do not support the hypothesis that changes in cortisol concentrations plays a significant role in the 'ram effect'. PMID:25660621

McCosh, R B; Berry, E M; Wehrman, M E; Redden, R R; Hallford, D M; Berardinelli, J G

2015-03-01

400

Superficial soft tissue sarcomas (S-STS): A study of 367 patients from the French Sarcoma Group (FSG) database  

Microsoft Academic Search

AimThe specific natural history of superficial soft tissue sarcomas (S-STS) has been rarely considered. We describe the clinical characteristics of a large series of S-STS (N=367) from the French Sarcoma Group (GSF-GETO) database and analyse the prognostic factors affecting outcome.

Sébastien Salas; Eberhard Stoeckle; Françoise Collin; Binh Bui; Philippe Terrier; Louis Guillou; Martine Trassard; Dominique Ranchere-Vince; Fleur Gregoire; Jean-Michel Coindre

2009-01-01

401

Transmissible Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) in Saliva of Men with a History of Kaposi's Sarcoma  

Microsoft Academic Search

We have evaluated the physical state and infectious nature of Kaposi's sarcoma-associated herpesvirus (KSHV) in the saliva of nine persons with past or current Kaposi's sarcoma (KS). KSHV DNA in saliva had the physical characteristics of DNA present in virions. Inoculation of 293 cells with cell-free saliva fluid resulted in the persistence of KSHV DNA in culture for at least

JEFFREY VIEIRA; MEEI-LI HUANG; DAVID M. KOELLE; LAWRENCE COREY

1997-01-01

402

Cixutumumab and Doxorubicin Hydrochloride in Treating Patients With Unresectable, Locally Advanced, or Metastatic Soft Tissue Sarcoma  

ClinicalTrials.gov

Adult Angiosarcoma; Adult Desmoplastic Small Round Cell Tumor; Adult Epithelioid Sarcoma; Adult Extraskeletal Myxoid Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Mesenchymoma; Adult Malignant Peripheral Nerve Sheath Tumor; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Adult Unclassified Pleomorphic Sarcoma of Bone; Childhood Anaplastic Rhabdomyosarcoma; Childhood Angiosarcoma; Childhood Desmoplastic Small Round Cell Tumor; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Mesenchymoma; Childhood Malignant Peripheral Nerve Sheath Tumor; Childhood Mixed Alveolar Rhabdomyosarcoma; Childhood Synovial Sarcoma; Dermatofibrosarcoma Protuberans; Malignant Adult Hemangiopericytoma; Malignant Childhood Hemangiopericytoma; Metastatic Childhood Soft Tissue Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Untreated Childhood Rhabdomyosarcoma

2015-04-09

403

Outcome analysis in patients with uterine sarcoma  

PubMed Central

Purpose To analyze the prognostic factors for survivals and to evaluate the impact of postoperative whole pelvic radiotherapy (WPRT) on pelvic failure in patients with uterine sarcoma treated with radical surgery. Materials and Methods We retrospectively analyzed 75 patients with uterine sarcoma who underwent radical surgery with (n = 22) or without (n = 53) radiotherapy between 1990 and 2010. There were 23 and 52 patients with carcinosarcoma and non-carcinosarcoma (leiomyosarcoma, 22; endometrial stromal sarcoma, 25; others, 5), respectively. The median follow-up period was 64 months (range, 17 to 269 months). Results The 5-year overall survival (OS) and pelvic failure-free survival (PFFS) of total patients was 64.2% and 83.4%, respectively. Multivariate analysis revealed that mitotic count (p = 0.006) was a significant predictor of OS. However, factors were not found to be associated with PFFS. On analyzing each of the histologic subtypes separately, postoperative WPRT significantly reduced pelvic failure in patients with carcinosarcoma (10.0% vs. 53.7%; p = 0.046), but not in patients with non-carcinosarcoma (12.5% vs. 9.9%; p = 0.866). Among the patients with carcinosarcoma, 4 patients (17%) had recurrence within the pelvis and 3 patients (13%) had recurrence in other sites as an initial failure, whereas among the patients with non-carcinosarcoma, 3 patients (6%) experienced pelvic failure and 13 patients (25%) experienced distant failure. Conclusion The most significant predictor of OS was mitotic count. Based on the improved PFFS after postoperative WPRT only in patients with carcinosarcoma and the difference in patterns of failure between histologic subtypes, optimal adjuvant treatment options should be offered to patients based on the risk of recurrence patterns. PMID:25874175

Yu, Tosol; Wu, Hong-Gyun; Ha, Sung Whan; Song, Yong-Sang; Park, Noh-Hyun; Kim, Jae-Won

