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).

Hiramoto N, Kobayashi Y, Nomoto J, et al.
Ewing sarcoma arising after treatment of diffuse large B-cell lymphoma.
Jpn J Clin Oncol. 2013; 43(4):417-21 [PubMed]
We report the case of a patient in whom the diagnosis of Ewing sarcoma arising from a soft tissue was made after successful treatment of diffuse large B-cell lymphoma. A 65-year-old woman presented with a rapidly growing mass in her left scapular region 8 years after successful chemotherapy with the cyclophosphamide, hydroxydaunomycin hydrochloride, vincristine, prednisolone regimen for diffuse large B-cell lymphoma. Computed tomographic examination and magnetic resonance imaging of the thorax revealed an intramuscular tumour measuring 40 mm in size in the left scapular region. Histopathological examination of an open biopsy specimen revealed a small round cell tumour that showed positive staining for CD99. Fluorescence in situ hybridization showed a split signal by a break-apart probe for the EWS gene in chromosome 22q12. Reverse transcriptase-polymerase chain reaction confirmed the expression of EWS-FLI1 fusion transcripts. Based on these findings, the patient was diagnosed as having secondary Ewing sarcoma. Despite adjuvant chemotherapy, however, she died of pulmonary metastases 2 years after the diagnosis of Ewing sarcoma. Therapy-related haematological malignancies with balanced translocations have been reported previously. A mechanism similar to that underlying the development of secondary malignancy might explain the occurrence of this solid cancer.


Mounessi FS, Lehrich P, Haverkamp U, et al.
Pelvic Ewing sarcomas. Three-dimensional conformal vs. intensity-modulated radiotherapy.
Strahlenther Onkol. 2013; 189(4):308-14 [PubMed]
PURPOSE: The goal of the present work was to assess the potential advantage of intensity-modulated radiotherapy (IMRT) over three-dimensional conformal radiotherapy (3D-CRT) planning in pelvic Ewing's sarcoma.
PATIENTS AND METHODS: A total of 8 patients with Ewing sarcoma of the pelvis undergoing radiotherapy were analyzed. Plans for 3D-CRT and IMRT were calculated for each patient. Dose coverage of the planning target volume (PTV), conformity and homogeneity indices, as well as further parameters were evaluated.
RESULTS: The average dose coverage values for PTV were comparable in 3D-CRT and IMRT plans. Both techniques had a PTV coverage of V95 > 98 % in all patients. Whereas the IMRT plans achieved a higher conformity index compared to the 3D-CRT plans (conformity index 0.79 ± 0.12 vs. 0.54 ± 0.19, p = 0.012), the dose distribution across the target volumes was less homogeneous with IMRT planning than with 3D-CRT planning. This difference was statistically significant (homogeneity index 0.11 ± 0.03 vs. 0.07 ± 0.0, p = 0.035). For the bowel, Dmean and D1%, as well as V2 to V60 were reduced in IMRT plans. For the bladder and the rectum, there was no significant difference in Dmean. However, the percentages of volumes receiving at least doses of 30, 40, 45, and 50 Gy (V30 to V50) were lower for the rectum in IMRT plans. The volume of normal tissue receiving at least 2 Gy (V2) was significantly higher in IMRT plans compared with 3D-CRT, whereas at high dose levels (V30) it was significantly lower.
CONCLUSION: Compared to 3D-CRT, IMRT showed significantly better results regarding dose conformity (p = 0.012) and bowel sparing at dose levels above 30 Gy (p = 0.012). Thus, dose escalation in the radiotherapy of pelvic Ewing's sarcoma can be more easily achieved using IMRT.


Gorelik N, Dickson BC, Wunder JS, Bleakney R
Ewing's sarcoma of the patella.
Skeletal Radiol. 2013; 42(5):729-33 [PubMed]
Ewing's sarcoma is a relatively rare malignancy, occurring mainly between 4 and 25 years of age. It usually arises from the pelvis, followed by the femur, tibia, and remainder of both the long bones of the extremities and flat bones of the axial skeleton. To the best of our knowledge, Ewing's sarcoma of the patella has never been reported previously. Patellar tumors occur infrequently and represent an uncommon etiology of anterior knee pain. We describe the rare case of a 41-year-old man who presented with a 3-4 month history of escalating right anterior knee pain and swelling. Imaging demonstrated an aggressive patellar tumor with an adjacent soft tissue mass. The diagnosis of Ewing's sarcoma was confirmed by pathology. Physicians should be aware of atypical locations for Ewing's sarcoma and, conversely, of rare tumors arising in the patella and accounting for anterior knee pain. Early recognition of such malignancies allows prompt initiation of treatment, hence improving prognosis.


