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PubMedDate not supplied

[Severe neuropathy after chemo- and radiotherapy of Ewing sarcoma].

A 15 year old patient presenting with a lumbar Ewing's Sarcoma was treated according to the EICESS-92 pilot study (EVAIA branch). Local therapy consisted of definitive irradiation given simultaneously to chemotherapy courses 5 to 7. Close to the end of treatment the patient developed progressive peripheral neurologic deficits. Such combined toxic treatment side effects are unique and unforeseen in the study protocol.

Adolescent↗

PubMed2005

Once-per-cycle pegfilgrastim versus daily filgrastim in pediatric patients with Ewing sarcoma.

The use of the recombinant human granulocyte colony-stimulating factor filgrastim to shorten the duration of severe neutropenia after cytotoxic chemotherapy has become an integral part of supportive care. However, due to its short serum half-life, filgrastim must be injected daily. Pegfilgrastim, a new long-lasting form of filgrastim administrated once per cycle, has been shown in adults to be as effective in reducing the duration of severe neutropenia as daily filgrastim. The aim of this study was to evaluate the effects of pegfilgrastim in pediatric patients. Five children with Ewing sarcoma were alternately treated with a single 100 microg/kg pegfilgrastim dose or daily doses of 10 microg/kg Filgrastim after a total number of 58 chemotherapy cycles. Pegfilgrastim was well tolerated. The duration of severe neutropenia and the incidence of febrile neutropenia after pegfilgrastim and filgrastim were comparable. By using pegfilgrastim, the number of subcutaneous injections could be reduced to one single injection per cycle.

Adolescent↗

PubMed1996

Olfactory neuroblastoma is a peripheral primitive neuroectodermal tumor related to Ewing sarcoma.

Olfactory neuroblastoma (ONB) is a malignant tumor of the nasal mucosa whose histogenesis is unclear. A relationship to neuroblastoma (NB), a pediatric tumor of the sympathetic nervous system, is based on morphologic similarities and the expression of similar neural antigens. However, the clinical presentation of ONB differs from that of NB, and MYCN amplification characteristic of NB is not observed. We have therefore examined the relationship of this malignancy to other classes of neural tumors. In previous studies, two ONB cell lines demonstrated cytogenetic features and patterns of protooncogene expression suggestive of a relationship to the Ewing sarcoma family of childhood peripheral primitive neuroectodermal tumors (pPNETs). The pPNETs show t(11;22)(q24;q12) or t(21;22)(q22;q12) chromosomal translocations fusing the EWS gene from 22q12 with either the FL11 gene on 11q24 or the ERG gene on 21q22. We therefore analyzed ONBs for the presence of pPNET-associated gene fusions. Both cell lines showed rearrangement of the EWS gene, and fluorescence in situ hybridization (FISH) of each case demonstrated fusion of EWS and FL11 genomic sequences. Moreover, both lines expressed EWS/FL11 fusion transcripts with in-frame junctions between exon 7 of EWS and exon 6 of FL11 as described for pPNETs. We identified similar gene fusions in four of six primary ONB cases. None of the cases expressed tyrosine hydroxylase, a catecholamine biosynthetic enzyme widely expressed in NB. Our studies indicate that ONB is not a NB but is a member of the pPNET family.

Adult↗

PubMed1997

EWS-ERG fusion transcript produced by chromosomal insertion in a Ewing sarcoma.

The EWS gene is fused in Ewing sarcoma-like tumors by a chromosomal translocation to one of the four ETS-family genes: FLI1, ERG, ETV1, and E1AF. The orientation of EWS and FLI1 on chromosomes 22 and 11, respectively, is 5' centromeric and 3' telomeric, whereas that of ERG on chromosome 21 is the reverse. Although 10% of Ewing-family tumors express the EWS-ERG fusion transcript, there have been no reports on tumors with t(21;22)(q22;q12) identified by banding cytogenetics. We found the karyotype 50, XY, +8, +8, +12, +mar in all metaphase cells from a tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis performed on the tumor and direct sequencing of the products identified the EWS-ERG fusion transcript. Subsequent two-color fluorescence in situ hybridization (FISH) analysis with EWS and ERG clones showed the fused signals on the der(21) chromosome, but no ERG signals on the chromosome 22 homologs. Thus, our RT-PCR and FISH analyses indicated that the chromosome 22 fragment containing the 5' portion of EWS had been inverted and inserted into chromosome 21 and had fused to the 3' portion of ERG. This subtle chromosome aberration could not be identified by routine cytogenetics. A chromosomal inversion/insertion has also been described in acute leukemia with the MLL-AF10 fusion gene, and this may be a common pathway for producing fusion of reverse-oriented genes in leukemias and solid tumors.

