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Introduction: Spinal tumors (ST) often result in dire prognosis, carrying risks such as permanent paralysis, sensory loss, and sphincter dysfunction. Data on their incidence and etiology in pediatric populations are markedly scant. Our study investigates the etiology, clinical manifestation, treatment, and outcomes of pediatric ST. Methods: We conducted a retrospective review of our institutional pediatric oncology and neurosurgery database, examining 14 patients under 18 years admitted with ST due to oncological diseases since 2005. We analyzed the clinical presentations, evaluations, molecular diagnostics and treatments for these patients. Results: The study spanned 15 years and included 14 pediatric patients, each diagnosed with distinct spinal tumor entity. The mean patient age was approximately 19.6 ± 10.1 months. Severe axial pain along the vertebral column was observed in 13 patients, while acute neurological deterioration manifested in 7 patients. As a first-line intervention, 13 patients underwent decompressive surgery through laminectomy and tumor resection, and only one patient received chemotherapy solely. Before surgery, seven patients were unable to walk; post-surgery, six of them regained their ability to ambulate. The diagnosis encompassed a range of neoplasms: two instances of Ewing sarcoma, 3 instances of teratoma, one case presenting an atypical teratoid Rhabdoid tumor, two instances each of low-grade astrocytoma and neuroblastoma, and single instances of ependymoma, meningioma, rhabdomyosarcoma, and embryonal tumors with multilayered rosettes (ETMRs). Three patients succumbed two years after initiating therapy. Conclusion: Despite their rarity, intraspinal tumors in pediatric patients pose substantial therapeutic challenges. The intertwined complexities of the disease entity and the patient's neurological status demand swift initiation of an individualized therapeutic strategy. This crucial step helps optimize outcomes for this patient cohort, who frequently grapple with debilitating health conditions. Inclusion of these patients within a registry is mandatory to optimize treatment outcomes due to their rarity in pediatric population. [ABSTRACT FROM AUTHOR]

Purpose: To construct and validate nomograms for predicting lung metastasis probability in patients with malignant primary osseous spinal neoplasms (MPOSN) at initial diagnosis and predicting cancer-specific survival (CSS) in the lung metastasis subgroup. Methods: A total of 1,298 patients with spinal primary osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma were retrospectively collected. Least absolute shrinkage and selection operator (LASSO) and multivariate logistic analysis were used to identify the predictors for lung metastasis. LASSO and multivariate Cox analysis were used to identify the prognostic factors for 3- and 5-year CSS in the lung metastasis subgroup. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analyses (DCA) were used to estimate the accuracy and net benefits of nomograms. Results: Histologic type, grade, lymph node involvement, tumor size, tumor extension, and other site metastasis were identified as predictors for lung metastasis. The area under the curve (AUC) for the training and validating cohorts were 0.825 and 0.827, respectively. Age, histologic type, surgery at primary site, and grade were identified as the prognostic factors for the CSS. The AUC for the 3- and 5-year CSS were 0.790 and 0.740, respectively. Calibration curves revealed good agreements, and the Hosmer and Lemeshow test identified the models to be well fitted. DCA curves demonstrated that nomograms were clinically useful. Conclusion: The nomograms constructed and validated by us could provide clinicians with a rapid and user-friendly tool to predict lung metastasis probability in patients with MPOSN at initial diagnosis and make a personalized CSS evaluation for the lung metastasis subgroup. [ABSTRACT FROM AUTHOR]

Introduction: 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). Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Introduction: FTLD-FET is a newly described subtype of frontotemporal lobar degeneration (FTLD characterized by pathologic inclusions of FET proteins: fused in sarcoma (FUS), Ewing sarcoma, and TATA-binding protein-associated factor 2N (TAF15)). Severe caudate volume loss on MRI has been linked to FTLD-FUS, yet glucose hypometabolism in FTLD-FET has not been studied. We assessed [18F] fluorodeoxyglucose PET (FDG-PET) hypometabolism in FTLD-FET subtypes and compared metabolism to FTLD-tau and FTLD-TDP. Methods: We retrospectively reviewed medical records of 26 autopsied FTLD patients (six FTLD-FET, ten FTLD-Tau, and ten FTLD-TDP) who had completed antemortem FDG-PET. We evaluated five regions, caudate nucleus, medial frontal cortex, lateral frontal cortex, and medial temporal using a 0–3 visual rating scale and validated our findings quantitatively using CORTEX-ID suite Z scores. Results: Of the six FTLD-FET cases (three females) with median age at onset = 36, three were atypical FTLD-U (aFTLD-U) and three were neuronal intermediate filament inclusion disease (NIFID). bvFTD was the most common presentation. Four of the six FTLD cases (3 aFTLD-U + 1 NIFID) showed prominent caudate hypometabolism relatively early in the disease course. FTLD-tau and FTLD-TDP did not show early prominent caudate hypometabolism. Hypometabolism in medial and lateral temporal cortex was associated with FTLD-TDP, while FTLD-tau had normal-minimal regional metabolism. Discussion: Prominent caudate hypometabolism, especially early in the disease course, appears to be a hallmark feature of the aFTLD-U subtype of FTLD-FET. Assessing caudate and temporal hypometabolism on FDG-PET will help to differentiate FTLD-FET from FTLD-tau and FTLD-TDP. [ABSTRACT FROM AUTHOR]

NUT carcinoma is a rare, aggressive malignancy defined as a carcinoma with a chromosomal rearrangement affecting the nuclear protein in testis (NUTM1) gene. This small round blue cell tumor classically exhibits focal abrupt keratinization and immunohistochemical positivity for keratin and squamous markers. However, keratinization is not always present and reports of positivity for other markers that may obscure the diagnosis are increasing. It is also noteworthy that gene fusions involving NUTM1 are not restricted to NUT carcinoma. Herein, we report a NUT carcinoma arising in the mediastinum of a male patient in his 40 s with morphological and immunohistochemical overlap with Ewing family sarcoma and poorly differentiated synovial sarcoma given a round cell morphology, diffuse strong immunoreactivity for CD99, and patchy strong immunoreactivity for TLE1. Squamous differentiation by morphology and p40 expression were notably absent in this case. Classification as NUT carcinoma was ultimately possible when the morphological and immunohistochemical findings were considered in the context of a BRD4::NUTM1 gene fusion identified by next-generation sequencing. While the patient initially responded to palliative radiotherapy, he died approximately one month later. To our knowledge, this is the first report of TLE1 immunoreactivity in NUT carcinoma. This case highlights a potential diagnostic pitfall and emphasizes the need for molecular confirmation in equivocal situations. [ABSTRACT FROM AUTHOR]