Rowe RG, Thomas DG, Schuetze SM, et al.
Ewing sarcoma of the kidney: case series and literature review of an often overlooked entity in the diagnosis of primary renal tumors.
Urology. 2013; 81(2):347-53 [PubMed]
OBJECTIVE: To evaluate our own experience with primary Ewing sarcoma family tumors (ESFTs) of the kidney and to review cases of this in published reports.
MATERIALS AND METHODS: Institutional cases of renal ESFT were identified in our pathology database. The retrieved records were reviewed for relevant data. Published cases of renal ESFTs were identified from the National Library of Medicine Medline database and restricted to English language studies. The factors associated with initial surgical management (diagnostic biopsy vs surgical resection) were analyzed using chi-square analysis.
RESULTS: We diagnosed and treated 10 cases of renal ESFT from 2002 to 2011 and identified an additional 97 published cases describing this tumor. A review of these 107 cases revealed that renal ESFTs more often presented with distant metastases than did ESFTs of the bone or soft tissue. Moreover, patients rarely received preoperative (neoadjuvant) chemotherapy, the current standard of care for ESFT, often because of early total tumor resection without diagnostic biopsy. Younger patients and patients with distant metastases were more likely to undergo diagnostic biopsy as initial management (P <.0001), allowing for use of neoadjuvant chemotherapy.
CONCLUSION: ESFTs of the kidney should be considered in the differential diagnosis of renal masses. Preoperative biopsy should be considered to identify these tumors to allow for delivery of neoadjuvant chemotherapy.


Jiang L, Tao C, He A
Prognostic significance of p53 expression in malignant bone tumors: a meta-analysis.
Tumour Biol. 2013; 34(2):1037-43 [PubMed]
Osteosarcoma and Ewing's sarcoma are the two most common primary malignant bone tumors, and findings of prognostic factors are important for clinicians to decide treatment options. High p53 expression has been implicated in tumor development and progression, but studies investigating the prognostic role of p53 overexpression in malignant bone tumors report conflicting findings. We performed a meta-analysis to assess the relationship between p53 overexpression and the survival of malignant bone tumors. A meta-analysis of 13 studies with a total of 703 patients was carried out to evaluate the association between p53 overexpression and overall survival (OS) and disease-free survival (DFS) in patients with malignant bone tumors. The pooled hazard ratio (HR) with its 95 % confidence interval (CI) was used as the effect size estimate. There was no between-study heterogeneity in both OS studies (I (2) = 0.0 %) and DFS studies (I(2) = 0.0 %). Overall, high p53 expression predicted both poor OS (HR 2.13, 95 % CI 1.81-2.52, P < 0.001) and poor DFS (HR 2.06, 95 % CI 1.58-2.69, P < 0.001) in patients with malignant bone tumors. Subgroup analyses by tumor types suggested that p53 expression predicted poor OS in both osteosarcoma patients (HR 2.15, 95 % CI 1.78-2.60, I (2) = 15.2 %, P < 0.001) and Ewing's sarcoma patients (HR 2.09, 95 % CI 1.47-2.97, I(2) = 0.0 %, P < 0.001). Besides, p53 expression also predicted poor DFS in both osteosarcoma patients (HR 2.38, 95 % CI 1.60-3.52, I(2) = 0.0 %, P < 0.001) and Ewing's sarcoma patients (HR 1.83, 95 % CI 1.28-2.63, I(2) = 0.0 %, P = 0.001). Egger's test also did not suggest evidence for publication bias in both OS studies (P = 0.615) and DFS studies (P = 0.258). High p53 expression indicates a poorer prognosis for patients with osteosarcoma and Ewing's sarcoma.


Machado I, Traves V, Cruz J, et al.
Superficial small round-cell tumors with special reference to the Ewing's sarcoma family of tumors and the spectrum of differential diagnosis.
Semin Diagn Pathol. 2013; 30(1):85-94 [PubMed]
Superficial/cutaneous small round-cell tumors comprise a heterogeneous group of neoplasms including sarcoma, carcinoma, melanoma, and lymphomas. Among superficial sarcomas, the Ewing's sarcoma family of tumors (ESFT) represents a poorly understood rare variant, having a behavioral difference characterized by a relative favorable prognosis. Several problems are still to be resolved in superficial ESFT, including the differential diagnosis between ESFT of bone (intraosseous or periosteal) with superficial infiltration and superficial ESFT with bone infiltration, especially in the fingers. Our aim is to review the most common types of small round-cell tumors included in the differential diagnosis of superficial ESFT, analyzing the histopathology, phenotype, and molecular alterations of each entity.


Hauer K, Calzada-Wack J, Steiger K, et al.
DKK2 mediates osteolysis, invasiveness, and metastatic spread in Ewing sarcoma.
Cancer Res. 2013; 73(2):967-77 [PubMed]
Ewing sarcoma, an osteolytic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. In this study, we identified the pro-metastatic gene DKK2 as a highly overexpressed gene in Ewing sarcoma compared with corresponding normal tissues. Using RNA interference, we showed that DKK2 was critical for malignant cell outgrowth in vitro and in an orthotopic xenograft mouse model in vivo. Analysis of invasion potential in both settings revealed a strong correlation of DKK2 expression to Ewing sarcoma invasiveness that may be mediated by the DKK effector matrix metalloproteinase 1 (MMP1). Furthermore, gene expression analyses established the ability of DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2, and TGFβ1 that are associated with homing, invasion, and growth of cancer cells in bone tissue as well as genes important for osteolysis, including HIF1α, JAG1, IL6, and VEGF. DKK2 promoted bone infiltration and osteolysis in vivo and further analyses defined DKK2 as a key factor in osteotropic malignancy. Interestingly, in Ewing sarcoma cells, DKK2 suppression simultaneously increased the potential for neuronal differentiation while decreasing chondrogenic and osteogenic differentiation. Our results provide strong evidence that DKK2 is a key player in Ewing sarcoma invasion and osteolysis and also in the differential phenotype of Ewing sarcoma cells.


