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Ewing's Sarcoma

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).

Guzel Tanoglu E, Ozturk S
miR-145 suppresses epithelial-mesenchymal transition by targeting stem cells in Ewing sarcoma cells.
Bratisl Lek Listy. 2021; 122(1):71-77 [PubMed] Related Publications
OBJECTIVES: We aimed to examine the performance of stem cell markers and epithelial-mesenchymal transition (EMT) process in miR-145 transfected EWS cells (TC71, TC106).
METHODS: EWS cells were utilized for functional analysis of mir-145. Proliferation, migration, invasion and soft agar colony assay were performed to observe the alterations in migration behavior of transfected cells. Caspase assay was used to investigate the underlying reasons of proliferative inhibition in cells in whichmiR-145 is overexpressed. QRT-PCR was used to determine the role of miR-145 in EMT transcription markers and mir-145 targeted genes, KLF4, SOX2 and OCT4 expression levels.
RESULTS: The miR-145 expression has been shown to be down-regulated in EWS. The miR-145 overexpression caused inhibition of proliferation and reduced migration in EWS cells through induction of apoptosis. Mir-145 suppresses EMT capacity and SOX2, KLF4 and OCT4 expression levels.
CONCLUSION: This is the first time in the literature we have shown deregulation of miR-145 inhibits EMT process by targeting stem cell properties leading to the inhibition of tumor growth and metastasis in TC71 and TC106 cells. Based on these results, we propose that miR-145, as an important regulator of SOX2, KLF4 and OCT4 carries crucial roles in EWS tumorigenesis and EMT (Tab. 1, Fig. 4, Ref. 26).

Liu Y, Eckenrode JM, Zhang Y, et al.
Mithramycin 2'-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy.
J Med Chem. 2020; 63(22):14067-14086 [PubMed] Article available free on PMC after 25/11/2021 Related Publications
Mithramycin A (MTM) inhibits the oncogenic transcription factor EWS-FLI1 in Ewing sarcoma, but poor pharmacokinetics (PK) and toxicity limit its clinical use. To address this limitation, we report an efficient MTM 2'-oxime (MTM

Gao F, Zhou Y, Zhao R, Ren Y
Establishing a novel prognostic tool for Ewing sarcoma patients: Surveillance, Epidemiology, and End Results database analysis.
Medicine (Baltimore). 2020; 99(46):e23050 [PubMed] Article available free on PMC after 25/11/2021 Related Publications
Patients diagnosed with Ewing sarcoma (ES) usually experience poor outcomes. Accurate prediction of ES patients' prognosis is essential to improve their survival. Given that ES is a relatively rare tumor with a low incidence, we aim at developing a prognostic nomogram of ES patients based on a large sample analysis.We used the Surveillance, Epidemiology, and End Results (SEER) database to screen eligible patients diagnosed ES of bone. This retrospective study presented the clinicopathological characteristics and prognosis of ES. We randomly assigned all ES patients to 2 sets (training set and validation set) with an equal number of patients. In order to identify independent factors of survival, we performed univariate and multivariate Cox analysis in the training set. Then, we constructed novel nomograms to predict survival of ES patients by integrating significant independent variables from the training set. The prognostic performance of constructed nomograms was examined using concordance index (C-index) and calibration curves in both training and validation set.We included a total of 988 eligible cases diagnosed ES of bone between 2000 and 2015. Age >18 years, distant metastasis, tumor size >10 cm, and no surgery were independent risk factors for poorer survival. Our survival prediction nomograms were established based on those 4 independent risk factors. Good calibration plots were achieved in internal and external validation. The internal validation C-indexes of the nomogram for overall survival (OS) and cancer-specific survival (CSS) were 0.733 and 0.737, respectively. Similar good results were also achieved in external validation setting.The established nomograms show good performance and allow for better evaluating the prognosis of ES patients and recommending appropriate instructions.

Cheng L, Xu Y, Song H, et al.
A rare entity of Primary Ewing sarcoma in kidney.
BMC Surg. 2020; 20(1):280 [PubMed] Article available free on PMC after 25/11/2021 Related Publications
BACKGROUND: Ewing sarcoma (ES) or primitive neuroectodermal tumors (PNET) represents a spectrum of poorly differentiated and aggressive malignancies. It rarely arises from the kidney and accounts for less than 1% of renal mass. Given the uncharacteristic clinical symptoms and imaging features, renal Ewing sarcoma (RES) is often diagnosed by postoperative pathology.
CASE PRESENTATION: Herein, we depicted a case of RES, which was administrated in our institution by chief complaints of intermittent left plank pain and palpable abdominal mass. We demonstrated the aggressive behavior of this renal malignancy and summarized its therapeutic modalities and outcomes.
CONCLUSION: The diagnosis of RES relies on integrated analysis including histomorphology, immunohistochemical staining and confirmation of molecular-genetic testing. Despite the surgery and adjuvant therapy, optimized and potent therapeutic regimes are still urgently needed to improve the poor prognosis of RES.