Bone Neoplasms↗

PubMed1993

A disease-associated germline deletion maps the type 2 neurofibromatosis (NF2) gene between the Ewing sarcoma region and the leukaemia inhibitory factor locus.

RFLP typing of members of a neurofibromatosis type 2 (NF2) family suggested that affected individuals were hemizygous at the neurofilament heavy chain (NEFH) locus, possibly as a result of a disease-associated deletion. Conventional karyotyping revealed no evidence for a deletion and all or a majority of the affected family members were heterozygous for closely linked markers which mapped proximal to the NEFH locus (D22S1 and D22S56) and for the distal marker D22S32. FISH analysis confirmed a disease-associated germinal deletion on 22q which encompassed the NEFH locus, which is known to be very closely linked to NF2, but did not extend as far as the proximal Ewing sarcoma region or the distal leukaemia factor (LIF) locus. PFGE analysis with a LIF cosmid subclone identified patient-specific NotI and MluI fragments and suggested that the deletion is about 700 kb in length. Although this large deletion could be expected to eliminate a considerable fraction, and possibly all of the NF2 gene, the resulting phenotype is the mild, so-called Gardner subtype of NF2. The deletion should provide a useful mapping resource for characterising the chromosomal region containing the NF2 locus.

Alleles↗

PubMed1976

[Improved prognosis of Ewing-sarcoma by combined irradiation and chemotherapy (author's transl)].

Until recently Ewing's sarcoma has been considered the most lethal malignant bone tumor with the poorest prognosis. An 8-year-old girl with Ewing's sarcoma is described who survived without recurrent disease for nearly 5 years now. 5-year-survival rates among large groups in the literature are reported, and different kinds of therapy compared. There are indications for a tendency that combined radio- and chemotherapy probably have the best results, since in most cases at the time of diagnosis the tumor already has metastasized or, like Lichtenstein believes, Ewing's sarcoma, primarily is of multicentric origin.

Bone Neoplasms↗

PubMed2000

Adenovirus 5 early region 1A does not induce expression of the ewing sarcoma fusion product EWS-FLI1 in breast and ovarian cancer cell lines.

The adenovirus 5 early region 1A (E1A) can function as a tumor suppressor gene and is being used in clinical trials as a therapeutic agent for advanced breast, ovarian, and head and neck cancer. Recently, there has been a dispute regarding whether transfection with the E1A gene can induce expression of the Ewing sarcoma oncogenic fusion transcript EWS-FLI1 (Sanchez-Prieto et al., Nat. Med., 5: 1076-1079, 1999; Melot and Delattre, Nat. Med., 5: 1331, 1999; Kovar et al., Cancer Res., 60: 1557-1560, 2000). In an effort to settle the controversy, we tested several stable E1A transfectants of cell lines MDA-MB-231, MCF-7, MDA-MB-435 (breast cancer), SKOV3-ipl (ovarian cancer), and PC-3 (prostate cancer), as well as parental and vector-transfected controls, HEK 293 cells, and RD-ES (Ewing sarcoma) cells, for the EWS-FLI1 fusion product. The EWS-FLI1 transcript could not be identified with reverse transcription-PCR in any of the 13 E1A-transfected cell lines analyzed. Furthermore, the EWS-FLI1 fusion protein could not be detected by Western blot analysis in E1A-transfected cell lines. These results suggest that E1A transfection does not necessarily lead to expression of the oncogenic EWS-FLI1 fusion transcript. Thus, the potential induction of this gene rearrangement by E1A gene therapy is unlikely to be clinically significant in the treatment of advanced malignant disease.

Adenovirus E1A Proteins↗

PubMed1983

[Ewing sarcoma. Diagnostic and therapeutic problems in children].