Zheng H, Shen H, Oprea I, et al.
β-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing's sarcoma.
Proc Natl Acad Sci U S A. 2012; 109(50):20620-5 [PubMed] Free Access to Full Article
Owing to its essential role in cancer, insulin-like growth factor type 1 receptor (IGF-1R)-targeted therapy is an exciting approach for cancer treatment. However, when translated into clinical trials, IGF-1R-specific antibodies did not fulfill expectations. Despite promising clinical responses in Ewing's sarcoma (ES) phase I/II trials, phase III trials were discouraging, requiring bedside-to-bench translation and functional reevaluation of the drugs. The anti-IGF-1R antibody figitumumab (CP-751,871; CP) was designed as an antagonist to prevent ligand-receptor interaction but, as with all anti-IGF-1R antibodies, it induces agonist-like receptor down-regulation. We explored this paradox in a panel of ES cell lines and found their sensitivity to CP was unaffected by presence of IGF-1, countering a ligand blocking mechanism. CP induced IGF-1R/β-arrestin1 association with dual functional outcome: receptor ubiquitination and degradation and decrease in cell viability and β-arrestin1-dependent ERK signaling activation. Controlled β-arrestin1 suppression initially enhanced CP resistance. This effect was mitigated on further β-arrestin1 decrease, due to loss of CP-induced ERK activation. Confirming this, the ERK1/2 inhibitor U0126 increased sensitivity to CP. Combined, these results reveal the mechanism of CP-induced receptor down-regulation and characteristics that functionally qualify a prototypical antagonist as an IGF-1R-biased agonist: β-arrestin1 recruitment to IGF-1R as the underlying mechanism for ERK signaling activation and receptor down-regulation. We further confirmed the consequences of β-arrestin1 regulation on cell sensitivity to CP and demonstrated a therapeutic strategy to enhance response. Defining and suppressing such biased signaling represents a practical therapeutic strategy to enhance response to anti-IGF-1R therapies.


Owens C, Laurence V, Benboubker L, et al.
Phase II study of cisplatin and oral VP16 in patients with refractory or relapsed Ewing sarcoma.
Cancer Chemother Pharmacol. 2013; 71(2):399-404 [PubMed]
BACKGROUND: Phase II trials demonstrate the activity of cisplatin in patients with refractory Ewing sarcoma family tumours (ESFT) and also the feasibility of giving cisplatin with oral VP16 in a variety of different cancers. This trial was conducted to evaluate the activity and toxicity profile of this combination delivered as outpatient therapy in patients with refractory/relapsed ESFT.
METHODS: Cisplatin was administered on days 1, 8 and 15 and days 29, 36 and 43 (70 mg/m(2)/dose for patients <21 years of age and 50 mg/m(2)/dose ≥21 years). VP16 was administered at a dose of 50 mg/m(2) on days 1-15 and days 29-43 inclusive. A three-stage Fleming statistical design was used for analysis.
RESULTS: Between January 2003 and October 2006, 45 patients aged between 5 and 46 years (median 19) were enrolled. Thirty-eight were evaluable for response. Patients had previously received one to three lines of chemotherapy (median = one). Seventy-three per cent of the patients had grade 3/4 neutropenia, 20 % developed fever, 40 % had grade 3/4 anaemia, 68 % grade 3/4 thrombocytopenia and 16 % grade 2/3 ototoxicity. Measured response after 2 cycles: 0 CR, 7 PR (18 %), 13 SD (34 %), 18 PD (48 %). There was excellent concordance between unidimensional and bidimensional criteria in 31 of 33 responses (94 %). PFS at 1 year was 39 %, with a median PFS of 6 months. Overall survival at 1 year was 44 %; median survival was 11 months.
CONCLUSIONS: Cisplatin combined with oral VP16 is well tolerated and has acceptable side effects, but limited clinical activity in refractory/relapsed ESFT.


Froeb D, Ranft A, Boelling T, et al.
Ewing sarcoma of the hand or foot.
Klin Padiatr. 2012; 224(6):348-52 [PubMed]
PURPOSE: Ewing Sarcoma (ES) of the hand or foot is a rare clinical condition. Due to the critical site, it is of major importance to choose an optimal procedure for local control in terms of outcome and function. Local therapeutic options for these patients range from: surgery (OP), surgery followed by radiotherapy (OP & RT), or radiotherapy (RT) alone.
PATIENTS AND METHODS: Data from 80 patients with ES of the hand or foot were analyzed. All patients received chemotherapy according to the protocols of the Cooperative Ewing Sarcoma Study Group (CESS) from 1991 to 2009 (EICESS-92 and EURO-E.W.I.N.G.99). Local therapy consisted of: OP in 39%, OP & RT in 44%, and RT in 12%. In 5% of the patients no local therapy (noL) was performed. Primary endpoint of our study was the event-free-survival (EFS).
RESULTS: The 3-year overall EFS was 62% (95%CI 0.50-0.72). Patients with localized disease had a significantly better outcome with an EFS of 77% (95%CI 0.63-0.86), compared to patients with primary disseminated disease with an EFS of 30% (95%CI 0.14-0.49; p<0.001). In comparing local treatment modalities, no significant difference was observed. The 3-year EFS for OP was 61% (95% CI 0.40-0.76), for OP & RT 66% (95%CI 0.47-0.79) and for RT only 70% (95%CI 0.32-0.89) (p=0.253). Patients who did not receive local treatment had an unfavourable prognosis (3-year EFS=0.25; 95%CI 0.01-0.67; p=0.024). A multivariate analysis which included local treatment modality and known prognosticators, showed that primary dissemination was the only significant prognostic factor.Ewing sarcoma of the hand or foot is associated with a favourable outcome.
CONCLUSION: Our data analysed a limited group of patients and thus did not provide a clear indication for a preferred local treatment modality.


