Ewing's Sarcoma
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Ewing's sarcoma / Peripheral Primitive Neuroectodermal Tumours (PNET) of bone is a type of cancer usually found in children and young adults. The peak incidence is between ages 10 and 20, it is less common in children under 5 or in adults over 30. Ewing's s can occur in any bone in the body; the most common sites are the pelvis, thigh, lower leg, upper arm, and rib. The tumour is composed of small round blue cells. Ewing's sarcoma can also arise in soft tissue (extra-skeletal); see Soft Tissue Sarcoma in this guide.

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See also: Genetic features of Ewing's Sarcoma

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Jahangiri FR, Al Eissa S, Jahangiri AF, Al-Habib A
Intraoperative neurophysiological monitoring during sacrectomy procedures.
Neurodiagn J. 2013; 53(4):312-22 [PubMed] Related Publications
Previously intraoperative neurophysiological monitoring (IONM) has not been used along with a computer based navigation system for en bloc resection of a sacral Ewing sarcoma. In order to improve the post-operative neurological outcome of the patient we decided to include IONM in our procedure. A partial or complete resection of a sacral tumor may result in the loss of neurological functions due to close proximity of vascular, neural, and visceral structures. A prolonged two-stage surgical procedure may be a high risk procedure for position related brachial plexus injury. An 18-year-old male presented with left lower extremity weakness, which worsened with gait. His MRI was consistent with a sacral mass causing compression on the left S1 and S2 roots. A surgical resection was planned with anterior and posterior approaches. IONM helped guide the surgical team to prevent damaging the sacral roots on the normal side (right) and position related upper extremity brachial plexus injuries. Our technique involving IONM can be used safely for accurate en bloc removal of a sacral tumor with a safe margin while protecting the neural function and minimizing recurrence. This case report demonstrates that intraoperative neurophysiological monitoring was useful in identifying and reversing impending nerve injury during sacrectomy surgery. Significant changes were seen in ulnar and posterior tibial somatosensory evoked potentials (SSEPs). We recommend that IONM should be considered for safe margin en bloc sacral tumor resection and prevention of injury to the sacral root and brachial plexus.

Elbashier SH, Nazarina AR, Looi LM
Cytokeratin immunoreactivity in Ewing sarcoma/ primitive neuroectodermal tumour.
Malays J Pathol. 2013; 35(2):139-45 [PubMed] Related Publications
Ewing sarcoma (ES)/ primitive neuroectodermal tumour (PNET) is an aggressive malignant neoplasm affecting mainly children and young adults. The tumour is included with other primitive neoplasms under the category of small round cell tumour. Cytokeratin expression in ES/PNET has been described in sporadic case reports as well as a few systemic series. We studied this feature in Malaysian patients diagnosed in University Malaya Medical Centre on the basis of typical morphology and immunohistochemical assays. Immunohistochemical staining for AE1/AE3 and MNF116 were performed in 43 cases. Cytokeratin was expressed in 17 cases (39.5%) in focal, intermediate or diffuse patterns. There was no significant association between cytokeratin immunoreactivity and the following parameters: patient age, sex, skeletal and extraskeletal primary location as well as primary, metastastic or recurrent tumours or chemotherapy treatment. A significant association between cytokeratin and neuron specific enolase (NSE) expression was demonstrated. Our study supports evidence of epithelial differentiation in ES/PNET and emphasizes that the expression of cytokeratin does not exclude ES/PNET in the differential diagnosis of small round cell tumours.

Huang WY, Tan WL, Geng DY, et al.
Imaging findings of the spinal peripheral Ewing's sarcoma family of tumours.
Clin Radiol. 2014; 69(2):179-85 [PubMed] Related Publications
AIM: To present the neuroradiological and clinical characteristics of Ewing's sarcoma family of tumours (ESFTs) and to increase awareness of this neoplasm.
MATERIALS AND METHODS: The magnetic resonance imaging (MRI) features and clinical presentations of seven patients with pathologically documented ESFTs were retrospectively analysed. The tumour location, morphological features, signal intensity, contrast enhancement characteristics, involvement of the paraspinal soft tissues, and adjacent bony structures were assessed.
RESULTS: Most of the ESFTs in young adults were well-circumscribed. The present study demonstrated that ESFTs often have a hypo- or iso-intense signal on T1-weighted imaging and an iso-intense signal on T2-weighted imaging. Spinal ESFTs tended to present homogeneous signal intensity and diffuse enhancement. ESFTs are more likely to occur in the thoracic spine and later to infiltrate into the paraspinal area or vertebral bone. A broad dural attachment is another common feature in the cases presented here.
CONCLUSIONS: ESFT is a rare neoplasm that can have significant overlap in imaging appearance compared with other spinal neoplasms. A well-demarcated extradural mass invading the paraspinal soft or vertebral bones, with iso-intense on T2 weighted imaging and homogeneous enhancement could facilitate the diagnosis of spinal ESFT.

