Sarcoma Family Research Articles

Role of 18F-FDG-PET/CT in the initial staging of very high-risk Ewing Sarcoma in a prospective multicentric Phase II Study: Is there still a place for bone marrow sampling?

The Ewing Sarcoma Family of Tumors (ESFT) constitutes a group of rare malignancies, wherein approximately one-third of cases exhibit metastatic spread, particularly impacting prognosis when bone and/or bone marrow (BM) are involved. Primary extra-pulmonary metastatic ESFT often necessitates intensified therapeutic approaches. Accurate staging plays a pivotal role in clinical decision-making, with fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) currently serving as a non-invasive modality for assessing ESFT's BM extent. In the French phase II COMBINAIR3 (NCT03011528) study, a comprehensive approach for patients with extra-pulmonary ESFT metastasis was evaluated. We prospectively compared the efficacy of PET/CT to BM aspiration and biopsy (BMAB) analysis in patients undergoing initial staging. Among the 42 patients analyzed (median age 14 y, 2:1 male/female ratio), 45% presented with pelvic primary tumors and 83% had bone/BM involvement at diagnosis. Our findings showed PET/CT had 100% specificity and 83.3% sensitivity in detecting initial BM involvement. Overall, PET/CT correctly classified 92.8% of patients, reaching 100% accuracy in patients identified with bone involvement, thus surpassing the standard BMAB. These results suggest that the conventional use of BMAB in the initial staging of high-risk ESFT patients can be omitted, promoting PET/CT as a non-invasive alternative, thus improving staging accuracy and treatment decisions in ESFT management.

Axillary lesion in a young adult ends up to a peculiar diagnosis: primitive neuro-ectodermal tumor (PNET) of ulnar nerve: a rare case report

Introduction and importance: Primitive neuro-ectodermal tumor (PNET) is a highly aggressive tumor composed of small round blue cells, mostly developing in children and young adults. Being a member of Ewing’s Sarcoma Family of Tumors (ESFT); it has been discussed in two subcategories of central and peripheral PNET. PNETs of peripheral nerves are very uncommon pathologic findings, as to the best of our knowledge only 12 well-documented cases have been yet reported. Case presentation: A 30-year-old male presented with progressive paresthesia of his right hand’s little finger and painless swelling of the right axilla. Magnetic resonance (MR) neurography demonstrated a heterogeneous, high-signal, round mass within the right axilla fossa in proximity to the medial aspect of brachial plexus branches. The clinical and radiological study failed to an accurate diagnosis, thus surgical resection of the tumor was done for tissue evaluation. Histopathologic study of the lesion revealed a neoplasm comprising sheets of small, round, blue cells (Hematoxylin and Eosin stain), which immunohistochemically consisted with the diagnosis of PNET. Clinical discussion: The differential diagnosis of axillary fossa masses, focusses on peripheral nerve tumors like Schwannoma and PNET. MR neurography aids in evaluation, but tissue diagnosis remains crucial. Treatment involves surgical resection, chemotherapy, and radiotherapy tailored to individual patients. Conclusion: Although pPNET is not apparently the first differential diagnosis coming to mind when encountering a rapidly growing mass in the axillary fossa with peripheral nerve origin, its highly malignant behavior, makes it crucial to be considered in the differential diagnoses.

HER2 expression-independent antitumor effect of trastuzumab deruxtecan (T-DXd) on pediatric solid tumors.

