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Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies. EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2–49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667. Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0–84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55–0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3–5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%]). Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma. The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK.

Ewing sarcoma (ES) and Ewing-like sarcomas are highly aggressive round cell mesenchymal neoplasms, most often occurring in children and young adults. The identification of novel molecular alterations has greatly contributed to a profound reappraisal of classification, to the extent that the category of undifferentiated round cell sarcoma has significantly shrunk. In fact, in addition to Ewing sarcoma, we currently recognize three main categories: round cell sarcomas with EWSR1 gene fusion with non-ETS family members, CIC-rearranged sarcomas, and BCOR-rearranged sarcomas. Interestingly, despite significant morphologic overlap, most of these entities tend to exhibit morphologic features predictive of the underlying molecular alteration. Ewing sarcoma is the prototype of round cell sarcoma whereas in CIC sarcomas, focal pleomorphism and epithelioid morphology can predominate. BCOR sarcomas often exhibit a spindled neoplastic cell population. NFATC2 sarcoma may exhibit remarkable epithelioid features, and PATZ1 sarcomas often feature a sclerotic background. The differential diagnosis for these tumors is rather broad, and among round cell sarcomas includes alveolar rhabdomyosarcoma, desmoplastic small round cell tumor, poorly differentiated round cell synovial sarcoma, small cell osteosarcoma, and mesenchymal chondrosarcoma. A combination of morphologic, immunohistochemical, and molecular findings allows accurate classification in most cases. A granular diagnostic approach to Ewing sarcoma and Ewing-like sarcomas is justified by significant differences in terms of both response to chemotherapy and overall survival. As all these entities are in part defined by specific fusion genes, a molecular diagnostic approach based on NGS technology should be considered. In consideration of the extreme rarity of many of these tumor entities, referral to expert rare cancer centers or to rare cancer networks represents the best strategy in order to minimize diagnostic inaccuracy, and allow proper patient management.

Ewing sarcoma (EWS) is a rare bone cancer that is most usually detected in children. Neutrophil extracellular traps (NETs) are closely related to the prognosis of cancer, but the significance of NET-related features in EWS remains uncertain. We constructed a NET signature utilizing four crucial NET-related genes in EWS to forecast prognosis and investigate the potential immunological value of this signature in EWS. EWS data were collected from the International Cancer Genome Consortium and Gene Expression Omnibus databases. We identified the subtypes mediated by NET-related genes in EWS and analyzed the function infiltration and immune signature of NET-related subtypes in EWS. The expression levels of proteins in EWS cells were detected via western blotting analysis. NET could distinguish EWS patients into two NET-related subtypes: C1 and C2. EWS patients with the C1 subtype exhibited a more unfavorable prognosis and higher levels of TIDE and T cell dysfunction when compared to individuals with the C2 subtype. C1 and C2 subtypes had different immune characteristics. A NET-related prognostic model including AKT1, MAPK3, ATG7, and SELPLG was established to predict the prognosis of EWS patients. The risk score model was an independent prognostic factor for EWS, and high-risk EWS patients exhibited significantly inferior prognosis. AKT1 and ATG7 expression was significantly increased in EWS samples. The protein levels of AKT1 and ATG7 were increased in EWS cells, while the protein levels of SELPLG was decreased. The NET-related prognostic model is a critical biomarker for predicting prognosis, defining molecular subtypes, and describing immune signatures in patients with EWS.

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers. Liquid biopsies enable minimally invasive applications for diagnosis and treatment monitoring. Here the authors analyse fragmentation patterns of circulating tumour DNA on multiple levels and develop a bioinformatic tool, LIQUORICE, to accurately detect and classify paediatric cancers with low mutational burden.

[...]we filtered for those genes whose overexpression was significantly negatively correlated with patients’ overall survival in a dataset of matched gene expression and survival data of 166 EwS patients [5] that covered 280 of the 292 overexpressed genes (96%) (Fig. 1c), identifying 22 candidates (Supplementary Table 1). [...]we focused on druggable targets possessing kinase or other enzymatic functions for which specific inhibitors and their pharmacokinetic data were available, but were still not (pre)clinically tested in EwS. [...]differential effect on sensitivity towards triapine was not observed in A-637 cells expressing a non-targeting control shRNA. [...]we observed an ~ twofold increase of RRM2 expression in triapine-resistant A-673 (A-673/TR) compared to parental A-673 EwS cells, suggesting that RRM2 upregulation can be a potential mechanism for acquiring triapine-resistance in A-673 EwS cells (Supplementary Fig. 3d). [...]despite our data strongly support RRM2 as an actionable and valuable drug target in EwS, and triapine as a potential lead candidate drug for preferential RRM2 inhibition, the development of even more specific RRM2 inhibitors is desirable.

Ewing sarcoma is characterized by the expression of the chimeric EWSR1-FLI1 transcription factor. Proteomic analyses indicate that the decrease of EWSR1-FLI1 expression leads to major changes in effectors of the dynamics of the actin cytoskeleton and the adhesion processes with a shift from cell-to-cell to cell-matrix adhesion. These changes are associated with a dramatic increase of in vivo cell migration and invasion potential. Importantly, EWSR1-FLI1 expression, evaluated by single-cell RT-ddPCR/immunofluorescence analyses, and activity, assessed by expression of EWSR1-FLI1 downstream targets, are heterogeneous in cell lines and in tumours and can fluctuate along time in a fully reversible process between EWSR1-FLI1 high states, characterized by highly active cell proliferation, and EWSR1-FLI1 low states where cells have a strong propensity to migrate, invade and metastasize. This new model of phenotypic plasticity proposes that the dynamic fluctuation of the expression level of a dominant oncogene is an intrinsic characteristic of its oncogenic potential.