Background: No previous reports have characterized national bone sarcoma profiles overall. We examined the nationwide statistics for bone sarcoma in Japan using data from the National Cancer Registry (NCR), a population-based cancer registry. Methods: We identified 3,755 patients with bone sarcomas entered in the NCR during 2016–2019 using International Classification of Diseases-Oncology, Third Edition codes for cancer topography and morphology. We extracted data on patient demographics, tumor details (reason for diagnosis, tumor location, histology, extent of disease), hospital volume/type, treatment, and prognosis for each patient. Results: Bone sarcoma showed a slight male preponderance. The age distribution peaked at ages 10–20 and 60–80; approximately 44% of patients were aged over 60 years. Chordoma, chondrosarcoma, and malignant fibrous histiocytoma of bone peaked in the elderly, and Ewing's sarcoma peaked in children. Osteosarcoma had two peaks in Japan as well as in Western countries. The most frequent tumor locations were the limb (45%) and the pelvis (21%). Extent of disease was categorized as: "localized" (39%), "regional" (27%), and "distant" (11%). We found significant associations between overall survival and age, tumor location, facility type, hospital volume, histologic subtype, reason for diagnosis, and extent of disease. The latter had the poorest survival. Conclusions: This is the first study to outline the epidemiology, clinical features, treatment, prognosis, and significant factors affecting prognosis of bone sarcoma in Japan using the NCR. Documenting our data regarding elderly patients' outcomes is essential so other countries showing similar population-aging trends can learn from our experiences. Level of evidence: Prognostic studies, Level III. [ABSTRACT FROM AUTHOR]

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. Case presentation: 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. [ABSTRACT FROM AUTHOR]

Plain Language Summary 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. 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. 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. [ABSTRACT FROM AUTHOR]

Background: Ewing sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. Despite more intensive chemotherapy regimens and improved local control therapy, there is still a considerable rate of recurrent/progressive disease. Methods: A retrospective study of 50 relapsed/progressive ES patients who were treated at the National Cancer Institute (NCI), Cairo University, during the period from 1st of January 2008 to the end of December 2018, to assess different prognostic variables and disease outcomes. Results: Out of fifty eligible cases, 32 patients (64%) had disease recurrence, and 18 (36%) developed disease progression on treatment. The median follow-up period was 7.4 months. The median overall survival (OS) was 7.5 months, and the cumulative OS was 64% at 6 months and 32.6% at 1 year. The cumulative event-free survival (EFS) was 41.3% at 6 months and 22.3% at 1 year. Patients with disease recurrence had better OS and EFS than patients with disease progression (p = 0.019). Patients who underwent local control at relapse/progression had a significantly better outcome than patients who received chemotherapy only (p < 0.001). Recurrence > 2 years from initial diagnosis was the only independent predictor of better survival outcome. Conclusions: Patients with relapsing/progressive ES portended a poor outcome, with disease progression on treatment faring worse than relapse. Better outcome was observed in patients who experienced recurrence > 2 years after diagnosis, patients with disease recurrence rather than disease progression on treatment, and patients who underwent local control along with intensive chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Ewing sarcoma family tumors are the second most common bone cancer affecting adolescents and young adults. Outcomes are poor in patients with metastatic or relapsed disease, and new treatments are urgently needed. MERTK is a protein found in leukemia, melanoma, lung cancer, and other cancer types where it promotes cancer cell survival and resistance to therapies. MRX-2843 is a new drug that targets MERTK and is currently in clinical trials. We show that MERTK is present on Ewing sarcoma cells and that MRX-2843 has therapeutic activity against these cells. MRX-2843 is even more effective against Ewing sarcoma cells when combined with other drugs, venetoclax or navitoclax, that target a protein called BCL-2. These results suggest that MRX-2843 could be useful to treat Ewing sarcoma in patients. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The chemotherapy regimens recommended for both rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) patients are myelosuppressive and can reduce the absolute neutrophil count (ANC) and subsequently increase the risk of febrile neutropenia (FN). However, only a few studies have focused on the efficacy and safety of granulocyte-colony stimulating factor (G-CSF) drugs in pediatric and adolescent patients with RMS and ES. Our objective was to investigate the efficacy and safety of mecapegfilgrastim, a biosimilar of pegfilgrastim, in prophylaxis of FN for pediatric and adolescent patients with RMS or ES. Methods: In this single-arm, single-center, prospective study, pediatric and adolescent patients with RMS or ES were enrolled to receive either VAC (vincristine, cyclophosphamide, dactinomycin) regimen or VDC (vincristine, cyclophosphamide, doxorubicin) regimen in a 3-week cycle, followed by treatment with mecapegfilgrastim (100 μg/kg, maximum 6 mg) given at 24 h after completing chemotherapy. The primary endpoint was the incidence rate of FN. Secondary endpoints included the incidence rate of grade 4 neutropenia, duration of ANC ≤ 0.5 × 109/L, incidence rate of chemotherapy delay or reduction, use of antibiotics, and safety profile. Results: In total, 2 of the 30 (6.7%, 95% CI: 0.82–22.07) patients experienced FN after the first cycle of chemotherapy. Eight (26.7%, 95% CI: 12.28–45.89) patients experienced grade 4 neutropenia after receiving prophylactic mecapegfilgrastim. Eight patients experienced ANC ≤ 0.5 × 109/L with a median duration of 4.5 days; among them, 6 patients reached the lowest point of their ANC level on day 7, and 5 of them recovered by day 10. No dose reductions, delays, or discontinuation of chemotherapy was reported. Twenty-one (70.0%) patients received antibiotics during the treatment period. No patient experienced FN in the 0–5 years and the 13–18 years groups, and 2 patients experienced FN in the 6–12 years group. Two patients, 6 patients, and no patient experienced grade 4 neutropenia in the 0–5 years, 6–12 years, and 13–18 years groups, respectively. Conclusion: Mecapegfilgrastim showed acceptable efficacy and safety profile in pediatric and adolescent patients with RMS or ES. Further randomized studies with large sample size are warranted. Trial registration: This clinical trial was registered at Chictr.org.cn (No.ChiCTR1900022249). Registered on March 31, 2019. [ABSTRACT FROM AUTHOR]

Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor is a highly aggressive malignant tumor that typically presents in bone and soft tissue. Primary ES of the intestine is relatively rare, which poses a challenge in distinguishing it from other primary tumors of the small intestine through imaging. This article details a case study of ES originating in the intestine. Computed tomography (CT) imaging suggested a small intestinal stromal tumor, and so the patient underwent resection of the small bowel and omental tumor. Pathology results confirmed the diagnosis of ES of the small intestine. Following surgery, the patient underwent six cycles of chemotherapy, and a follow-up positron emission tomography-CT revealed widespread dissemination of the disease with intraperitoneal metastasis, ultimately resulting in the death of the patient. [ABSTRACT FROM AUTHOR]

Introduction: The management of spinal sarcomas is complex, given their widespread involvement and high recurrence rates. Despite consensus on the need for a multidisciplinary approach with surgery at its core, there is a lack of definitive guidelines for clinical decision-making. This study examines a case series of primary spinal sarcomas, focusing on the surgical strategies, clinical results, and survival data to inform and guide therapeutic practices. Methods: We conducted a retrospective analysis of patients who underwent surgical resection for primary spinal sarcomas between 2005 and 2022. The study focused on gathering data on patient demographics, surgical details, postoperative complications, overall hospital stay, and mortality within 90 days post-surgery. Results: The study included 14 patients with a primary diagnosis of spinal sarcoma, with an average age of 48.6 ± 12.6 years. Chondrosarcoma emerged as the most common tumor type, representing 57.1% of cases, followed by Ewing sarcoma at 35.7%, and synovial sarcoma at 7.1%. Patients with chondrosarcoma were treated with en-bloc resection, while the patient with synovial sarcoma underwent intra-lesional excision and those with Ewing sarcoma received decompression and tumor debulking. Postoperative assessments revealed significant improvements in neurological conditions. Notably, functional status as measured by the Karnofski Performance Index (KPI), improved substantially post-surgery (from 61.4 to 80.0%) The mean follow-up was 34.9 ± 9.2 months. During this time period one patient experienced fatal bleeding after en-bloc resection complications involving the vena cava. None of the patient needed further surgery. Conclusions: Our 16-year study offers vital insights into managing primary spinal sarcomas, showcasing the effectiveness of surgical intervention, particularly en-bloc resection. Despite their rarity and complexity, our multidisciplinary treatment approach yields improved outcomes and highlights the potential for refined surgical strategies to become standardized care in this challenging domain. [ABSTRACT FROM AUTHOR]