2015-01-01

404

100 years of Rous sarcoma virus  

PubMed Central

The discovery of Rous sarcoma virus, which was reported by Peyton Rous in the Journal of Experimental Medicine 100 years ago, opened the field of tumor virology. It showed that some cancers have infectious etiology, led to the discovery of oncogenes, and laid the foundation for the molecular mechanisms of carcinogenesis. Rous spent his entire research career at The Rockefeller Institute, and he was the JEM’s longest serving editor. Here, we comment briefly on the life of this remarkable scientist and on the importance of his discoveries. PMID:22110182

2011-01-01

405

100 years of Rous sarcoma virus.  

PubMed

The discovery of Rous sarcoma virus, which was reported by Peyton Rous in the Journal of Experimental Medicine 100 years ago, opened the field of tumor virology. It showed that some cancers have infectious etiology, led to the discovery of oncogenes, and laid the foundation for the molecular mechanisms of carcinogenesis. Rous spent his entire research career at The Rockefeller Institute, and he was the JEM's longest serving editor. Here, we comment briefly on the life of this remarkable scientist and on the importance of his discoveries. PMID:22110182

Weiss, Robin A; Vogt, Peter K

2011-11-21

406

Histological variants of cutaneous Kaposi sarcoma  

PubMed Central

This review provides a comprehensive overview of the broad clinicopathologic spectrum of cutaneous Kaposi sarcoma (KS) lesions. Variants discussed include: usual KS lesions associated with disease progression (i.e. patch, plaque and nodular stage); morphologic subtypes alluded to in the older literature such as anaplastic and telangiectatic KS, as well as several lymphedematous variants; and numerous recently described variants including hyperkeratotic, keloidal, micronodular, pyogenic granuloma-like, ecchymotic, and intravascular KS. Involuting lesions as a result of treatment related regression are also presented. PMID:18655700

Grayson, Wayne; Pantanowitz, Liron

2008-01-01

407

Soft Tissue Sarcomas, CSR 1975-2007  

Cancer.gov

Percents may not sum to 100 due to rounding. a Sarcomas include histologies 8680, 8700-8711, 8800-8805, 8810-8814, 8830-8833, 8840-8841, 8850-8855, 8857-8860, 8890-8910, 8920-8931, 8935-8936, 8964, 8990-8991, 9040-9054, 9120-9124, 9130-9150, 9161-9221, 9231-9260, 9330, 9370-9372, 9490-9506, 9540-9561, 9580-9581. b Epidermoid Carcinoma includes histologies 8051-8131. c Adenocarcinoma includes histologies 8050, 8140-8147, 8160-8162, 8180-8221, 8250-8507, 8514, 8520-8560, 8570-8574, 8576, 8940-8941.

408

The effect of maternal nutritional status during mid-gestation on placental characteristics in ewes.  

PubMed

The aim of this study was to determine the effects of maternal nutritional status during mid-gestation on placental characteristics in ewes. Time of estrus of 3-5 years old Karayaka breed ewes was synchronized and mating was monitored to determine the day 0 of gestation. The ewes had similar body weights (47.8±0.7kg) and loin eye muscle values (thickness; 20.9±1.0mm and fat thickness; 4.7±0.5mm) at mating. The ewes were allocated into two treatment groups at day 30 of gestation; under-fed (UF; n=12) and well-fed (WF; n=13) groups. The ewes in UF group were fed with a diet to provide 50% of their daily requirement from day 30 to day 80 of gestation and 100% of their daily requirement during the rest of the gestation period. The ewes in WF group were fed at least 100% of their daily requirement throughout gestation. The singleton bearing ewes in the UF group had a lesser (P<0.05) placental weight (354.1 compared with 378.3g), average cotyledon weight (1.50 compared with 1.82g) and lamb birth weight (3.8 compared with 4.2kg) than singleton bearing ewes in the WF group. There were positive correlations between placental weight and lamb birth weight (r=.469; P<0.05), placental weight and average cotyledon weight (r=.695; P<0.01), average cotyledon weight and lamb birth weight (r=.742; P<0.01) and placental efficiency and cotyledon density (r=.853; P<0.01) for ewes in WF group. Additionally, the pattern of weight gain/loss was different (P<0.05) between the two groups. Ewes in UF group lost body weight progressively from day 30 of gestation until day 80. The results of present study show that under-feeding of ewes during mid-gestation may cause an insufficient placental development and hence alter fetal development resulting in a reduced birth weight from singleton pregnancies. PMID:23273533