Jarzyna PA, Deddens LH, Kann BH, et al.
Tumor angiogenesis phenotyping by nanoparticle-facilitated magnetic resonance and near-infrared fluorescence molecular imaging.
Neoplasia. 2012; 14(10):964-73 [PubMed] Free Access to Full Article
One of the challenges of tailored antiangiogenic therapy is the ability to adequately monitor the angiogenic activity of a malignancy in response to treatment. The α(v)β(3) integrin, highly overexpressed on newly formed tumor vessels, has been successfully used as a target for Arg-Gly-Asp (RGD)-functionalized nanoparticle contrast agents. In the present study, an RGD-functionalized nanocarrier was used to image ongoing angiogenesis in two different xenograft tumor models with varying intensities of angiogenesis (LS174T > EW7). To that end, iron oxide nanocrystals were included in the core of the nanoparticles to provide contrast for T(2)*-weighted magnetic resonance imaging (MRI), whereas the fluorophore Cy7 was attached to the surface to enable near-infrared fluorescence (NIRF) imaging. The mouse tumor models were used to test the potential of the nanoparticle probe in combination with dual modality imaging for in vivo detection of tumor angiogenesis. Pre-contrast and post-contrast images (4 hours) were acquired at a 9.4-T MRI system and revealed significant differences in the nanoparticle accumulation patterns between the two tumor models. In the case of the highly vascularized LS174T tumors, the accumulation was more confined to the periphery of the tumors, where angiogenesis is predominantly occurring. NIRF imaging revealed significant differences in accumulation kinetics between the models. In conclusion, this technology can serve as an in vivo biomarker for antiangiogenesis treatment and angiogenesis phenotyping.


Womer RB, West DC, Krailo MD, et al.
Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group.
J Clin Oncol. 2012; 30(33):4148-54 [PubMed] Article available free on PMC after 20/11/2013
PURPOSE: Chemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome.
PATIENTS AND METHODS: This was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750×10(6)/L and a platelet count greater than 75×10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734).
RESULTS: Five hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar.
CONCLUSION: For localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.


Hamdane MM, Charfi L, Driss M, et al.
Ewing-like adamantinoma.
Orthop Traumatol Surg Res. 2012; 98(7):845-9 [PubMed]
The Ewing-like variation of adamantinoma is a rare entity, leading to challenge its differential diagnosis, notably with Ewing's sarcoma. We are reporting a case of a 20-year-old male who presented with swelling in the left leg that had progressed over a 2-year period. X-rays revealed a tumour in the tibia that was intracortical, osteolytic, multilocular and invaded the soft tissues. A surgical biopsy was performed. Histopathology examination showed a tumour growth with small round cells expressing CD99. A diagnosis of Ewing's sarcoma was made. Since the patient declined surgical treatment, chemotherapy was administered. Two years later, the patient returned because the tumour had grown in size. A second biopsy was performed. Microscopic evaluation showed a tumour growth with osteofibrous and epithelial components, which expressed pankeratin and vimentin, but was negative for CD99. A diagnosis of Ewing-like adamantinoma was made.


Parida L, Fernandez-Pineda I, Uffman J, et al.
Clinical management of Ewing sarcoma of the bones of the hands and feet: a retrospective single-institution review.
J Pediatr Surg. 2012; 47(10):1806-10 [PubMed]
BACKGROUND/PURPOSE: Bones of the hands and feet are uncommon sites for Ewing sarcoma. In this study, we reviewed our experience in the management of these tumors.
METHODS: We retrospectively reviewed clinical presentation, management, and outcome of patients with Ewing sarcoma of the bones of hands and feet treated at our institution (1981-2006).
RESULTS: The cohort included 6 males and 3 females (8 white, 1 African American; median age at diagnosis, 15 years). Primary tumor site was the hand in 6 and the foot in 3 patients. Three patients had distant metastatic disease at diagnosis (lung [n = 2]; ipsilateral axillary lymph node[(n = 1]). All patients had painful swelling at the primary site, and 2 (22%) had pathological fracture. All patients received chemotherapy and local control measures (surgery [n = 6], radiation [n = 2], surgery and radiation [(n = 1]). Three patients received radiotherapy for distant metastases. Three patients had systemic recurrence (lungs [n = 2], lung and brain [n = 1]); none had local tumor recurrence. Median follow-up was 5 years. Five patients (55.6%) are alive at last follow-up.
CONCLUSIONS: Chemotherapy and surgical excision of primary tumor are the mainstays of treatment. Radiotherapy is recommended for local control of lesions in the hand for patients declining excisional therapy.