Pan B, Bu X, Cao M, et al.
Inactivation of ICAM1 inhibits metastasis and improves the prognosis of Ewing's sarcoma.
J Cancer Res Clin Oncol. 2021; 147(2):393-401 [PubMed] Related Publications
BACKGROUND: Ewing's sarcoma (ES) is a kind of malignant tumor, which often occurs in the long bone, pelvis, and other bone tissues, as well as some soft tissues. It often occurs in children and adolescents, second only to osteosarcoma and rhabdomyosarcoma. In the past 30 years, little progress has been made on the genomic mechanism of ES metastasis.
METHODS: The gene expression sequence of ES metastasis samples was compared with that of primary tumor samples to obtain differentially expressed genes (DEGs). Subsequently, we annotated the gene functions and enriched pathways of DEGs. Additionally, the protein and protein interaction network were constructed to screen key genes that can lead to the metastasis in ES. Then, cell and molecular biology experiments were conducted to verify the results obtained from the bioinformatics analysis. Finally, we assessed the correlation of expression between the key genes EWSR and FLI1, and conducted a survival analysis of ICAM1.
RESULTS: Our study revealed 153 DEGs. Of these, 82 (53.59%) were upregulated and the remaining 71 (46.41%) were downregulated. The bioinformatics analysis showed that ICAM1 was the key gene leading to the invasion and metastasis of ES. Through cell biology and molecular biology experiments, inactivation of ICAM1 inhibited the metastasis of ES cells. The survival and correlation analyses showed that ICAM1 was a risk factor in patients with ES, and that ICAM1 expression was correlated with EWSR and FLI1 expression.
CONCLUSION: Our study shows that inactivation of ICAM1 inhibits metastasis and improves the prognosis of ES. Additionally, our findings provide a better understanding of the underlying mechanisms of metastatic ES, a basis for an accurate diagnosis, and therapeutic targets for ES patients.

Shi X, Zheng Y, Jiang L, et al.
EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma.
Nucleic Acids Res. 2020; 48(20):11434-11451 [PubMed] Article available free on PMC after 25/11/2021 Related Publications
Core regulatory circuitry (CRC)-dependent transcriptional network is critical for developmental tumors in children and adolescents carrying few gene mutations. However, whether and how CRC contributes to transcription regulation in Ewing sarcoma is unknown. Here, we identify and functionally validate a CRC 'trio' constituted by three transcription factors (TFs): KLF15, TCF4 and NKX2-2, in Ewing sarcoma cells. Epigenomic analyses demonstrate that EWS-FLI1, the primary fusion driver for this cancer, directly establishes super-enhancers of each of these three TFs to activate their transcription. In turn, KLF15, TCF4 and NKX2-2 co-bind to their own and each other's super-enhancers and promoters, forming an inter-connected auto-regulatory loop. Functionally, CRC factors contribute significantly to cell proliferation of Ewing sarcoma both in vitro and in vivo. Mechanistically, CRC factors exhibit prominent capacity of co-regulating the epigenome in cooperation with EWS-FLI1, occupying 77.2% of promoters and 55.6% of enhancers genome-wide. Downstream, CRC TFs coordinately regulate gene expression networks in Ewing sarcoma, controlling important signaling pathways for cancer, such as lipid metabolism pathway, PI3K/AKT and MAPK signaling pathways. Together, molecular characterization of the oncogenic CRC model advances our understanding of the biology of Ewing sarcoma. Moreover, CRC-downstream genes and signaling pathways may contain potential therapeutic targets for this malignancy.

Perdigón Martinelli C, Morell C, González C, Nova-Lozano C
Metastatic pulmonary dissemination as differential diagnosis of COVID-19 disease.
BMJ Case Rep. 2020; 13(10) [PubMed] Article available free on PMC after 25/11/2021 Related Publications
A 13-year-old boy presented to hospital with 3-day self-limited fever, followed by dry cough, persistent asthenia and impaired general condition of 2 weeks' duration. Blood analyses showed a severe inflammatory status and chest X-ray images were consistent with bilateral COVID-19 pneumonia. He developed an acute respiratory failure that required paediatric intensive care admission and non-invasive ventilation. A targeted COVID-19 treatment was initiated with hydroxicloroquine, corticosteroids, enoxaparine and a single dose of tocilizumab. Repeated serological tests and real-time reverse transcription PCR for SARS-CoV-2 were negative. Other infectious pathogens were also ruled out. Thoracic high resolution CT showed an intense bilateral pulmonary dissemination with lytic vertebral bone lesions. After diagnostic investigations, Ewing's sarcoma with metastatic pulmonary dissemination was diagnosed. Nowadays, in the context of SARS-CoV-2 community pandemic, we cannot forget that COVID-19 clinical presentation is not specific and other entities can mimic its clinical features.

Newman ET, van Rein EAJ, Theyskens N, et al.
Diagnoses, treatment, and oncologic outcomes in patients with calcaneal malignances: Case series, systematic literature review, and pooled cohort analysis.
J Surg Oncol. 2020; 122(8):1731-1746 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Malignant tumors of the calcaneus are rare but pose a treatment challenge.
AIMS: (1) describe the demographics of calcaneal malignancies in a large cohort; (2) describe survival after amputation versus limb-salvage surgery for high-grade tumors.
METHODS: Study group: a "pooled" cohort of patients with primary calcaneal malignancies treated at two cancer centers (1984-2015) and systematic literature review. Kaplan-Meier analyses described survival across treatment and diagnostic groups; proportional hazards modeling assessed mortality after amputation versus limb salvage.
RESULTS: A total of 131 patients (11 treated at our centers and 120 patients from 53 published studies) with a median 36-month follow-up were included. Diagnoses included Ewing sarcoma (41%), osteosarcoma (30%), and chondrosarcoma (17%); 5-year survival rates were 43%, 73% (70%, high grade only), and 84% (60%, high grade only), respectively. Treatment involved amputation in 52%, limb salvage in 27%, and no surgery in 21%. There was no difference in mortality following limb salvage surgery (vs. amputation) for high-grade tumors (HR 0.38; 95% CI 0.14-1.05), after adjusting for Ewing sarcoma diagnosis (HR 5.15; 95% CI 1.55-17.14), metastatic disease at diagnosis (HR 3.88; 95% CI 1.29-11.64), and age (per-year HR 1.04; 95% CI 1.02-1.07).
CONCLUSIONS: Limb salvage is oncologically-feasible for calcaneal malignancies.

