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Simple Summary Ewing sarcoma is a highly aggressive malignancy affecting primarily children and adolescents. It is the second most common bone sarcoma among children, affecting between 1 and 3 persons per million inhabitants. The tumor typically carries a pathognomonic chromosomal translocation resulting in a fusion transcript (EWSR1-FLI1), which plays an orchestral role in tumor development. While the fusion transcript has been known for decades, targeted treatment has been disappointing. However, new molecular techniques such as next-generation sequencing have significantly increased our understanding of this rare disease. Moreover, new closely related tumors with similar morphology but different characteristics have evolved. Treatment today consists of multiagent chemotherapy, radiation treatment, and surgery, all of which are associated with significant short- and long-term side effects. In this review article, we describe the currently existing diagnostic- and treatment-related challenges as well as the most important ongoing or recently conducted studies. Abstract Ewing sarcoma is the second most common bone sarcoma in children after osteosarcoma. It is a very aggressive malignancy for which systemic treatment has greatly improved outcome for patients with localized disease, who now see survival rates of over 70%. However, for the quarter of patients presenting with metastatic disease, survival is still dismal with less than 30% of patients surviving past 5 years. Patients with disease relapse, local or distant, face an even poorer prognosis with an event-free 5-year survival rate of only 10%. Unfortunately, Ewing sarcoma patients have not yet seen the benefit of recent years’ technical achievements such as next-generation sequencing, which have enabled researchers to study biological systems at a level never seen before. In spite of large multinational studies, treatment of Ewing sarcoma relies entirely on chemotherapeutic agents that have been largely unchanged for decades. As many promising modern therapies, including monoclonal antibodies, small molecules, and immunotherapy, have been disappointing to date, there is no clear candidate as to which drug should be investigated in the next large-scale clinical trial. However, the mechanisms driving tumor development in Ewing sarcoma are slowly unfolding. New entities of Ewing-like tumors, with fusion transcripts that are related to the oncogenic EWSR1-FLI1 fusion seen in the majority of Ewing tumors, are being mapped. These tumors, although sharing much of the same morphologic features as classic Ewing sarcoma, behave differently and may require a different treatment. There are also controversies regarding local treatment of Ewing sarcoma. The radiosensitive nature of the disease and the tendency for Ewing sarcoma to arise in the axial skeleton make local treatment very challenging. Surgical treatment and radiotherapy have their pros and cons, which may give rise to different treatment strategies in different centers around the world. This review article discusses some of these controversies and reproduces the highlights from recent publications with regard to diagnostics, systemic treatment, and surgical treatment of Ewing sarcoma.

Ewing sarcomas (ESs) are aggressive sarcomas driven by EWS fusion genes. We sought to investigate whether whole‐transcriptome sequencing (RNA‐seq) could be used to detect patterns associated with chemotherapy response or tumor progression after first‐line treatment. Transcriptome sequencing (RNA‐seq) of 13 ES cases was performed. Among the differentially expressed pathways, we identified IGF2 expression as a potential driver of chemotherapy response and progression. We investigated the effect of IGF2 on proliferation, radioresistance, apoptosis, and the transcriptome pattern in four ES cell lines and the effect of IGF2 expression in a validation series of 14 patients. Transcriptome analysis identified differentially expressed genes (adj. P, Transcriptome profiling may provide prognostic information in the incipient age of genetic‐driven personalized oncology. In this study, Chen et al. identified expression signatures associated with tumor progression and chemotherapy resistance in Ewing sarcomas, including IGF2 expression which was associated with an aggressive clinical course. Transcriptome analysis could potentially become a complementary tool to predict the clinical behavior of rare tumors.

Background The long-term risks and time trends of subsequent primary neoplasms (SPNs) among Ewing (ES) and osteosarcoma (OS) survivors are not fully understood. Methods We performed a nationwide study of all ES and OS patients identified in the Swedish Cancer Registry from 1958 to 2015 with up to 58 years of follow-up. The risk of SPN was compared with that of the general population using standardised incidence ratios (SIRs) and absolute excess risks (AERs). Results One hundred and fifteen SPNs were diagnosed among 1779 patients with ES or OS, yielding an overall SIR of 2.3 (95% confidence interval (CI), 1.9–2.7). The risk remained significantly increased in the latest treatment era (SIR2000-2015 2.0; 95% CI, 1.1–3.5). The highest absolute excess risks (AER) was due to breast cancer (AER 15.2/10,000 person-years; 95% CI, 5.0–29.8) followed by female genital malignancies (AER 9.5/10,000 person-years; 95% CI, 2.4–21.5). The excess breast cancer risk among ES survivors was noted also after 30 years of follow-up with 127 extra breast cancers/10,000 person-years (95% CI, 6.6–419). Conclusions Breast- and female genital malignancies contribute most to the excess risk of SPN among ES and OS survivors. Importantly, excess risks did not decline over calendar time or long-term follow-up.

BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.

