TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.

P2, N=30, Recruiting, Shanghai Pharmaceuticals Holding Co., Ltd | Not yet recruiting --> Recruiting

Priming the leukemic cells with 5-Azacitidine enhanced the cytotoxic effects of TK216 on pediatric leukemia cells...Consistent with this, TK216 also potentiated the cytotoxic effects of Bcl-2 inhibition in venetoclax-resistant cells. The sustained survival benefit provided to leukemic cells in the presence of bone-marrow-derived conditioned media is also found to be modulated by TK216. Taken together, our data indicates that TK216 could be a promising targeted therapeutic agent for the treatment of acute myeloid and B-lymphoid leukemia.

We report the first case of primary intracranial Ewing sarcoma invading the superior sagittal sinus and causing middle segment occlusion, accompanied by EWSR1-FLI1 gene fusion and EWSR1 gene mutation. Subsequently, we conducted a literature review to characterize the clinical information of primary intracranial Ewing sarcomas.

We found that the main effects seen upon EWSR1::CREM knockdown can be reproduced by directly silencing ODC1 expression. These findings provide novel insights into pathogenesis of tumors harboring a EWSR1::CREM fusion gene, hopefully facilitating the development of novel therapeutic strategies.

Conclusively, EMC may manifest superficial or osseous lesions harboring EWSR1::NR4A3, under-recognized solid or anaplastic histology, and pan-Trk expression, posing tremendous challenges. Most TAF15::NR4A3-positive cases were >10 cm in size, i.e., the crucial independent prognosticator, while pathogenic KIT mutation rarely occurred.

The RNA panel detected specific fusions in several cases where no conclusive diagnosis can be made based on the morphology and immunohistochemistry results. Data collected in this study demonstrate that the RNA fusions panel can better classify STS subtypes and serve as a good supplement for histopathology, exhibiting a great potential for the STS precise diagnosis.

A tissue microarray of 102 conventional AdCC, including many in major salivary gland sites was examined for EWSR1 and FUS by fluorescence in situ hybridization and showed that these novel fusions were isolated to this histology and nonmajor salivary gland location. In summary, complex and striking tubular hypereosinophilia and diverse architectures are present within the spectrum of AdCC, particularly in seromucous gland sites, and may show variant EWSR1/FUS::MYB fusions.

ALK expression appears to be a common feature of tumors harboring EWSR1/FUS::ATF1/CREB1 fusion but is unlikely to predict therapeutic response to ALK inhibition. Future advances in our understanding of these unusual tumors will hopefully lead to improved nomenclature.

This review summarizes and structures recent findings demonstrating that hypoxia and HIFs play a role in EwS at multiple levels. We propose to view hypoxia and HIFs as independent protagonists in the story of EwS and give a perspective on their potential clinical relevance as prognostic markers and therapeutic targets in EwS treatment.

This study, therefore, shows that a group of malignant TSCTs resembling seminoma is characterized by α-inhibin and steroidogenic factor-1 positivity, no expression of nuclear β-catenin, frequent CD30 positivity and recurrent EWSR1::ATF1 fusions. We have descriptively termed these neoplasms "inflammatory and nested TSCT." Importantly, inflammatory and nested TSCTs show significant differences in morphology, immunoprofile, molecular biology, and, likely, clinical behavior from Sertoli cell tumors, not otherwise specified and should be classified separately.

Triple-negativity and PD-L1 positivity suggest a window of opportunity for immunotherapy in these patients. The EGFR/AREG axis activation, coupled with the mutational patterns in PI3K/AKT/mTOR and cell cycle pathways warrants caution in considering MECs as low-risk neoplasms.

Molecular tests are not mandatory, but in selected cases FISH analysis can prove useful as about 50% of myoepitheliomas show EWSR1 (or rarely FUS) rearrangements and mixed tumors show PLAG1 rearrangements. Here, we present a case of a mixed tumor of the soft tissue occuring in the hand with expression of PLAG1 in immunohistochemistry.

These sequences, coupled with HLA-peptide binding data, are used to identify potential sequences of cancer-specific immunogenic peptides for Ewing sarcoma or DSRCT patients. This information may also be useful for immune monitoring (e.g., circulating T-cells with fusion-peptide specificity) to detect vaccine candidates, responses, or residual disease.

In addition to soft tissue, SEF is more likely to involve the viscera and the abdominal cavity and has morphological variants. Familiarity with its distinctive clinical and pathological features helps avoid misdiagnosis.

Histological clues and IHC helped streamline a small subset of potential candidates. Although FISH is a powerful technology for identifying NTRK rearrangements, RNA-/DNA-based NGS is recommended for highly suspected cases in which FISH signal patterns are not discernible as classic positive patterns, particularly if targeted therapy is considered.

Targeted RNA sequencing revealed an NR4A3 fusion (fusion partners were EWSR1 in three cases and CITED2 and NIPBL in one case each). The nosology and behavior of this morphomolecularly defined novel peritoneal mesothelial neoplasm of uncertain biological potential and its distinction from adenomatoid variants of conventional mesothelioma merit further delineation as more cases become recognized.

Genomic DNA profiling has facilitated discovery of several new CNS tumor entities, however, traditional methods, such as immunohistochemistry, DNA or RNA sequencing, and cytogenetic studies, including fluorescence in situ hybridization, remain necessary for their accurate biological classification and diagnosis.

RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.

The EWSR1-mCherry rescued the high incidence of aneuploidy of EWSR1 knockdown cells, whereas EWSR1-mCherry:R565A failed to rescue the phenotype. Together, we demonstrate that EWSR1 prevents the induction of lagging chromosomes, and of aneuploidy through the interaction with Aurora B.