A pathological X-ray of the skeleton with the clinical correlation "painful swelling of soft tissue" is always an alarming sign in childhood. Radiology is our most important device to decide if the disease is of traumatic, inflammatory, incretory or neoplasmatic as well as of degenerative origin. Considering the group of "neoplasmatic alterations" there are more than 50 different entities. The differential diagnosis of a "bone tumor" requires large experience from the radiologist. Supporting the oncologist an experienced pathologist must be capable to distinguish a reticulosarcoma, a neuroblastoma metastasis, a leukemic bone-infiltrate or an embryonal rhabdo-myosarcoma from an Ewing's sarcoma. An experienced surgeon is of the same importance capable of not only collecting detritus out of necrotic tumor centres or altered tissues, but of gathering several samples from vital tumor tissue. This experienced team is especially required when children are in concern, as this age represents the peak of manifestation of malignant bone-sarcoma as Ewing's sarcoma or osteosarcoma. The quoted case-descriptions point our how difficult it may be to find the proper biopsy location and how initial false diagnosis lets valuable time pass by and prevents early diagnosis.

Adolescent↗

PubMed2005

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

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

Biomarkers, Tumor↗

PubMedDate not supplied

[The German Society of Pediatric Oncology Cooperative Ewing Sarcoma Studies CESS 81/86: report after 6 1/2 years].

The GPO Cooperative Ewing's Sarcoma Study (CESS 81 with 10 months four-drug combination chemotherapy (vincristine, actinomycin D, cyclophosphamide, and adriamycin = VACA) and local control with surgery and/or radiation, following week 18, resulted in a Kaplan-Meier estimated disease-free survival of 51% after 6 1/2 years (51/93 patients disease-free). Tumor volume and histological response to primary chemotherapy were identified as most significant prognostic factors. As a consequence, the CESS 86 regimen was stratified according to risk of relapse. Standard risk patients (extremity tumors less than 100 ml tumor volume) were continued on VACA chemotherapy. In high risk patients (extremity tumors greater than 100 ml tumor volume, central tumors), cyclophosphamide in conventional dose (1200 mg/m2/course) was replaced by high doses of ifosfamide (6 g/m2/course) with mesna uroprotection (VAIA). Local control was obtained following week 9. Patients with radiation were randomised for conventional fractionation or accelerated split-course hyperfractionation. The study was piloted from February to December 1985: 27/37 patients were disease-free on October 1, 1987. The ongoing trial was started on January 1, 1986. On October 1, 1987. 63/66 patients were disease-free. In patients with large primaries, according to Kaplan-Meier life-table analysis, the disease-free survival was significantly better in patients receiving VAIA chemotherapy, compared to the previous VACA regimen. The toxicity of both combination chemotherapy regimens was comparable.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

Exposure on cell surface and extensive arginine methylation of ewing sarcoma (EWS) protein.

In contrast to the knowledge regarding the function of chimeric Ewing sarcoma (EWS) fusion proteins that arise from chromosomal translocation, the cellular function of the RNA binding EWS protein is poorly characterized. EWS protein had been found mainly in the nucleus. In this report we show that EWS protein is not only found in the nucleus and cytosol but also on cell surfaces. After cell-surface biotinylation, isoelectric focusing of membrane fraction, avidin-agarose extraction of biotinylated proteins, and SDS-polyacrylamide gel electrophoresis, EWS protein was identified by matrix-assisted laser desorption ionization and nanoelectrospray tandem mass spectrometry of in-gel-digested peptides. These analyses revealed that the protein, having repeated RGG motifs, is extensively asymmetrically dimethylated on arginine residues, the sites of which have been mapped by mass spectrometric methods. Out of a total of 30 Arg-Gly sequences, 29 arginines were found to be at least partially methylated. The Arg-Gly-Gly sequence was present in 21 of the 29 methylation sites, and in contrast to other methylated proteins, only 11 (38%) methylated arginine residues were found in the Gly-Arg-Gly sequence. The presence of Gly on the C-terminal side of the arginine residue seems to be a prerequisite for recognition by a protein-arginine N-methyltransferase (PRMT) catalyzing this asymmetric dimethylation reaction. One monomethylarginine and no symmetrically methylated arginine residue was found. The present findings imply that RNA-binding EWS protein shuttles from the nucleus to the cell surface in a methylated form, the role of which is discussed.