Ren EH, Deng YJ, Yuan WH, et al.
An immune-related gene signature for determining Ewing sarcoma prognosis based on machine learning.
J Cancer Res Clin Oncol. 2021; 147(1):153-165 [PubMed] Related Publications
PURPOSE: Ewing sarcoma (ES) is one of the most common malignant bone tumors in children and adolescents. The immune microenvironment plays an important role in the development of ES. Here, we developed an optimal signature for determining ES patient prognosis based on immune-related genes (IRGs).
METHODS: We analyzed the ES gene expression profile dataset, GSE17679, from the GEO database and extracted differential expressed IRGs (DEIRGs). Then, we conducted functional correlation and protein-protein interaction (PPI) analyses of the DEIRGs and used the machine learning algorithm-iterative Lasso Cox regression analysis to build an optimal DEIRG signature. In addition, we applied ES samples from the ICGC database to test the optimal gene signature. We performed univariate and multivariate Cox regressions on clinicopathological characteristics and optimal gene signature to evaluate whether signature is an important prognostic factor. Finally, we calculated the infiltration of 24 immune cells in ES using the ssGSEA algorithm, and analyzed the correlation between the DEIRGs in the optimal gene signature and immune cells.
RESULTS: A total of 249 DEIRGs were screened and an 11-gene signature with the strongest correlation with patient prognoses was analyzed using a machine learning algorithm. The 11-gene signature also had a high prognostic value in the ES external verification set. Univariate and multivariate Cox regression analyses showed that 11-gene signature is an independent prognostic factor. We found that macrophages and cytotoxic, CD8 T, NK, mast, B, NK CD56bright, TEM, TCM, and Th2 cells were significantly related to patient prognoses; the infiltration of cytotoxic and CD8 T cells in ES was significantly different. By correlating prognostic biomarkers with immune cell infiltration, we found that FABP4 and macrophages, and NDRG1 and Th2 cells had the strongest correlation.
CONCLUSION: Overall, the IRG-related 11-gene signature can be used as a reliable ES prognostic biomarker and can provide guidance for personalized ES therapy.

Breitegger B, Holzer LA, Beham-Schmid C, et al.
Bone marrow aspirations in Ewing sarcomas: Are they still necessary? A single-center retrospective analysis and review of the literature.
J Cancer Res Ther. 2020 Jul-Sep; 16(4):713-717 [PubMed] Related Publications
Background and Objectives: Currently, one of the most useful prognostic indicators in Ewing sarcomas (ES) is the presence of metastatic disease at diagnosis. According to various clinical guidelines, the assessment of bone marrow (BM) metastases, using light microscopy examination of bone marrow aspirates and biopsies (BMAB) is mandatory. However, the prognostic value of BM positivity is discussed controversially. Therefore, the primary aim of this study was to retrospectively review BM samples from patients with ES.
Materials and Methods: This retrospective single centre study included 31 patients that were newly diagnosed with ES between 2000 and 2014. Twenty-seven patients had skeletal ES and in 4 patients the tumour was localized in the soft tissue only. Metastases at diagnosis were present in 5 out of 31 patients. BM samples were morphologically and immunohistochemically searched and screened for the presence or absence of BM metastases. Furthermore, in 15 of the 31 patients BM samples were still available and were reanalysed, using nested-polymerase chain reaction.
Results: All BM samples of our 31 ES patients, including the 5 metastatic patients, were, morphologically and immunohistochemically tested negative for tumour cell appearance. The nested-PCR results were also negative in all of our 15 retested patients, including two patients with metastatic disease.
Conclusions: Based on our results and on the contradictory results reported in the literature we recommend a re-evaluation of the necessity and the prognostic value of BMAB in the initial staging process of newly diagnosed ES patients.

Lin SH, Sampson JN, Grünewald TGP, et al.
Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.
PLoS One. 2020; 15(9):e0237792 [PubMed] Article available free on PMC after 25/11/2021 Related Publications
BACKGROUND: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.
METHODS: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).
RESULTS: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).
CONCLUSIONS: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.
IMPACT: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.

Lin TA, Ludmir EB, Liao KP, et al.
Relationship between treatment center case volume and survival for localized Ewing sarcoma: The role of radiotherapy timing.
Pediatr Blood Cancer. 2020; 67(11):e28685 [PubMed] Related Publications
In the treatment of localized Ewing sarcoma (EWS), delays in local therapy are known to adversely impact overall survival (OS). However, the role of treatment center volume in EWS outcomes, and the interaction between center volume and local therapy timing with definitive radiotherapy, remains unknown. Using the National Cancer Database, we demonstrate that treatment at the lowest EWS volume centers is associated with reduced OS, explained partly by higher rates of delayed local therapy. Treatment at the highest volume centers results in improved OS, but appears independent of radiotherapy timing. Future efforts to improve care for EWS patients across treatment centers are imperative.

Pérez-Heras I, Fernandez-Escobar V, Del Pozo-Carlavilla M, et al.
Two Cases of SARS-CoV-2 Infection in Pediatric Oncohematologic Patients in Spain.
Pediatr Infect Dis J. 2020; 39(11):1040-1042 [PubMed] Related Publications
Since December 2019, severe acute respiratory syndrome coronavirus 2 infection has spread worldwide. We all are concerned about immunocompromised children, especially hematologic and oncologic pediatric patients. We want to share our experience with 2 pediatric cancer patients with severe acute respiratory syndrome coronavirus 2 infection. Both presented mild disease and good outcome. No respiratory symptoms were identified, but both developed diarrhea, one probably secondary to lopinavir/ritonavir. Pediatric cancer patients may have milder disease than adults, but larger studies are needed to make conclusions.