Object: Many patients with Ewing sarcoma (ES) of the mobile spine present with neurologic symptoms leading to emergency decompressive surgery. Only rarely is optimal treatment involving neo-adjuvant chemotherapy followed by en bloc excision possible. The purpose of this study was to study treatment, neurologic and oncologic outcome in patients with ES of the mobile spine.Methods: Twenty-four patients diagnosed between 1986 and 2012 were identified through the Scandinavian Sarcoma Group registry. Charts were reviewed in order to assess details in patient characteristics, neurologic status, treatment and outcome. Prognostic factors were analyzed with respect to local control, disease-free survival and overall survival.Results: Neurologic symptoms were frequently observed at presentation, being present in 19/23 patients with documented neurologic status. Most (13/19) patients had a complete neurologic recovery regardless of whether or not emergency decompressive surgery was performed. The majority (18/24) of patients were treated with definitive radiotherapy. However, only 9/17 received the recommended dose of ≥ 50.4 Gy. The disease-free and overall survival rates at 10 years were 48% and 57%, respectively. The local recurrence rates were 19% and 27% at 5 and 10 years, respectively. Only year of diagnosis, categorized into periods with significant changes in chemotherapy protocols, was a significant factor for local recurrence, but there was a trend (p = 0.06) for an increased risk of a local recurrence if emergency decompressive surgery was performed.Conclusion: Patients with ES of the mobile have a relatively favorable prognosis. Nonetheless, local recurrence rate is high for this group of patients for which local treatment mainly relies on definitive radiotherapy.Emergency decompressive surgery may increase the risk for local recurrence. Keywords: Ewing sarcoma, Ewing´s sarcoma, Spine, Oncology, Surgery, Radiation treatment

Background Treatment of Ewing sarcoma of the pelvic bones remains one of the most difficult tasks in the treatment of bone sarcomas. Whether surgery or radiation therapy is the best local treatment is still a matter of debate. The aim of the present study was to compare sacral and nonsacral sites with regard to the treatment and outcome of pelvic Ewing sarcomas. Methods Patients with Ewing sarcoma of the osseous pelvis diagnosed between 1986 and 2011 were identified through the Scandinavian Sarcoma Group registry. Data regarding tumor size, local treatment (surgery or radiation therapy), metastatic disease, surgical margins, local recurrence, and overall survival were analyzed. Results Of the 117 patients examined, eighty-eight had tumors in the innominate bones and twenty-nine, in the sacrum. Radiation therapy was the sole local treatment for 40% of the innominate bone tumors in contrast to 79% of the sacral tumors. The five-year disease-free survival rate in the latter group (66%) was greater than that in the group with tumors in the innominate bones (40%) (p = 0.02 adjusted for size). Conclusions Disease-free survival among patients with Ewing sarcoma was improved when the tumor was localized in the sacrum compared with the innominate bones, where these tumors are generally larger. Local radiation therapy alone appears to result in good local tumor control and may be the treatment of choice for sacral tumors.

AimsSolitary fibrous tumour (SFT) is an infrequently metastasising mesenchymal tumour defined by the NAB2–STAT6 fusion gene. Activating mutations in the telomerase reverse transcriptase (hTERT) gene promoter has been reported to associate with adverse patient outcome in SFTs.MethodsWe analysed the hTERT gene for promoter mutations and copy number alterations in 43 primary extrameningeal SFTs (9 malignant and 34 benign tumours according to WHO 2013 criteria), six local recurrences and three metastatic lesions.ResultsActivating −124 C>T (n=12) or −148 C>T (n=2) mutations were found in 33% of the tumours and associated with older age (P=0.006), necrosis (P=0.009), higher mitotic rate (P=0.003), nuclear atypia (P=0.002), malignant histological diagnosis (P=0.04) and worse progression-free survival (P=0.023). We also observed frequent (24%) hTERT promoter mutations in histologically benign tumours without metastasis (mean follow-up >9 years), and in 14%–18% of low-risk SFTs as determined by three risk-stratification models. Mutations were seen in 2/6 metastatic tumours and metastatic lesions. hTERT copy number gain was seen in 11/28 hTERT promoter wild-type cases.ConclusionsActivating hTERT promoter mutations associate with aggressive histopathological features, indicating a role in tumour progression. Given the comparatively high prevalence of hTERT promoter mutations in low-risk and non-metastasising lesions, further studies are required to clarify the prognostic value of hTERT promoter analysis before implementing the analysis in clinical diagnostics.

Chondrosarcomas are malignant skeletal tumors with chondroid differentiation. Prognosis is largely dependent on histological grading, which suffer from significant interobserver variability. Telomerase activity and abundant telomerase reverse transcriptase (hTERT) expression has previously been associated with chondrosarcoma grade and metastasis. We therefore analyzed the hTERT promoter in clinicopathologically well-characterized chondrosarcomas (grade 1–3) from 87 patients. Using Sanger sequencing we identified an activating −124 C > T mutation in 23 cases (26%). Promoter mutations were significantly associated with increased histological grade (8% of grade 1, 32% of grade 2 and 46% of grade 3, P = 0.002), suggesting a role in tumor progression. In four chondrosarcomas where the histopathological grade was heterogenous, the hTERT mutation was only identified in the higher-grade areas. Additionally, hTERT promoter mutations were significantly associated with worse metastasis-free survival (P = 0.018), chondrosarcoma-specific survival (P = 0.022) and older patient age (P = 0.003). These data suggest that hTERT promoter mutations are common in high grade conventional chondrosarcomas. Granted that additional studies can confirm these findings; hTERT promoter analysis could potentially serve as an adjuvant prognostic marker in routine chondrosarcoma grading. This study reinforces the rationale of telomerase targeted therapy in a subset of chondrosarcomas.

Background and purpose Recent data suggest that percutaneous sclerotherapy is a safe alternative to surgery for treatment of aneurysmal bone cysts (ABCs). We present our experience of this method. Methods We retrospectively analyzed data from 38 consecutive patients treated with repeated injections of polidocanol. Each injection consisted of 2–4 mg polidocanol per kg body weight. Radiological and clinical assessments were performed until healing. Results All cycts except 1 healed after a median of 4 (1–11) injections. A lesion failed to heal in 1 patient, who was operated. 3 patients experienced minor local inflammatory reactions. Interpretation Our results show that percutaneus sclerotherapy with polidocanol has high efficacy in the treatment of ABCs, with a low frequency of side effects. Our findings corroborate data presented in previous publications. We believe that the method will be especially valuable in ABCs of the pelvis and sacrum, where surgery is associated with considerable morbidity.