Liquid-liquid phase separation (LLPS) facilitates the formation of membraneless organelles within cells, with implications in various biological processes and disease states. AT-rich interactive domain-containing protein 1A (ARID1A) is a chromatin remodeling factor frequently associated with cancer mutations, yet its functional mechanism remains largely unknown. Here, we find that ARID1A harbors a prion-like domain (PrLD), which facilitates the formation of liquid condensates through PrLD-mediated LLPS. The nuclear condensates formed by ARID1A LLPS are significantly elevated in Ewing's sarcoma patient specimen. Disruption of ARID1A LLPS results in diminished proliferative and invasive abilities in Ewing's sarcoma cells. Through genome-wide chromatin structure and transcription profiling, we identify that the ARID1A condensate localizes to EWS/FLI1 target enhancers and induces long-range chromatin architectural changes by forming functional chromatin remodeling hubs at oncogenic target genes. Collectively, our findings demonstrate that ARID1A promotes oncogenic potential through PrLD-mediated LLPS, offering a potential therapeutic approach for treating Ewing's sarcoma. ARID1A is a chromatin remodeling protein frequently mutated in cancer. Here the authors report that ARID1A plays a role in forming membraneless organelles through liquid-liquid phase separation (LLPS). ARID1A condensates were elevated in Ewing's sarcoma patients. [ABSTRACT FROM AUTHOR]

Liquid biopsies are emerging as an alternative source for pediatric cancer biomarkers with potential applications during all stages of patient care, from diagnosis to long-term follow-up. While developments within this field are reported, these mainly focus on dedicated items such as a specific liquid biopsy matrix, analyte, and/or single tumor type. To the best of our knowledge, a comprehensive overview is lacking. Here, we review the current state of liquid biopsy research for the most common non-central nervous system pediatric solid tumors. These include neuroblastoma, renal tumors, germ cell tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and other soft tissue sarcomas, and liver tumors. Within this selection, we discuss the most important or recent studies involving liquid biopsy-based biomarkers, anticipated clinical applications, and the current challenges for success. Furthermore, we provide an overview of liquid biopsy-based biomarker publication output for each tumor type based on a comprehensive literature search between 1989 and 2023. Per study identified, we list the relevant liquid biopsy-based biomarkers, matrices (e.g., peripheral blood, bone marrow, or cerebrospinal fluid), analytes (e.g., circulating cell-free and tumor DNA, microRNAs, and circulating tumor cells), methods (e.g., digital droplet PCR and next-generation sequencing), the involved pediatric patient cohort, and proposed applications. As such, we identified 344 unique publications. Taken together, while the liquid biopsy field in pediatric oncology is still behind adult oncology, potentially relevant publications have increased over the last decade. Importantly, steps towards clinical implementation are rapidly gaining ground, notably through validation of liquid biopsy-based biomarkers in pediatric clinical trials. [ABSTRACT FROM AUTHOR]

Data on gonadotoxicity of chemotherapies are essential to better counsel young females and males about the risk of infertility and to better indicate fertility preservation measures before cancer therapies. However, such data have not recently been reviewed for bone cancer. Therefore, a systematic literature search was conducted considering papers published since 2000. This study is part of the FertiTOX® project, which aims to improve the lack of data regarding gonadotoxicity of cancer therapies to enable more accurate counseling regarding fertility preservation. Only relapse-free women and men were included. Gonadotoxic therapy-induced suspected infertility was defined as very low anti-mullerian hormone, high gonadotropin concentration, amenorrhea, oligomenorrhea, azoospermia, or oligozoospermia. The quality of the individual studies was assessed using the Newcastle–Ottawa Scale (NOS). In total, 11 out of 831 studies were included in the review. Suspected infertility was found in 10/190 (5.1%, range 0%–66%) of female patients with osteosarcoma (six studies), in 24/46 (52.2%, range 46%–100%) of male patients with osteosarcoma (three studies), in 18/138 (13.0%, range 3%–18%) of female patients with Ewing's sarcoma (three studies), and in 34/38 (89.5%) of male patients with Ewing's sarcoma (one study). A risk calculation in relation to specific chemotherapies was not possible. Risk of suspected infertility tends to be higher in Ewing's sarcoma in which all patients received chemotherapies with alkylating agents. Two of the 11 included studies received a high NOS quality score, whereas the remaining nine studies received a low quality score, mainly because of the lack of a comparator group. Published data are too limited for precise estimation of the gonadotoxicity. However, data indicate clinically relevant risk for infertility, supporting counseling patients before chemotherapy about fertility preservation measures. [ABSTRACT FROM AUTHOR]

Extraskeletal Ewing sarcoma (EES) is a rare entity, accounting for only 3% of lesions encountered in upper extremity. We present two paediatric patients, who were initially diagnosed with a vascular malformation based on clinical assessment and imaging. Final histopathology revealed Ewing sarcoma of soft tissue origin, confirmed by immunohistochemical analysis. Hand surgeons, who are routinely approached for a myriad of hand pathologies, should be wary and consider EES as a differential when treating such lesions. A multidisciplinary approach with an appropriate treatment algorithm can help in a speedy diagnosis, improving the long-term prognosis of the disease. Level of Evidence: Level V (Therapeutic) [ABSTRACT FROM AUTHOR]

Background: Multidrug chemotherapy for Ewing sarcoma can lead to severe myelosuppression. We proposed two clinical questions (CQ): CQ #1, "Does primary prophylaxis with G-CSF benefit chemotherapy for Ewing sarcoma?" and CQ #2, "Does G-CSF-based intensified chemotherapy improve Ewing sarcoma treatment outcomes?". Methods: A comprehensive literature search was conducted in PubMed, Cochrane Library, and Ichushi web databases, including English and Japanese articles published from 1990 to 2019. Two reviewers assessed the extracted papers and analyzed overall survival (OS), febrile neutropenia (FN) incidence, infection-related mortality, quality of life (QOL), and pain. Results: Twenty-five English and five Japanese articles were identified for CQ #1. After screening, a cohort study of vincristine, ifosfamide, doxorubicin, and etoposide chemotherapy with 851 patients was selected. Incidence of FN was 60.8% with G-CSF and 65.8% without; statistical tests were not conducted. Data on OS, infection-related mortality, QOL, or pain was unavailable. Consequently, CQ #1 was redefined as a future research question. As for CQ #2, we found two English and five Japanese papers, of which one high-quality randomized controlled trial on G-CSF use in intensified chemotherapy was included. This trial showed trends toward lower mortality and a significant increase in event-free survival for 2-week interval regimen with the G-CSF primary prophylactic use compared with 3-week interval. Conclusion: This review indicated that G-CSF's efficacy as primary prophylaxis in Ewing sarcoma, except in children, is uncertain despite its common use. This review tentatively endorses intensified chemotherapy with G-CSF primary prophylaxis for Ewing sarcoma. [ABSTRACT FROM AUTHOR]

