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PubMedDate not supplied

[Results of treatment of primary metastatic Ewing sarcoma. A retrospective analysis of 48 patients].

The clinical presentation of the disease and the results of treatment in 48 patients with metastases at diagnosis of Ewing's sarcoma, entered into the Cooperative Ewing's Sarcoma Studies (CESS) 1981 and 1986 of the German Society of Pediatric Oncology (GPO), were analysed. The period of observation ranged from 1 to 82 months, the median relapse-free time was 26 months. There was a male predominance of 35 to 13, which was even more pronounced in patients older than 15 years. The predominant localization of the primary tumor was the pelvic region, followed by the extremities, the chest wall, and the spine. The most common site of primary metastases were the lungs, followed by bone and bone marrow. Nine patients presented with combined metastases. The disease-free survival according to Kaplan-Meier life-table analysis was 18% after 7 years. Best results were obtained in patients with pulmonary metastases only, who underwent surgical resection of the primary tumor and received radiation to the lungs. Without bone marrow transplantation the prognosis of patients with bone metastases was extremely poor.

Adolescent↗
PubMed2006

Oncogenic serine-threonine kinase receptor-associated protein modulates the function of Ewing sarcoma protein through a novel mechanism.

Although much is known about the oncogenic functions of chimeric Ewing sarcoma (EWS) fusion proteins that result from chromosomal translocations, the cellular role of the normal EWS protein is not well characterized. We have previously identified a WD domain-containing protein, serine-threonine kinase receptor-associated protein (STRAP), which inhibits transforming growth factor beta (TGF-beta) signaling through interaction with receptors and Smad7 and promotes growth and enhances tumorigenicity. Here, we report the interaction between STRAP and EWS using matrix-assisted laser desorption/ionization, time-of-flight and tandem mass spectrometry. Although STRAP is localized in both cytoplasm and nucleus, nuclear STRAP colocalizes and associates specifically with EWS in the nucleus through its NH(2) and COOH termini. We have found that normal EWS protein is up-regulated in human cancers, which correlates with the up-regulation of STRAP in 71% of colorectal cancers and 54% of lung cancers, suggesting a cooperative role of these two proteins in human cancers. TGF-beta has no effect on STRAP and EWS interaction. However, EWS, like STRAP, attenuates TGF-beta-dependent transcription. STRAP inhibits EWS-dependent p300-mediated transactivation of EWS target genes, such as ApoCIII and c-fos, in a TGF-beta-independent manner. Interestingly, we have shown that STRAP blocks the interaction between EWS and p300, whereas the complex formation between STRAP and EWS is not affected by p300. These results suggest that STRAP inhibits the transactivation function of EWS by displacing p300 from the functional transcriptional complex. Thus, this study provides a novel TGF-beta-independent function of STRAP and describes a mechanism by which STRAP regulates the function of oncogenic EWS protein.

Animals↗
PubMed2006

An in vitro enzymatic assay coupled to proteomics analysis reveals a new DNA processing activity for Ewing sarcoma and TAF(II)68 proteins.

Based on structural and functional similarities, translocated in liposarcoma/fusion (TLS/FUS) protein, Ewing sarcoma (EWS) protein and human TATA binding protein-associated factor (hTAF(II)68) have been grouped in the TLS-EWS-TAF(II)68 (TET) protein family. Translocations involving their genes lead to sarcomas. Polypyrimidine tract-binding protein-associated splicing factor (PSF), although not grouped in this family, presents structural and functional similarities with TET proteins and is involved in translocation leading to carcinoma. Beside their role in RNA metabolism, the precise cellular functions of these multifunctional proteins are not yet fully elucidated. We previously showed that both TLS/FUS and PSF display activities able to pair homologous DNA on membrane in an in vitro assay. In the present study, we address the question whether EWS and hTAF(II)68 also display pairing on membrane activities, and to a larger extent whether other proteins also exhibit such activity. We applied the pairing on membrane assay to 2-DE coupled to MS analysis for a global screening of DNA pairing on membrane activities. In addition to TLS/FUS and PSF, this test allowed us to identify EWS and hTAF(II)68, but no other proteins, indicating a feature specific to a protein family whose members share extensive structural similarities. This common activity suggests a role for TET proteins and PSF in genome plasticity control.