Sen, U; Sirin, E; Kuran, M

2013-02-01

409

Copper Status of Ewes Fed Increasing Amounts of Copper from Copper Sulfate or Copper Proteinate1  

Microsoft Academic Search

The Cu status of mature, crossbred ewes fed two sources (CuSO4 vs Cu proteinate) and three levels (10, 20, or 30 mg\\/kg) of dietary Cu was determined in a 73-d feeding trial. Ewes (n = 30) were fed a basal diet containing rice meal feed, cottonseed hulls, cottonseed meal, meat and bone meal, cracked corn, and vitamin-mineral supplements at 2.5%

G. E. Eckert; L. W. Greene; G. E. Carstens; W. S. Ramsey

2010-01-01

410

Parenteral Administration of l-Arginine Prevents Fetal Growth Restriction in Undernourished Ewes12  

PubMed Central

Intrauterine growth restriction (IUGR) is a major health problem worldwide that currently lacks an effective therapeutic solution. This study was conducted with an ovine IUGR model to test the hypothesis that parenteral administration of l-arginine (Arg) is effective in enhancing fetal growth. Beginning on d 28 of gestation, ewes were fed a diet providing 100% (control-fed) or 50% (underfed) of NRC-recommended nutrient requirements. Between d 60 of gestation and parturition, underfed ewes received i.v. infusions of saline or 155 ?mol Arg-HCl/kg body weight 3 times daily, whereas control-fed ewes received only saline. The birth weights of lambs from saline-infused underfed ewes were 23% lower (P < 0.01) than those of lambs from control-fed dams. Administration of Arg to underfed ewes increased (P < 0.01) concentrations of Arg (69%), ornithine (55%), proline (29%), methionine (37%), leucine (36%), isoleucine (35%), cysteine (19%), and FFA (43%) in maternal serum, decreased maternal circulating levels of ammonia (18%) and triglycerides (32%), and enhanced birth weights of lambs by 21% compared with saline-infused underfed ewes. There was no difference in birth weights of lambs between the control-fed and the Arg-infused underfed ewes. These novel results indicate that parenteral administration of Arg to underfed ewes prevented fetal growth restriction and provide support for its clinical use to ameliorate IUGR in humans. The findings also lay a new framework for studying cellular and molecular mechanisms responsible for the beneficial effects of Arg in regulating conceptus growth and development. PMID:20505020

Lassala, Arantzatzu; Bazer, Fuller W.; Cudd, Timothy A.; Datta, Sujay; Keisler, Duane H.; Satterfield, M. Carey; Spencer, Thomas E.; Wu, Guoyao

2010-01-01

411

Technical note: comparison of salivary and serum cortisol concentrations after adrenocorticotropic hormone challenge in ewes.  

PubMed

An ACTH challenge was conducted to determine if salivary cortisol concentration reflects serum cortisol concentration in ewes. Twelve yearling ewes (64.0 +/- 1.2 kg) were administered ACTH (100 IU, intravenously) or saline. Serum and salivary samples were collected at 30-min intervals for 2 h before ACTH administration, at 15-min intervals for 2 h after treatment, and at 30-min intervals for an additional 3 h, and cortisol concentration was determined by RIA. Although ewes responded to ACTH and saline, cortisol concentration was greater (P < 0.001) in ACTH-treated ewes from 15 to 120 min and tended to be greater (P = 0.054) at 150 min after challenge in serum. In saliva, cortisol concentration was greater (P < 0.001) in ACTH-treated ewes from 30 to 120 min and tended to be greater (P = 0.092) at 15 min after challenge. No difference was observed between ACTH-treated ewes and controls for time to peak serum cortisol concentration (P = 0.126) and time to peak salivary cortisol concentration (P = 0.109), or between saliva and serum for time to peak cortisol concentration (P = 0.220) and return to baseline cortisol concentration (P = 0.341). The serum (P = 0.009) and salivary (P = 0.050) cortisol areas under the curve between 0 and 150 min were greater for ACTH-treated ewes than controls, and serum (P = 0.002) and salivary (P < 0.001) cortisol return to baseline concentration was longer for ACTH-treated ewes. The correlation coefficient between serum and salivary cortisol concentrations was 0.88 (P < 0.001). These data indicate that salivary cortisol concentration is closely related to serum cortisol concentration and that the former may represent a suitable noninvasive alternative to blood collection for measurement of cortisol in sheep. PMID:19854993

Yates, D T; Ross, T T; Hallford, D M; Yates, L J; Wesley, R L

2010-02-01

412

Intrauterine bacterial inoculation and level of dietary methionine alter amino acid metabolism in nulliparous yearling ewes.  