Kerschner-Morales SL, Kühne M, Becker S, et al.
Anticancer effects of the PLK4 inhibitors CFI-400945 and centrinone in Ewing's sarcoma cells.
J Cancer Res Clin Oncol. 2020; 146(11):2871-2883 [PubMed] Article available free on PMC after 25/11/2021 Related Publications
PURPOSE: Polo-like kinase 4 (PLK4) inhibitors, such as CFI-400945 and centrinone, are emerging as promising antineoplastic agents. However, their effectiveness against Ewing's sarcoma, a highly aggressive childhood cancer, remains to be established.
METHODS: CFI-400945 and centrinone were tested in three Ewing's sarcoma cell lines with different TP53 status. Effects were assessed by flow-cytometric analyses of cell death, dissipation of the mitochondrial transmembrane potential and cell cycle distribution, by cell viability assay as well as by caspase 3/7 activity measurement, by immunoblotting and by immunofluorescence microscopy.
RESULTS: CFI-400945 and centrinone elicited cell death in p53 wild-type and mutant Ewing's sarcoma cells. Both agents induced mitochondrial membrane depolarisation, caspase 3/7 activation, PARP1 cleavage and DNA fragmentation, indicating an apoptotic form of cell death. In addition, the PLK4 inhibitors induced a G2/M cell cycle arrest, particularly when cell killing was attenuated by the pan-caspase inhibitor z-VAD-fmk. Moreover, CFI-400945 treatment produced polyploidy.
CONCLUSION: Our findings show that PLK4 inhibitors were effective against Ewing's sarcoma cells in vitro and thus provide a rationale for their evaluation in vivo.

Ottóffy G, Komáromy H
Extraskeletal, intradural, non-metastatic Ewing's sarcoma. Case report.
Ideggyogy Sz. 2020; 73(7-08):286-288 [PubMed] Related Publications
Intracranial localization of Ewing's sarcoma is considerably very rare. Herein, we present clinical and neuroimaging findings regarding a 4-year-old boy with intracranial Ewing's sarcoma. He was born prematurely, suffered intraventricular haemorrhage, posthaemorrhagic hydrocephalus developed, and a ventriculoperitoneal shunt was inserted in the newborn period. The patient endured re-gular follow ups, no signs of shunt malfunction nor increased intracranial pressure were observed. The last neuroima-ging examination was performed at 8 months of age. Upon reaching the age of 4 years, repeated vomiting and focal seizures began, and symptoms of increased intracranial pressure were detected. A brain MRI depicted a left frontoparietal space-occupying lesion infiltrating the superior sagittal sinus. The patient underwent a craniotomy resulting in the total excision of the tumour. The histological examination of the tissue revealed a small round blue cell tumour. The diagnosis was confirmed by the detection of EWSR1 gene translocation with FISH (fluorescent in situ hybridization). No additional metastases were detected during the staging examinations. The patient was treated in accordance to the EuroEwing 99 protocol. Today, ten years onward, the patient is tumour and seizure free and has a reasonably high quality of life.

Englisch A, Altvater B, Kailayangiri S, et al.
VEGFR2 as a target for CAR T cell therapy of Ewing sarcoma.
Pediatr Blood Cancer. 2020; 67(10):e28313 [PubMed] Related Publications
BACKGROUND: T cells engineered to express chimeric antigen receptors (CARs) are a novel modality to treat refractory cancers. The development of CAR T cells against Ewing sarcoma (EwS) is limited by a lack of targetable surface antigens. We investigated vascular endothelial growth factor receptor 2 (VEGFR2) expressed on tumor-associated blood vessels as potential CAR target in this cancer.
METHODS: Expression of VEGFR2 was studied by immunohistochemistry in human EwS biopsies and in murine xenografts and by flow cytometry in EwS cell lines. CARs with short, medium, and long hinge domains against either human or murine VEGFR2 were generated and expressed in human T cells by retroviral gene transfer. The capacity of the individual CARs to activate T cells in response to VEGFR2-expressing cells was compared in vitro.
RESULTS: Tumor-associated endothelial cells in human EwS biopsies and in xenografts expressed VEGFR2. Tumor cells in the majority of EwS biopsies were also VEGFR2-positive. Following modification with anti-mouse or anti-human VEGFR2-specific CAR genes, T cells specifically lysed VEGFR2-expressing target cells of the respective species. CAR T cells with short-length or medium-length hinge domains were functionally superior over those with the long hinge region by in vitro parameters, including antigen-specific degranulation responses, lysis of tumor spheroids, tumor necrosis factor α secretion, sequential killing, and proliferation.
CONCLUSIONS: VEGFR2 is consistently expressed on endothelial cells of the tumor stroma in EwS and thus is a candidate target for CAR T cells in this cancer. Among various VEGFR2-specific CARs, a construct with a short hinge domain was chosen to be further developed toward clinical translation.