Cell Line, Transformed↗
PubMedDate not supplied

[Immunocytochemical and biochemical studies of an Ewing sarcoma cell line: evidence for neural differentiation in vitro].

A cell line established from a Ewing's sarcoma removed from the fibula of a 19-year-old female was investigated for morphology and hormone sensitivity. Cells in culture expressed neurofilaments and showed positive immunostaining for neuron-specific enolase (NSE), Leu-7-antigen (HNK-1) and S-100 protein. The cells also contained PAS-positive, diastase-digestible cytoplasmic material, indicative of glycogen inclusions. Moreover, the cells responded to dopamine as well as to beta-adrenergic agonists and prostaglandins to stimulate cyclic AMP synthesis and 3H-glycogen hydrolysis. In conclusion, the morphological and biochemical data show evidence for a neural differentiation pattern of Ewing's sarcoma cells in vitro.

Antigens, Differentiation↗
PubMedDate not supplied

Extensive primary Ewings' sarcoma in the greater wing of the sphenoid bone.

We describe a rare case of an extensive primary cranial Ewing's sarcoma located in the greater wing of the sphenoid bone with extension to the orbit, the endocranium, the parapharyngeal and infratemporal space. The patient presented with diplopia, anosmia and prolapse of the left eye. He was given chemo- and radiotherapy and was free of symptoms on re-examination 1.5 years later. The prognosis of Ewing's sarcoma in the absence of surgery is uncertain, but prompt treatment appears to have a satisfactory therapeutic outcome. In the future, more cases should be studied in order to investigate the biological behaviour of a primary cranial Ewing's sarcoma.

Adult↗
PubMed2026

Targeting of the oncogenic fusion EWSR1-FLI1 in Ewing sarcoma by CRISPR/dCas9 silencers.

Despite the revolutionary impact of genome engineering tools in medicine, the safe and effective intracellular delivery of CRISPR remains a major obstacle to clinical applications. Here, we utilize precision molecular targeting and delivery strategies based on CRISPR-nuclease-dead Cas9 (dCas9) systems adapted for epigenetic repression (dCas9-Krüppel-associated box [KRAB]) to silence oncogenic drivers with high selectivity. As proof of principle, we target the EWSR1-FLI1 translocation, which encodes a chimeric and hard-to-drug oncogenic transcription factor driving approximately 85% of the cases of Ewing sarcoma (EWS)-an aggressive childhood malignancy. We describe the development of a programmable, non-viral polymeric system for the delivery of dCas9-KRAB as ribonucleoprotein (RNP) payloads for EWSR1-FLI1 repression. We demonstrate highly efficient intracellular delivery of RNPs loaded in polyamide-amine (PAMAM) polymers functionalized by guanidino groups, resulting in robust silencing of EWSR1-FLI1 both in established cell line xenografts and in EWS-related patient-derived xenografts (PDXs) of EWS. We show that silencing of EWSR1-FLI1 is accompanied by potent anti-tumor effects. Collectively, we characterize an effective non-viral platform for in vivo delivery of dCas9-KRAB/RNPs, which could be adapted for the repression of any oncogene. We further outline dCas9/RNP formulations for future therapeutic applications to treat poor-prognosis cancers driven by hard-to-drug oncogenes.

CRISPR-dCas9↗
PubMed1991

Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing's sarcoma.

