Impact of <i>EWS-ETS</i> Fusion Type on Disease Progression in Ewing's Sarcoma/Peripheral Primitive Neuroectodermal Tumor: Prospective Results From the Cooperative Euro-E.W.I.N.G. 99 Trial

Deley, Marie-Cécile Le; Delattre, Olivier; Schaefer, Karl‐Ludwig; Burchill, S A; Koehler, Gabriele; Hogendoorn, Pancras C.W.; Lion, Thomas; Poremba, Christopher; Marandet, Julien; Ballet, Steven; Pierron, Gaëlle; Brownhill, Samantha; Nesslböck, Michaela; Ranft, Andreas; Dirksen, Uta; Oberlin, Odile; Lewis, Ian; Craft, Alan; Jürgens, Heribert; Kovar, Heinrich

doi:10.1200/jco.2009.23.3585

Cited by 177 publications

(104 citation statements)

References 19 publications

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“…99 and the COG group did not confirm this clinical significance. 19,20 Patients with resistant disease are unlikely to proceed to HDT and in our analysis they were excluded to avoid the bias in favour of the HDT group. Our observation confirms that consolidation of the first-line treatment with BuMel improves the outcome in ES patients with HR features.…”

Section: Autologous Transplantation K Drabko Et Almentioning

confidence: 99%

Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing’s sarcoma

Drabko

Raciborska²,

Bilska³

et al. 2012

Bone Marrow Transplant

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According to the published report on current practice of hematopoietic SCT in Europe, high-dose therapy (HDT) with autologous stem cell support is a standard of care in paediatric patients with high risk (HR) or relapsed Ewing 0 s sarcoma (ES). Randomized trials, however, have not confirmed the value of this procedure yet. In this retrospective analysis we intended to evaluate the role of HDT as a consolidation therapy in first remission of ES. A total of 102 patients were included in the analysis and divided according to the following risk factors: metastatic disease at presentation, feasibility of surgery and histological response after induction. Forty-one patients were classified as standard risk (SR) patients, while the remaining 61 children, with at least one risk factor, were classified as HR patients. HR group patients were non-randomized and qualified according to the decision of the local clinician to give a conventional consolidation (CC) or to perform high-dose chemotherapy and radiotherapy in selected patients. Twenty-six children were given CC while 35 patients were treated with HDT. The HDT consisted of oral BU 4 mg/kg p.o. in divided doses daily for 4 days (total dose 16 mg/kg) followed by melphalan 140 mg/m 2 i.v. on day À 2. Probability of relapse-free survival (RFS) in median observation time was significantly worse in HR patients who were given CC therapy as compared with children with HR features receiving high-dose chemotherapy (0.27 vs 0.66 (P ¼ 0.008); OS 0.31 vs 0.71 (P ¼ 0.007), respectively). Patients from the SR group had a probability of RFS of 0.72 and OS of 0.75, and the difference between SR and HR patients after HDT was NS (P ¼ 0.37). Our observation confirms that the consolidation of the first-line treatment with BU and melphalan improves the outcome in ES patients with HR features.

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Section: Autologous Transplantation K Drabko Et Almentioning

confidence: 99%

Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing’s sarcoma

Drabko

Raciborska²,

Bilska³

et al. 2012

Bone Marrow Transplant

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“…Given that the primary event (EWS-ETS) is now known to lack prognosis value (Le Deley et al, 2010;van Doorninck et al, 2010), secondary genetic alterations have emerged as likely candidates to account for the most aggressive forms of ES, and could eventually become molecular targets of specific therapies.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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Despite extensive characterization of the role of the EWS-ETS fusions, little is known about secondary genetic alterations and their clinical contribution to Ewing sarcoma (ES). It has been demonstrated that the molecular structure of EWS-ETS lacks prognostic value. Moreover, CDKN2A deletion and TP53 mutation, despite carrying a poor prognosis, are infrequent. In this scenario identifying secondary genetic alterations with a significant prevalence could contribute to understand the molecular mechanisms underlying the most aggressive forms of ES. We screened a 67 ES tumor set for copy number alterations by array comparative genomic hybridization. 1q gain (1qG), detected in 31% of tumor samples, was found markedly associated with relapse and poor overall and disease-free survival and demonstrated a prognostic value independent of classical clinical parameters. Reanalysis of an expression dataset belonging to an independent tumor set (n ¼ 37) not only validated this finding but also led us to identify a transcriptomic profile of severe cell cycle deregulation in 1qG ES tumors. Consistently, a higher proliferation rate was detected in this tumor subset by Ki-67 immunohistochemistry. CDT2, a 1q-located candidate gene encoding a protein involved in ubiquitin ligase activity and significantly overexpressed in 1qG ES tumors, was validated in vitro and in vivo proving its major contribution to this molecular and clinical phenotype. This integrative genomic study of 105 ES tumors in overall renders the potential value of 1qG and CDT2 overexpression as prognostic biomarkers and also affords a rationale for the application of already available new therapeutic compounds selectively targeting the protein-ubiquitin machinery.