Sasaki T, Onishi T, Yabana T, Hoshina A
Ewing's sarcoma/primitive neuroectodermal tumor arising from the adrenal gland: a case report and literature review.
Tumori. 2013 May-Jun; 99(3):e104-6 [PubMed] Related Publications
We report a rare case of Ewing's sarcoma (ES)/primitive neuroectodermal tumor (PNET) arising from the adrenal gland. A 17-year-old Japanese woman presented with left upper abdominal pain and high fever. Computed tomography and magnetic resonance imaging revealed a 15 × 10 cm tumor replacing the adrenal gland. Preoperative diagnosis was an adrenocortical carcinoma. Resection of the tumor was performed. We obtained the final diagnosis of ES/PNET by immunohistochemical molecular study with positive staining for the MIC2 gene product (CD99) and a Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangement. Local recurrence was observed one month after the surgery. The patient was then treated with systemic chemotherapy and localized radiotherapy.

Related: MIC2 Expression in Cancer EWSR1 gene

Aryee DN, Niedan S, Ban J, et al.
Variability in functional p53 reactivation by PRIMA-1(Met)/APR-246 in Ewing sarcoma.
Br J Cancer. 2013; 109(10):2696-704 [PubMed] Article available free on PMC after 12/11/2014 Related Publications
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-1(Met), 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 p21(WAF1) 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.

Related: Apoptosis Bone Cancers TP53

Pérez-Muñoz I, Grimer RJ, Spooner D, et al.
Use of tissue expander in pelvic Ewing's sarcoma treated with radiotherapy.
Eur J Surg Oncol. 2014; 40(2):197-201 [PubMed] Related Publications
INTRODUCTION: The local treatment option for pelvic Ewing sarcoma (ES) remains uncertain and challenging as surgery is often disabling while radiotherapy alone has a higher risk of local recurrence but not necessarily a worse survival. The aim is to analyse the outcome of patients with pelvic ES after radiotherapy as the primary local treatment in combination with a temporary intrapelvic surgically placed tissue expander (TE) to reduce bowel complications.
MATERIALS AND METHODS: 20 patients were retrospectively analysed. All patients had neoadjuvant and adjuvant chemotherapy. We identified survival, time to develop local recurrence and metastasis, dose of radiotherapy administered, local complications related to the use of the tissue expander and bowel effects of radiotherapy.
RESULTS: The median follow-up was 41 months. 14 patients were stage IIb and six stage III. There were no problems after insertion of the TE and only one patient who developed mild diarrhoea. Local recurrence occurred in six patients. At the last follow-up 12 patients have died from sarcoma, five are disease free and three have had recurrent disease.
CONCLUSIONS: In this paper we reviewed pelvic Ewing sarcoma with all the special considerations that this entails. We think that tissue expander can be safely used when radiotherapy is chosen to treat pelvic ES. It does appear to prevent bowel problems and is a low morbidity procedure. New treatment approaches should be considered to give a chance of cure to those patients with "bad prognostic" pelvic ES.

Related: Bone Cancers

Sankar S, Tanner JM, Bell R, et al.
A novel role for keratin 17 in coordinating oncogenic transformation and cellular adhesion in Ewing sarcoma.
Mol Cell Biol. 2013; 33(22):4448-60 [PubMed] Article available free on PMC after 01/05/2014 Related Publications
Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma.

Related: Bone Cancers FLI1 gene AKT1 Signal Transduction GLI

Morland B, Platt K, Whelan JS
A phase II window study of irinotecan (CPT-11) in high risk Ewing sarcoma: a Euro-E.W.I.N.G. study.
Pediatr Blood Cancer. 2014; 61(3):442-5 [PubMed] Related Publications
BACKGROUND: The prognosis for patients with nonpulmonary metastatic Ewing sarcoma remains poor with survival in the order of 15-20%. The need to introduce effective new agents into clinical practice is clear. Based on a preclinical rationale of responses in xenografts and backed by a phase I study in children, the Euro-E.W.I.N.G consortium planned a phase II window study of irinotecan in newly diagnosed high risk metastatic patients with Ewing sarcoma.
PROCEDURES: Patients were recruited between April 2004 and December 2007. Two courses of irinotecan were administered at a dose of 600 mg/m(2) as a 1 hour infusion at 21 day intervals. Response evaluation was determined after the second course of treatment by radiological assessment of primary and metastatic sites and, where appropriate bone marrow sampling.
RESULTS: Twenty-three patients were recruited. Two patients were deemed inevaluable for response. Five patients (24%) demonstrated a partial response. Grade 3 or 4 diarrhoea was seen in 4/43 course of treatment and was managed with loperamide.
CONCLUSIONS: This is the first report of single agent irinotecan activity in an untreated population of patients with Ewing sarcoma. In common with other paediatric tumours and other camptothecin analogues such as topotecan, single agent activity is only modest. The exact role for the use of irinotecan in patients with ES, dose schedule and combinations with other agents still requires further investigation.

