Ewing Sarcoma

The prognosis of these tumors is highly dependent on factors such as tumor location and stage at diagnosis, and given their aggressive nature, a multidisciplinary approach may be required that combines surgical resection, chemotherapy, and radiation therapy, among other options. In this review, we provide a synopsis of the pathophysiology of DSRCTs and the latest diagnostic advancements, including the utility of molecular profiling and novel biomarkers.

Genomic profiling of sarcomas offers valuable insights into their molecular drivers and can support personalized therapeutic approaches. Further research is needed to validate these findings and optimize treatment strategies for sarcoma patients.

About 20% of interval cancers were evident on screening mammograms. The most common radiologic finding in interval cancers was asymmetry/mass. Interval cancers are diagnosed at a more advanced stage than cancers identified at screening, so they sre more often treated by mastectomy. Reviewing interval cancers is essential for quality control in screening programs.

P1, N=321, Recruiting, Inhibrx Biosciences, Inc | N=240 --> 321 | Trial completion date: Jul 2026 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Jun 2026

Further analysis shows that the RPA1-ETAA1 axis is significantly associated with multiple metastasis mediators and unfavorable liver cancer progression, with higher expression observed in advanced stages and poorly differentiated subgroups. These findings expand the role of the RPA1-ETAA1 axis beyond DNA repair, highlighting its potential as a target for cancer therapy.

P1/2, N=48, Active, not recruiting, Sarcoma Alliance for Research through Collaboration | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P2, N=163, Active, not recruiting, UNICANCER | Recruiting --> Active, not recruiting | Trial completion date: Mar 2026 --> Jun 2025 | Trial primary completion date: Sep 2025 --> Oct 2024

Our results indicate that restoring canonical p53 activity provides a promising strategy for developing improved therapies for pediatric sarcomas with unfavorable stem-like traits.

P3, N=312, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

This case underscores the clinical significance of EES, a rare variant presenting diagnostic challenges. Our findings highlight the importance of prompt diagnosis and early management to improve outcomes for patients with this aggressive malignancy.

P1, N=20, Recruiting, Valent Technologies, LLC | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P1/2, N=31, Active, not recruiting, National Cancer Institute (NCI) | N=23 --> 31 | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Sep 2024

In conclusion, although the histopathological appearance of EWSR1::PATZ1 gene fusion CNS tumors is diverse, there are consistent imaging features. Recognition of these features can be valuable in the diagnostic process, as radiologists can be the first to suggest the diagnosis.

While each of these entities is less common than Ewing sarcoma, it is important to distinguish these tumors for correct diagnosis, prognostication, and potential treatment management. The focus of this review will cover CIC-rearranged sarcoma, BCOR-altered sarcomas, and EWSR1-non-ETS sarcomas to include recent developments in desmoplastic small round cell tumor as well as sarcomas with EWSR1/FUS::NFATc2 and EWSR1::PATZ1 gene fusions, highlighting the clinical, morphologic, and immunophenotypic clues to the diagnosis with recognition of each molecular diagnostic hallmark.

Our study identifies the C domain of the ECM protein TNC as a promising CAR T-cell therapy for pediatric solid tumors and brain tumors. While we focus here on pediatric cancer, our work has relevance to a broad range of adult cancers that express C.TNC.

P2, N=22, Recruiting, Fudan University

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.

The investigation emphasizes the significance of understanding the molecular behavior of EWS-FLI1 for effective treatment development, utilizing computational methods such as density functional theory. The findings suggest that EWS-FLI1 is a compact, electrophilic protein with localized reactive sites, providing valuable insights for potential drug development and enhancing our knowledge of Ewing sarcoma for targeted treatments.

Despite the typically benign nature of extraosseous Ewing tumors, they can rarely metastasize in less than 20% of cases, as exemplified by this rare case. Accurate diagnosis requires a combined clinic-radio-immunohistochemical approach, and general practitioners should be aware of this clinical entity in neck masses considering its variable clinical presentation and poor prognosis in certain patient's population.

Complete suppression of EWSR1-FLI1 induced a reversible cell cycle arrest at the G 1 -S checkpoint, and we identified a core set of transcripts downstream of EWSR1-FLI1 across multiple cell lines and degron systems. Additionally, depletion of EWSR1-FLI1 potently suppressed tumor growth in xenograft models validating efforts to directly target EWSR1-FLI1 in Ewing's sarcoma.

By profiling chromatin accessibility and genome-wide EWSR1::FLI1 binding, we find that the fusion oncogene hijacks developmental enhancers for neural crest to mesoderm reprogramming during cancer initiation. These findings show how a single mutation profoundly alters embryonic cell fate decisions to initiate a devastating childhood cancer.