e15016 Background: Treatment of pediatric solid tumors shows limited improvement even with intensification of conventional chemotherapy, suggesting novel approaches such as targeted therapies are needed. Trastuzumab Deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate, exhibits significant anti-cancer activity in breast cancers with a broad range of HER2 expression. T-DXd might be a promising agent for refractory or relapsed pediatric solid tumors, but its efficacy in pediatric tumors needs to be studied. Methods: Anti-cancer efficacy of T-DXd and its payload DXd were assessed in vitro by utilizing our in-house cancer cell line models. Cytotoxicity assays were performed for 60 pediatric cancer cell lines, including Neuroblastoma (NB) = 25, Ewing sarcoma / Ewing sarcoma family of tumors (EWS / EWSFT) = 17, Rhabdomyosarcoma (RMS) = 10, Others (Osteosarcoma, Brain tumor, Wilms tumor, Hepatoblastoma, and Malignant rhabdoid tumor (MRT) = 8, and 2 breast cancer cell lines expressing HER2 high or low (IHC score 2+ or 0) as positive or low control, respectively. We analyzed HER2 expression on the cell surface by flow cytometry and evaluated relative mean fluorescence intensity (MFI) values. Results: In the flow cytometric assessment, pediatric cancer cell lines showed smaller median MFI of 1.40 (0.67 - 2.71) compared with breast cancer control with HER2 high expression (33.77). The median MFI of each cell lines were 0.94 in NB, 1.76 in EWS / EWSFT, 1.42 in RMS, 1.52 in other pediatric cancers. Although low or no expression of HER2, certain inhibitory activities to the cell growth were observed for T-DXd against a part of NB, EWS, RMS and MRT cell lines, with the minimum IC50 values of 14.5 nM, 6.5 nM, 10.2 nM, 8.1 nM, respectively. In NB, EWS and RMS, a wide range of sensitivity to T-DXd were seen among different cell lines in the same disease. Most of cell lines showed high sensitivity to DXd (Median IC50 value: 0.90 nM [0.08 - 6.46 nM]), but, among them, cell lines with lower sensitivity to DXd tend to show less sensitivity to T-DXd. There was no clear correlation between sensitivity to T-DXd and HER2 expression among pediatric cancer cell lines, indicating that other mechanism such as intrinsic sensitivity to payload might affect antitumor activity of T-DXd. Conclusions: T-DXd exhibited antitumor efficacy against pediatric solid tumors in vitro irrespective of HER2 expression. Our results suggest that T-DXd might be an alternative therapy for pediatric solid tumor cases for whom conventional chemotherapies and other targeting therapies are ineffective. This study supports further investigation for T-DXd in this population.

Primary intracranial peripheral primitive neuroectodermal tumor: lessons from an exceptionally rare neoplasm. Illustrative case.

The primary intracranial peripheral primitive neuroectodermal tumor (pPNET) is a lesion subtype within the Ewing sarcoma family of tumors. pPNETs are extremely uncommon pathologies, accounting for 0.03% of intracranial tumors and 1% to 2% of Ewing sarcoma cases. Given its histological aspect similar to other highly proliferative malignant neuroectodermal neoplasms, pPNET merits extensive workup for accurate diagnosis and treatment. A 36-year-old male presented to the emergency department with a 1-year history of headaches in the right frontoparietal area, generalized tonic-clonic seizures, and a history of the resection of a tumor labeled as a meningioma 5 years before admission. He was neurologically intact. Brain magnetic resonance imaging revealed a heterogeneous focal lesion of 25 × 35 × 23 mm with a necrotic center and neoformative appearance in the right frontal cortex. The patient underwent multimodal treatment with gross-total resection, radiotherapy, and chemotherapy. Histopathological examination results supported the diagnosis of pPNET. At the 2-year follow-up, the patient had no new-onset symptoms, and brain imaging revealed absent signs of tumor recurrence. The present case describes an extraordinary pPNET case, initially confounded as a clear cell meningioma. Managing pPNET requires thorough investigation, careful differentiation from similar neuroectodermal lesions, and multimodal treatment to improve the patient's prognosis.