Related: Bone Cancers Irinotecan

Bazzocchi A, Bacci A, Serchi E, et al.
Intradural extramedullary Ewing's sarcoma. Recurrence with acute clinical presentation and literature review.
Neuroradiol J. 2013; 26(4):476-81 [PubMed] Related Publications
The intradural extramedullary space is an extremely unusual site for the onset of Ewing's sarcoma. We describe a case of recurrence of intradural extramedullary Ewing's sarcoma and review the literature available on this topic.

Sharib J, Horvai A, Gray Hazard FK, et al.
Comparison of Latino and non-Latino patients with Ewing sarcoma.
Pediatr Blood Cancer. 2014; 61(2):233-7 [PubMed] Related Publications
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.

Related: Bone Cancers

Redini F, Odri GA, Picarda G, et al.
Drugs targeting the bone microenvironment: new therapeutic tools in Ewing's sarcoma?
Expert Opin Emerg Drugs. 2013; 18(3):339-52 [PubMed] Related Publications
INTRODUCTION: Ewing's sarcoma (ES) is the second most frequent malignant primary bone tumour in children, adolescents and young adults. The overall survival is 60 - 70% at 5 years but still very poor for patients with metastases, disease relapse or for those not responding to chemotherapy. For these high risk patients, new therapeutic approaches are needed beyond conventional therapies (chemotherapy, surgery and radiation) such as targeted therapies.
AREAS COVERED: Transcriptomic and genomic analyses in ES have revealed alterations in genes that control signalling pathways involved in many other cancer types. To set up more specific approaches, it is reasonable to think that the particular microenvironment of these bone tumours is essential for their initiation and progression, including in ES. To support this hypothesis, preclinical studies using drugs targeting bone cells (bisphosphonate zoledronate, anti-receptor activator of NF-κB ligand strategies) showed promising results in animal models. This review will discuss the new targeted therapeutic options in ES, focusing more particularly on the ones modulating the bone microenvironment.
EXPERT OPINION: Targeting the microenvironment represents a new option for patients with ES. The proof-of-concept has been demonstrated in preclinical studies using relevant animal models, especially for zoledronate, which induced a strong inhibition of tumour progression in an orthotopic bone model.

Related: Bone Cancers

Dazzi F
Cancer makes new friends with old tricks.
Blood. 2013; 122(7):1093-4 [PubMed] Related Publications
In this issue of Blood, Zhang and colleagues report the identification of a novel subset of circulating myeloid cells with immunosuppressive activity in pediatric patients with metastatic sarcomas.

Related: Rhabdomyosarcoma

Stoll G, Surdez D, Tirode F, et al.
Systems biology of Ewing sarcoma: a network model of EWS-FLI1 effect on proliferation and apoptosis.
Nucleic Acids Res. 2013; 41(19):8853-71 [PubMed] Article available free on PMC after 01/05/2014 Related Publications
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.

Related: Apoptosis Bone Cancers FLI1 gene Signal Transduction

Subbiah V, Brown RE, Jiang Y, et al.
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).
PLoS One. 2013; 8(7):e68985 [PubMed] Article available free on PMC after 01/05/2014 Related Publications
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.

Related: Desmoplastic Small Round Cell Tumor FLI1 gene Signal Transduction WT1 Wilms' Tumour Wilms Tumour

Trizzino A, Ziino O, Parafioriti A, et al.
Dramatic response to Cisplatin window therapy in a boy with advanced metastatic ewing sarcoma.
J Pediatr Hematol Oncol. 2013; 35(6):478-81 [PubMed] Article available free on PMC after 01/05/2014 Related Publications
Ewing sarcoma (ES) is the second most common type of primary bone malignancy, and retains a high propensity to metastasize; the prognosis of patients with disseminated disease is very poor, with an event-free survival rate of <20%. Current multimodality treatment for ES consists of combined chemotherapy before and concurrent with surgery and local radiotherapy for the involved bone. Cisplatin is one of the most widely used drugs for the treatment of bone tumors in children, but is not currently used in ES. We describe a child with multifocal ES, treated with a phase II trial including a single-drug window therapy, which displayed a dramatic response to 2 courses of cisplatin and had a favorable outcome.