The research purpose is to review the surgical approach and evaluate the results in adult patients with head and neck sarcomas. The histopathology varied, including two leiomyosarcomas, six malignant fibrous histiocytomas, two malignant peripheral nerve sheath tumors, four dermatofibrosarcomas protuberans, three osteosarcomas, two angiosarcomas, one liposarcoma, one Ewing sarcoma, one synovial sarcoma, two unclassified/non-differentiated sarcomas and one solitary fibrous tumor. Surgical resection included maxillectomy, mandibulectomy, craniectomy, parotidectomy, scalp resection, face skin resection and laminectomy. The reconstruction was performed with one rectus abdominis flap, four radial forearm flaps, two latissimus dorsi flaps, two vascularized fibula flaps, two pectoralis major myocutaneous flaps, two trapezius flaps, two temporalis flaps, seven scalp flaps and two nasolabial flaps. The total patient number was 24. The hospitalization was uncomplicated, followed by postoperative radiotherapy in the majority of cases. In a mean 15-year follow-up period, 11 patients are still alive and disease-free. There were four recurrences treated with palliative radiotherapy. The surgical approach for head and neck sarcomas, including the achievement of a functionally acceptable result by organ sparing techniques, remains challenging. Wide resection combined with the appropriate reconstruction, particularly with microsurgical techniques, and followed by adjuvant radiotherapy or chemotherapy offer improved prognosis and quality of life. [ABSTRACT FROM AUTHOR]

Background: Heel pain in children is a common condition. The aetiology can be ascribed to fractures, osteochondrosis, tendinitis, calcaneal-navicular or talo-calcaneal coalition, osteomyelitis, rheumatic diseases, anatomic variants, malignant tumours (osteosarcoma, Ewing's sarcoma), and benign lesions (bone cyst, aneurismal bone cyst, osteoid osteoma, or exostosis). In particular, this manuscript focuses on a case of calcaneal exostosis in the paediatric age, aiming to highlight its rarity. Osteochondromas are benign tumours of the surface of the bone and the overlying cartilage. They grow until skeletal maturity and can cause stiffness, pain, cosmetic alterations, tendinitis, and neuro-vascular compression. The calcaneus is an extremely rare site for these tumours. Only two case reports of paediatric exostosis of the calcaneus bone are available. Methods: We describe a case of a girl of 16 years of age, affected by multiple cartilaginous exostosis, who presented with a painful mass on the inferior margin of the foot in the calcaneal region, which was diagnosed as an exostosis. The neoformation was excised, and the girl underwent clinical follow-up. Results: The patient was promptly discharged in good condition, and on the 25th postoperative day, she was completely pain-free and allowed weight bearing. Conclusions: In the case of heel pain resistant to conservative treatment, the presence of an osteochondroma should be considered after excluding more common causes. If symptomatic, calcaneal osteochondromas could require surgical excision. [ABSTRACT FROM AUTHOR]

Sarcomas comprise between 10-15% of all pediatric malignancies. Osteosarcoma and Ewing sarcoma are the two most common pediatric bone tumors diagnosed in children and young adults. These tumors are commonly treated with surgery and/or radiation therapy and combination chemotherapy. However, there is a strong need for the development and utilization of targeted therapeutic methods to improve patient outcomes. Towards accomplishing this goal, pre-clinical models for these unique malignancies are of particular importance to design and test experimental therapeutic strategies prior to being introduced to patients due to their origination site and propensity to metastasize. Pre-clinical models offer several advantages for the study of pediatric sarcomas with unique benefits and shortcomings dependent on the type of model. This review addresses the types of pre-clinical models available for the study of pediatric solid tumors, with special attention to the bone sarcomas osteosarcoma and Ewing sarcoma. [ABSTRACT FROM AUTHOR]

Ewing sarcoma is an uncommon neoplasm considered in the differential diagnosis of tumors with "small round cell" morphology, but its occurrence in the gynecologic tract has only been sporadically documented. Herein, we describe the largest cohort of Ewing sarcoma localized to the female genital tract to date, and emphasize their clinicopathologic resemblance to more common gynecologic neoplasms. Ewing sarcoma (n= 21) was retrospectively identified from 5 institutions. The average patient age was 35 (range 6-61) years. Tumor sites included uterus (n= 8), cervix (n=4), vulva (n= 5), vagina (n= 1), broad ligament (n=1), inguinal area (n =1), and pelvis (n= 1). Nine of 18 cases in which slides were available for review demonstrated only classic round cell morphology, with the remainder showing a variable combination and prominence of variant ovoid/spindle or epithelioid appearance. Tumors showed diffuse membranous reactivity for CD99 (20/20) and were positive for NKX2.2 (8/8, diffuse) and cyclin D1 (7/7, of which 3/7 were patchy/multifocal and 4/7 were diffuse). They were negative for ER (0/6) and CD10 (0/6). Three cases were initially diagnosed as endometrial stromal sarcomas. EWSR1 rearrangement was confirmed in 20/21 by fluorescence in situ hybridization (n=15) and/or sequencing (n= 8). Of the eight tumors that underwent sequencing, 6 harbored FLI1, 1 ERG, and 1 FEV as the fusion partner. Of 11 patients with available follow-up, 5 died of disease, 1 developed lung metastases and 5 are alive with no evidence of disease. Ewing sarcoma of the gynecologic tract is a rare, aggressive entity that shares some morphologic and immunohistochemical features with other more common gynecologic neoplasms. In addition to the typical round cell appearance, variant spindled/ovoid to epithelioid morphology may also be observed and should prompt consideration of this entity with appropriate immunohistochemical and/or molecular studies. [ABSTRACT FROM AUTHOR]

Background: Ewing's sarcoma is a primary bone tumor predominantly observed in children and adolescents, necessitating a multidisciplinary treatment approach. While localized cases have a 5-year survival rate of 60–70%, the prognosis is significantly worse in pelvic advanced cases with metastasis. Moreover, pelvic Ewing's sarcoma has the unique problem of leading to high rates of postoperative infection. Case presentation: We present the case of a Japanese 14-year-old boy with left iliac Ewing's sarcoma and multiple metastases. At the initial visit, imaging revealed a large tumor in the left iliac bone with extraosseous extension and metastasis to multiple sites. Neoadjuvant chemotherapy resulted in significant tumor reduction. Surgical resection was performed without pelvic ring reconstruction to enable early postoperative chemotherapy and minimize postoperative infection risk. Despite complete abductor muscle removal, the patient achieved a stable gait postoperatively by centering the load axis. Conclusion: Our case highlights the successful management of a left iliac Ewing's sarcoma with multiple metastases, with a focus on functional preservation and infection risk reduction. Pelvic ring reconstruction was not performed to avoid postoperative complications, emphasizing the importance of early postoperative chemotherapy. The patient achieved a stable gait postoperatively, demonstrating the potential benefits of this approach in similar cases. [ABSTRACT FROM AUTHOR]