Abstract 4425: Metabolic vulnerabilities of dedifferentiated liposarcoma

Abstract Dedifferentiated liposarcoma (DDLPS) is a rare, life-threatening malignancy in the family of adipocytic sarcomas. DDLPS, which usually arises in the retroperitoneum of middle-aged adults, has a poor prognosis. This is due to the propensity of DDLPS to metastasize and recur locally, combined with a dearth of effective systemic therapies. A longstanding curiosity is that DDLPS has non-lipogenic morphology and no lipid droplets, while its less aggressive sister sarcoma, well-differentiated liposarcoma (WDLPS), resembles benign adipose tissue and contains large lipid droplets. How DDLPS metabolizes lipids and the metabolic vulnerabilities of DDLPS in patients, which may form new therapeutic targets, are unknown. In our project, we investigate the metabolism of DDLPS versus WDLPS using patient samples and cell lines. Snap-frozen tissues from patients were obtained from the Dana-Farber/Harvard Cancer Center specimen bank of DDLPS and WDLPS. We performed metabolomics and lipidomics on these samples. We complemented these results with publicly available transcriptional profiles of separate cohorts of DDLPS, WDLPS, and other cancers. In vitro, we made use of a panel of multiple DDLPS-derived cell lines, WDLPS-derived cells, benign preadipocytes, and benign adipocytes. We measured mitochondrial function and the cellular effects of perturbing various metabolites in screens in culture. Overall, our initial results indicate strong alterations in mitochondrial metabolism in DDLPS in patients. In culture, DDLPS is susceptible to multiple metabolic perturbations related to mitochondrial dysfunction. These metabolic vulnerabilities of DDLPS provide potential therapeutic opportunities. Work is ongoing to optimize the targeting of these vulnerabilities in vivo, elucidate the molecular roles of specific metabolites, and complete a blueprint of DDLPS metabolic weaknesses in patients. Citation Format: Jamie O. Brett, Ji Seul Han, Choah Kim, Liam P. Kelley, SeongJun Han, Dylan Boone, Joseph Crowley, Shakchhi Joshi, Chandrajit P. Raut, Anna Greka, Marcia C. Haigis. Metabolic vulnerabilities of dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4425.

Operative treatment of pulmonary primitive neuroectodermal tumor: a case report and literature review

BackgroundPulmonary primitive neuroectodermal tumor (PNET), a member of the Ewing sarcoma family of tumors, is a rare malignancy that is associated with a grim prognosis. To date, fewer than 30 cases of pulmonary PNET have been reported. In this case report, we present the clinical details of a 12-year-old girl with pulmonary PNET who underwent surgical treatment. We also conducted an analysis and summary of other relevant studies and the surgical outcomes.Case presentationIn May 2018, a 12-year-old girl was admitted with symptoms of cough and blood-tinged phlegm. A computed tomography scan revealed a large mass, measuring 12.9 cm × 8.1 cm, in the right middle and lower lungs. A percutaneous lung biopsy confirmed poorly differentiated tumor cells with a nested growth pattern. Immunohistochemical staining demonstrated positive expression of CD99, CD56, Vimentin, and Synaptophysin. The patient was diagnosed with pulmonary PNET. Following three cycles of neoadjuvant chemotherapy, a substantial reduction in tumor volume was observed. Subsequently, the patient underwent a surgical procedure involving pneumonectomy and partial resection of the left atrium with the assistance of cardiopulmonary bypass. The patient was discharged 37 days after surgery. During a three-year follow-up period, she exhibited no signs of tumor recurrence and has successfully returned to school.ConclusionsThis case highlights the successful management of an advanced PNET with neoadjuvant chemotherapy, pneumonectomy, and partial resection of the left atrium employing cardiopulmonary bypass. The patient remained disease-free after three years. Our analysis of surgically treated cases indicates that neoadjuvant chemotherapy can contribute to improved prognoses for PNET patients. It is crucial to emphasize that complete surgical excision remains the cornerstone of treatment, underscoring the importance of surgeons considering radical surgical approaches whenever feasible for patients with pulmonary PNETs.

Extraskeletal Ewing sarcoma arising from stomach and ovary: A case series of two rare sites

Ewing sarcoma is the second most common tumor in children and young adults. Primitive neuroectodermal tumors/Ewing sarcoma family consist of small round cell of neuroectodermal origin. Ewing sarcoma commonly arises from long bones and pelvic region but extraskeletal Ewing sarcoma (EES) is a very rare tumor with highly malignant potential associated with poor outcome. We present a case series of two cases, one is from the ovary in a 24-year-old young, married, multiparous woman who presented with metastatic disease and was treated with palliative chemotherapy. The second is an Ewing sarcoma arising from the stomach in a 33-year-old male who underwent surgery followed by adjuvant chemotherapy. EES is usually an uncommon tumor and many times, the diagnosis becomes delayed and presents with metastatic disease. Immunohistochemical and molecular analysis is a must to diagnose the EES. There are no standard treatment guidelines. Surgery, various chemotherapy regimens, and radiotherapy are given for treatment. Early diagnosis and interventions are required for better outcomes.