Related: Bone Cancers Cisplatin

Berger M, Fagioli F, Abate M, et al.
Unusual sites of Ewing sarcoma (ES): a retrospective multicenter 30-year experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP) and Italian Sarcoma Group (ISG).
Eur J Cancer. 2013; 49(17):3658-65 [PubMed] Related Publications
PURPOSE: The aim of this study was to describe the Italian Association of Pediatric Hematology and Oncology (AIEOP) and Italian Sarcoma Group (ISG) experience from 1980 to 2009 on 112 patients with Ewing sarcoma (ES) occurring in unusual sites such as the craniofacial bones (CF), hands or feet (HF), or the mobile spine. These sites were grouped because their rarity as ES localisations.
PATIENT AND METHODS: Twenty-six patients had CF ES (23%), 37 patients had HF ES (33%) and 49 patients had mobile spine ES (44%). A total of 26 patients presented with synchronous metastatic disease (23%). The local treatment with surgery and/or radiotherapy differed among ES sites. Systemic therapy was administrated according to the protocols in use over the years.
RESULTS: From the data available, the histological/radiological response was higher for HF-patients even not statistical significant (good responders: CF 41%, HF 65% and mobile spine 39%, P = 0.NS) and the probability of achieving complete response was similar among the three sites (CF 87%, HF 83% and spine 74%, P = 0.44). Ten year overall survival (OS) was 61% (95% confidence interval [CI] 39-82), 63% (95% CI 37-89) and 64% (95% CI 49-79) for CF, HF or vertebral ES, respectively (P = NS). Ten year OS for non-metastatic patients was 60% (95% CI 36-83), 75% (95% CI 56-94) and 67% (95% CI 47-89) for CF, HF and mobile spine patients respectively (P = NS). Ten year OS was 45% (95% CI, 31-84) and 70% (95% CI, 61-85, [p = 0.01]) for metastatic and localised ES, respectively.
CONCLUSIONS: The probability of successful treatment did not differ from ES of the extremities. Furthermore, our series confirm the poor prognosis for patients with metastatic disease. Our data do not strengthen the need for a specific protocol for unusual site ES.

Related: Bone Cancers

Yang Y, Li H, Zhang F, et al.
Clinical and biological significance of hepatoma-derived growth factor in Ewing's sarcoma.
J Pathol. 2013; 231(3):323-34 [PubMed] Related Publications
We sought to investigate the clinicopathological significance and biological function of hepatoma-derived growth factor (HDGF) in Ewing's sarcoma. Our results showed that HDGF expression is up-regulated in Ewing's sarcoma. Nuclear HDGF expression is significantly associated with tumour volume (p < 0.001), metastases at diagnosis (p < 0.001), low overall survival rate (p < 0.001) and low disease-free survival rate (p < 0.001). HDGF knock-down results in significant reduction of Ewing's sarcoma cell growth, proliferation and enhances tumourigenesis, both in vitro and in vivo. Meanwhile, HDGF knock-down causes cell cycle arrest and enhanced sensitization to serum starvation-induced apoptosis. Furthermore, recombinant HDGF promotes proliferation and colony formation of Ewing's sarcoma cells. Ninety-eight candidate HDGF downstream genes were identified in Ewing's sarcoma cells using cDNA microarray analysis. In addition, we found that HDGF knock-down inhibited FLI1 expression in Ewing's sarcoma cells at the mRNA and protein levels. Our findings suggest that HDGF exhibits oncogenic properties and may be a novel prognostic factor in Ewing's sarcoma. Targeting HDGF might be a potential therapeutic strategy for Ewing's sarcoma.

Related: Apoptosis Bone Cancers

Yew A, Kimball J, Pezeshkian P, Lu DC
Minimally invasive palliative resection of lumbar epidural metastasis.
Neurosurg Focus. 2013; 35(2 Suppl):Video 18 [PubMed] Related Publications
Spinal metastatic lesions are the most common tumors encountered by spinal surgeons. As with procedures for degenerative disease, minimally invsive surgery techniques have been applied to minimize muscle and soft tissue destruction in procedures for tumor resection. Here, we present a 23-year-old female with radiculopathy and foot drop secondary to nerve root compression by epidural metastases from Ewing's sarcoma. This patient had a history of previous resection and instrumentation as well as multiple rounds of chemotherapy and radiation that failed to control her disease. The patient presented with three weeks of radicular pain and foot drop that was continuing to worsen at the time of her operation. The decision was therefore made to perform a palliative resection and decompression for relief of her progressive symptoms. In this video, we demonstrate a palliative tumor debulking and nerve root decompression utilizing an MIS approach. The video can be found here: http://youtu.be/tq4kbvKTebI.