The goal of this study was to use dose-intensity analyses of published Ewing's sarcoma and osteogenic sarcoma trials to determine which agents were most closely associated with a favorable response. The percentage of patients with more than 90% tumor necrosis following neoadjuvant chemotherapy was the end point for analysis of osteogenic sarcoma trials, and disease-free survival and percentage of patients with distant-only relapse were the end points for analysis of Ewing's sarcoma trials. The data were analyzed using logistic regression analysis to circumvent the distortion of univariate analysis resulting from the correlation between doxorubicin dose intensity and the dose intensity of other agents. Our analysis suggests that doxorubicin dose intensity is an important determinant of favorable outcome for both Ewing's sarcoma and osteogenic sarcoma and that the dose intensities of other agents do not contribute as significantly to outcome as does doxorubicin dose intensity. Increasing dactinomycin dose intensity was associated with a poorer outcome in treatment of osteogenic sarcoma and Ewing's sarcoma, most likely resulting from regimens with a higher dactinomycin dose intensity having a lower doxorubicin dose intensity. While our analysis of osteogenic sarcoma trials is consistent with significant activity for cisplatin and high-dose methotrexate (and likely ifosfamide), a rank ordering of the efficacy of these agents when given with doxorubicin in multiagent regimens is not possible. Our analysis illustrates the importance of analyzing the contributions of individual agents to combination chemotherapy regimens. In the design of future clinical trials for osteogenic sarcoma and Ewing's sarcoma, careful attention should be given to optimizing doxorubicin dose intensity in regimens to be tested.

Dose-Response Relationship, Drug↗
PubMed1982

Autoradiographic in vitro study of the cell kinetics of osteogenic sarcomas and Ewing's sarcomas in children.

Proliferation kinetic parameters of 9 osteogenic sarcomas (6 primary tumours, 3 lung metastases) and 3 Ewing's sarcomas were determined using an autoradiographic in vitro method (single and double labelling with 3H- and 14C-thymidine, and 3H-uridine). Osteogenic sarcomas and Ewing's sarcomas, respectively, showed clearly individual pattern of proliferation. The following values were obtained: The average 3H-thymidine labelling indices of 13.8/8.7%, the DNA synthesis times of 12.2/14.4 hours, mitosis times of 1.1/1.9 hours, and mean cell cycle times of 58.0/78.2 hours. The potential tumour doubling times determined with the inclusion of the growth fraction averaged 4.8/5.0 days. Using 3H-uridine labelling of tumours, autoradiography allowed the determination of the growth fraction fair accuracy. It is between 0.26 and 0.71 for osteogenic sarcomas, the average being 0.49. In vitro results were compared with the volume doubling times of metastases of osteogenic and Ewing's sarcomas, reported in the literature which had been determined from series of lung radiographs. The importance of cell kinetic studies of human tumours therapy is demonstrated by a "cell kinetic therapy index".

Autoradiography↗
PubMedDate not supplied

[The Cooperative Ewing Sarcoma Study CESS 81 of the German Pediatric Oncology Society--analysis after 4 years].

In 1981 the cooperative Ewing's sarcoma study CESS 81 was initiated with initial 18-weeks-chemotherapy consisting of vincristine, actinomycin D, cyclophosphamide and adriamycin (VACA) followed by local therapy consisting of either radical surgery with complete resection of the involved bone or incomplete resection followed by radiation with 36 gy or radiotherapy only. Patients with radiation only for local therapy and extremity tumor sites are randomised for 46 gy vs 60 gy tumor dose. Following local therapy chemotherapy is continued for an additional 18 weeks. The actuarial results of 83 consecutive patients entered from 51 participating institutions from January 1, 1981, until November 15, 1984 are presented. 68/83 patients were off therapy and under observation for longer than one year following diagnosis. The longest follow-up was 41 months. On November 15, 1984, 39/68 (57%) patients were disease free. According to the site of the primary tumor patients with distal extremity lesions had a more favourable prognosis as compared to proximal extremity and central lesions. According to local therapy patients with radical surgery had a better prognosis as compared to those with resection followed by radiation and those with radiation only for local control. Analysis according to tumor volume revealed the strong interaction between tumor site, local therapy and tumor volume. According to life-table-analysis the disease free survival for patients with a tumor volume less than 100 ml was 75% after 41 months compared to 10% for patients with a tumor volume greater than or equal to 100 ml. The consequences of this analysis for a stratified treatment regimen for patients with primary Ewing's sarcoma of bone are discussed.

Adolescent↗
PubMed1995

[Extraskeletal Ewing sarcoma: differential diagnosis of a soft tissue tumor].