For cases in which additional information was available, the behavior of these neoplasms was aggressive with local spread and/or distant metastases. Although further studies are needed to confirm the functional significance of our findings, POU2AF3 fusions to EWSR1 or FUS may define a novel type of POU2AF3-rearranged sarcomas with aggressive, malignant behavior.

Clinical and pathologic features are similar to conventional CCS of soft tissue. Primary bone CCS may pursue an aggressive clinical course.

None of >10,000 epithelial and mesenchymal neoplasms tested at the authors' centers during the same period showed this fusion, highlighting rarity of tumors carrying this gene fusion. Accordingly, molecular testing of unclassified sinonasal malignancies/sarcomas showing round and spindle cell morphology is recommended to enhance the identification and further characterization of this entity.

Fusions were detected in the plasma from 10 of 12 patients with Ewing sarcoma and in two of two patients with ARMS. Combined, these data demonstrate the clinical applicability of our LB platform to evaluate pediatric patients with a variety of solid tumors.

Genetic modulation of these proteins similarly inhibits proliferation and alters chromatin in Ewing sarcoma cells. The use of an oncogene-associated chromatin signature as a target allows for a direct approach to screen for unrecognized modulators of epigenetic machinery and provides a framework for using chromatin-based assays for future therapeutic discovery efforts.

No abstract available

We previously demonstrated the application of SIFTER to polymeric protein complexes comprising the cytoskeleton for single trypsinized cells in suspension. Here we will describe our latest iterations of SIFTER incorporating on-chip 3D single-cell culture for measurement of protein complexes critical to phenotypic heterogeneity and therapeutic response of Ewing sarcoma.

The molecular landscape of PeM is still a work in progress; however, some findings, such as ALK gene rearrangements and EWSR1/FUS-ATF1 fusions, are specifically seen in PeM of young patients. The biological behavior of PeM is variable; however, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have markedly improved the survival of patients affected by this disease.

To our knowledge, this is the first report of an EWSR1-MYB fusion in AdCC with a solid-basaloid component and a poor prognosis. Our findings may extend the genetic understanding of AdCC and aid in the clinical diagnosis of AdCC.

She completed radiotherapy with concurrent and adjuvant temozolomide (TMZ) per Stupp protocol...She failed bevacizumab (bev) alone or in combination with TMZ. Therefore, BEEP (Bev 15mg/kg D0, etoposide 70/m2 D1-D3, cisplatin 70/m2 D1, Q21D) was given for salvage...Nested RT-PCR or NGS are better options. Legal entity responsible for the study The authors.

While this aggressive subset is small, it is of particular therapeutic interest given the availability of EZH2 inhibitors and because overexpressed CTAs may also make it a candidate for immunotherapy. Legal entity responsible for the study The authors.

While the exact mechanisms responsible for the ectopic ACTH secretion are beyond the scope of this study, overexpressed fusion proteins might be involved in promoter-mediated overexpression of pre-ACTH precursors in analogy to the mechanisms postulated for EWSR1::CREB1-mediated paraneoplastic phenomena in certain mesenchymal neoplasms. The genetic background of the ACTH-producing non-pancreatic NENs remains to be further studied.

Although a tumor-specific target, EWSR1::FLI1-targeted therapy has yet to be developed, largely due to insufficient understanding of EWSR1::FLI1 upstream and downstream signaling, and the challenges in targeting transcription factors with small molecules. In this review, we summarize the contemporary molecular understanding of Ewing sarcoma, and the post-transcriptional and post-translational regulatory mechanisms that control EWSR1::FLI1 function.

Also, despite its rarity, PCES should be included in the differential diagnosis of small, round, blue cell tumors at cutaneous sites. Our case also exemplifies common biases in medical decision-making, including premature closure and anchoring bias which can result in misdiagnosis or diagnostic delay and associated delay in appropriate management.

The presented study, which is the first from an Indian oncology center, showed NKX2.2 IHC is quite reliable in diagnosis of ES in the right clinicopathological context. With remarkable sensitivity and specificity of NKX2.2 IHC for diagnosis of ES, we propose that combined positivity of CD99 and NKX2.2 IHC can obviate or minimize the need of EWSR1 gene rearrangement molecular testing for diagnosis of ES.

We show that squelching of ETV6 with a dominant-interfering peptide phenocopies these effects and suppresses Ewing sarcoma growth in vivo. These findings reveal targeting of ETV6 as a strategy for neutralizing the EWS-FLI1 oncoprotein by reprogramming of genomic occupancy.

This case underscores the utility of fusion analysis when confronted with a sinonasal spindle cell neoplasm which does not neatly fit into any specific category. It remains to be seen if EWSR1::BEND2 sinonasal sarcoma represents a distinct entity.

Local recurrence might occur when incompletely excised. Familiarity with its clinicopathological features is helpful in distinguishing it from other spindle cell neoplasms that tend to occur at acral sites.

We discuss here the potential mechanisms of immune escape in these tumors, including low representation of tumor-specific antigens, low expression levels of MHC-I antigen-presenting molecules, accumulation of immunosuppressive M2 macrophages and myeloid proinflammatory cells, and release of extracellular vesicles (EVs) which are capable of reprogramming host cells in the tumor microenvironment and systemic circulation. We also discuss the vulnerabilities of EwS and OS and potential novel strategies for their targeting.

Pan-sarcoma fusion analysis detected an EWSR1 (Exon7)-CREB1 (Exon7) fusion gene. The lesion was diagnosed as angiomatoid fibrous histiocytoma with paraneoplastic syndrome presentation of several years' duration.

We performed a detailed molecular genetic analysis of five cases of CCC. As a result, we identified a novel partner gene for EWSR1, LARP4, in indolent CCC. Importantly, HGT and poor prognosis were caused by whole genome doubling and subsequent genomic aberrations.