Blas JV, Smith ML, Wasif N, et al.
Ewing sarcoma of the adrenal gland: a rare entity.
BMJ Case Rep. 2013; 2013 [PubMed] Related Publications
A 63-year-old man was referred to our office with an enlarging left adrenal mass found on work-up for prostate cancer. Imaging performed over the course of 6 months demonstrated an increasing left adrenal mass from 2.8 to 3.6 cm. Functional testing of the adrenal lesion was performed. The adrenal mass was non-functional. Owing to the enlarging size, the patient underwent a laparoscopic left adrenalectomy without complication and was discharged home the following day. Gross pathological evaluation demonstrated a 3.2 cm, well-encapsulated, partially cystic mass. Histological evaluation demonstrated a small round blue cell tumour suspicious of sarcoma. Immunohistochemical testing revealed strong CD99 positivity consistent with Ewing family of tumours. Reverse transcriptase PCR demonstrated the presence of the Ewing sarcoma fusion transcript. The patient is currently enrolled in an ongoing research chemotherapy protocol at our institution using vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide.

Mackintosh C, Madoz-Gúrpide J
Mining sarcomas by proteomics approaches: Ewing sarcoma on the spotlight.
Recent Pat Biotechnol. 2013; 7(2):98-111 [PubMed] Related Publications
Sarcomas are a class of tumors defined by their mesenchymal origin that comprise very different neoplasms. Although some sarcomas harbor pathogenomic molecular alterations (i.e. specific balanced translocations and their associated chimeric fusion genes), others still lack an ultimate diagnostic tool, which could be of great interest as in some cases different sarcomas share a similar clinical manifestation. High throughput tools are contributing new ways to molecularly delineate the boundaries of each sarcoma subtype. Moreover, they are also shedding light into other research subjects of immediate concern: (i) the elucidation of the molecular targets of chimeric fusion proteins and their interactome; (ii) the discovery of new biomarkers and therapeutic targets; and (iii) the delineation of the response to therapeutic agents. Here we review the application of proteomics approaches to sarcomas, with special emphasis in Ewing sarcoma. Proteomics strategies offer the focus, the analytical potential, and the high throughput capabilities to decipher the hidden agenda of the biology of sarcomas, a knowledge that will surely be the subject of future patents intended to develop new diagnostic and therapeutic tools.

Related: Bone Cancers

De Visschere P, De Potter A, Claus F, et al.
PNET/Ewing's sarcoma of the kidney: imaging findings in two cases.
JBR-BTR. 2013 Mar-Apr; 96(2):75-7 [PubMed] Related Publications
The CT-imaging findings of primary renal PNET/Ewing's sarcoma in two patients were retrospectively assessed. A large renal mass with heterogenous contrast enhancement and necrotic and hemorrhagic areas were the predominant characteristics. In adolescents or young adults presenting with a large renal mass, PNET/Ewing's sarcoma may be included in the differential diagnosis.

Related: Kidney Cancer

Liebsch L, Kailayangiri S, Beck L, et al.
Ewing sarcoma dissemination and response to T-cell therapy in mice assessed by whole-body magnetic resonance imaging.
Br J Cancer. 2013; 109(3):658-66 [PubMed] Article available free on PMC after 06/08/2014 Related Publications
BACKGROUND: Novel treatment strategies in Ewing sarcoma include targeted cellular therapies. Preclinical in vivo models are needed that reflect their activity against systemic (micro)metastatic disease.
METHODS: Whole-body magnetic resonance imaging (WB-MRI) was used to monitor the engraftment and dissemination of human Ewing sarcoma xenografts in mice. In this model, we evaluated the therapeutic efficacy of T cells redirected against the Ewing sarcoma-associated antigen GD2 by chimeric receptor engineering.
RESULTS: Of 18 mice receiving intravenous injections of VH-64 Ewing sarcoma cells, all developed disseminated tumour growth detectable by WB-MRI. All mice had lung tumours, and the majority had additional manifestations in the bone, soft tissues, and/or kidney. Sequential scans revealed in vivo growth of tumours. Diffusion-weighted whole-body imaging with background signal suppression effectively visualised Ewing sarcoma growth in extrapulmonary sites. Animals receiving GD2-targeted T-cell therapy had lower numbers of pulmonary tumours than controls, and the median volume of soft tissue tumours at first detection was lower, with a tumour growth delay over time.
CONCLUSION: Magnetic resonance imaging reliably visualises disseminated Ewing sarcoma growth in mice. GD2-retargeted T cells can noticeably delay tumour growth and reduce pulmonary Ewing sarcoma manifestations in this aggressive disease model.

