Search

Background Immune cells can regulate disease progression and response to treatment in multiple tumor types, but their activities in human soft tissue sarcoma are poorly characterized. Methods Marker-defined immune cell subsets were characterized from a tumor microenvironmental perspective in two independent cohorts of human soft tissue sarcoma by multiplex IHC, quantitative PCR and/or bioinformatics. Results B cell profiling revealed a prognostic role for CD20 protein (cohort 1, 33 patients) and MS4A1 gene expression (cohort 2, 265 patients). Multiplex IHC and gene correlation analysis supported a role in antigen presentation, immune cell differentiation and T cell activation. The prognostic role of MS4A1 expressing B cells was only observed in an IL10low, PTGS2low or CD163low tumor microenvironment according to the transcriptomic data. IL10 levels consistently correlated with the M2-like macrophage marker CD163, which also defined the majority of macrophages. A polarization of these cells toward a pro-tumoral phenotype was further supported by lack of correlation between CD163 and M1 markers like NOS2, as well as by low abundance of CD80 positive cells in tissue. Conclusions Analysis of CD20/MS4A1 expression in soft tissue sarcoma merits further attention as a promising candidate prognostic tool for survival, but not in patients with a pronounced immunosuppressive tumor microenvironment. Macrophages are ubiquitous and polarized toward a protumoral phenotype. This provides a rationale for further studies on B cell function and immunotherapy targeting M2-polarized macrophages. Electronic supplementary material The online version of this article (10.1007/s00262-019-02322-y) contains supplementary material, which is available to authorized users.

Chondrosarcomas are the second most common malignant bone tumor. Activating promoter mutations in telomerase reverse transcriptase (TERT) was recently described by us and others as a frequent mutation in high-grade chondrosarcoma. In this study, we investigate the prognostic significance of TERT promoter mutations in 241 chondrosarcomas from 190 patients collected over 24 years (1994–2017). The TERT promoter was sequenced after microdissection of 135 chondrosarcomas from 106 patients in addition to data from our previous cohort. The TERT promoter mutation at −124 C > T was found in 45% of all patients and was significantly associated (p > 0,001) with higher tumor grade, shorter metastasis-free survival, and disease-specific survival. Additionally, TERT promoter-mutated tumors were associated with a more aggressive metastatic pattern. Shorter survival was observed in patients with wild-type primary tumors who developed a mutated metastasis indicative of tumor progression. Primary tumor genetic heterogeneity and altering mutational status between nonsynchronous metastatic lesions suggests that chondrosarcoma is a multiclonal disease progressing through a branching evolution. Conclusion: TERT promoter mutation seems to be a central event in chondrosarcoma progression with association to metastatic disease and disease-related mortality. As an easily analyzed marker, there is future potential to utilize TERT promoter mutation status as a prognostic marker and investigate telomerase-targeted therapy in chondrosarcomas.

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.

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.