Ernst E, Kjærsgaard M, Birkebæk NH, et al.
Case report: stimulation of puberty in a girl with chemo- and radiation therapy induced ovarian failure by transplantation of a small part of her frozen/thawed ovarian tissue.
Eur J Cancer. 2013; 49(4):911-4 [PubMed]
AIM OF THE STUDY: To induce puberty by transplantation of frozen/thawed ovarian tissue collected prior to gonadotoxic treatment for a cancer.
PATIENTS AND METHODS: A 9-year-old girl with Ewing sarcoma had one ovary excised and cryopreserved prior to chemo- and radiotherapy. Functional activity of the remaining ovary was destroyed during treatment. Four and a half years later the girl remained pre-pubertal with postmenopausal levels of FSH. Two of ten pieces of frozen/thawed cortex were transplanted to the remaining ovary in order to stimulate puberty.
RESULTS: Four months after the transplantation FSH returned to low levels. During the following year puberty gradually progressed to Tanner stage B4 and P3 and regular menstrual cycles started. However, after 19 months the function of the graft ceased.
CONCLUSIONS: We have shown for the first time in a girl treated for cancer that transplanted ovarian tissue can regain function and secrete estradiol in a sufficient amount to induce puberty. In addition, the majority of her ovarian tissue remains frozen with a possibility to support fertility in adult life.


Felgenhauer JL, Nieder ML, Krailo MD, et al.
A pilot study of low-dose anti-angiogenic chemotherapy in combination with standard multiagent chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma family of tumors: A Children's Oncology Group (COG) Phase II study NCT00061893.
Pediatr Blood Cancer. 2013; 60(3):409-14 [PubMed]
BACKGROUND: The aims of this study were to determine the feasibility of the combination of low dose, anti-angiogenic chemotherapy with standard therapy for patients with metastatic Ewing sarcoma (ES), and to obtain preliminary outcome data.
PROCEDURES: Patients with metastatic ES were eligible. Therapy consisted of alternating cycles of ifosfamide-etoposide, and vincristine, doxorubicin, cyclophosphamide. Vinblastine and celecoxib were concomitantly administered. Surgical, radiotherapeutic, or combination local control therapy was given per institutional preference.
RESULTS: Thirty-five eligible patients were enrolled. Ninety percent received at least 75% of planned vinblastine/celecoxib doses. There was no excess of neurologic, infectious, hemorrhagic, or cardiovascular toxicities. However, 7 of 21 patients who received pulmonary irradiation prior to experiencing pulmonary toxicity did develop grade 2 or greater pulmonary toxicity, including two deaths of apparent radiation pneumonitis. Fourteen of 16 patients with pelvic disease received local irradiation. Hemorrhagic cystitis developed in six patients, five of whom had received pelvic irradiation. The overall 24-month event free survival was 35% (19-51%); 71% (26-92%) for the seven with isolated pulmonary metastases, 26% (10-45%) for all others.
CONCLUSION: The combination of vinblastine/celecoxib metronomic therapy with standard ES treatment was feasible according to the protocol definitions. However, excess toxicity in irradiated areas was noted and limits the usefulness of this protocol. The 24-month EFS for those with isolated pulmonary metastases is better than historical controls, although the number of patient number is small, follow up short and we are lacking contemporaneous controls.


Greve B, Sheikh-Mounessi F, Kemper B, et al.
Survivin, a target to modulate the radiosensitivity of Ewing's sarcoma.
Strahlenther Onkol. 2012; 188(11):1038-47 [PubMed]
BACKGROUND AND PURPOSE: Radiotherapy constitutes an essential element in the multimodal therapy of Ewing's sarcoma. Compared to other sarcomas, Ewing tumors normally show a good response to radiotherapy. However, there are consistently tumors with a radioresistant phenotype, and the underlying mechanisms are not known in detail. Here we investigated the association between survivin protein expression and the radiosensitivity of Ewing's sarcoma in vitro.
MATERIAL AND METHODS: An siRNA-based knockdown approach was used to investigate the influence of survivin expression on cell proliferation, double-strand break (DSB) induction and repair, apoptosis and colony-forming ability in four Ewing's sarcoma cell lines with and without irradiation.
RESULTS: Survivin protein and mRNA were upregulated in all cell lines tested in a dose-dependent manner. As a result of survivin knockdown, STA-ET-1 cells showed reduced cell proliferation, an increased number of radiation-induced DSBs, and reduced repair. Apoptosis was increased by knockdown alone and increased further in combination with irradiation. Colony formation was significantly reduced by survivin knockdown in combination with irradiation.
CONCLUSION: Survivin is a radiation-inducible protein in Ewing's sarcoma and its down-regulation sensitizes cells toward irradiation. Survivin knockdown in combination with radiation inhibits cell proliferation, repair, and colony formation significantly and increases apoptosis more than each single treatment alone. This might open new perspectives in the radiation treatment of Ewing's sarcoma.