Related: Bone Cancers

Miller BJ, Lynch CF, Buckwalter JA
Conditional survival is greater than overall survival at diagnosis in patients with osteosarcoma and Ewing's sarcoma.
Clin Orthop Relat Res. 2013; 471(11):3398-404 [PubMed] Article available free on PMC after 01/11/2014 Related Publications
BACKGROUND: Conditional survival is a measure of the risk of mortality given that a patient has survived a defined period of time. These estimates are clinically helpful, but have not been reported previously for osteosarcoma or Ewing's sarcoma.
QUESTIONS/PURPOSES: We determined the conditional survival of patients with osteosarcoma and Ewing's sarcoma given survival of 1 or more years.
METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) Program database to investigate cases of osteosarcoma and Ewing's sarcoma in patients younger than 40 years from 1973 to 2009. The SEER Program is managed by the National Cancer Institute and provides survival data gathered from population-based cancer registries. We used an actuarial life table analysis to determine any cancer cause-specific 5-year survival estimates conditional on 1 to 5 years of survival after diagnosis. We performed a similar analysis to determine 20-year survival from the time of diagnosis.
RESULTS: The estimated 5-year survival improved each year after diagnosis. For local/regional osteosarcoma, the 5-year survival improved from 74.8% at baseline to 91.4% at 5 years-meaning that if a patient with localized osteosarcoma lives for 5 years, the chance of living for another 5 years is 91.4%. Similarly, the 5-year survivals for local/regional Ewing's sarcoma improved from 72.9% at baseline to 92.5% at 5 years, for metastatic osteosarcoma 35.5% at baseline to 85.4% at 5 years, and for metastatic Ewing's sarcoma 31.7% at baseline to 83.6% at 5 years. The likelihood of 20-year cause-specific survival from the time of diagnosis in osteosarcoma and Ewing's sarcoma was almost 90% or greater after 10 years of survival, suggesting that while most patients will remain disease-free indefinitely, some experience cancer-related complications years after presumed eradication.
CONCLUSIONS: The 5-year survival estimates of osteosarcoma and Ewing's sarcoma improve with each additional year of patient survival. Knowledge of a changing risk profile is useful in counseling patients with time. The presence of cause-specific mortality decades after treatment supports lifelong monitoring in this population.
LEVEL OF EVIDENCE: Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.

Related: Bone Cancers USA

Risi E, Iacovelli R, Altavilla A, et al.
Clinical and pathological features of primary neuroectodermal tumor/Ewing sarcoma of the kidney.
Urology. 2013; 82(2):382-6 [PubMed] Related Publications
OBJECTIVE: To collect and analyze clinical and pathological features of primitive neuroectodermal tumor (PNET)/Ewing sarcoma (EWS), a rare tumor occurring most commonly in bone and soft tissues of young people, which rarely occurs as a primary renal neoplasm and exhibits highly aggressive biological behavior.
METHODS: All cases of PNET/EWS published from 1975 to February 2012 were collected. When available, clinical and pathological data were extracted for each case. Survivals were estimated with the Kaplan-Meier method and compared with the log-rank test with 95% confidence interval (CI).
RESULTS: A total of 116 cases were found. All patients had clinical symptoms as first presentation of disease such as pain (54%), hematuria (29%), and bulky renal mass (28%). Sixty-six percent of patients had stage IV disease at diagnosis. Median disease-free survival (DFS) was 5.0 months (95% CI 2.4-7.6). The probability to be alive at 18 months was 60% and 85% for patients with metastatic disease (M1) or not (M0) at diagnosis, respectively. Median overall survival (OS) was 24 months (95% CI 4.5-15.1) in patients with M1 disease, whereas it was not reached in patients with M0 disease (P <.001). In patients with M0 disease, 50% received neoadjuvant chemotherapy and the 12-month OS was 93% compared to 75% of untreated patients (P = .092). In patients with M1 disease who underwent treatment, the median progression-free survival (PFS) was 22.0 months (95% CI 17.9-26.1) with a clinical benefit in 74% of cases.
CONCLUSION: Our findings suggest that PNET/EWS is a rare aggressive tumor affecting principally young people, with a poor prognosis for patients with M1 disease; chemotherapy is an effective strategy in M1 disease and probably also in M0 disease.

