Ewing Sarcoma

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P2, N=0, Withdrawn, Nicklaus Children's Hospital f/k/a Miami Children's Hospital | N=10 --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.

In this context, the tumour underwent genome-wide near haploidisation resulting in a massive overexpression of pro-inflammatory cytokines. Recruitment of defective neutrophils fostered rapid evolution of this EWS.

P1/2, N=114, Recruiting, Milton S. Hershey Medical Center | Not yet recruiting --> Recruiting

The undifferentiated epithelioid morphology and unusual aberrant neuroendocrine marker expression posed significant diagnostic challenges. The major differential diagnoses were discussed in this report.

P1, N=22, Suspended, University of Wisconsin, Madison | Recruiting --> Suspended

Genotoxicity-induced activation of the NLRC4-ATR-ATRIP-ETAA1 complex drove the tumor-suppressing DNA damage response and CHK1 activation, and further attenuated the accumulation of DNA damage. These findings demonstrate a noninflammatory function of an inflammasome protein in promoting the DNA damage response and mediating protection against cancer.

Respiratory management is difficult in patients with mucopolysaccharidosis, especially under general anesthesia. Orthopedic surgeons should be aware that surgical planning must be performed carefully when soft tissue sarcomas occur in patients with mucopolysaccharidosis.

Nineteen analogs were then prepared and evaluated to investigate the structure-activity relationships, several of which inhibited the growth of SK-N-MC Ewing sarcoma cells in vitro. Compound 3 emerged as one of the most potent growth inhibitors (IC50 = 0.33 ± 0.04 µM), demonstrating the ability to induce apoptosis and cell cycle arrest in SK-N-MC cells in vitro, and to slow the growth of Ewing sarcoma in vivo in a zebrafish model.

In addition, Enavatuzumab can significantly inhibit the migratory ability of the Ewing sarcoma cell line RD-ES. This groundbreaking study provides unprecedented mechanistic insights into the progression of bladder ES/PNET and introduces a potential therapeutic avenue for treating this challenging malignancy.

Although Ewing sarcoma of the lumbar spine is rare, it should always be considered among pediatric populations developing localized fever and pain. Early detection is crucial to avoid undesired outcomes.

P2, N=9, Active, not recruiting, National Cancer Institute (NCI) | N=49 --> 9 | Trial completion date: Sep 2024 --> Oct 2025

DUX4 IHC is a highly sensitive and specific surrogate marker for the presence of CIC::DUX4 fusion, demonstrating its utility in establishing a diagnosis of CRS.

P300-inhibited senescent ES cells can then be eliminated by senolytics targeting the PI3K signaling pathway. The vulnerability of ES cells to this combination therapy suggests an appealing synergistic strategy for future therapeutic exploration.

This case underscores the importance of thorough diagnostics, long-term follow-up, and improved healthcare infrastructure. This case report emphasizes the importance of a multidisciplinary approach, regular follow-ups, and timely detection for effective management of MPMs.

P1/2, N=27, Not yet recruiting, University of Florida

P1/2, N=253, Not yet recruiting, Milton S. Hershey Medical Center | Trial completion date: Jul 2034 --> Dec 2034 | Initiation date: Sep 2024 --> Dec 2024 | Trial primary completion date: Jul 2032 --> Dec 2032

Given the often non-specific histology and immunophenotype of mesenchymal nonmeningothelial tumors of uncertain differentiation, molecular techniques have become indispensable for accurate diagnosis. This review provides a comprehensive overview of primary mesenchymal non-meningothelial CNS tumors, including their clinical, radiological, histopathological, and molecular characteristics and treatment strategies.ABBREVIATIONS: ALK: Anaplastic lymphoma kinase; ATF1: activating transcriptase factor-1; CREB: cAMP response element-binding protein; CREM: cAMP response element modulator; CIC: Capicua transcriptional receptor; EWSR1: Ewing sarcoma RNA binding protein; FUS: fused in sarcoma; NAB2: nerve growth factor-inducible protein A binding protein 2; STAT6: signal transducer and activator of transcription 6; WHO: World Health Organization WHO CNS5: World Health Organization Classification of Tumors of the Central Nervous System, fifth edition.

However, targeting condensate formation is challenging due to the transient nature of the interactions involved, complicating the development of effective inhibitors. This work underscores the importance of further investigation into therapeutic strategies aimed at disrupting condensate formation in Ewing sarcoma and other related malignancies.

Moreover, menin can either suppress or promote tumorigenesis in the breast and prostate depending on hormone receptor status and may also have mixed roles in hepatocellular carcinoma. Here, we review the rapidly expanding literature on the role and function of menin across a broad array of different cancer types, outlining tumor-specific differences in menin's function and mechanism of action, as well as identifying its therapeutic potential and highlighting areas for future investigation.

This mutant ENL forms condensates in hematopoietic stem/progenitor cells at the genomic loci of key leukemogenic genes, including Meis1 and Hoxa cluster genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Furthermore, they show that small-molecule inhibition of the acetyl-binding activity displaces ENL mutant condensates from oncogenic target loci, and this inhibitor significantly impairs the onset and progression of AML driven by mutant ENL in vivo.

P=N/A, N=60, Recruiting, Mayo Clinic | N=180 --> 60

Elevated ENO-1+CD81+ extracellular vesicles in the serum of patients before treatments distinguished patients with Ewing sarcoma from healthy individuals with an area under the curve value of 0.92 (P < 0.001) and reflected the tumor burden in patients with Ewing sarcoma during multidisciplinary treatments. Collectively, circulating ENO-1+CD81+ extracellular vesicle detection could represent a novel tool for tumor monitoring of Ewing sarcoma.

P2, N=650, Active, not recruiting, St. Jude Children's Research Hospital | Recruiting --> Active, not recruiting