Computational Exploration of Single-Nucleotide Polymorphisms in the Human hRAS Gene: Implications and Insights.

Background A group of genes called oncogenes includes the Harvey rat sarcoma virus (hRAS) gene. Along with hRAS, Kirsten rat sarcoma viral oncogene homolog (kRAS) and neuroblastoma RAS viral oncogene homolog(nRAS) genes belong to the Rat sarcoma (Ras) family of oncogenes. These three genes result in Rho guanosine triphosphate hydrolases (GTPases) as their protein product. Instructions for producing the protein hRAS, which is mainly involved in controlling cell division, are provided by the hRAS gene. The hRAS protein transfers signals from outside through a process called signal transduction.Because the hRAS protein is a GTPase, it changes the chemical guanosine-5'-triphosphate (GTP) into guanosine diphosphate (GDP). GTP and GDP molecules operate as switches to turn on and off the hRAS. This study aimed to anticipate the structure and stability of the protein resulting from missense single-nucleotide polymorphisms (SNPs) in the human hRAS genes. Methodology To investigate the possible negative effects associated with these SNPs, bioinformatic analysis is typically essential. The following tools were employed for forecasting harmful SNPs: Scale-Invariant Feature Transform (SIFT), Protein Analysis Through Evolutionary Relationships (PANTHER), non-synonymous SNP by Protein Variation Effect Analyzer (PROVEAN), and non-synonymous SNP by Single Nucleotide Polymorphism Annotation Platform (SNAP). Results The present study identified a total of 11 SNPs using the SIFT approach, which were shown to have functional significance. Only two of these 11 SNPs were determined to be tolerable, whereas nine were shown to be detrimental. Among the 11 SNPs analyzed, seven (Q61H, Q99H, K117R, A121D, A146V, R169W, R169Q) were classified as possibly damaging,and four (G13V, Q22K, Q61K, Q13V) were categorized as probably benign according to the predictions made by PANTHER tools. Therefore, the seven SNPs were identified as high-risk SNPs. Conclusions Given that SNPs have the potential to be candidates for cellular alterations brought on by mutations that are associated with cancer, this study provides vital information about how SNPs might be utilized as a diagnostic marker for cancer.

Report and literature review of four cases of EWSR1::NFATC2 round cell sarcoma

BackgroundEWSR1::NFATC2 rearranged sarcomas are a group of rare round, undifferentiated sarcomas with clinicopathological features different from those of Ewing's sarcoma (ES) family and other non-ES sarcomas. We report 4 cases of this rare sarcoma and review their features.Materials and methodsFour cases of EWSR1::NFATC2 rearranged round cell sarcoma of the bone from the Pathology Department of Peking University People's Hospital were retrospectively studied. Clinical and pathological data were summarized, and immunohistochemical staining, fluorescence in situ hybridization (FISH), and Next-generation sequencing (NGS) were performed. Relevant literature reports were also reviewed.ResultsAmong the four cases of EWSR1::NFATC2 rearranged round cell sarcoma, three were male, and one was female, with the age ranged from 14 to 34 years old at diagnosis (mean age: 27.5 years). All tumors were located in the femur and ranged in size from 4 to 8cm (mean 6cm), involving the surrounding soft tissues. All four patients underwent surgical treatment, and three received chemotherapy and radiotherapy postoperatively. Follow-up results showed that all four patients were alive. Histologically, the tumors exhibited small round cell sarcoma phenotype, with the stroma rich in mucin or exhibiting a glassy appearance. The tumor cells diffusely expressed CD99, NKX2.2, NKX3.1 and focal expression of CK and EMA was observed. FISH analysis showed that EWSR1 gene rearrangement was detected in all 4 cases, accompanied by 5' locus amplification. EWSR1::NFATC2 fusion probe demonstrated multi yellow fusion signals. NGS identified EWSR1::NFATC2 breakpoints in exon 9 and exon 3 in all 4 cases. The average follow-up duration of the study group was 88 months (range from 26—180 months). One case experienced both local recurrence and metastasis to the lung and chest wall. One case presented with local recurrence. The remaining two cases did not have the recurrence or metastasis.ConclusionAlthough the disease can locally recur and metastasize to the lungs, its mortality rate is significantly lower than that of Ewing sarcoma and other high-grade small round cell undifferentiated sarcomas. Therefore, it supports to classify this tumor as a separate subtype of small round cell sarcoma.

