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Pediatric sarcomas present heterogeneous morphology, genetics and clinical behavior posing a challenge for an accurate diagnosis. DNA methylation is an epigenetic modification that coordinates chromatin structure and regulates gene expression, determining cell type and function. DNA methylation-based tumor profiling classifier for sarcomas (known as sarcoma classifier) from the German Cancer Research Center (Deutsches Krebsforschungszentrum) was applied to 122 pediatric sarcomas referred to a reference pediatric oncology hospital. The classifiers reported 88.5% of agreement between histopathological and molecular classification confirming the initial diagnosis of all osteosarcomas and Ewing sarcomas. The Ewing-like sarcomas were reclassified into sarcomas with BCOR or CIC alterations, later confirmed by orthogonal diagnostic techniques. Regarding the CNAs profile, osteosarcomas had several chromosomal gains and losses as well as chromothripsis, whereas Ewing sarcomas had few large events, such as amplifications of chromosomes 8 and 12. The molecular classification together with clinical and histopathological assessment could improve the diagnosis of pediatric sarcomas although there are limitations to deal with more rare classes. This study provides an increase in the number of sarcomas evaluated for DNA methylation profiling in the pediatric population.

Purpose of ReviewOsteosarcoma (OSA) is the most common primary tumor of bone, mainly affecting children and adolescents. Here we discuss recent advances in surgical and systemic therapies, and highlight potentially new modalities in preclinical evaluation and prognostication.Recent FindingsThe advent of neoadjuvant and adjuvant chemotherapy has markedly improved the disease-free recurrence and overall survival of OSA. However, treatment efficacy has been stagnant since the 1980s. This plateau has prompted preclinical and clinical research into in precision surgery, inhaled chemotherapy to increase pulmonary drug concentration without systemic side effects, and novel immunomodulators intended to block molecular pathways associated with OSA proliferation and metastasis.SummaryWith the advent of novel surgical techniques and new forms and vectors for chemotherapy, it is hoped that OSA treatment outcomes will exceed their currently sustained plateau in the near future.

Purpose of ReviewThe prognosis of pediatric patients who present with metastatic or recurrent sarcomas remains poor. In this review, we summarize the advances in the management of metastatic and relapsed pediatric sarcoma by highlighting recent and future clinical trials.Recent FindingsResearch into the identification of novel therapies for refractory pediatric sarcomas continues to advance. Outcomes have not improved in several decades underlying a need for improved understanding of the biology behind these tumors and the identification of novel therapeutic molecular targets that can be exploited pharmacologically. Multiple challenges remain for novel therapy in sarcomas such as the selection of effective targets, management of toxicities, and the tumor microenvironment.SummaryMany unique challenges remain in the treatment of patients with refractory pediatric sarcomas. Multiple strategies and targets are under investigation that hold promise.

Sarcomas are cancers arising from the mesenchymal layer that affect children, adolescents, young adults, and adults. Although most sarcomas are localized, many display a remarkable predilection for metastasis to the lungs, liver, bones, subcutaneous tissue, and lymph nodes. Additionally, many sarcoma patients presenting initially with localized disease may relapse at metastatic sites. While localized sarcomas can often be cured through surgery and often radiation, controversies exist over optimal management of patients with metastatic sarcoma. Combinations of chemotherapy are the most effective in many settings, and many promising new agents are under active investigation or are being explored in preclinical models. Metastatic sarcomas are excellent candidates for novel approaches with additional agents as they have demonstrated chemosensitivity and affect a portion of the population that is motivated toward curative therapy. In this paper, we provide an overview on the common sarcomas of childhood (rhabdomyosarcoma), adolescence, and young adults (osteosarcoma, Ewing sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor) and older adults (leiomyosarcoma, liposarcoma, and undifferentiated high grade sarcoma) in terms of the epidemiology, current therapy, promising therapeutic directions and outcome with a focus on metastatic disease. Potential advances in terms of promising therapy and biologic insights may lead to more effective and safer therapies; however, more clinical trials and research are needed for patients with metastatic sarcoma.

While promising, immunotherapy has yet to be fully unlocked for the preponderance of cancers where conventional chemoradiation reigns. This remains particularly evident in pediatric sarcomas where standard of care has not appreciably changed in decades. Importantly, pediatric bone sarcomas, like osteosarcoma and Ewing’s sarcoma, possess unique tumor microenvironments driven by distinct molecular features, as do rhabdomyosarcomas and soft tissue sarcomas. A better understanding of each malignancy’s biology, heterogeneity, and tumor microenvironment may lend new insights toward immunotherapeutic targets in novel platform technologies for cancer vaccines and adoptive cellular therapy. These advances may pave the way toward new treatments requisite for pediatric sarcomas and patients in need of new therapies.

Purpose of ReviewThis review presents a selection of regulatory molecules of tumor microenvironmental properties and metastasis. Signaling pathways controlling mesenchymal biology in bone and soft-tissue sarcomas found in children and adolescents are prioritized.Recent FindingsThe tumor microenvironment of pediatric tumors is still relatively unexplored. Highlighted findings are mainly on deregulated genes associated with cell adhesion, migration, and tumor cell dissemination. How these processes are involved in a mesenchymal phenotype and metastasis is further discussed in relation to the epithelial to mesenchymal transition (EMT) in epithelial tumors. Cell plasticity is emerging as a concept with impact on tumor behavior.SummarySarcomas belong to a heterogeneous group of tumors where local recurrence and tumor spread pose major challenges despite intense multimodal treatments. Molecular pathways involved in the metastatic process are currently being characterized, and tumor-regulatory properties of structural components, and infiltrating, non-malignant cell types should be further investigated.