Patócs B, Németh K, Garami M, et al.
Utilisation of fluorescent multiplex PCR and laser-induced capillary electrophoresis for the diagnosis of Ewing family of tumours in formalin-fixed paraffin-embedded tissues.
J Clin Pathol. 2012; 65(12):1112-8 [PubMed]
AIMS: The localisation of the translocation breakpoint of the Ewing sarcoma family of tumours shows significant variability on relatively large regions of fusion partner genes. As a consequence, many alternative forms of EWSR1-ETS translocation exist which make the RNA-based molecular diagnostics of Ewing sarcoma family of tumours complicated. In addition to the heterogeneity of fusion transcripts, the degradation of RNA also presents a significant difficulty in the molecular analysis of formalin-fixed paraffin-embedded (FFPE) tissues. Our aim was to establish a sensitive method which is able to identify all combinatorially possible EWSR1-FLI1 and EWSR1-ERG translocation transcripts in FFPE tissue samples despite significant RNA-degradation.
METHODS: The combination of fluorescent multiplex PCR with laser-induced capillary electrophoresis was used to detect and identify EWSR1-FLI1 and EWSR1-ERG chimeric transcripts on the basis of amplicon size, and forward primers labelled by distinct fluorophores.
RESULTS: Using this method, we processed 60 FFPE samples of Ewing sarcoma family of tumours, and identified six types EWSR1-FLI1 and one type EWSR1-ERG chimeric transcripts acceptable for RT-PCR analysis in 27 out of 45 samples. This result shows 60% sensitivity for detecting the most frequent Ewing family of tumour (EFT)-related fusion transcripts.
CONCLUSIONS: The utilisation of fluorescent multiplex PCR and laser-induced fluorescent capillary electrophoresis is effective for the diagnosis of EFT in FFPE tissue, and after the defined modifications it can offer a sensitive method to overcome the diagnostic difficulties connected with heterogeneity of the variant translocations in EFT.


Hanly L, Figueredo R, Rieder MJ, et al.
The Effects of N-acetylcysteine on ifosfamide efficacy in a mouse xenograft model.
Anticancer Res. 2012; 32(9):3791-8 [PubMed]
BACKGROUND/AIM: Nephrotoxicity is observed in 30% of children treated with ifosfamide. We have shown that n-acetylcysteine (NAC) successfully mitigates nephrotoxicity of ifosfamide in cell and rodent models. However, before this treatment is evaluated clinically, it must be established that NAC does not interfere with the efficacy of ifosfamide.
MATERIALS AND METHODS: Mice implanted with Ewing's sarcoma tumours received the following treatments: saline, ifosfamide, ifosfamide + NAC concurrently, pre-treatment with NAC + ifosfamide, or NAC alone.
RESULTS: Median volumes of EW-7 tumour xenografts in mice treated with ifosfamide (n=8), ifosfamide with concurrent NAC therapy (n=7), and NAC pre-treatment (n=6) (p<0.05) were significantly reduced compared to median tumour volumes of control mice (n=6). None of the NAC treatments affected ifosfamide-mediated reduction in tumour volumes.
CONCLUSION: NAC does not interfere with the efficacy of ifosfamide in a EW-7 xenograft model. These results support the clinical evaluation of NAC as a strategy against ifosfamide-induced nephrotoxicity in children.


David E, Tirode F, Baud'huin M, et al.
Oncostatin M is a growth factor for Ewing sarcoma.
Am J Pathol. 2012; 181(5):1782-95 [PubMed]
Primary bone tumors, osteosarcomas and chondrosarcomas, derive from mesenchymal stem cells committed into osteoblasts and chondrocytes; in Ewing sarcomas (ESs), the oncogenic fusion protein EWS-FLI1 prevents mesenchymal differentiation and induces neuroectodermic features. Oncostatin M (OSM) is a cytokine from the IL-6 family that modulates proliferation and differentiation in numerous cells. The basis for inhibition versus induction of proliferation by this cytokine is obscure, although MYC was described as a potent molecular switch in OSM signaling. We show herein that, in contrast to osteosarcomas and chondrosarcomas, for which OSM was cytostatic, OSM induced proliferation of ES cell lines. Knockdown experiments demonstrated that growth induction by OSM depends on both types I [leukemia inhibitory factor receptor (LIFR)] and II [OSM receptor (OSMR)] receptors, high STAT3 activation, and induction of MYC to a high expression level. Indeed, ES cell lines, mice xenografts, and patient biopsy specimens poorly expressed LIF, precluding LIFR lysosomal degradation and OSMR transcriptional induction, thus leading to a high LIFR/OSMR ratio. Because other neuroectodermic tumors (ie, glioma, medulloblastoma, and neuroblastoma) had a similar expression profile, the main role of EWS-FLI1 could be through maintenance of stemness and neuroectodermic features, characterized by a low LIF, a high LIFR/OSMR ratio, and high MYC expression. Thus, this study on rare bone malignancies gives valuable insights on more common cancer regulatory mechanisms and could provide new therapeutic opportunities.


Özkaya Ö, Egemen O, Bingöl D, Akan M
Use of deepithelialized medial sural artery perforator flap for the correction of postoncologic facial contour deformity.
J Craniofac Surg. 2012; 23(5):e491-4 [PubMed]
We report a case of young patient with a postoncologic right buccomandibular defect in which the deepithelialized medial sural artery perforator flap was used to obtain a symmetric contour of the defective side. The aim of this study was to compare treatment strategies of facial contour deformities and to give detailed information about medial sural artery flap dissection with a clinical presentation.