One Hundred Percent Tumor Necrosis is Associated with Survival in Ewing Sarcoma

Background and Objectives:Ewing sarcoma is a primary malignancy affecting both bone and soft tissue. Following preoperative chemotherapy and surgical resection, histologic response (tumor necrosis) is correlated with patient survival. The most prognostic cutoff for tumor necrosis continues to be debated. The objective of this study was to explore several cutoffs and determine their prognostic value in a contemporary cohort of Ewing sarcoma patients. Methods:The National Cancer Database was used to identify 564 patients with osseous and soft tissue tumors in the Ewing sarcoma family from 2010 to 2015. All patients had documented preoperative chemotherapy, surgical resection, and vital status. Survival was stratified by tumor necrosis using Kaplan Meier analysis. 356 patients with osseous tumors were included in multivariate logistic and cox regression analyses to identify predictors of histologic response and survival, respectively. Results:In a combined soft tissue and osseous tumor cohort, there was a significant difference (p = 0.01, log-rank test) in overall survival between patients with 100% necrosis and patients with less than 100% necrosis. This was observed over the 5-year study period. Other cutoffs were not statistically different. In patients with osseous tumors, less than 100% necrosis was negatively associated with survival (HR 3.48 [95% CI 1.19-10.13]; p< 0.05), with only skip metastasis having a stronger negative association (HR 4.31 [95% CI 1.22-15.29]; p< 0.05). Male sex (OR 0.50 [95% CI 0.28-0.90]; p<0.05), tumors located in the axial skeleton (OR 0.30 [95% CI 0.12- 0.77]; p<0.05), and positive surgical margins (OR 0.28 [95% CI 0.08-0.95]; p<0.05) were negatively associated with 100% necrosis. Conclusion and Implications:A cutoff of 100% tumor necrosis was associated with improved survival in Ewing sarcoma. This association was strong relative to other commonly used prognostic factors in osseous cases and is a valuable tool to counsel patients and guide future clinical trials.

Ewings Sarcoma Mimicking a Schwannoma: MRI Findings of a Rare Case

Ewing’s sarcoma is among the most frequent yet highly aggressive neoplasms of the bones presenting in adolescents and children under the age of ten with a slight male predilection. It is now broadly categorized into a set of tumors recognized as Ewing’s sarcoma family based on the same histology and genotype of these tumors. This group of tumors includes Ewing’s sarcoma of bones, the 2nd most frequent bone malignancy, Askin tumors, PNET, and those rarely occurring extraosseous Ewing sarcoma (peripheral neuroepithelioma). Extra-osseous Ewing’s is a rare presentation occurring in only 5% of patients. Here we present such a case of an extra-osseous Ewing’s sarcoma in a 13-year-old female presenting to our hospital with a large mass in the sacral region. The interesting imaging findings and his histopathology are discussed.

Ewing’s Sarcoma of the Mandible with Extensive Bony Metastasis in a Young Male: A Case Report

Ewing’s Sarcoma Family of Tumours (ESFTs) comprises locally aggressive, undifferentiated small round blue-cell tumours of neuroectodermal origin, predominantly seen in adolescents. These tumours arise from non random chromosomal translocations involving the Ewing’s Sarcoma (EWS) gene. ESFTs in the mandible are uncommon. A 14-year-old male patient presented with a painless swelling in the right jaw. Plain radiographs, ultrasonography, contrast-enhanced Computed Tomography (CT), and Magnetic Resonance Imaging (MRI) revealed a large, partially well-defined, highly vascular soft tissue mass in the right mandibular region. It measured approximately 80×82×75 mm (anteroposterior x transverse x craniocaudal), with both solid and cystic components. The mass was destroying the underlying right temporomandibular joint, head, ramus and posterior body of the right hemimandible, including extensive sunray-type bony spiculations. There were multiple lytic lesions in the skull and facial bones, as well as, altered marrow signal intensity in the calvarium, bilateral humeri and clavicles, and cervical and thoracic vertebrae, indicating a locally aggressive tumour with extensive metastasis into the bones and marrow. The diagnosis was confirmed by histopathology, which showed fibrocollagenous tissue infiltrated by sheets of small round cells with scanty eosinophilic cytoplasm and prominent nuclei. Management typically involves a combination of chemotherapy, radiation and surgery. However, metastatic Ewing’s Sarcoma has a poor prognosis.