Related: Kidney Cancer MUC1 gene FLI1 gene

Roundhill E, Burchill S
Membrane expression of MRP-1, but not MRP-1 splicing or Pgp expression, predicts survival in patients with ESFT.
Br J Cancer. 2013; 109(1):195-206 [PubMed] Article available free on PMC after 09/07/2014 Related Publications
BACKGROUND: Primary Ewing's sarcoma family of tumours (ESFTs) may respond to chemotherapy, although many patients experience subsequent disease recurrence and relapse. The survival of ESFT cells following chemotherapy has been attributed to the development of resistant disease, possibly through the expression of ABC transporter proteins.
METHODS: MRP-1 and Pgp mRNA and protein expression in primary ESFTs was determined by quantitative reverse-transcriptase PCR (RT-qPCR) and immunohistochemistry, respectively, and alternative splicing of MRP-1 by RT-PCR.
RESULTS: We observed MRP-1 protein expression in 92% (43 out of 47) of primary ESFTs, and cell membrane MRP-1 was highly predictive of both overall survival (P<0.0001) and event-free survival (P<0.0001). Alternative splicing of MRP-1 was detected in primary ESFTs, although the pattern of splicing variants was not predictive of patient outcome, with the exception of loss of exon 9 in six patients, which predicted relapse (P=0.041). Pgp protein was detected in 6% (38 out of 44) of primary ESFTs and was not associated with patient survival.
CONCLUSION: For the first time we have established that cell membrane expression of MRP-1 or loss of exon 9 is predictive of outcome but not the number of splicing events or expression of Pgp, and both may be valuable factors for the stratification of patients for more intensive therapy.

Raciborska A, Bilska K, Drabko K, et al.
Vincristine, irinotecan, and temozolomide in patients with relapsed and refractory Ewing sarcoma.
Pediatr Blood Cancer. 2013; 60(10):1621-5 [PubMed] Related Publications
BACKGROUND: Patients with metastatic, progressive or recurrent Ewing sarcoma (ES) have a dismal outcome. The combination of irinotecan and temozolomide has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination with vincristine for patients with relapsed and refractory ES.
MATERIALS AND METHODS: Twenty-two patients with relapsed or refractory ES were treated with the combination of vincristine (1.5 mg/m(2) i.v. day 1), irinotecan (50 mg/m(2) /day i.v. days 1-5) and temozolomide (125 mg/m(2) /day p.o. days 1-5) (VIT) during the period 2008-2012. All toxicities were documented.
RESULTS: A total of 91 cycles (median 4.1 cycles/patient) were administered. A complete response (CR) was achieved in five patients, partial response (PR) in seven patients, stable disease (SD) in three patients, and progression disease (PD) in seven patients, with an overall response rate of 68.1%. Median time to progression was 3.0 months (range 1.1-37.1 months). Five patients (22.7%) are alive with no evidence of disease with a median follow-up of 10.3 months (range 2.1-46.5); four of them received consolidation with high-dose chemotherapy and autologous hematopoietic stem cell transplant after responding to VIT. Outcome was better for patients with relapsed ES compared with patients who progressed to initial therapy (estimated 2 year overall survival 36.4% vs. 0%, respectively). There were no significant toxicities.
CONCLUSIONS: The shorter, 5-day VIT regimen is an active and well-tolerated regimen in refractory ES. This combination deserves further investigation in the upfront management of patients with metastatic disease.

Related: Dacarbazine Vincristine Irinotecan Temozolomide

Yang JC, Wexler LH, Meyers PA, et al.
Intensity-modulated radiation therapy with dose-painting for pediatric sarcomas with pulmonary metastases.
Pediatr Blood Cancer. 2013; 60(10):1616-20 [PubMed] Related Publications
BACKGROUND: We examined patterns of failure in pediatric patients with thoracic sarcoma and pulmonary metastases treated with intensity-modulated radiation therapy with dose-painting (DP-IMRT).
PROCEDURE: Eleven pediatric patients, five with Ewing sarcoma family tumors (ESFT) and six with rhabdomyosarcoma (RMS), with primary thoracic tumors and pulmonary metastases underwent DP-IMRT with chemotherapy for definitive treatment. Eight patients also underwent surgery. Median time to RT was 21 (15-31) weeks. Nine patients received 45-50.4-Gy in 1.8 Gy fractions to the primary tumor (n = 3) or post-operative tumor bed (n = 6). Two patients ≤4 years received 12 Gy intraoperative radiation therapy and 30.6-36 Gy IMRT postoperatively to the tumor bed. All patients received 14-16.8 Gy in 0.54-0.88 Gy fractions to the whole lungs (n = 6) or hemithorax (n = 5) using dose-painting technique. A representative case was re-planned with IMRT plus standard AP/PA whole lung irradiation (WLI) for dosimetric comparison.
RESULTS: With 27-month median follow-up, 3-year pulmonary relapse-free survival in all patients was 61%: 80% for RMS and 40% for ESFT. Five patients (4 ESFT and 1 RMS) experienced pulmonary relapse at median 16 (9-41) months. There were no local failures. Our representative case demonstrated more homogeneous target volume coverage of the whole lungs and decreased mean dose to esophagus (15%), heart (31%), spinal cord (15%), and liver (19%) with DP-IMRT.
CONCLUSIONS: The treatment of children with a primary thoracic tumor and pulmonary metastases poses a significant challenge. DP-IMRT is one solution to this technical problem. Initial data from this small series suggest DP-IMRT is feasible and produces superior sparing of critical normal tissues.