Background: Undifferentiated small round-cell sarcomas (uSRCSs) are a subgroup of sarcomas that are difficult to diagnose. Some uSRCSs have specific gene re-arrangements, but others do not. Currently, there is no specific treatments for advanced uSRCSs, and its treatment is largely based on general experience with sarcomas, which includes chemotherapy, targeted therapy, and immunotherapy. In this article, we report a patient with uSRCS who responded to treatment with anti-VEGF inhibitor surufatinib and anti-PD-1 inhibitor camrelizumab after progression on first-line chemotherapy, secondline anlotinib combined with immunotherapy, and third-line chemotherapy. Case description: In July 2020, a 37-year-old female patient was diagnosed with advanced uSRCS. Results for the Ewing sarcoma RNA binding protein 1 and Wilms tumor suppressor (EWSR1/WT1) fusion gene were negative. The patient was also negative with BCOR (BCL6 co-repressor) and CIC (capicua transcriptional repressor) fusion gene. The next-generation sequencing results revealed point mutations on Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Beta (PIK3CB), Transcription Factor Binding To IGHM Enhancer 3 (TFE3), Mucin 16 (MUC16), and AXL (Axl, also called UFO, ARK, and Tyro7, is part of a family of receptor tyrosine kinases). The patient received 4 cycles of the Ifosfamide and epirubicin hydrochloride regimen, and her best objective response was stable disease. On November 3, 2020, a computed tomography (CT) scan revealed progressive disease (PD). Two cycles of camrelizumab (a programmed death-1 inhibitor) plus anlotinib (an antivascular endothelial growth factor drug) were administered, but PD was again observed. Thus, a regimen of gemcitabine plus docetaxel was adopted. Unfortunately, the disease progressed once again after two cycles of the treatment. On February 4, 2021, the patient began to receive targeted therapy with surufatinib combined with camrelizumab. A CT scan showed that the tumor achieved a partial response. As of April 2023, the patient had a progression-free survival time of 26 months. Conclusions: Surufatinib in combination with camrelizumab could be effective in the treatment of advanced uSRCSs. [ABSTRACT FROM AUTHOR]

Background: Cuproptosis is copper-induced cell death. Copper metabolism related genes (CMRGs) were demonstrated that used to assess the prognosis out of tumors. In the study, CMRGs were tested for their effect on TME cell infiltration in Ewing's sarcoma (ES). Methods: The GEO and ICGC databases provided the mRNA expression profiles and clinical features for downloading. In the GSE17674 dataset, 22prognostic-related copper metabolism related genes (PR-CMRGs) was identified by using univariate regression analysis. Subsequently, in order to compare the survival rates of groups with high and low expression of these PR-CMRGs, Kaplan-Meier analysis was implemented. Additionally, correlations among them were examined. The study employed functional enrichment analysis to investigate probable underlying pathways, while GSVA was applied to evaluate enriched pathways in the ES (Expression Set). Through an unsupervised clustering algorithm, samples were classified into two clusters, revealing significant differences in survival rates and levels of immune infiltration. Results: Using Lasso and step regression methods, five genes (TFRC, SORD, SLC11A2, FKBP4, and AANAT) were selected as risk signatures. According to the Kaplan-Meier survival analysis, the high-risk group had considerably lower survival rates than the low-risk group(p=6.013e-09). The area under the curve (AUC) values for the receiver operating characteristic (ROC) curve were 0.876, 0.883, and 0.979 for 1, 3, and 5 years, respectively. The risk model was further validated in additional datasets, namely GSE63155, GSE63156, and the ICGC datasets. To aid in outcome prediction, a nomogram was developed that incorporated risk levels and clinical features. This nomogram's performance was effectively validated through calibration curves. Additionally, the study evaluated the variations in immune infiltration across different risk groups, as well as high-expression and low-expression groups. Importantly, several drugs were identified that displayed sensitivity, offering potential therapeutic options for ES. Conclusion: The findings above strongly indicate that CMRGs play crucial roles in predicting prognosis and immune status in ES. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusions Multitargeted tyrosine kinase inhibitors (TKIs) have been approved as second‐line therapy in refractory sarcoma, prolonging progression‐free survival (PFS) but with short‐lived duration of disease control. Fruquintinib is a TKI that specifically inhibits vascular endothelial growth factor receptor‐1,2,3 with no metabolism by liver enzymes. In this retrospective study, we assessed the efficacy and safety of fruquintinib‐based treatment in patients with refractory sarcoma after developing several lines of TKI resistance.We retrospectively analyzed the clinical data of patients with refractory sarcoma after they had developed several lines of resistance to TKIs and who received fruquintinib‐based treatment from November 2021 to August 2023. The primary endpoint was the progression‐free survival rate at 4 months (4m‐PFSR). Secondary endpoints were the median PFS, overall survival (OS), objective response rate, disease control rate, and adverse effects (AEs). PFS and OS were estimated using the Kaplan–Meier method. A log‐rank test was used to compare survival curves between different clinical and pathological factors. Cox proportional hazards analysis was performed to identify PFS‐related prognostic factors.We included 124 patients: 56 (45.2%) with osteosarcoma, 28 (22.6%) with Ewing sarcoma, seven (5.6%) with chondrosarcoma, and 33 (26.6%) with soft tissue sarcomas (STS). Only 18 (14.5%) patients received monotherapy with fruquintinib. With a median follow‐up time of 6.8 (interquartile range [IQR], 4.6–9.4) months, 22 (17.7%) patients had partial response and 78 (62.9%) had stable disease. The 4m‐PFSR was 58.4% (95% confidence interval [CI], 49.6%–67.1%). The median PFS and OS were 4.4 (95% CI, 3.9–5.0) months and 11.4 (95% CI, 10.3–12.5) months. In multivariate analysis, a high hazard ratio for progression was associated with target lesions located outside the lung and bone with 1.79 (95% CI, 1.10–2.93; p = 0.020). Eighty‐eight AEs were recorded in 47 (37.9%) patients; the most common were pneumothorax (18/124, 14.5%), diarrhea (8/124, 6.5%), oral mucositis (7/124, 5.6%), and thrombocytopenia (7/124, 5.6%).Fruquintinib may be a potential option for patients with refractory sarcoma after developing several lines of TKI resistance, with a satisfactory efficacy and safety profile in combination therapy. However, the degree of contribution of fruquintinib to results is unclear when combined with other effective substances. Additional prospective trials of fruquintinib should be conducted, especially involving different pathological types and combination regimens. [ABSTRACT FROM AUTHOR]