Jagodzińska-Mucha P, Ługowska I, Świtaj T, et al.
The clinical prognostic factors and treatment outcomes of adult patients with Ewing sarcoma.
Int J Clin Oncol. 2020; 25(11):2006-2014 [PubMed] Related Publications
BACKGROUND: The data about treatment results of Ewing sarcoma in adult patients are limited. The aim of our study was to analyze prognostic factors and outcomes of therapy in this group of patients.
METHODS: Between 2000 and 2018, 180 patients at the age of > 18 years old diagnosed with Ewing sarcoma were treated in referral center according to multimodal protocols. In 50 patients (28%) treatment was initiated outside our hospital, and 23 of them had started recommended therapy after 3 months since the date of biopsy/unscheduled operation. We analyzed clinical prognostic factors and overall survival (OS).
RESULTS: The median age was 28 years (18-67 years), primary tumor was localized axially in 114 patients (63%), metastases at presentation were detected in 51 pts (28%). 5-year OS rate was 65% for patients with localized disease, in metastatic disease it was 15%; the presence and the number of metastases was a prognostic factor. 5-year PFS was significantly better in patients treated at referral center (or when the patients were admitted to referral center within 3 months from the date of biopsy, which was performed outside referral center), comparing to patients treated initially outside referral center; 5-year PFS rates in total population were 28 and 13%, respectively. In terms of OS, unfavorable prognostic factor showing a statistical trend (p = 0.098) was lower dose density of neoadjuvant chemotherapy due to toxicity.
CONCLUSIONS: Approximately two-third of adult patients with localized Ewing sarcoma survive 5 years. In order to improve survival of this patients the multidisciplinary treatment in referral center is mandatory.

Saleh MM, Abdelrahman TM, Madney Y, et al.
Multiparametric MRI with diffusion-weighted imaging in predicting response to chemotherapy in cases of osteosarcoma and Ewing's sarcoma.
Br J Radiol. 2020; 93(1115):20200257 [PubMed] Related Publications
OBJECTIVE: To evaluate the multiparametric MRI in predicting chemotherapy response in pathologically proven cases of osteosarcoma and Ewing's sarcoma. Correlation between the tumor size changes and internal breakdown using RECIST 1.1, modified RECIST, quantitative apparent diffusion coefficient (ADC) and tumor volume as well as dynamic contrast-enhanced MRI (DCE-MRI).
METHODS: The study included 104 patients pathologically proved osteosarcoma (53) and Ewing`s sarcoma (51) underwent MRI examinations; before and after chemotherapy. All patients were assessed using the RECIST 1.1 criteria, m-RECIST, quantitative ADC, and tumor volume evaluation. 21 patients underwent DCE-MRI curve type with quantitative parameters. Correlation between the different evaluations was carried out. Results were correlated with the post-operative pathology in 42 patients who underwent surgery and for statistical evaluation, Those patients were classified into responders (≥90% necrosis) and non-responders (<90% necrosis).
RESULTS: The initial mean ADC of 104 patients of osteosarcoma and Ewing's sarcoma (0.90 ± 0.29) and (0.71 ± 0.16) respectively, differed significantly from that after treatment (1.62 ± 0.46) and (1.6 ± 0.39) respectively with (
CONCLUSION: Quantitative diffusion-weighted imaging with ADC mapping and ADC % after chemotherapy allows a detailed analysis of the treatment response in osteosarcoma and Ewing's sarcoma. The therapeutic response can be underestimated using RECIST 1.1, so the modified RECIST should be also considered.
ADVANCES IN KNOWLEDGE: Quantitative ADC especially ADC% provided an accurate non-invasive tool in the assessment of post-therapeutic cases of osteosarcoma and Ewing's sarcoma.

Parambil BC, Vora T, Sankaran H, et al.
Outcomes with nondose-dense chemotherapy for Ewing sarcoma: A practical approach for the developing world.
Pediatr Blood Cancer. 2020; 67(11):e28604 [PubMed] Related Publications
BACKGROUND: The current multidisciplinary approach in the treatment of Ewing sarcoma has improved cure rates, with contemporary dose-dense chemotherapy attaining 5-year event-free survival (EFS) of 73% in localized cases. Dose-intense and dose-dense chemotherapy is difficult in the majority of resource-limited settings with limited access to optimal supportive care. We report on patients with Ewing sarcoma treated on EFT-2001, a nondose-dense chemotherapy protocol.
PROCEDURE: A retrospective analysis was conducted of patients (<15 years) with Ewing sarcoma treated with curative intent during January 2013-June 2017 with an institutional ethics committee-approved nondose-dense protocol (EFT-2001). Local therapy was planned after 9-12 weeks of chemotherapy with metastatic sites addressed with radiotherapy. The study assessed outcomes and prognostic factors.
RESULTS: We analysed 200 patients with M:F ratio of 1.27:1 and metastases in 41 patients (20.5%). At a median follow up of 41.5 months (range 4.5-81.8 months), respective 3-year EFS and overall survival (OS) of the whole cohort is 65.3% (95% confidence interval [CI]: 58.1-71.7%) and 79.3% (95% CI: 72.8-84.5%); for localized and metastatic cohort, 70.9% (95% CI: 62.9-77.5%) and 82.8% (95% CI: 75.7-89.0%); and for metastatic cohort, 42.8% (95% CI: 28.0-58.6%) and 65.3% (95% CI: 47.7-78.3%). Presence of residual disease (morphologic/metabolic) on positron emission tomography-computed tomography scan done 3 months post definitive radiotherapy (hazard ratio [HR] 7.92 [95% CI: 3.46-18.14]) and delay in any form of local control >4 months (HR 3.42 [95% CI: 1.32-8.89]) affected outcomes. Nonrelapse mortality during treatment was 6.5%, mainly due to cardiomyopathy (3.0%) and bacterial sepsis (1.5%). Cardiotoxicity was seen in 11.5% of patients.
CONCLUSIONS: Nondose-dense chemotherapy provides good outcomes with manageable toxicities in a multidisciplinary treatment approach, while reducing cumulative drug exposures in the developing world where dose-intense or dose-dense chemotherapy could potentially increase toxicity, and hence seems a feasible approach in resource-limited settings. Presence of any residual disease post definitive radiotherapy or delay in local control portends poor outcome.