Amino Acid Motifs↗

PubMed1986

[Argument for the multidisciplinary treatment of Ewing sarcoma with surgery].

The authors summarize the literature on the local treatment of Ewing's sarcoma. They remind us that including surgery in local treatment increases disease free survival rate by 20-25% while it reduces functional sequelae and radioinduced sarcoma risk. They underline the major interest of histologic examination of in bloc resected tumor to guide postoperative chemotherapy. They advocate that local treatment of Ewing's sarcoma should always be surgical and conservative with the help when necessary of massive homograft and lengthening prosthesis.

Bone Neoplasms↗

PubMedDate not supplied

[Prognosis in Ewing sarcoma patients with initial pathological fractures of the primary tumor site].

In this retrospective analysis, data of 52 patients with Ewing's sarcoma or PNET with a pathological fracture in the area of the primary tumor were evaluated. All patients were treated according to the trials CESS 81, CESS 86 P, CESS 86, CESS 91 P and EICESS 92 of the German Society of Pediatric Oncology and Haematology (GPOH). At the date of evaluation (15. September 1994) all patients had completed treatment and had been under observation for at least one year following diagnosis. The median follow-up time was 28 months. 22 patients were female, 30 male. The median age was 12 years. 75% of primary tumors had a volume of > or = 100 ml. 30 patients presented with fractures in proximal, 12 in central and 10 in distal parts of the skeleton. 10 patients had primary metastases. The histological definition was Ewing's sarcoma (including atypical Ewing's sarcoma) in 43 patients, PNET in 8 and small-cell osteosarcoma in 1 patient. For local therapy the patients underwent surgery, definitive radiotherapy or a combination of both. The percentage of primary metastases in the group of the patients with pathological fractures is comparable to the whole reference group. The present analysis focuses on those patients with pathological fractures who had no metastases at diagnosis. The relapse-free survival of patients with a pathological fracture and no primary metastases is 58%, the overall survival 65%. These rates are similar to those of the reference group of protocol patients without pathological fractures at diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2004

NF-kappaB activation prevents apoptotic oxidative stress via an increase of both thioredoxin and MnSOD levels in TNFalpha-treated Ewing sarcoma cells.

Repression of activation of c-Jun N-terminal kinase (JNK) participates in the anti-apoptotic effect of nuclear factor-kappaB (NF-kappaB) in TNFalpha-treated Ewing sarcoma cells. As oxidative stress is one of the most prominent activators of JNK, we investigated the relationship between TNFalpha-induced NF-kappaB activation and the control of oxidative stress. Inhibition of NF-kappaB activation resulted in an increase in TNFalpha-induced ROS production, lipid peroxidation and protein oxidation. Those ROS and lipid peroxides were both involved in TNFalpha-induced apoptosis, whereas only ROS elevation triggered sustained JNK activation. TNFalpha increased the level of two antioxidant enzymes, thioredoxin and manganese superoxide dismutase by an NF-kappaB-dependent mechanism. Inhibition of expression or activity of these enzymes sensitized cells to TNFalpha-induced apoptosis, indicating their functional role in protection from cell death. Thus, agents that inhibit activities of these enzymes may prove helpful in the treatment of Ewing tumors.

Adolescent↗

PubMed2005

Ewing sarcoma of the mandible in a child: interdisciplinary treatment concepts and surgical reconstruction.

Ewing's sarcoma is the second most common primary bone malignancy in childhood and adolescence. We present a standardized interdisciplinary treatment protocol according to the EURO-E.W.I.N.G. 99 study, applied in the treatment of a 7-year-old patient with localized Ewing's sarcoma of the left mandible. After six blocks of VIDE (vincristine/ifosfamide/doxorubicin/etoposide) chemotherapy and stem cells rescue, intensity modulated external radiation with 48.6 Gy and subsequent high dose therapy with busulphan-melphalan were administered. Tumor resection and immediate bony reconstruction was performed using a microvascular fibula graft 10 weeks after radiation. Because of the effective neoadjuvant treatment, no extensive soft tissue resection was necessary. Healing of the osteosynthesis was uneventful. No local or systemic recurrence and no signs of significant facial deformity were found after 12 month follow-up. The presented case underlines the requirement for multidisciplinary protocols involving radiologists, pathologists, oncologists, radiation oncologists, and surgeons for accurate diagnosis and appropriate therapy. To preserve cosmetics and function within the craniofacial area after tumor resection in children, microvascular reconstructive procedures can be successfully performed with a vascularized fibular graft.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Specificity and function of monoclonal antibodies directed against Ewing sarcoma cells.