CIC‐rearranged sarcomas comprise a group of exceptionally aggressive round‐cell sarcomas. These tumors most commonly demonstrate CIC::DUX4 fusion and show similar histopathology to Ewing sarcomas, though lesions mimicking vascular neoplasms have recently been described. Here, we describe a case of a patient with CIC::DUX4 fusion sarcoma identified using RNA‐based molecular testing who was initially diagnosed with an endothelial neoplasm. The tumor showed extensive vasoformative growth, complete WT1 negativity, and global positive staining for ERG, CD31, and DUX4 by immunohistochemistry. Methylation testing of the tumor clustered more closely with angiosarcomas than with CIC‐rearranged sarcomas. Our findings suggest that CIC::DUX4 fused neoplasms may demonstrate a more diverse phenotypic range than previously appreciated and offer evidence that both molecular and immunohistochemical studies are needed for accurate diagnosis. [ABSTRACT FROM AUTHOR]

Background: Macrophages play important roles in phagocytosing tumor cells. However, tumors escape macrophage phagocytosis in part through the expression of anti-phagocytic signals, most commonly CD47. In Ewing sarcoma (ES), we found that tumor cells utilize dual mechanisms to evade macrophage clearance by simultaneously over-expressing CD47 and down-regulating cell surface calreticulin (csCRT), the pro-phagocytic signal. Here, we investigate the combination of a CD47 blockade (magrolimab, MAG) to inhibit the anti-phagocytic signal and a chemotherapy regimen (doxorubicin, DOX) to enhance the pro-phagocytic signal to induce macrophage phagocytosis of ES cells in vitro and inhibit tumor growth and metastasis in vivo. Methods: Macrophages were derived from human peripheral blood monocytes by granulocyte–macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). Flow cytometry- and microscopy-based in-vitro phagocytosis assays were performed to evaluate macrophage phagocytosis of ES cells. Annexin-V assay was performed to evaluate apoptosis. CD47 was knocked out by CRISPR/Cas9 approach. ES cell-based and patient-derived-xenograft (PDX)-based mouse models were utilized to assess the effects of MAG and/or DOX on ES tumor development and animal survival. RNA-Seq combined with CIBERSORTx analysis was utilized to identify changes in tumor cell transcriptome and tumor infiltrating immune cell profiling in MAG and/or DOX treated xenograft tumors. Results: We found that MAG significantly increased macrophage phagocytosis of ES cells in vitro (p < 0.01) and had significant effect on reducing tumor burden (p < 0.01) and increasing survival in NSG mouse model (p < 0.001). The csCRT level on ES cells was significantly enhanced by DOX in a dose- and time-dependent manner (p < 0.01). Importantly, DOX combined with MAG significantly enhanced macrophage phagocytosis of ES cells in vitro (p < 0.01) and significantly decreased tumor burden (p < 0.01) and lung metastasis (p < 0.0001) and extended animal survival in vivo in two different mouse models of ES (p < 0.0001). Furthermore, we identified CD38, CD209, CD163 and CD206 as potential markers for ES-phagocytic macrophages. Moreover, we found increased M2 macrophage infiltration and decreased expression of Cd209 in the tumor microenvironment of MAG and DOX combinatorial therapy treated tumors. Conclusions: By turning "two keys" simultaneously to reactivate macrophage phagocytic activity, our data demonstrated an effective and highly translatable alternative therapeutic approach utilizing innate (tumor associated macrophages) immunotherapy against high-risk metastatic ES. [ABSTRACT FROM AUTHOR]

Background and purpose: Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable efficacy in treating hematological and lymphatic system tumors, but its effectiveness in solid tumors is relatively poor, which is partly attributed to target selection. For Ewing sarcoma (ES), CD99 can be a potential target for CAR-T cells. However, due to T cells’ endogenous expression of CD99 protein, CAR-T cells targeting CD99 face limitations in their expansion capacity in vitro. This study aimed to identify the optimal conditions for preparing CD99 CAR-T cells by incorporating CD99 knockdown short hairpin RNA (shRNA), optimizing the multiplicity of infection (MOI) for lentiviral transduction, and screening for the best culture medium and container for CAR-T cell expansion. Methods: shRNA sequences were screened to enhance the expansion capacity of CD99 CAR-T cells. Different MOI, culture media, and containers were used to assess CAR-T cell transduction efficiency, cell viability, proliferation capacity, specific killing ability, and interferon-γ (IFN-γ) release levels under various conditions, in order to identify the optimal cell preparation conditions. Results: The expansion level of KO-CD99 CAR-T cells obtained through shRNA knockdown was significantly higher than that of CD99 CAR-T cells [(16.40±0.40) vs (6.33±1.53), P<0.01]. The optimal expansion effect was observed when the transduction MOI was between 0.25 and 1.0, and OptiVitro was used as the culture medium. CAR-T cells cultured in ventilated flasks exhibited significantly higher expansion rates compared to cells cultured in bags [MOI=0.25: (50.23±3.32) vs (13.02±4.82); MOI=0.50: (49.96±0.83) vs (18.25±2.88); MOI=1.00: (48.27±5.08) vs (13.16±6.26); P<0.01], with better cell phenotype and higher specific killing ability. Conclusion: KO-CD99 CAR-T cells obtained through shRNA technology can achieve stable expansion. Based on the optimization of expansion conditions, KO-CD99 CAR-T cells exhibit superior expansion capacity and a higher proportion of memory T cells when the MOI is between 0.25 and 1.00, OptiVitro is used as the culture medium, and ventilated flasks are used as the culture container. These findings lay a solid foundation for further clinical trials of CD99 CAR-T cell therapy for ES. [ABSTRACT FROM AUTHOR]

Background: While the list of fusion‐driven soft tissue neoplasms is expanding rapidly, their importance among cutaneous and superficial mesenchymal and adnexal neoplasms remains poorly understood. This challenge is especially evident in cases with ambiguous histopathology that are difficult to classify based on morphology. Aims: Our goal was to investigate the benefits of next‐generation sequencing in diagnosing complex cutaneous neoplasms. Materials & Methods: Departmental archives were searched for fusion‐driven cutaneous neoplasms. Slides were retrieved and clinical information including follow‐up was obtained. Results: Fifteen cases occurred in eight female and seven male patients, with a median age of 26 years (range: 1–83) at diagnosis. Tumors involved the extremities (9), scalp (5), and head and neck (1). Predominant features included myoepithelial (5), nested spindled with clear cytoplasm (2), atypical adnexal/squamoid (2), small round blue cell (2), cellular spindled (3), and fibrohistiocytic morphology (1). Most frequently encountered fusions involved EWSR1 (6) fused to ERG (1), FLI1 (1), CREB1 (2), CREM (1), PBX3 (1), followed by PLAG1 (4) with LIFR (2), TRPS1 (1) and CHCHD7. Additional fusions encountered were YAP1::NUTM1, EML4::ALK, SS18::SSX1 (2), and a novel fusion: ACTB::ZMIZ2. Integration of histologic features and molecular findings led to final diagnoses of primary cutaneous Ewing sarcoma (2), soft tissue myoepithelioma (4), cutaneous syncytial myoepithelioma (1), cutaneous adnexal carcinoma (1), porocarcinoma (1), inflammatory myofibroblastic tumor (1), synovial sarcoma (2), clear cell sarcoma (2), and angiomatoid fibrous histiocytoma (1). Discussion and conclusion: Our results show that fusion testing can be a helpful diagnostic tool, especially in cases with unusual or uncommon morphology in superficial sites. Furthermore, it can allow for the identification of potential therapeutic targets in some instances. [ABSTRACT FROM AUTHOR]