Extraosseous Ewing sarcoma of the pancreas: a case report.

Extraosseous Ewing sarcoma is a rare and aggressive malignancy belonging to the Ewing sarcoma family of tumors, primarily affecting soft tissues such as the pelvis, retroperitoneum, and chest wall. Although it predominantly involves these soft tissues, extraosseous Ewing sarcoma can also occur in solid organs, including the pancreas. Here, we present a rare case of a 4-year-old girl diagnosed with primary extraosseous Ewing sarcoma of the pancreas.

Primary Chest Wall Ewing Sarcoma with Indolent Behavior in an Elderly Male

Abstract Introduction/Objective Ewing sarcoma (ES) is the second most common primary malignant bone tumor, primarily affecting children and young adults within the first two decades of life. Over 80% of cases are positive for CD99 and exhibit a characteristic t(11;22) translocation resulting in an EWSR1::FLI1 fusion. Extraosseous ES is extremely rare and most reported cases occur in patients less than 50 years old. We report an unusual case of extraosseous ES arising from the chest wall in an elderly male that showed slow interval progression on imaging studies. Methods/Case Report An 83-year-old male with a past medical history of COPD and tobacco use presented to the emergency department for a mechanical ground level fall and a worsening cough over the prior week. Of note, he was found to have a 6.1 cm pleural based mass seven years prior. The patient was ultimately discharged home with recommended oncologic follow-up for this long-standing chest wall mass due to an increase in size on imaging. A PET scan showed a hypermetabolic subpleural mass in the right lower chest wall measuring 7.6 cm with invasion through the adjacent ribs and intercostal spaces into the adjacent soft tissue. A core biopsy was performed, which demonstrated a small round blue cell tumor diffusely positive for CD99 and Bcl-2, lacking significant mitotic activity and necrosis. Given the unusual clinical features, a next generation sequencing (NGS) panel for sarcoma fusions was performed and identified an EWSR1::FLI1 fusion, supporting the diagnosis of ES/primitive neuroectodermal tumor (PNET). Results (if a Case Study enter NA) NA Conclusion ES is relatively common as a primary bone tumor in children and young adults, but is rare in the chest wall and pleura and is extremely rare in the elderly. The clinical course for ES is typically aggressive. Diagnosis of ES can be challenging as CD99 positivity is nonspecific. The characteristic t(11;22) EWSR1::FLI1 fusion can be identified through FISH or NGS. At 83 years old, this is, to our knowledge, the oldest patient reported in the literature with this diagnosis. The slow interval growth of this mass over a period of seven years is also unusual. These combined clinicopathologic features are exceedingly unique and expand upon the reported spectrum and behavior of the Ewing’s family of sarcomas. The use of broad NGS panels among pathologists may result in increased identification of ES in unusual clinical settings in the future, while also providing more confident pathologic classification in challenging situations.

Case Report: Cytodiagnosis of primitive neuroectodermal tumor (PNET) of sinonasal tract

Malignant sinonasal tumors are rarely encountered in the practice of oncology as they constitute only 1% of total body tumors. The occurrence of primitive neuroectodermal tumor (PNET) in the sinonasal tract is even more uncommon. The PNET belongs to Ewing sarcoma family and forms the differential diagnosis of a large group of lesions generally described as malignant round cell tumors. The unique pathogenetic chromosomal alteration in this lesion is the EWS FLI1 fusion gene. This case report describes the unusual occurrence of PNET for its cytomorphological diagnosis along with its clinical features, radioimaging findings and immunohistochemistry. Such case reports are scarce in literature and cytodiagnosis of PNET in sinonasal tracts warrants its sharing with medical fraternity as such diagnoses are stumbled along rarely in clinical practice.