Turkyilmaz Z, Sonmez K, Karabulut R, et al.
Extraskeletal Ewing sarcoma of the mesocolon in a child.
J Pediatr Surg. 2012; 47(9):E1-3 [PubMed]
Ewing sarcoma (ES) is a malignant neoplasm usually affecting the skeletal system. Extraskeletal ES is a rare tumor. To date, only 1 case of primary mesocolon ES has been previously reported in an adult. Herein, we present the first case of ES in the mesocolon in a child.


Hingorani P, Dickman P, Garcia-Filion P, et al.
BIRC5 expression is a poor prognostic marker in Ewing sarcoma.
Pediatr Blood Cancer. 2013; 60(1):35-40 [PubMed]
BACKGROUND: BIRC5 (Survivin), an inhibitor of apoptosis protein (IAP), is over-expressed in several human cancers and increased expression is associated with poor prognosis. The goal of the current study was to evaluate the role of BIRC5 in Ewing sarcoma (ES), the second most common pediatric bone sarcoma.
PROCEDURE: BIRC5 protein expression was determined in ES cell lines using Western Blot analysis. Functional role of survivin on growth and viability of ES cells was assessed by siRNA knockdown of BIRC5 and by using a small molecule inhibitor YM155. Immunohistochemical analysis for BIRC5 protein was performed on patient tumor samples using an anti-survivin antibody. The degree of BIRC5 protein expression was correlated with clinical parameters and patient outcome.
RESULTS: BIRC5 is over-expressed in a panel of ES cell lines. Gene silencing of BIRC5 in the ES cell line TC-71 decreases cell growth by more than 50% for each BIRC5 siRNA construct compared to non-silencing siRNA control constructs. YM155 also reduces ES cell growth and viability with an EC(50) ranging from 2.8 to 6.2 nM. BIRC5 protein is expressed in majority of the ES tumor samples with minimal expression in normal tissue (P < 0.005). Tumors with more than 50% expression are associated with worse overall survival than tumors with less than 50% expression (Hazard Ratio: 6.05; CI: 1.7-21.4; P = 0.04).
CONCLUSION: BIRC5 is over-expressed in ES cell lines and tumor samples. Further, it plays an important role in cell growth and viability in vitro. Higher degree of expression in patients is an independent poor prognostic factor.


Kuperman AA, Kornreich L, Feinmesser M, et al.
Regression of mesenchymal hamartoma of the liver with sarcoma chemotherapy.
J Pediatr Hematol Oncol. 2013; 35(1):e25-6 [PubMed]
We present a young patient with metastatic Ewing sarcoma that had hepatic lesions. As we were unaware of hepatic metastases in Ewing sarcoma, liver biopsy was performed. The pathologic findings were diagnostic of mesenchymal hamartoma of the liver. Surprisingly, the combined chemotherapy for metastatic sarcoma resulted in almost complete resolution of the hamartoma in the liver. This option may be useful in extreme cases when resection is not feasible.


Puri A, Gulia A
The results of total humeral replacement following excision for primary bone tumour.
J Bone Joint Surg Br. 2012; 94(9):1277-81 [PubMed]
Rarely, the extent of a malignant bone tumour may necessitate resection of the complete humerus to achieve adequate oncological clearance. We present our experience with reconstruction in such cases using a total humeral endoprosthesis (THER) in 20 patients (12 male and eight female) with a mean age of 22 years (6 to 59). We assessed the complications, the oncological and functional outcomes and implant survival. Surgery was performed between June 2001 and October 2009. The diagnosis included osteosarcoma in nine, Ewing's sarcoma in eight and chondrosarcoma in three. One patient was lost to follow-up. The mean follow-up was 41 months (10 to 120) for all patients and 56 months (25 to 120) in survivors. There were five local recurrences (26.3%) and 11 patients were alive at time of last follow-up, with overall survival for all patients being 52% (95% confidence interval (CI) 23.8 to 74) at five years. The mean Musculoskeletal Tumor Society score for the survivors was 22 (73%; 16 to 23). The implant survival was 95% (95% CI 69.5 to 99.3) at five years. The use of a THER in the treatment of malignant tumours of bone is oncologically safe; it gives consistent and predictable results with low rates of complication.


Surdez D, Benetkiewicz M, Perrin V, et al.
Targeting the EWSR1-FLI1 oncogene-induced protein kinase PKC-β abolishes ewing sarcoma growth.
Cancer Res. 2012; 72(17):4494-503 [PubMed]
Ewing sarcoma is a rare but aggressive disease most common in young adults. This cancer is driven by a unique chimeric fusion oncogene but targeted strategies have been elusive. Here we report the identification of the protein kinase PKC-ß (PRKCB) as a disease-specific druggable target for treatment of Ewing sarcoma. We found that transcriptional activation of PRKCB was directly regulated by the chimeric fusion oncogene EWSR1-FLI1 that drives this cancer. PRKCB phosphorylated histone H3T6 to permit global maintenance of H3K4 trimethylation at a variety of gene promoters. PRKCB loss induced apoptosis in vitro and prevented tumor growth in vivo. Gene expression profiling revealed a strong overlap between genes modulated by EWSR1-FLI1 and PRKCB in regulating crucial signaling pathways. Taken together, our findings offer a preclinical proof-of-concept for PRKCB as a promising therapeutic target in Ewing sarcoma.