This corrigendum published in FEBS Letters corrects errors in the original article titled "A logical model of Ewing sarcoma cell epithelial-to-mesenchymal transition supports the existence of hybrid cellular phenotypes." The errors were related to the figures and table in the article. The authors apologize for any confusion caused by these errors and clarify that they do not affect the conclusions of the article. The corrigendum provides specific corrections for each figure and table, including changes to the interaction between nodes, states of certain rows, and the number of stable states identified. The corrected figures and table are included in the corrigendum. [Extracted from the article]

Pediatric tumors of the eye and orbit can be benign or malignant as well as congenital or acquired and are usually distinctively different than those seen in adults. Although most of these neoplasms are benign (eg, dermoid cyst, chalazion, molluscum), their location near and within a vital organ can result in serious dermatologic and ophthalmologic sequelae. Lesions discussed include vascular lesions, retinoblastomas (the most common primary pediatric intraocular malignancy), rhabdomyosarcoma (the most common primary pediatric orbital malignancy), Langerhans cell histiocytosis, and metastatic lesions to the orbit (neuroblastoma, Ewing sarcoma). Although cysts and ocular melanoma can occur within the pediatric population, these conditions are covered in other contributions in this issue of Clinics in Dermatology. [ABSTRACT FROM AUTHOR]

Metastatic tumors to the eye and eyelid are generally seen in patients with disseminated metastases in the setting of advanced disease. Occasionally, they can present as the first sign of occult malignancy. The choroid is the most common site of intraocular metastases secondary to its dense vascular supply. Similar to the eye, metastatic tumors to the eyelid can present with a variety of clinical findings and are most often seen in patients with a known history of cancer. The most common skin malignancy that can spread to ocular structures is cutaneous melanoma, whereas the most common noncutaneous malignancy is breast cancer followed by lung cancer. In pediatric patients, metastatic disease to the eye is rare and can be seen in neuroblastoma and Ewing sarcoma. The overall prognosis of metastatic lesions involving the eye and eyelid is typically poor, with a mean survival of months. Ophthalmologists play an important role in the diagnosis of metastatic disease of the eye and eyelid; therefore, it is imperative for patients to undergo a complete ophthalmic examination and systemic workup if they have new-onset vision changes and a known history of cancer. Early diagnosis and management with systemic and local therapies can maximize quality of life and preserve vision. [ABSTRACT FROM AUTHOR]

Background/Aim: Cold physical plasma (CPP) has emerged as an effective therapy in oncology by inducing cytotoxic effects in various cancer cells, including chondrosarcoma (CS), Ewing's sarcoma (ES), and osteosarcoma (OS). The current study investigated the impact of CPP on cell motility in CS (CAL-78), ES (A673), and OS (U2-OS) cell lines, focusing on the actin cytoskeleton. Materials and Methods: The CASY Cell Counter and Analyzer was used to study cell proliferation and determine the optimal concentrations of fetal calf serum to maintain viability without stimulation of cell proliferation. CellTiter-BlueCell viability assay was used to determine the effects of CPP on the viability of bone sarcoma cells. The Radius assay was used to determine cell migration. Staining for Deoxyribonuclease I, G-actin, and F-actin was used to assay for the effects on the cytoskeleton. Results: Reductions in cell viability and motility were observed across all cell lines following CPP treatment. CPP induced changes in the actin cytoskeleton, leading to decreased cell motility. Conclusion: CPP effectively reduces the motility of bone sarcoma cells by altering the actin cytoskeleton. These findings underscore CPP's potential as a therapeutic tool for bone sarcomas and highlight the need for further research in this area. [ABSTRACT FROM AUTHOR]

Introduction: We aim to share the experience of a single center in the management of eight cases of renal primitive neuroectodermal tumor (PNET) which are uncommon, aggressive tumors. The objectives were to study the presentation of the disease, the treatment offered and its outcomes, and the comparison of the treatment with published literature. Methods: The single-center renal PNET data of all patients were retrospectively reviewed from 2011 to 2022. Renal PNET was seen in eight patients. Minimum follow-up period of 1 year was required. Results: Male-to-female ratio was 7:1. The mean age was 26.5 years. All were locally advanced tumors on presentation. One patient had an inferior vena cava thrombus, one patient had metastases on presentation, and two patients had tumor extending to paranephric space. The diagnosis was made by histopathology supported by immunohistochemistry showing CD99 positivity. All patients were treated with radical nephrectomy, followed by chemotherapy in all and radiotherapy in three patients. Two patients expired at 3% and 6 years after surgery, the remaining six are alive at a median follow-up period of 34.5 months. Conclusion: Renal PNET is an uncommon renal tumor which is aggressive and requires multimodal therapy for prolonged survival. [ABSTRACT FROM AUTHOR]

Abstract Background Ewing’s sarcoma is a primary bone tumor predominantly observed in children and adolescents, necessitating a multidisciplinary treatment approach. While localized cases have a 5-year survival rate of 60–70%, the prognosis is significantly worse in pelvic advanced cases with metastasis. Moreover, pelvic Ewing’s sarcoma has the unique problem of leading to high rates of postoperative infection. Case presentation We present the case of a Japanese 14-year-old boy with left iliac Ewing’s sarcoma and multiple metastases. At the initial visit, imaging revealed a large tumor in the left iliac bone with extraosseous extension and metastasis to multiple sites. Neoadjuvant chemotherapy resulted in significant tumor reduction. Surgical resection was performed without pelvic ring reconstruction to enable early postoperative chemotherapy and minimize postoperative infection risk. Despite complete abductor muscle removal, the patient achieved a stable gait postoperatively by centering the load axis. Conclusion Our case highlights the successful management of a left iliac Ewing’s sarcoma with multiple metastases, with a focus on functional preservation and infection risk reduction. Pelvic ring reconstruction was not performed to avoid postoperative complications, emphasizing the importance of early postoperative chemotherapy. The patient achieved a stable gait postoperatively, demonstrating the potential benefits of this approach in similar cases.

Abstract Background Ewing’s sarcoma is a rare form of bone cancer that can also affect soft tissues. In some cases, it can spread to other parts of the body, including the testicles, causing testicular metastases. To our knowledge, no testicular metastasis of Ewing’s sarcoma has been reported in the literature. Summary We report an original case of an 18-year-old patient who presented with bilateral testicular masses revealing an exceptional metastasis of metastatic bone Ewing sarcoma under chemotherapy for one year. It was difficult to diagnose synchronous bilateral testicular metastases of Ewing’s sarcoma due to the low frequency of these metastases. However, given the history of metastatic cancer, the data from the clinical examination, and the results of ultrasound, it should be considered and included in the differential diagnosis. Conclusion Despite the uncommon occurrence of secondary testicular metastasis, it should be considered in the differential diagnosis when encountering such a clinical presentation.