Renal Ewing sarcoma with extensive neuroectodermal differentiation: Case report and literature review

Abstract Ewing sarcoma with renal localization is one of the rarest members of the Ewing sarcoma family with less than 200 cases reported in the Medline database. Considering the fact that the majority of data published on the Ewing sarcoma with neuroectodermal differentiation is obtained through a few case reports and case series, it becomes understandable why we currently have no universally accepted treatment regimens. Case summary: A 33-year-old patient presented to the Emergency Department with right lumbar pain following a mild trauma and an episode of macroscopic hematuria. Physical examination confirmed hematuria and flank pain and a palpable flank mass was identified. MRI showed a cystic lesion of the upper pole of the right kidney of 127/110/123 mm. After prior agreement of the multidisciplinary team, a 3D laparoscopic right radical nephrectomy was done. The histopathological diagnosis revealed an Ewing sarcoma with extensive neuroectodermal differentiation staged as pT3N1M0L1V2R0. Despite swift implementation of the chemotherapy protocol, the progression of the disease was quickly noted. Currently, one year after diagnosis, the disease is still progressing despite the chemotherapy treatment, the patient being a third line chemotherapy candidate. As renal localization of Ewing sarcoma with extensive neuroectodermal differentiation is extremely rare, multimodal treatment strategies must be established by a multidisciplinary team. Despite its aggressive biological behavior, a proper therapeutic management might increase patient life expectancy.

KDM2B-Rearranged Soft Tissue Sarcomas Expand the Concept of BCOR-Associated Sarcoma

Sarcomas with BCOR genetic alterations (BCOR-associated sarcomas) represent a recently recognized family of soft tissue and bone tumors characterized by BCOR fusion, BCOR internal tandem duplication, or YWHAE::NUTM2B fusion. Histologically, the tumors demonstrate oval to spindle cell proliferation in a variably vascular stroma and overexpression of BCOR and SATB2. Herein, we describe 3 soft tissue sarcomas with KDM2B fusions that phenotypically and epigenetically match BCOR-associated sarcomas. The cases included 1 infant, 1 adolescent, and 1 older patient. All tumors showed histologic findings indistinguishable from those of BCOR-associated sarcomas and were originally diagnosed as such based on the phenotype. However, none of the tumors had BCOR or YWHAE genetic alterations. Instead, targeted RNA sequencing identified in-frame KDM2B::NUTM2B, KDM2B::CREBBP, and KDM2B::DUX4 fusions. KDM2B fusions were validated using reverse-transcription PCR, Sanger sequencing, and in situ hybridization assays. Genome-wide DNA methylation analysis matched all 3 tumors with BCOR-associated sarcomas using the Deutsches Krebsforschungszentrum (DKFZ) classifier and t-distributed stochastic neighbor embedding analysis. One localized tumor showed a flat genome-wide copy number profile, and the patient remained disease-free after treatment. The other tumors showed multiple copy number alterations, including MDM2/CDK4 amplification and/or CDKN2A/B loss, and both tumors metastasized, leading to the patient’s death in one of the cases. When tested using KDM2B immunohistochemistry, all 3 KDM2B-rearranged sarcomas showed diffuse strong staining, and all 13 sarcomas with BCOR genetic alterations also demonstrated diffuse, strong, or weak staining. By contrast, among 72 mimicking tumors, only a subset of synovial sarcomas showed focal or diffuse weak KDM2B expression. In conclusion, our study suggests that KDM2B-rearranged soft tissue sarcomas belong to the BCOR-associated sarcoma family and expand its molecular spectrum. This may be related to the known molecular relationship between KDM2B and BCOR in the polycomb repressive complex 1.1. Immunohistochemical analysis of KDM2B is a potentially valuable diagnostic tool for BCOR-associated sarcomas, including those with KDM2B rearrangement.

Antitumor Effects of β-Elemene Through Inducing Autophagy-Mediated Apoptosis in Ewing Sarcoma Family Tumor Cells.