CSI rather than focal radiotherapy should be considered for patients with IEES limited to the cerebrospinal axis. PBT may be used as an alternative to photon radiotherapy to better spare organs at risk.

Our findings confirm the distinctive clinicopathological features of this very rare, recently described entity and expand its molecular genetic spectrum. Reflecting these findings, we propose modifying the name of this entity to "superficial neurocristic FET::ETS fusion tumor".

A good knowledge of the usual histomorphology, uncommon variants and diagnostic pitfalls remains essential even in centres with access to a full molecular testing arsenal. This review aims to give an overview of the current classification of USRCS not by going over each entity, but instead going over the molecular, morphological, immunophenotypic and clinical features step by step to allow easy comparison of these features between the separate entities.

The combination of Panobinostat with Doxorubicin or Etoposide, both of which are used as standard of care in upfront treatment, leads to a synergistic effect in EWS cells. Overall, our data indicate that HDAC2 is overexpressed in many EWS tumor samples and HDAC inhibition is effective in targeting EWS cells, alone and in combination with standard-of-care chemotherapy agents. This work suggests that the addition of an HDAC inhibitor to upfront treatment may improve response.

Both EWS::FLI1 and CD99 are regulated targets of the DREAM complex, but the CD99 expression specifically impacted genes that are the targets of FOXM1 and are involved in the setting of the G2/M phase of the cell cycle. Most CD99-regulated FOXM1-targeted genes were found to correlate with bad prognosis in two public clinical datasets (R2 platform), further supporting the clinical relevance of CD99-mediated regulation of EwS gene expression.

Our findings provide insight on the clinical presentation and appropriate management of extraosseous ES, specifically in the ethmoid sinus in the adult population.

We present an intriguing case report of a 5-year-old boy diagnosed with a moderately cellular mandibular spindle cell tumor exhibiting BCOR-ITD rearrangement which was initially misdiagnosed as an odontogenic fibromyxoma. This case report illustrates the histological and immunophenotypic findings of BCOR-ITD rearranged sarcoma, requiring a comprehensive immunohistochemical panel and additional molecular tests for accurate diagnosis.

P2, N=202, Active, not recruiting, St. Jude Children's Research Hospital | Trial completion date: Oct 2024 --> Oct 2029

P2, N=83, Active, not recruiting, Memorial Sloan Kettering Cancer Center

P2, N=0, Withdrawn, Nicklaus Children's Hospital f/k/a Miami Children's Hospital | N=10 --> 0 | Active, not recruiting --> Withdrawn

P=N/A, N=400, Recruiting, Istituto Ortopedico Rizzoli | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Jul 2024 --> Dec 2024

P1, N=22, Recruiting, University of Wisconsin, Madison | Suspended --> Recruiting | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

Thus, trabectedin enhances both the direct virus-mediated killing of tumor cells and the viral-induced activation of cytotoxic effector lymphocytes to cause tumor regressions across models. Our data provide a strong rationale for clinical translation as both mechanisms should be simultaneously active in human patients.

STAG1 is unable to compensate for STAG2 loss and chromatin-bound cohesin is severely decreased, while levels of the processivity factor NIPBL remain unchanged, likely affecting DNA looping dynamics. These results illuminate how STAG2 loss modifies the chromatin interactome of Ewing sarcoma cells and provide a list of potential biomarkers and therapeutic targets.

KCNN1 is involved in the regulation of ES cell proliferation, with its silencing being associated with a slowing of the cell cycle, and its expression modulates membrane potential and therefore calcium flux. These results highlight that KCNN1 is a direct target of EWS::FLI1 and EWS::ERG and demonstrate that KCNN1 is involved in the regulation of intracellular calcium activity and ES cell proliferation, making it a promising therapeutic target in ES.

P2, N=23, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

These genetic features might be relevant to metastasis and resistance to chemotherapy. To summarize, the novel patient-derived ES cell line we developed closely mimics the phenotype and genotype of patient tumors, making it a reliable tool for research on metastatic ES.

P1/2, N=64, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Despite undergoing radical surgery and receiving systemic treatments including VeIP (vinblastine, ifosfamide, cisplatin), and VDC (vincristine, doxorubicin, cyclophosphamide) regimens, the patient succumbed to death due to disease progression. With the implementation of NGS, we anticipate that more cases with SMARCA4 mutations will be diagnosed in the future. Further research is necessary to unveil therapeutic targets associated for this oncogenic alteration.

P2, N=4, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

Importantly, we show that edaravone treatment in preclinical models delays glioblastoma tumorigenesis, sensitizes their response to IR, and prolongs the lifespan of animals. Our data suggest that repurposing of edaravone is a promising therapeutic strategy for patients with glioblastoma.