El-Hennawy G, Moustafa H, Omar W, et al.
Pediatr Blood Cancer. 2020; 67(11):e28605 [PubMed] Related Publications
BACKGROUND: The histological response to neoadjuvant chemotherapy (NAC) in pediatric patients with Ewing sarcoma family of tumors (ESFT) can predict the disease-free survival. Therefore, a noninvasive method for response assessment is needed. Using the currently established imaging modalities, mass reduction does not always correlate with the percentage of necrosis.
OBJECTIVE: To determine the potential role of
METHODS: Thirty-six patients who were treated with NAC and surgery at the Children's Cancer Hospital, Egypt, were prospectively included in this study. All patients underwent two studies; a PET/CT study before NAC and another one after NAC completion. Metabolic PET parameters were measured in each study. The ability of each of these parameters, their pretreatment and pre-local control values, as well as the percentage reduction between their pretreatment and pre-local control values, were evaluated to differentiate between good and poor responders using the histological response as a standard reference.
RESULTS: Neither the pretreatment value nor the percentage reduction of any of the measured PET parameters predicted poor histological response. After NACcompletion, metabolic tumor volume (MTV) at the threshold of an SUV of 2.5 isocontour (MTV(2.5)
CONCLUSION: FDG PET parameters can predict poor histological response to NAC in ESFT patients. MTV and TLG at the thresholds of an SUV of 2.5 isocontour and hepatic reference SUVmean are the two most promising thresholds in predicting the response of patients. The cutoff value of SUVmax

Kono M, Miwa T, Sakamoto Y, et al.
Exchange Cranioplasty Using Bioabsorbable Hydroxyapatite and Collagen Complex After Removal of an Extensive Frontal Bone Tumor in an Infant.
World Neurosurg. 2020; 142:375-378 [PubMed] Related Publications
BACKGROUND: Forehead reconstruction is challenging. Reconstruction of the innate curvature of the forehead is difficult, and the forehead is an esthetically important part of the face. Although synthetic implants and autologous split bone grafts are useful, these cannot be used in infants.
CASE DESCRIPTION: A 4-month-old girl was presented with a right frontal bone Ewing sarcoma. The tumor was removed, and the defect was reconstructed with an autologous contralateral parietal bone graft. The parietal bone defect was repaired with a bioabsorbable hydroxyapatite and collagen complex. Good reconstruction of the forehead and ossification of the donor site was achieved within 3 years after surgery.
CONCLUSIONS: After removal of an extensive frontal bone tumor in an infant, exchange cranioplasty with an autograft using a bioabsorbable hydroxyapatite and collagen complex at the donor site yielded good results.

Alder KD, Morris MT, Hao Z, et al.
Avoiding Limb-Length Discrepancy with Reconstruction of a Massive Tibial Defect Using a Bone Allograft and a Minimally Invasive Lengthening System in a Pediatric Patient: A Case Report.
JBJS Case Connect. 2020 Apr-Jun; 10(2):e0456 [PubMed] Related Publications
CASE: A 7-year-old boy was found to have Ewing sarcoma of the left tibia. The sarcoma was resected, and the defect was reconstructed using a humeral head allograft and intramedullary limb-lengthening nail.
CONCLUSIONS: Limb-salvage reconstruction in children can be complicated by the sacrifice of epiphyseal plates and limb-length discrepancies and thus requires techniques tailored to each case.

Xu M, Liu Y, Zeng S, et al.
Primary vaginal Ewing sarcoma with uterine fibroid: A case report.
Medicine (Baltimore). 2020; 99(27):e20859 [PubMed] Article available free on PMC after 25/11/2021 Related Publications
RATIONALE: Extra osseous Ewing sarcoma (ES), an uncommon malignant neoplasm, accounts for about 15% of Ewing sarcoma, which mainly affects paravertebral region, lower extremity, chest wall, retroperitoneum, pelvis, and hip. Here is a 54-year-old woman of primary vaginal Ewing sarcoma with uterine fibroid, which has been fewly known or reported.
PATIENT CONCERNS: The patient was admitted to our hospital because of vaginal pain. Her uterus showed as parallel position and enlarged as about 3 months of pregnancy size.
DIAGNOSIS: Magnetic resonance imaging (MRI) and ultrasonography (US) demonstrated 2 heterogeneous masses in the vagina and uterus, respectively. Ultrasound-guided puncture biopsy revealed a malignant tumor in the right lateral vaginal wall.
INTERVENTIONS: The patient was treated by hysterectomy, bilateral salpingo-oophorectomy, and tumors excision, with the subsequent treatment of chemotherapy.
OUTCOMES: The patient recovered well without local recurrence for >1 year.
LESSONS: Primary vaginal Ewing sarcoma is extremely rare. The treatments of uterine fibroid include uterine artery embolization and surgical options, While wide local excision followed by adjuvant chemotherapy and/or radiotherapy should be recommended for the vaginal ES.

Keil L
Bone Tumors: Primary Bone Cancers.
FP Essent. 2020; 493:22-26 [PubMed] Related Publications
The three most common primary bone cancers are osteosarcoma, Ewing sarcoma, and chondrosarcoma. Osteosarcoma occurs most often in children and young adults, with a peak incidence at ages 10 to 14 years. It also can occur later in life due to malignant transformation of benign bone lesions. Osteosarcoma occurs most commonly around the knee, but can occur in other bones. Management varies depending on tumor characteristics and involves chemotherapy and surgery. Ewing sarcoma is most common in teenagers. It occurs most commonly in long bones but can occur in the pelvis and other bones. Management involves surgical resection when possible, along with chemotherapy and occasionally radiation therapy. Chondrosarcoma typically occurs in patients 40 years and older. It can occur as a primary tumor or from malignant transformation of benign bone tumors. Chondrosarcomas are relatively resistant to chemoradiation, so surgery is the standard therapy. When any of these tumors is suspected, patients should be instructed to avoid weight-bearing on the affected extremity to help prevent pathologic fracture while evaluation is completed. Imaging with x-rays and occasionally magnetic resonance imaging study are the initial diagnostic steps. If imaging suggests a primary bone cancer, prompt referral to an orthopedic oncology subspecialist is indicated.