PubMed

Using an intrauterine bacterial inoculation method, our objective was to determine the effects of acute sepsis and level of dietary metabolizable Met (MM) on splanchnic metabolism of AA in ewes. Twenty-four nulliparous yearling Rambouillet-cross ewes (initial BW = 65.1 +/- 0.6 kg), surgically fitted with chronic-indwelling catheters in hepatic and portal veins, a mesenteric vein and artery, and the uterine lumen, were assigned to a 2 x 2 factorial arrangement of treatments. Factors were intrauterine bacterial inoculation (noninoculated vs. inoculated) and level of MM [low (2.28 g/d) vs. high (3.91 g/d)]. Beginning 12 h before sampling, inoculated and noninoculated ewes received 10-mL intrauterine infusions of Escherichia coli (9.69 x 10(11) cfu) + Arcanobacterium pyogenes (2.76 x 10(12) cfu) and of sterile saline, respectively. Uterine infection was induced in ewes that received intrauterine bacterial inoculations, but not in ewes infused with sterile saline. Bacterial inoculation resulted in increased hepatic release and plasma concentrations of aromatic AA used for acute-phase protein synthesis, increased hepatic removal and decreased plasma concentrations of AA used for glutathione synthesis, and decreased plasma concentrations of some gluconeogenic and acetogenic AA used for glucose recycling and anaerobic energy production, respectively (P < 0.05). In ewes fed high-MM diets, compared with low-MM diets, a consistent net hepatic uptake of Phe occurred throughout the sampling period, more Asp was released from the portal-drained viscera, and hepatic vein glucose concentrations were greater (P < 0.05). We conclude that Met seemed to be limiting in low-MM ewes, and as such, would continue to be limiting during sepsis. However, additional MM, in excess of the dietary requirement, would not necessarily result in a benefit to ewes experiencing acute sepsis. PMID:17785602

Thelen, T M; Löest, C A; Taylor, J B; Wang, S; Lewis, G S

2007-12-01

413

Equine chorionic gonadotrophin administration to rams improves their effectiveness to stimulate anoestrous ewes (the "ram effect").  

PubMed

Ewes' response to ram effect is related to the strength of androgen-dependent ram signals. Experiment 1 aimed to determine if the administration of a single dose of 1000IU of eCG to rams three days before joining them with ewes enhance their ability to stimulate females. Based on the results of Experiment 1, in a second experiment rams received two doses seven and three days before their introduction to females. In Experiment 1, rams treated or not with eCG were joined with ewes, and estrous was recorded until Day 5 (Day 0=rams and ewes were joined), and from Day 15 to Day 23. In addition, serum testosterone concentration was measured in all rams in the first recorded period. Testosterone values were greater in eCG-E1 than in Con-E1 rams on Days 0 and 2. The percentage of ewes in estrus was similar in both groups. In Experiment 2, rams were treated with two doses of eCG on Days -7 and -3 or remained as untreated controls. Estrous was recorded until Day 5, and pregnancy rate on Day 46; testosterone was measured in samples collected from all rams. Testosterone concentration was greater in eCG-E2 than Con-E2 rams from Day -5 to Day 1, and tended to do so on Day 2. More eCG-E2 than Con-E2 ewes came into estrus and became pregnant. It was concluded that treatment of rams with two high doses of eCG before joining them with anestrous ewes, enhanced their ability to induce ewes' cyclic activity (the "ram effect"). PMID:25059200

Ungerfeld, Rodolfo; Clemente, Neftali; Bonjour, Lorena; Orihuela, Agustin

2014-10-01

414

Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors  

ClinicalTrials.gov

Retinoblastoma; Clear Cell Sarcoma; Renal Cell Carcinoma; Rhabdoid Tumor; Wilms Tumor; Hepatoblastoma; Neuroblastoma; Germ Cell Tumors; Ewings Sarcoma; Non-rhabdomyosarcoma Soft Tissue Sarcoma; Osteosarcoma; Rhabdomyosarcoma

2015-03-11

415

Impact of megatherapy in children with high-risk Ewing's tumours in complete remission: a report from the EBMT Solid Tumour Registry.  

PubMed

The European BMT Solid Tumour Registry (EBMT-STR) received reports from 21 European transplant centers on 63 patients (50 Ewing's sarcomas and 13 peripheral neuroectodermal tumours) in first (n = 32) or second CR (n = 31) consolidated with megatherapy and BM and/or PSC rescue between December 1982 and November 1992. There were 31 males and 32 females with a median a