Related: Rhabdomyosarcoma

Owens C, Abbott LS, Gupta AA
Optimal management of Ewing sarcoma family of tumors: recent developments in systemic therapy.
Paediatr Drugs. 2013; 15(6):473-92 [PubMed] Related Publications
The Ewing sarcoma family of tumors (ESFT) is defined by cell surface expression of CD99 and a translocation involving EWS and an ETS partner. Cytotoxic chemotherapy remains the benchmark of first- and second-line therapy, and although the majority of patients with localized disease are cured, almost one third of patients relapse or progress from their disease. Moreover, cure remains elusive in most patients who present with distant metastases. In recent years, the ESFT literature has been dominated by reports of attempts at modulating the insulin-like growth factor (IGF) receptor (IGFR). Unfortunately, three phase II studies examining inhibiting antibodies to IGFR-1 published disappointing results. Whether these results were due to failure to modulate the pathway or other limitations in study design and/or patient selection remain unclear. Other novel strategies currently being investigated in ESFT include tyrosine kinase, mammalian target of rapamycin (mTOR), and poly(ADP-ribose) polymerase (PARP) inhibitors.

Related: Bone Cancers

Zhang H, Maric I, DiPrima MJ, et al.
Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer.
Blood. 2013; 122(7):1105-13 [PubMed] Article available free on PMC after 15/08/2014 Related Publications
Fibrocytes are hematopoietic stem cell-derived fibroblast precursors that are implicated in chronic inflammation, fibrosis, and wound healing. Myeloid-derived suppressor cells (MDSCs) expand in cancer-bearing hosts and contribute to tumor immune evasion. They are typically described as CD11b⁺HLA-DR⁻ in humans. We report abnormal expansions of CD11b⁺HLA-DR⁺ myeloid cells in peripheral blood mononuclear fractions of subjects with metastatic pediatric sarcomas. Like classical fibrocytes, they display cell surface α smooth muscle actin, collagen I/V, and mediate angiogenesis. However, classical fibrocytes serve as antigen presenters and augment immune reactivity, whereas fibrocytes from cancer subjects suppressed anti-CD3-mediated T-cell proliferation, primarily via indoleamine oxidase (IDO). The degree of fibrocyte expansion observed in individual subjects directly correlated with the frequency of circulating GATA3⁺CD4⁺ cells (R = 0.80) and monocytes from healthy donors cultured with IL-4 differentiated into fibrocytes with the same phenotypic profile and immunosuppressive properties as those observed in patients with cancer. We thus describe a novel subset of cancer-induced myeloid-derived suppressor cells, which bear the phenotypic and functional hallmarks of fibrocytes but mediate immune suppression. These cells are likely expanded in response to Th2 immune deviation and may contribute to tumor progression via both immune evasion and angiogenesis.

Related: GATA3 gene IL4 Rhabdomyosarcoma

Cote GM, Choy E
Role of epigenetic modulation for the treatment of sarcoma.
Curr Treat Options Oncol. 2013; 14(3):454-64 [PubMed] Related Publications
OPINION STATEMENT: Sarcoma is a disease that includes many different subtypes that can present with a wide range of differing clinical findings, prognosis, and treatment options. For certain subsets (e.g., Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, gastrointestinal stromal tumor [GIST]), extensive clinical trials have delineated effective treatment regimens often involving combination therapy, including surgery, radiation, systemic chemotherapy, and small molecular inhibitors of tyrosine kinases (as in the case of GIST). For nearly all patients with sarcoma who have relapsed or developed metastasis, the therapeutic benefit of chemotherapy has reached a plateau and as such new treatment approaches are needed to move this field forward. We recommend that all patients have the opportunity to participate in clinical trials where available. Recently, in our clinic we have started to increase our use of molecular testing and DNA sequencing studies to help identify potential treatment options for patients. One area of evolving basic and clinical research in sarcomas is the field of epigenetic therapeutics. The enclosed article reviews the basics of epigenetics and highlights some completed and ongoing clinical trials of epigenetic treatments in sarcoma. We anticipate in the future that diagnostic platforms will be developed to help clinicians determine if an epigenetic therapy could be effective for an individual patient with sarcoma.

Related: Soft Tissue Sarcomas

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