We report on a 30-year-old man from Vietnam who complained about diffuse pain in the left epigastrium. Using the ultrasound a pleural effusion in the left recessus costodiaphragmaticus was found. The chest X-ray showed a paravertebral soft-tissue tumor at the left side, with CT and NMR a sarcoma was suspected. The patient was treated by local resection of the tumor, histologically an extraosseous Ewing's sarcoma was identified. Due to the following chemotherapy and local radiation therapy no local recurrence and metastases have developed for 32 months.

Adult↗
PubMed1996

A novel chimera gene between EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein, in extraosseous Ewing's sarcoma.

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 of EWS/FLI-1 or EWS/ERG chimeric 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 gene between the transactivation domain of EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein. Since E1A-F is known to activate matrix metalloproteinase genes, the chimera gene may possibly be involved in tumor progression and could be a novel tumor marker for Ewing's sarcoma/PNET.

Adenovirus E1A Proteins↗
PubMed2026

Circulating Tumor DNA Profiling Defines Risk Classification in Patients With Ewing Sarcoma: A Report From the Children's Oncology Group and the LEOPARD Study.

PURPOSE: Identification of discrete risk groups remains a high priority for patients with Ewing sarcoma (EWS). We sought to prospectively validate circulating tumor DNA (ctDNA) as a prognostic factor and develop clinical-molecular risk groups. METHODS: We conducted a prospective investigator-initiated biology study for patients with localized EWS (LEOPARD) and embedded ctDNA analysis into the North American frontline metastatic study AEWS1221. Eligible patients were younger than 50 years with newly diagnosed EWS. All patients provided a baseline blood sample for analysis, which was subjected to ultralow-pass whole-genome sequencing and hybrid capture panel sequencing for ctDNA quantification, fusion detection, and characterization of STAG2 and TP53 alterations. Serial ctDNA sequencing was conducted on a subset of patients in each study. We tested for associations between ctDNA burden and secondary genomic events, and clinical features and outcomes. RESULTS: One hundred forty patients with localized disease and 255 with metastatic disease provided evaluable pretreatment samples for ctDNA analysis. Elevated baseline ctDNA was associated with stage, tumor size, primary site, indeterminate pulmonary nodules, and metastatic pattern. Elevated pretreatment ctDNA burden was associated with inferior outcomes in patients with localized (n = 140, hazard ratio [HR] = 2.36, P = .032) and metastatic disease (n = 255, HR = 2.15, P = .001). Patients with metastatic disease and TP53 variants and/or persistent on-therapy ctDNA had dismal outcomes. Patients with localized disease, low ctDNA, small tumors, and favorable genomics had no events and constitute a novel low-risk group. Among patients with metastatic disease, those with lung-only disease, low ctDNA, and favorable genomics represent an intermediate-risk group. CONCLUSION: This study prospectively validates pretreatment ctDNA burden as prognostic in EWS. Risk groups that integrate ctDNA burden with clinical-molecular features differentiate patients with low-, intermediate-, and high-risk disease.

Journal Article↗
PubMed2007

Juvenile Ewing sarcoma presenting as a pelvic mass.

A teen aged girl with rapidly developing pelvic mass, associated with weight loss and left leg weakness, was evaluated and found to have Ewing's sarcoma of non-osseous origin from pelvis, which is a rare situation. She was treated by a multidisciplinary approach by surgery, chemotherapy and rehabilitation by physiotherapy to effective response.

Adolescent↗
PubMed2006

Primary Ewings sarcoma of the spine: case report.

Primary malignant sarcomas of the spine are extremely rare. Because of biological heterogeneity, these tumors have variable sensitivity to radiation and chemotherapy. Adequate local control through complete tumor removal is an important therapeutic goal. However, aggressive resection of tumors in the spinal column must be coupled with restoration of spinal column stability and minimization of neural deficits. The balance of these factors makes treatment of primary sarcomas of the spine challenging, and dictates an individual approach to treatment. We report on a 18 years old man with primary Ewing's sarcoma of the nonsacral spine. The clinical picture and imaging characteristics were analyzed as well as the management modalities and outcome.

