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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.

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.

SummaryBackgroundPatients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma. MethodsWe did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0–1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m 2) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605. FindingsBetween April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4–35·4) for patients with Ewing sarcoma and 31·1 months (24·4–31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13–42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4–26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20–50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects. InterpretationCabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation. FundingInstitut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.

[...]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.

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.

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.

Primary intraarticular sarcomas are rare. We describe a unique case of intraarticular Ewing sarcoma arising in Hoffa fat pad of knee in a woman. The patient was treated successfully with chemotherapy and left knee arthroplasty; however, the tumor recurred after 3 years. We review the literature on primary intraarticular sarcomas and Hoffa fat pad masses in the knee.