Ewing sarcoma family tumors (ESFTs) are a group of aggressive tumors mainly affecting children and young people. A compound derived from Curcuma wenyujin plant or lemon grass, β-elemene, has exhibited antitumor effects to ESFT cells, the mechanism of which remains to be clarified further. Autophagy is involved in the antitumor effects of various drugs, whereas the role of autophagy in the antitumor effects of β-elemene persists controversial. Herein we found that β-elemene treatment inhibited the viability of ESFT cells in a dose-dependent manner. The increase of LC3-II level and the decrease of p62 level were observed in β-elemene-treated cells, as well as the increase of autolysosomes, which indicated the promotion of autophagic flux. Sequentially the autophagy inhibition using 3-MA treatment or ATG5 depletion significantly reversed the viability repression and apoptosis induction by β-elemene treatment. In addition, autophagy was found to be important in the toxic effects induced by the combination treatment of β-elemene and IGF1R inhibition in ESFT cells. Our data suggested an essential role of autophagy in β-elemene-induced apoptosis in ESFT cells, which is anticipated to provide novel insights to the development of ESFT treatments.

Chemotherapeutic drugs for soft tissue sarcomas: a review.

Despite the low incidence of soft tissue sarcomas (STSs), hundreds of thousands of new STS cases are diagnosed annually worldwide, and approximately half of them eventually progress to advanced stages. Currently, chemotherapy is the first-line treatment for advanced STSs. There are difficulties in selecting appropriate drugs for multiline chemotherapy, or for combination treatment of different STS histological subtypes. In this study, we first comprehensively reviewed the efficacy of various chemotherapeutic drugs in the treatment of STSs, and then described the current status of sensitive drugs for different STS subtypes. anthracyclines are the most important systemic treatment for advanced STSs. Ifosfamide, trabectedin, gemcitabine, taxanes, dacarbazine, and eribulin exhibit certain activities in STSs. Vinca alkaloid agents (vindesine, vinblastine, vinorelbine, vincristine) have important therapeutic effects in specific STS subtypes, such as rhabdomyosarcoma and Ewing sarcoma family tumors, whereas their activity in other subtypes is weak. Other chemotherapeutic drugs (methotrexate, cisplatin, etoposide, pemetrexed) have weak efficacy in STSs and are rarely used. It is necessary to select specific second- or above-line chemotherapeutic drugs depending on the histological subtype. This review aims to provide a reference for the selection of chemotherapeutic drugs for multi-line therapy for patients with advanced STSs who have an increasingly long survival.

Systemic Review of Clot Retraction Modulators.

Through a process termed clot retraction, platelets cause thrombi to shrink and become more stable. After platelets are activated via inside-out signaling, glycoprotein αIIbβIII binds to fibrinogen and initiates a cascade of intracellular signaling that ends in actin remodeling, which causes the platelet to change its shape. Clot retraction is also important for wound healing. Although the detailed molecular biology of clot retraction is only partially understood, various substances and physiological conditions modulate clot retraction. In this review, we describe some of the current literature pertaining to clot retraction modulators. In addition, we discuss compounds from Cudrania trucuspidata, Arctium lappa, and Panax ginseng that diminish clot retraction and have numerous other health benefits. Caffeic acid and diindolylmethane, both common in plants and vegetables, likewise reduce clot retraction, as do all-trans retinoic acid (a vitamin A derivative), two MAP4K inhibitors, and the chemotherapeutic drug Dasatinib. Conversely, the endogenous anticoagulant Protein S (PS) and the matricellular protein secreted modular calcium-binding protein 1 (SMOC1) both enhance clot retraction. Most studies aiming to identify mechanisms of clot retraction modulators have focused on the increased phosphorylation of vasodilator-stimulated phosphoprotein and inositol 1,4,5-triphosphate receptor I and the decreased phosphorylation of various phospholipases (e.g., phospholipase A2 (PLA2) and phosphatidylinositol-specific phospholipase Cγ2 (PLCγ2), c-Jun N-terminal kinase, and (PI3Ks). One study focused on the decreased phosphorylation of Sarcoma Family Kinases (SFK), and others have focused on increased cAMP levels and the downregulation of inflammatory markers such as thromboxanes, including thromboxane A2 (TXA2) and thromboxane B2 (TXB2); prostaglandin A2 (PGE2); reactive oxygen species (ROS); and cyclooxygenase (COX) enzyme activity. Additionally, pregnancy, fibrinolysis, and the autoimmune condition systemic lupus erythematosus all seem to affect, or at least have some relation with, clot retraction. All the clot retraction modulators need in-depth study to explain these effects.