Silva DS, Sawitzki FR, De Toni EC, et al.
Ewing's sarcoma: analysis of single nucleotide polymorphism in the EWS gene.
Gene. 2012; 509(2):263-6 [PubMed]
We aimed to investigate single nucleotide polymorphisms (SNPs) in the EWS gene breaking region in order to analyze Ewing's sarcoma susceptibility. The SNPs were investigated in a healthy subject population and in Ewing's sarcoma patients from Southern Brazil. Genotyping was performed by TaqMan® assay for allelic discrimination using Real-Time PCR. The analysis of incidence of SNPs or different SNP-arrangements revealed a higher presence of homozygote TT-rs4820804 in Ewing's sarcoma patients (p=0.02; Chi Square Test). About 300 bp from the rs4820804 SNP lies a palindromic hexamer (5'-GCTAGC-3') and three nucleotides (GTC), which were previously identified to be in close vicinity of the breakpoint junction in both EWS and FLI1 genes. This DNA segment surrounding the rs4820804 SNP is likely to indicate a breakpoint region. If the T-rs4820804 allele predisposes a DNA fragment to breakage, homozygotes (TT-rs4820804) would have double the chance of having a chromosome break, increasing the chances for a translocation to occur. In conclusion, the TT-rs4820804 EWS genotype can be associated with Ewing's sarcoma and the SNP rs4820804 can be a candidate marker to understand Ewing's sarcoma susceptibility.


Anastasiades EN, El Abiad SA, Chouairy CJ
Ewing sarcoma/primitive neuroectodermal tumor (PNET) of the vulva. Case report and review of the literature.
J Med Liban. 2012 Apr-Jun; 60(2):113-6 [PubMed]
Ewing sarcoma is a rare highly malignant neoplasm that is mostly encountered as a primary bone tumor of childhood. Extra osseous occurrence is less frequent and cases involving the vulva are very rare with only twelve reported to date. We report the case of a Ewing sarcoma that presented as a vulvar mass in a 28-year-old Lebanese lady and briefly review the differential diagnosis as well as the published literature regarding the clinical presentation and prognosis.


Ackermann M, Morse BA, Delventhal V, et al.
Anti-VEGFR2 and anti-IGF-1R-Adnectins inhibit Ewing's sarcoma A673-xenograft growth and normalize tumor vascular architecture.
Angiogenesis. 2012; 15(4):685-95 [PubMed]
Increasing experimental evidence suggests that IGF-1 may modulate tumor angiogenesis via activation of the expression of VEGF in Ewing sarcomas and rhabdomyosarcomas. This study investigates the effects of the PEGylated Adnectins™ CT-322, a VEGFR2-inhibitor and AT580Peg40, an IGF-1R inhibitor, as monotherapy and in combination in a murine A673 xenograft tumor model. The combination of Adnectins CT-322 and AT580Peg40 revealed a 83% reduction in tumor growth, a nearly 5 times lower vessel density, less necrotic areas and less appearance of intussusceptive angiogenesis. Monotherapy with IGF-1R or CT-322 revealed equally a significant inhibition of tumor and vessel growth. Combinatory inhibition of IGF-1R and VEGFR2 shows a downregulation of IGF-binding protein 2 and a compensatory upregulation of VEGF levels. Immunohistological analysis showed remodeling vascular effects of CT-322-treatment or combination therapy. The vascular architecture in Adnectin-treated tumors was characterized by a strong normalization of vasculature. 3D-evaluation in microvascular corrosion casts showed significantly higher intervascular and interbranching distances in Adnectin-treated tumors. CT-322-treatment and combinatory inhibition reveal a significant reduction of intussusceptive angiogenesis. These pronounced effects on tumor vasculature suggest potential therapeutic benefit of combinatorial IGF1- and VEGF-pathways inhibition in Ewing's sarcoma.


Sohn EJ, Park J, Kang SI, Wu YP
Accumulation of pre-let-7g and downregulation of mature let-7g with the depletion of EWS.
Biochem Biophys Res Commun. 2012; 426(1):89-93 [PubMed]
EWS functions in RNA splicing and transcription by encoding an RNA binding protein, which results in the chromosomal translocation t(11;22)(q24;q12) found in Ewing sarcoma. EWS interacts with the microprocessor complex involving Drosha and DGCR8, which play roles as the cofactors of primary microRNA processing. However, the role of EWS in microRNA biogenesis has not been investigated. Here, we show that endogenous EWS interacts with endogenous Drosha by IP-western blotting. In addition, EWS knockout mouse decreased the expression of Drosha. The depletion of EWS results in the accumulation of precursor let-7g but down-regulates mature let-7g in U2OS cells. Consistently, mature let 7g was suppressed in both Ewing sarcoma cell and primary Ewing sarcoma. Also, expression levels of Dicer and CCND1 (Cyclin D1), which are known target genes of the let-7 family were upregulated. Our findings suggest that EWS mediates generation of mature let-7g from pre-let-7g.


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