Purpose In a preclinical drug screen, mithramycin was identified as a potent inhibitor of the Ewing sarcoma EWS–FLI1 transcription factor. We conducted a phase I/II trial to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of mithramycin in children with refractory solid tumors, and the activity in children and adults with refractory Ewing sarcoma. Patients and methods Mithramycin was administered intravenously over 6 h once daily for 7 days for 28 day cycles. Adult patients (phase II) initially received mithramycin at the previously determined recommended dose of 25 µg/kg/dose. The planned starting dose for children (phase I) was 17.5 µg/kg/dose. Plasma samples were obtained for mithramycin PK analysis. Results The first two adult patients experienced reversible grade 4 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation exceeding the MTD. Subsequent adult patients received mithramycin at 17.5 µg/kg/dose, and children at 13 µg/kg/dose with dexamethasone pretreatment. None of the four subsequent adult and two pediatric patients experienced cycle 1 DLT. No clinical responses were observed. The average maximal mithramycin plasma concentration in four patients was 17.8 ± 4.6 ng/mL. This is substantially below the sustained mithramycin concentrations ≥50 nmol/L required to suppress EWS–FLI1 transcriptional activity in preclinical studies. Due to inability to safely achieve the desired mithramycin exposure, the trial was closed to enrollment. Conclusions Hepatotoxicity precluded the administration of a mithramycin at a dose required to inhibit EWS–FLI1. Evaluation of mithramycin in patients selected for decreased susceptibility to elevated transaminases may allow for improved drug exposure.

Primary bone cancers include osteosarcoma, Ewing sarcoma, and chondrosarcoma. They account for less than 1% of diagnosed cancers each year and are associated with significant morbidity and mortality. Timely diagnosis is challenging because of late patient presentation, nonspecific symptoms that mimic common musculoskeletal injuries, and low suspicion by physicians. Plain radiography is the preferred diagnostic test. Radiographic suspicion of a bone malignancy should prompt quick referral to a cancer center for multidisciplinary care. Osteosarcoma, the most common bone cancer, most often occurs in children and adolescents. It typically develops in the metaphysis of long bones, specifically the distal femur, proximal tibia, and proximal humerus. Metastasis to the lungs is common. Use of neoadjuvant and adjuvant chemotherapy, in combination with surgery, has improved survival rates to nearly 80% for patients with localized disease, and 90% to 95% of patients do not require limb amputation. Ewing sarcoma is the second most common bone cancer and is similar to osteosarcoma in terms of presenting symptoms, age at occurrence, and treatment. Prognosis for osteosarcoma and Ewing sarcoma depends on the presence of metastasis, which lowers the five-year survival rate to 20% to 30%. Chondrosarcoma is the rarest bone cancer, primarily affecting adults older than 40 years. Survival rates are higher because most of these tumors are low-grade lesions.

BackgroundThe REGOBONE multi-cohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the Ewing sarcoma (ES) cohort.MethodsPatients with relapsed ES progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progression. The primary endpoint was the progression-free rate at 8 weeks. With one-sided α of 0.05, and 80% power, at least 14/24 progression-free patients at 8 weeks were needed for success.ResultsFrom September 2014 to November 2019, 41 patients were accrued. 36 patients were evaluable for efficacy: 23 on regorafenib and 13 on placebo. Thirteen patients (56%; one-sided 95% CI [37.5%–[)) were progression-free at 8 weeks on regorafenib vs. 1 (7.7%; 95% CI [0.4%–[) on placebo. Median PFS was 11.4 weeks on regorafenib, and 3.9 weeks on placebo. Ten placebo patients crossed over to receive regorafenib after progression. The most common grade ≥3 regorafenib-related adverse events were pain (22%), asthenia (17%), thrombocytopenia (13%) and diarrhoea (13%).ConclusionAlthough the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy.

While sarcomas account for approximately 1% of malignant tumors of adults, they are particularly more common in children and adolescents affected by cancer. In contrast to malignancies that occur in later stages of life, childhood tumors, including sarcoma, are characterized by a striking paucity of somatic mutations. However, entity-defining fusion oncogenes acting as the main oncogenic driver mutations are frequently found in pediatric bone and soft-tissue sarcomas such as Ewing sarcoma (EWSR1-FLI1), alveolar rhabdomyosarcoma (PAX3/7-FOXO1), and synovial sarcoma (SS18-SSX1/2/4). Since strong oncogene-dependency has been demonstrated in these entities, direct pharmacological targeting of these fusion oncogenes has been excessively attempted, thus far, with limited success. Despite apparent challenges, our increasing understanding of the neomorphic features of these fusion oncogenes in conjunction with rapid technological advances will likely enable the development of new strategies to therapeutically exploit these neomorphic features and to ultimately turn the “undruggable” into first-line target structures. In this review, we provide a broad overview of the current literature on targeting neomorphic features of fusion oncogenes found in Ewing sarcoma, alveolar rhabdomyosarcoma, and synovial sarcoma, and give a perspective for future developments.