Totadri S, Bansal D, Rao KLN, et al.
Challenges in the management of localized Ewing sarcoma in a developing country.
Pediatr Hematol Oncol. 2020; 37(7):610-619 [PubMed] Related Publications
Survival in pediatric Ewing sarcoma (ES) lags in low- and middle-income countries (LMICs). This study analyzed factors contributing to a lower outcome in an LMIC center. A retrospective case review of children with localized ES treated from January 2011 till December 2017 was performed. Neoadjuvant chemotherapy with alternating cycles of vincristine, doxorubicin, cyclophosphamide; and ifosfamide, etoposide was administered 3-weekly for 48 weeks. Reassessment was planned for week 12, followed by local therapy (surgery/radiotherapy or both) tailed by adjuvant chemotherapy. Forty-eight patients with mean age 8 years (range: 0.7-14) were evaluated. Extremity and central axis tumors were seen in 25 (52%) and 23 (48%) patients. Three patients died of neutropenic sepsis and five abandoned therapy. Local therapy included primary surgery, radiotherapy and a combination of surgery and radiotherapy in 7 (16%), 20 (45%) and 17 (39%) patients. The 3-year event-free survival (EFS) and disease-free survival (DFS) for the cohort were 47.7 ± 11% and 57.6 ± 11.2%. Time to local therapy >16 weeks was associated with inferior DFS

Amoroso L, Castel V, Bisogno G, et al.
Phase II results from a phase I/II study to assess the safety and efficacy of weekly nab-paclitaxel in paediatric patients with recurrent or refractory solid tumours: A collaboration with the European Innovative Therapies for Children with Cancer Network.
Eur J Cancer. 2020; 135:89-97 [PubMed] Related Publications
BACKGROUND: The phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study.
PATIENTS AND METHODS: Paediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m
RESULTS: Forty-two patients were enrolled, 14 each with Ewing sarcoma, neuroblastoma and rhabdomyosarcoma. The ORRs were 0%, 0% and 7.1% (1 confirmed PR), respectively. The DCRs were 30.8% (4 SD), 7.1% (1 SD) and 7.1% (1 confirmed PR and 0 SD) in the Ewing sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively. The median progression-free survival was 13.0, 7.4 and 5.1 weeks, respectively, and the 1-year overall survival rates were 48%, 25% and 15%, respectively. The most common grade III/4IVadverse events were haematologic (neutropenia [50%] and anaemia [48%]), and grade III/IV peripheral neuropathy occurred in 2 patients (14%) in the rhabdomyosarcoma group. Pharmacokinetics analyses revealed that paclitaxel tissue distribution was both rapid and extensive.
CONCLUSIONS: In this phase II study, limited activity was observed; however, the safety of nab-paclitaxel in paediatric patients was confirmed.
TRIAL REGISTRATION: NCT01962103 and EudraCT 2013-000144-26.

Sofulu Ö, Erol B
Evaluation of factors affecting survival rate in primary bone sarcomas with extremity and pelvis involvement.
Acta Orthop Traumatol Turc. 2020; 54(3):234-244 [PubMed] Article available free on PMC after 25/11/2021 Related Publications
OBJECTIVE: This study is an evaluation of the overall survival rate and factors affecting survival in patients with osteosarcoma, chondrosarcoma, or Ewing's sarcoma. This study aimed to determine the effect of factors related to the preoperative period, patient, tumor, treatment, and postoperative period on survival.
METHODS: A total of 114 patients (64 male and 50 female) with osteosarcoma, chondrosarcoma, or Ewing's sarcoma treated between 2005 and 2013 were included in this study. All the patients received standard treatment and were followed up regularly. In all, 44 cases of (conventional and telangiectatic) osteosarcoma, 30 cases of Ewing's sarcoma, and 40 cases of high-grade chondrosarcoma were identified using the Bone and Soft Tissue Tumor Registry. Gender, age, tumor size and localization, pathological fractures, histopathological type, grade, surgical treatment, adjuvant treatments, relapse of the disease, and postoperative complication data were obtained from follow-up forms. The learning curve of institutional expertise was also evaluated. The patient survival rate was calculated using the Kaplan-Meier method, and log-rank statistical methods were used to compare survival rates.
RESULTS: The mean length of survival of the patients was 72 months. There was a 56% 5-year survival rate, and the event-free survival rate was 53%. The survival of patients with Ewing's sarcoma whose prodromal period was less than 12 weeks was significantly higher than that of the other groups (p=0.031). The survival of patients with tumor size greater than 150 cc, with local recurrence and distant metastases was low for all groups. Survival rates were significantly lower in osteosarcoma and Ewing's sarcoma patients with stage III tumor or metastasis at diagnosis. The survival of patients with osteosarcoma diagnosed between 2010 and 2013 was significantly higher than that of the earlier group (p=0.02).
CONCLUSION: Decreasing the prodromal period (early diagnosis) can improve survival by preventing the local and systemic spread of the tumor. Increase in the surgical experience is likely to have a positive effect on survival rates, especially for patients with osteosarcoma. The relapse of the disease is a poor prognostic factor for survival despite aggressive surgery and adjuvant therapies.
LEVEL OF EVIDENCE: Level IV, Therapeutic study.

