We report an uncommon case of primitive neuroectodermal tumor/ Ewing\'s sarcoma of the lumbar and sacral nerve plexus in a 17years old boy who presented with an intense pain in the lower back radiating to legs. Magnetic resonance imaging showed a soft tissue mass with thickening of lumbar and sacral spinal nerve roots (L5-S3 level), along with widening of the corresponding foramina. There was also posterior scalloping of L5/S1 vertebrae and invasion of the sacral bone. A Partial resection has been performed, and the ensuing histopathology confirmed the diagnosis of PNET/Ewing\'s sarcoma. MRI in conjunction with histopathology are the key to narrow down the differential diagnoses list. PNET of lumbosacral area remain scarce, and only few cases have been reported nowadays. Given to the aggressivity of these tumors, the prognosis is poor despite appropriate treatment.

With the wide use of RNA sequencing technologies, the family of FET::CREB fusion mesenchymal neoplasms has expanded rapidly to include potentially aggressive neoplasms, not fitting any well established WHO entity. Recently, a group of intra-abdominal FET(EWSR1/FUS)::CREB(CREM/ATF1) fused unclassified neoplasms has been reported followed by recent recognition of an analogous extra-abdominal category of unclassified neoplasms carrying EWSR1::ATF1 fusions. We describe 9 additional tumors (5 extra-abdominal and 4 abdominal) carrying an EWSR1::CREM (n = 8) and FUS::CREM (n = 1) fusion. Patients were 7 females and 2 males aged 10 to 75 years (median, 34). Extra-abdominal tumors originated in the head and neck (2 sinonasal, 1 orbital) and soft tissues (1 gluteal, 1 inguinal). Abdominal tumors involved stomach (2), mesentery (1), and kidney (1). Tumor size ranged from 3.5 to 11 cm (median, 6). Treatment was radical surgery with (5) or without (2) neo/adjuvant radio/chemotherapy. Extended follow-up of 5 patients (21-52 months; median, 24) showed an aggressive course in two (40%); one died of disseminated metastases 52 months after several intensified chemotherapy regimens, and one was alive with progressive abdominal disease at 21 months. The immunophenotype of the two subcohorts was significantly overlapping with variable expression of EMA (7 of 8), keratin AE1/AE3 (5 of 9), CD99 (4 of 7), MUC4 (2 of 8), ALK (3 of 8), synaptophysin (3 of 9), chromogranin (1 of 8), CD34 (3 of 6), CD30 (1 of 6), PAX8 (1 of 7), and inhibin (1 of 7), but no reactivity with desmin (0 of 8), S100 (0 of 8), and SOX10 (0 of 8). This series further solidifies the notion that FET::CREB fusions are not limited to the triad of angiomatoid fibrous histiocytoma, clear cell sarcoma, and malignant gastrointestinal neuroectodermal tumor, but characterize an emerging family of potentially aggressive neoplasms occurring at both intra- and extra-abdominal sites. These tumors underscore the promiscuity of the FET::CREB fusions and highlight the pivotal role of phenotype-oriented classification of these neoplasms that share the same genotype, still featuring significant biological and behavioral distinctness.

UNASSIGNED: Alternative lengthening of telomeres (ALT) occurs in sarcomas and ALT cancers share common mechanisms of therapy resistance or sensitivity. Telomeric DNA C-circles are self-primed circular telomeric repeats detected with a PCR assay that provide a sensitive and specific biomarker exclusive to ALT cancers. We have previously shown that 23% of high-risk neuroblastomas are of the ALT phenotype. Here, we investigate the frequency of ALT in Ewing\'s family sarcoma (EFS), rhabdomyosarcoma (RMS), and osteosarcoma (OS) by analyzing DNA from fresh frozen primary tumor samples utilizing the real-time PCR C-circle Assay (CCA).
UNASSIGNED: We reviewed prior publications on ALT detection in pediatric sarcomas. DNA was extracted from fresh frozen primary tumors, fluorometrically quantified, C-circles were selectively enriched by isothermal rolling cycle amplification and detected by real-time PCR.
UNASSIGNED: The sample cohort consisted of DNA from 95 EFS, 191 RMS, and 87 OS primary tumors. One EFS and 4 RMS samples were inevaluable. Using C-circle positive (CC+) cutoffs previously defined for high-risk neuroblastoma, we observed 0 of 94 EFS, 5 of 187 RMS, and 62 of 87 OS CC+ tumors.
UNASSIGNED: Utilizing the ALT-specific CCA we observed ALT in 0% of EFS, 2.7% of RMS, and 71% of OS. These data are comparable to prior studies in EFS and OS using less specific ALT markers. The CCA can provide a robust and sensitive means of identifying ALT in sarcomas and has potential as a companion diagnostic for ALT targeted therapeutics.