Adolescent↗
PubMed2002

Frequent low level expression in Ewing sarcoma family tumors and widespread absence of the metastasis suppressor KAI1/CD82 in neuroblastoma.

The transmembrane 4 superfamily member KAI1/CD82, a metastasis suppressor, is correlated inversely with the progression and invasion of several tumors. It is capable of inhibiting metastasis without affecting tumorigenicity per se. KAI1/CD82 expression is down-regulated in the progression of common solid epithelial tumors of adulthood. Mutation of p53 is suggested to be involved in the modulation of KAI1. As little is known about its expression and possible prognostic impact in pediatric tumors, we investigated KAI1/CD82 expression in cell lines and primary tumor samples from pediatric tumors of neuroectodermal origin, neuroblastoma and Ewing's sarcoma family tumor. Twenty-four of 29 Ewing's sarcoma family tumor cell lines, independent of p53 status, showed KAI1 mRNA positivity by reverse transcription-PCR analysis in contrast to zero of eight neuroblastoma cell lines. Among 13 primary Ewing's sarcoma family tumor samples from patients with different disease extension, KAI1 mRNA expression was low as detected by reverse transcription-PCR. Twenty of 30 primary neuroblastoma specimens were KAI1-negative by immunofluorescence analysis whereas the remaining 10 gave weak to moderate staining patterns. There was no apparent correlation of KAI1 expression with any clinical or genetic features of the patients whose tumor samples were studied. Consequently, KAI1 may not be of prognostic relevance in this group of tumors although there may be some role for KAI1 modulation in the biology of these neuroectodermal tumors.

Antigens, CD↗
PubMed1995

[The European experience with megadose therapy and autologous bone marrow transplantation in solid tumors with poor prognosis Ewing sarcoma, germ cell tumors and brain tumors)].

Since 1984 a total of 2085 patients with solid tumors have been registered in the European Bone Marrow Transplantation Registry for Solid Tumors (EBMT-STR). The major aim of this registry is to supply data by retrospective analysis for the innovation of prospective, randomized studies. 104 Ewing's sarcoma patients received megatherapy followed by autologous bone marrow transplantation (MGT/ABMT). The 2-year overall survival was 31% in 14 patients with multifocal disease in first complete remission (CR1) and was 37% for 15 patients in second CR (CR2). (6 patients with local disease in CR1 have been excluded.) These results are better than observed under conventional dose chemotherapy. 67 patients were grafted with measurable disease showing a response rate of 72%. The 2-year overall survival was 25% during primary treatments and 33% and 10% for sensitive and resistant relapses, respectively. 201 patients with germ cell tumors received MGT (combinations of platinum derivates, VP16, cyclophosphamide, ifosfamide) followed by ABMT. The overall survival at 5 years was 10% in refractory patients and 58% for 113 responding patients not in CR1 (i.e. first partial remission, CR2 and sensitive relapses). Based on these results and a French randomized trial a prospective, randomized study is underway comparing MGT versus conventional chemotherapy in chemosensitive patients. 219 adults with malignant brain gliomas underwent a program consisting of surgery, MGT (BCNU in the majority)/ABMT and radiotherapy. The overall survival at 3 years was 12%, the median survival was 11 months after ABMT. Life quality after ABMT was good, but no major improvement in terms of prolonged survival was achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1998

[Considerations of biomechanics after clavicular resection. Case report of rower with Ewing sarcoma].

Because of poorly compartmentalized paraclavicular soft tissues, total extraperiostal claviculectomy in cases of malignoma with cortical destruction is always marginal. Due to different muscular compensation in the patients examined, literature disagrees on the biomechanical consequences of claviculectomy for the shoulder girdle. We present a case of total clavicula resection including chemotherapy and radiation in an 18-year-old rower with Ewing's sarcoma. Sixteen-month postoperative radiological and clinical examination revealed an excellent result. Thirty-six months postoperatively the patients is able to row symptom-free without any evidence of the disease. Biomechanical reflections on the significance of the trapezius muscle in compensating thoracoscapular instability provide information for rehabilitation.

Adolescent↗