A selection of 16 monoclonal antibodies has been produced against a fresh Ewing's sarcoma (ES) tumor mixed with a permanent ES cell line. The majority of antibodies identify an 80-kDa molecule, which is not detected on healthy tissues except on certain cultured monocytes. One antibody recognizes the CD2 ligand MIC2 and 2 antibodies (numbers 13 and 16) define a higher-molecular-mass antigen. Antibody 16 is also expressed on mesenchymal fibroblasts of bone marrow or fetal origin. Tumor-specific antigen expression is potentially linked to the chromosome 22 abnormality described in Ewing's sarcoma, products altered expression in tumors with the chromosome 11/22 translocation has not been shown. The putative chimeric protein on chromosome 11 is apparently not expressed to a great extent, as tested by Northern blotting; however, the fusion protein initiated on chromosome 22 and ending on chromosome 11 is readily seen on Northern blots. The altered expression of a number of cellular genes in addition to a novel gene product(s) originating from translocation events were expected to be identified by monoclonal antibodies selected by their unique binding pattern to Ewing's sarcoma (ES) cells.

Animals↗

PubMedDate not supplied

[Results of treatment of primary exclusively pulmonary metastatic Ewing sarcoma. A retrospective analysis of 41 patients].

41 patients presenting with primary metastatic Ewing's sarcoma or malignant peripheral neuroectodermal tumor (PNET) with initial metastases restricted to the lungs and/or pleural space were analysed with respect to clinical manifestation and treatment results retrospectively. All patients were treated according to the protocols CESS 81 and CESS 86 of the German Society of Pediatric Oncology and Hematology (GPOH). The time since diagnosis ranges from 19 to 137 months, with a median of 72 months. Median relapse-free survival time was 21.8 months. 18 patients were female, 23 were male. The majority of primary tumors exceeded 100 ml of volume. Preferred sites were the pelvis with 16 cases, the limbs with 14 cases and the chest wall with 6 cases. The histological specification of the tumor was Ewing's sarcoma in 22 and PNET in 11 patients, in 8 cases no specific distinction was given. As to local therapy of the primary tumor, 12 patients underwent radiotherapy, 11 surgery, and 18 a combination of both. Patients were allocated to one of these three options on an individual basis. Cytostatic drug treatment was given according to the GPOH-CESS 81 and CESS 86 protocols. As calculated by means of the Kaplan-Meier analysis, relapse-free survival was 30% ten years after diagnosis. Surgery or pulmonary irradiation of 12-20 Gy was applied to lung metastases. 12 of 27 patients are in continuous complete remission following this therapeutic approach.

Adolescent↗

PubMed1992

Tissue distribution of 125I-labeled fetal thyroid hormone in nude mice xenografted with Ewing sarcoma.

Biodistribution of fetal thyroid hormone (RT3) was studied in nude mice with Ewing's sarcoma xenografts. At 30 min and 1, 2, 4, 8, and 12 hr after injection, blood, tumor and normal organs were measured to determine the amount of radioactivity per gram of tissue. The amount of radioactivity in the blood of tumor-bearing mice decreased sharply from 7.64% of injected dose per gram of tissue (% ID/g) at 30 min after inoculation to 0.45%/ID/g at 12 hr. The % of injected dose per gram for 125I-labeled RT3 in the tumor reached 1.92 at 1 hr after injection and decreased to 0.22 at 12 hr. The radiolocalization indices for tumor to other organs at 12 hr ranged from 1.35 to 4.43. This study suggests increased localization of RT3 in the Ewing's sarcoma as compared to other tissues in the nude mouse.

Animals↗