Pediatric sarcomas, including osteosarcoma (OS), Ewing sarcoma (EwS) and rhabdomyosarcoma (RMS) carry low somatic mutational burden and low MHC-I expression, posing a challenge for T cell therapies. Our previous study showed that mediators of monocyte maturation sensitized the EwS cell line A673 to lysis by HLA-A*02:01/CHM1 -specific allorestricted T cell receptor (TCR) transgenic CD8 T cells (CHM1 CD8 T cells). In this study, we tested a panel of monocyte maturation cytokines for their ability to upregulate immunogenic cell surface markers on OS, EwS and RMS cell lines, using flow cytometry. xCELLigence, SRB and ELISpot assays were used to assess whether TNF pretreatment increases CD8 T cell cytotoxicity. We observed that TNF and IL-1β upregulated MHC class I, ICAM-1 as well as CD83 and PD-L1 on the surface of pediatric sarcoma cell lines, while IL-4, GM-CSF, IL-6 and PGE failed to induce respective effects. Although pretreatment of pediatric sarcoma cell lines with TNF did not improve unspecific peripheral blood mononuclear cells (PBMCs) cytotoxicity, TNF enhanced specific lysis of 1/3 HLA-A2 EwS cell lines by CHM1 CD8 T cells depending on MHC-I expression and ICAM-1 upregulation. Our study supports utilization of TNF or TNF-inducing regimens for upregulation of MHC-I and costimulatory surface molecules on pediatric sarcoma cells and for enhancing recognition of responsive HLA-A2 EwS tumor cells by antigen-specific CD8 T cells.

Pediatric sarcomas present a significant challenge in oncology. There is an urgent need for improved therapeutic strategies for high-risk patients and better management of long-term side effects for those who survive the disease. Liquid biopsy is emerging as a promising tool to optimize treatment in these patients by offering non-invasive, repeatable assessments of disease status. Circulating biomarkers can provide valuable insights into tumor genetics and treatment response, potentially facilitating early diagnosis and dynamic disease monitoring. This review examines the potential of liquid biopsies, focusing on circulating biomarkers in the most common pediatric sarcomas, i.e., osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma. We also highlight the current research efforts and the necessary advancements required before these technologies can be widely adopted in clinical practice.

Background While most pediatric sarcomas respond to front-line therapy, some bone sarcomas do not show radiographic response like soft-tissue sarcomas (rhabdomyosarccomas) but do show 90% necrosis. Though, new therapies are urgently needed to improve survival and quality of life in pediatric patients with sarcomas. Complex chromosomal aberrations such as amplifications and deletions of DNA sequences are frequently observed in pediatric sarcomas. Evaluation of copy number variations (CNVs) associated with pediatric sarcoma patients at the time of diagnosis or following therapy offers an opportunity to assess dysregulated molecular targets and signaling pathways that may drive sarcoma development, progression, or relapse. The objective of this study was to utilize publicly available data sets to identify potential predictive biomarkers of chemotherapeutic response in pediatric Osteosarcoma (OS), Rhabdomyosarcoma (RMS) and Ewing’s Sarcoma Family of Tumors (ESFTs) based on CNVs following chemotherapy (OS n  = 117, RMS n  = 64, ESFTs n  = 25 tumor biopsies). Methods There were 206 CNV profiles derived from pediatric sarcoma biopsies collected from the public databases TARGET and NCBI-Gene Expression Omnibus (GEO). Through our comparative genomic analyses of OS, RMS, and ESFTs and 22,255 healthy individuals called from the Database of Genomic Variants (DGV), we identified CNVs (amplifications and deletions) pattern of genomic instability in these pediatric sarcomas. By integrating CNVs of Cancer Cell Line Encyclopedia (CCLE) identified in the pool of genes with drug-response data from sarcoma cell lines ( n  = 27) from Cancer Therapeutics Response Portal (CTRP) Version 2, potential predictive biomarkers of therapeutic response were identified. Results Genes associated with survival and/recurrence of these sarcomas with statistical significance were found on long arm of chromosome 8 and smaller aberrations were also identified at chromosomes 1q, 12q and x in OS, RMS, and ESFTs. A pool of 63 genes that harbored amplifications and/or deletions were frequently associated with recurrence across OS, RMS, and ESFTs. Correlation analysis of CNVs from CCLE with drug-response data of CTRP in 27 sarcoma cell lines, 33 CNVs out of 63 genes correlated with either sensitivity or resistance to 17 chemotherapies from which actionable CNV signatures such as IGF1R, MYC, MAPK1, ATF1, and MDM2 were identified. These CNV signatures could potentially be used to delineate patient populations that will respond versus those that will not respond to a particular chemotherapy. Conclusions The large-scale analyses of CNV-drug screening provides a platform to evaluate genetic alterations across aggressive pediatric sarcomas. Additionally, this study provides novel insights into the potential utilization of CNVs as not only prognostic but also as predictive biomarkers of therapeutic response. Information obtained in this study may help guide and prioritize patient-specific therapeutic options in pediatric bone and soft-tissue sarcomas.