García-Domínguez DJ, Hontecillas-Prieto L, León EA, et al.
An inducible ectopic expression system of EWSR1-FLI1 as a tool for understanding Ewing sarcoma oncogenesis.
PLoS One. 2020; 15(6):e0234243 [PubMed] Article available free on PMC after 25/11/2021 Related Publications
The presence of the chimeric EWSR1-FLI1 oncoprotein is the main and initiating event defining Ewing sarcoma (ES). The dysregulation of epigenomic and proteomic homeostasis induced by the oncoprotein contributes to a wide variety of events involved in oncogenesis and tumor progression. Attempts at studying the effects of EWSR1-FLI1 in non-tumor cells to understand the mechanisms underlying sarcomagenesis have been unsuccessful to date, as ectopic expression of EWSR1-FLI1 blocks cell cycle progression and induces apoptosis in the tested cell lines. Therefore, it is essential to find a permissive cell type for EWSR1-FLI1 expression that allows its endogenous molecular functions to be studied. Here we have demonstrated that HeLa cell lines are permissive to EWSR1-FLI1 ectopic expression, and that our model substantially recapitulates the endogenous activity of the EWSR1-FLI1 fusion protein. This model could contribute to better understanding ES sarcomagenesis by helping to understand the molecular mechanisms induced by the EWSR1-FLI1 oncoprotein.

Yoon JW, Lamm M, Chandler C, et al.
Up-regulation of GLI1 in vincristine-resistant rhabdomyosarcoma and Ewing sarcoma.
BMC Cancer. 2020; 20(1):511 [PubMed] Article available free on PMC after 25/11/2021 Related Publications
BACKGROUND: The clinical significance of GLI1 expression either through canonical Hedgehog signal transduction or through non-canonical mechanisms in rhabdomyosarcoma (RMS) or Ewing sarcoma (EWS) is incompletely understood. We tested a role for Hedgehog (HH) signal transduction and GL11 expression in development of vincristine (VCR) resistance in RMS and EWS.
METHODS: We characterized baseline expression and activity of HH pathway components in 5 RMS (RD, Rh18, Ruch-2, Rh30, and Rh41) and 5 EWS (CHLA9, CHLA10, TC32, CHLA258, and TC71) cell lines. We then established VCR-resistant RMS and EWS cell lines by exposing cells to serially increasing concentrations of VCR and determining the IC
RESULTS: We found evidence for HH pathway activity and GLI1 expression in RMS and EWS cell lines at baseline, and evidence that GLI1 contributes to survival and proliferation of these sarcoma cells. We were able to establish 4 VCR-resistant cell lines (Ruch-2VR, Rh30VR, Rh41VR, and TC71VR). GLI1 was significantly up-regulated in the Rh30VR, Rh41VR, and TC71VR cells. The only other gene in the drug resistance panel that was significantly up-regulated in each of these VCR-resistant cell lines compared with their corresponding parental cells was the GLI1 direct target and multidrug resistance gene, ATP-binding cassette sub-family B member 1 (MDR1). We established major vault protein (MVP), which was up-regulated in both vincristine-resistant alveolar RMS cell lines (Rh30VR and Rh41VR), as another direct target of GLI1 during development of drug resistance. Treatment of the VCR-resistant cell lines with the small molecule inhibitor GANT61 or GLI1 siRNA together with VCR significantly decreased cell viability at doses that did not reduce viability individually.
CONCLUSIONS: These experiments demonstrate that GLI1 up-regulation contributes to VCR resistance in RMS and EWS cell lines and suggest that targeting GLI1 may benefit patients with RMS or EWS by reducing multidrug resistance.

Kalus S, Vidoni A, Oliveira I, Saifuddin A
Image-guided core needle biopsy for Ewing sarcoma of bone: a 10-year single-institution review.
Eur Radiol. 2020; 30(10):5308-5314 [PubMed] Related Publications
OBJECTIVE: To evaluate the performance of image-guided core needle biopsy (IGCNB) for the diagnosis of Ewing sarcoma of bone.
METHODS: All patients with a confirmed diagnosis of Ewing sarcoma who underwent IGCNB between January 2007 and December 2016 were included in this retrospective study. Analysis included mean age, skeletal distribution, imaging modality used for biopsy guidance, type of anaesthesia, needle type, number of passes, type of tissue sampled, and complications.
RESULTS: The study included 139 patients (94 males and 45 females; mean age 18.7 years) who underwent 141 image-guided core needle biopsies as the primary diagnostic test. Of these, 101 were CT-guided, 38 ultrasound-guided, and 2 utilised both CT and ultrasound guidance. A total of 97.9% were diagnostic at first procedure. Of the 3 non-diagnostic cases, 2 underwent a further IGCNB and were positive, while 1 patient required an open surgical procedure. Only 1 patient (0.7%) suffered an immediate complication, and there were no recorded delayed complications.
CONCLUSION: IGCNB is a safe procedure providing a positive diagnosis of Ewing sarcoma of bone in a very high percentage of cases. It should be the first-line method for establishing a diagnosis in suspected Ewing sarcoma of bone.
KEY POINTS: • Image-guided core needle biopsy is a safe procedure providing a positive diagnosis of Ewing sarcoma of bone in a very high percentage of cases. • Image-guided core needle biopsy should be the first-line method for establishing a definitive diagnosis in Ewing sarcoma and should be performed at a specialist sarcoma referral centre. • When technically feasible, extra-osseous soft tissue alone can be sampled with confidence as there is no difference in diagnostic performance whether bone or an extra-osseous soft tissue component of the tumour is sampled.

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