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BACKGROUND: Ewing sarcoma is a malignant round-cell tumor that primarily affects bones in children. It can also arise in extraosseous tissues, such as the lung, kidneys, and liver. The presentation symptoms of Ewing sarcoma may include cough, dyspnea, and chest pain.
METHODS: This report details the history of a 15-year-old Syrian boy with a previous diagnosis of Hodgkin lymphoma who presented with chronic shoulder pain. Imaging studies revealed an 80 mm mass in the apex of the left lung, which was confirmed through histopathological examination to be Ewing sarcoma following a computed-tomography-guided biopsy. The patient received multiple cycles of chemotherapy and subsequently underwent surgical resection of the remaining mass.
CONCLUSIONS: This case highlights the rare occurrence of Ewing sarcoma in the lung and the unusual clinical presentation of shoulder pain without other accompanying symptoms.

Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis of deoxyribonucleotides and the target of multiple chemotherapy drugs, including gemcitabine. We previously identified that inhibition of RNR in Ewing sarcoma tumors upregulates the expression levels of multiple members of the activator protein-1 (AP-1) transcription factor family, including c-Jun and c-Fos, and downregulates the expression of c-Myc. However, the broader functions and downstream targets of AP-1, which are highly context- and cell-dependent, are unknown in Ewing sarcoma tumors. Consequently, in this work, we used genetically defined models, transcriptome profiling, and gene-set -enrichment analysis to identify that AP-1 and EWS-FLI1, the driver oncogene in most Ewing sarcoma tumors, reciprocally regulate the expression of multiple extracellular-matrix proteins, including fibronectins, integrins, and collagens. AP-1 expression in Ewing sarcoma cells also drives, concurrent with these perturbations in gene and protein expression, changes in cell morphology and phenotype. We also identified that EWS-FLI1 dysregulates the expression of multiple AP-1 proteins, aligning with previous reports demonstrating genetic and physical interactions between EWS-FLI1 and AP-1. Overall, these results provide novel insights into the distinct, EWS-FLI1-dependent features of Ewing sarcoma tumors and identify a novel, reciprocal regulation of extracellular-matrix components by EWS-FLI1 and AP-1.

Outcomes are poor in patients with advanced or relapsed Ewing sarcoma (EWS) and current treatments have significant short- and long-term side effects. New, less toxic and more effective treatments are urgently needed. MER proto-oncogene tyrosine kinase (MERTK) promotes tumor cell survival, metastasis, and resistance to cytotoxic and targeted therapies in a variety of cancers. MERTK was ubiquitously expressed in five EWS cell lines and five patient samples. Moreover, data from CRISPR-based library screens indicated that EWS cell lines are particularly dependent on MERTK. Treatment with MRX-2843, a first-in-class, MERTK-selective tyrosine kinase inhibitor currently in clinical trials, decreased the phosphorylation of MERTK and downstream signaling in a dose-dependent manner in A673 and TC106 cells and provided potent anti-tumor activity against all five EWS cell lines, with IC50 values ranging from 178 to 297 nM. Inhibition of MERTK correlated with anti-tumor activity, suggesting MERTK inhibition as a therapeutic mechanism of MRX-2843. Combined treatment with MRX-2843 and BCL-2 inhibitors venetoclax or navitoclax provided enhanced therapeutic activity compared to single agents. These data highlight MERTK as a promising therapeutic target in EWS and provide rationale for the development of MRX-2843 for the treatment of EWS, especially in combination with BCL-2 inhibitors.