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“…Retrospective studies indicate a relationship between prognostic value and the specific exons involved in the translocation, 38,44,[57][58][59] but the results are often contradictory. Prognostic relevance of the transcripts in our series was outside the scope of the present study.…”

Section: Discussionmentioning

confidence: 99%

Molecular Diagnosis in Ewing Family Tumors

Gamberi

Cocchi

Benini

et al. 2011

The Journal of Molecular Diagnostics

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The Ewing's family of tumors (EFTs) are characterized by chimeric transcripts generated by specific chromosomal rearrangements. The most common fusions are between the EWSR1 gene on chromosome 22 and the ETS family of transcription factors; rarely, FUS (on chromosome 16) substitutes for EWSR1. The detection of specific translocations using molecular analysis is now a routine part of the pathological examination of EFT. Here, we report our experience with molecular diagnosis of EFT during the 4 years (2006 -2009) at the Rizzoli Institute. We analyzed 222 consecutive tumors with a presumptive diagnosis of EFT using molecular techniques and IHC. We found five distinct types of EWSR1-FLI1 fusion transcripts resulting from translocation t(11;22), three types of EWSR1-ERG transcripts resulting from t(21;22), and one type of t(2;22) resulting in EWSR1-FEV fusion. Molecular investigation validated 92% of cases ultimately diagnosed as EFT; IHC validated 76% of the cases. Thus, despite the difficulties and limitations associated with both molecular and IHC analysis on fresh and formalin-fixed, paraffin-embedded tissue, a combination of these techniques is the best approach to enhancing the accuracy of EFT diagnosis. We also present our method for choosing which molecular techniques to apply. Finally, we collected the most prevalent breakpoints reported in the literature, indicating which exons are involved, the sequence breakpoints, and the NCBI reference sequences. Ewing's sarcoma (ES) is a highly malignant small round cell tumor (SRCT) that can arise in both bone and soft tissues of children and young adults. Rarely, it occurs also in adults.1,2 It is the second most common pediatric bone tumor after osteosarcoma, accounting for ϳ30% of all primary bone tumors in this age group. 1,3,4 Based on their shared immunophenotypes and molecular parameters, several diagnostic entities that were previously considered distinct are now assembled as a single entity, the Ewing's sarcoma family of tumors (EFTs). These include bone and extraskeletal Ewing's sarcoma, primitive neuroectodermal tumor (PNET), and Askin tumor of the thoracopulmonary region. 1,5-7The histological evaluation of EFT is based on morphological, immunophenotypic, and molecular features. The morphology of ES is variable. These tumors are frequently composed of uniform small round cells with round nuclei containing fine chromatin, scanty clear or eosinophilic cytoplasm, and indistinct cytoplasmic membranes. In less differentiated cases, tumor cells are larger, with prominent nucleoli and irregular contours. The cytoplasm frequently contains PAS-positive diastase-resistant glycogen. PNET is characterized by HomerWright rosettes, which are typical of neuroectodermic differentiation. 6,8,9 Immunohistochemical analysis (IHC), the first ancillary technique used in pathology to confirm the diagnosis of EFT, can distinguish among different variants. The immunohistochemical features of ES are positivity for CD99, FLI1, and caveolin 1 antigens, whereas PNET also shows immun...

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Impact of EWS-ETS Fusion Type on Disease Progression in Ewing's Sarcoma/Peripheral Primitive Neuroectodermal Tumor: Prospective Results From the Cooperative Euro-E.W.I.N.G. 99 Trial

Cited by 177 publications

References 19 publications

Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing’s sarcoma

Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing’s sarcoma

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

Molecular Diagnosis in Ewing Family Tumors

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