UNASSIGNED: Ewing sarcoma (ES), a rare malignancy, comprises whatever the age, 4-15% of all primary bone tumors. It represents 1% of all malignant tumors in children and is the fourth most common bone malignancy after myeloma, osteosarcoma, and chondrosarcoma.
UNASSIGNED: A 12-year-old boy came to the Oral Surgery Department of Bretonneau Hospital referred by his dentist with a rapidly evolving swelling in the left mandibula for 6 weeks, which was initially diagnosed as a facial cellulitis. Cone beam computed tomography (CBCT) showed a poorly defined, expansile, and osteolytic tumor on the left side of the mandible. Clinical and radiographic findings were in favor of an aggressive primitive bone tumor. A mandibular biopsy under general anesthesia was performed in the Department of Surgical Oncology at Institut Curie in Paris, revealing an ES.
UNASSIGNED: Mandibular ES can mimic dental infections when swelling is the main clinical manifestation, which can lead to a delayed diagnosis. A correlation between clinical, radiological, histopathological, and immunohistochemical with cytogenetics is needed to confirm the diagnosis. Moreover, smaller tumors have better survival.Dentists must therefore be aware of the clinical signs of ES in order to quickly refer patients to a specialized department.
UNASSIGNED: Bellut N, Lutz CM, Lesnik M, et al. Ewing\'s Sarcoma of Mandible: A Case Report with Review of Literature. Int J Clin Pediatr Dent 2024;17(2):187-190.

Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in children, adolescents, and young adults. Debate and controversy remain in the management of relapsed/refractory ES (RR-ES). The authors leveraged the expertise assembled by the National Ewing Sarcoma Tumor Board, a multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES. In this review, they focus on select topics that apply to the management of patients with RR-ES. The specific topics covered include the initial approach of such patients and discussion of the goals of care, the role of molecular testing, chemotherapy regimens and novel agents to consider, the role of maintenance therapy, and the use of high-dose chemotherapy with autologous stem cell rescue. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, these guidelines are intended to support clinicians and provide some clarity and recommendations for the management of patients with RR-ES. PLAIN LANGUAGE SUMMARY: Ewing sarcoma (ES) is a bone and soft tissue cancer that most often occurs in teenagers and young adults. This article uses the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES and to address questions related to the treatment of patients with relapsed ES. Although not intended to replace the clinical judgement of treating physicians and limited by available data, these consensus recommendations will support clinicians who treat patients with this challenging malignancy, made even more difficult when it recurs.

BACKGROUND: Ewing sarcoma is an aggressive malignancy primarily affecting children and adolescents. Limited research is available on treatment practices, clinical course, and survival in adults.
METHODS: A multi-institution retrospective cohort study of all adults (>18 years) and children (≤18 years) with Ewing sarcoma treated in British Columbia, Canada between January 01, 2000 and December 31, 2018.
RESULTS: One-hundred seven individuals (66 adults, 41 children) were included in the analysis. 5-year OS was 58 % in adults and 75 % in children. For individuals with local disease, 5-year OS was 74 % in adults and 84 % in children. Adult status was associated with impaired PFS (HR, 1.8; 95 % CI, 1.0 - 3.1, p=0.04) and OS (HR, 1.8; 95 % CI, 0.9 - 3.5; p=0.088). A Charlson Comorbidity Index (CCI) ≥3 was associated with impaired survival in adults and children (HR, 3.9, 95 % CI, 2.0 - 7.5; p=<0.001); baseline CCIs were not significantly different between groups. Most adults (61/66; 92 %) and all children (41/41; 100 %) received systemic treatment with no significant difference in mean lines of therapy, treatment modalities or agents. Most children received interval-compressed chemotherapy (35/41; 85 %) compared to adults (19/61; 29 %; p=<0.001). Interval-compression was not significantly associated with improved survival in adults with local disease (HR, 0.51; 95 % CI 0.1 - 2.3; p=0.373). Children more often initiated treatment within 28 days of diagnosis (31/33; 94 %) compared to adults (41/64; 64 %, p=0.001). Treatment within 28 days was associated with improved survival in the entire cohort (HR, 2.04 95 % CI, 1.1 - 3.9; p = 0.03). This association was preserved in subanalysis of individuals with local disease (HR, 5.4; 95 % CI, 1.9 - 15; p = 0.001) and only adults (HR, 5.3, 95 % CI, 1.7 - 17; p = 0.005).
CONCLUSIONS: Survival for adults with Ewing sarcoma is inferior to children despite similarities in presentation, tumour characteristics and treatments. Further studies on the value of interval-compression in adults are required. Timely initation of treatment should be a priority for this disease.