Aims: Ilium is the most common site of pelvic Ewing’s sarcoma (ES). Resection of the ilium and iliosacral joint causes pelvic disruption. However, the outcomes of resection and reconstruction are not well described. In this study, we report patients’ outcomes after resection of the ilium and iliosacral ES and reconstruction with a tibial strut allograft. Methods: Medical files of 43 patients with ilium and iliosacral ES who underwent surgical resection and reconstruction with a tibial strut allograft between January 2010 and October 2021 were reviewed. The lesions were classified into four resection zones: I1, I2, I3, and I4, based on the extent of resection. Functional outcomes, oncological outcomes, and surgical complications for each resection zone were of interest. Functional outcomes were assessed using a Musculoskeletal Tumor Society (MSTS) score and Toronto Extremity Salvage Score (TESS). Results: The mean age of the patients was 17 years (SD 9.1). At a mean follow-up of 70.8 months (SD 50), the mean functional outcomes were 24.2 points (SD 6.3) for MSTS and 81 points (SD 11) for TESS. The mean MSTS and TESS scores were associated with the iliac resection zone (< 0.001). Nine patients (20.9%) had local recurrence. The recurrence was not associated with the zone of iliac resection (p = 0.324). The two-year disease-free survival of the patients was 69.4%. The mean time to graft union was longer in patients with the I4 resection zone (p < 0.001). The complication rate was 34.9%, and nerve palsy (11.6%) was the most common. The rate of surgical complications was not associated with the resection zone. Conclusion: Reconstruction using tibial strut allograft is an efficient procedure after the resection of the ilium and iliosacral ES. Functional outcomes and complications of iliac ES depend on the resection zone, and inferior outcomes could be generally expected when more segments of the pelvic ring are resected, even if it is reconstructed. Cite this article: Bone Jt Open 2024;5(5):385–393.

We describe exciting recent advances in fusion-driven sarcoma etiology, from an epigenetics perspective. By exploring the current state of the field, we identify and describe the central mechanisms that determine sarcomagenesis. Further, we discuss seminal studies in translational genomics, which enabled epigenetic characterization of fusion-driven sarcomas. Important context for epigenetic mechanisms include, but are not limited to, cell cycle and metabolism, core regulatory circuitry, 3-dimensional chromatin architectural dysregulation, integration with ATP-dependent chromatin remodeling, and translational animal modeling. Paradoxically, while the genetic requirements for oncogenic transformation are highly specific for the fusion partners, the epigenetic mechanisms we as a community have uncovered are categorically very broad. This dichotomy prompts the question of whether the investigation of rare disease epigenomics should prioritize studying individual cell populations, thereby examining whether the mechanisms of chromatin dysregulation are specific to a particular tumor. We review recent advances focusing on rhabdomyosarcoma, synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma, undifferentiated round cell sarcoma, Ewing sarcoma, myxoid/round liposarcoma, epithelioid hemangioendothelioma and desmoplastic round cell tumor. The growing number of groundbreaking discoveries in the field, motivated us to anticipate further exciting advances in the area of mechanistic epigenomics and direct targeting of fusion transcription factors in the years ahead. [ABSTRACT FROM AUTHOR]

Novel therapeutic approaches are needed for the treatment of Ewing sarcoma tumors. We previously identified that Ewing sarcoma cell lines are sensitive to drugs that inhibit protein translation. However, translational and therapeutic approaches to inhibit protein synthesis in tumors are limited. In this work, we identified that reactive oxygen species, which are generated by a wide range of chemotherapy and other drugs, inhibit protein synthesis and reduce the level of critical proteins that support tumorigenesis in Ewing sarcoma cells. In particular, we identified that both hydrogen peroxide and auranofin, an inhibitor of thioredoxin reductase and regulator of oxidative stress and reactive oxygen species, activate the repressor of protein translation 4E-BP1 and reduce the levels of the oncogenic proteins RRM2 and PLK1 in Ewing and other sarcoma cell lines. These results provide novel insight into the mechanism of how ROSinducing drugs target cancer cells via inhibition of protein translation and identify a mechanistic link between ROS and the DNA replication (RRM2) and cell cycle regulatory (PLK1) pathways. [ABSTRACT FROM AUTHOR]

Ewing sarcoma is a pediatric bone and soft tissue tumor treated with chemotherapy, radiation, and surgery. Despite intensive multimodality therapy, ~50% patients eventually relapse and die of the disease due to chemoresistance. Here, using phospho-profiling, we find Ewing sarcoma cells treated with chemotherapeutic agents activate TAM (TYRO3, AXL, MERTK) kinases to augment Akt and ERK signaling facilitating chemoresistance. Mechanistically, chemotherapy-induced JAK1-SQ phosphorylation releases JAK1 pseudokinase domain inhibition allowing for JAK1 activation. This alternative JAK1 activation mechanism leads to STAT6 nuclear translocation triggering transcription and secretion of the TAM kinase ligand GAS6 with autocrine/paracrine consequences. Importantly, pharmacological inhibition of either JAK1 by filgotinib or TAM kinases by UNC2025 sensitizes Ewing sarcoma to chemotherapy in vitro and in vivo. Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML and advanced solid tumors, enhances chemotherapy efficacy to further suppress Ewing sarcoma tumor growth in vivo. Our findings reveal an Ewing sarcoma chemoresistance mechanism with an immediate translational value. Due to limited therapeutic options, patients with Ewing sarcoma typically receive intensive chemotherapy which limits quality of life and often resistance develops. Here, the authors identify a chemotherapy-induced JAK-STAT-GAS6-TAM kinase signaling cascade in Ewing sarcoma and therapeutically target this axis with TAM kinase inhibition. [ABSTRACT FROM AUTHOR]

Ewing sarcoma is the second most common bone cancer in children, and while patients who present with metastatic disease at the time of diagnosis have a dismal prognosis. Ewing sarcoma tumors are driven by the fusion gene EWS/Fli1, and while these tumors are genetically homogenous, the transcriptional heterogeneity can lead to a variety of cellular processes including metastasis. In this study, we demonstrate that in Ewing sarcoma cells, the canonical Wnt/β-Catenin signaling pathway is heterogeneously activated in vitro and in vivo, correlating with hypoxia and EWS/Fli1 activity. Ewing sarcoma cells predominantly express β-Catenin on the cell membrane bound to CDH11, which can respond to exogenous Wnt ligands leading to the immediate activation of Wnt/β-Catenin signaling within a tumor. Knockdown of CDH11 leads to delayed and decreased response to exogenous Wnt ligand stimulation, and ultimately decreased metastatic propensity. Our findings strongly indicate that CDH11 is a key component of regulating Wnt//β-Catenin signaling heterogeneity within Ewing sarcoma tumors, and is a promising molecular target to alter Wnt//β-Catenin signaling in Ewing sarcoma patients. [ABSTRACT FROM AUTHOR]

Aim: Malignant chest wall tumors are rare in children. We aimed to study the management of the Ewing family of tumors (EFT) in the chest walls of children. Materials and Methods: The files of patients diagnosed with primitive neuro-ectodermal tumor and Ewing sarcoma of the chest wall in the prior 2 decades were retrospectively reviewed. Results: A total of 15 children with a median age of 10 (8-14) years were included. Their symptoms were palpable mass (n=6), chest pain (n=4), B symptoms (n=2), cough (n=2) and abdominal pain. Their history revealed delayed diagnoses in 1/3 of the patients due to a misinterpretation of the symptoms. All children except for one had tru-cut biopsy and upfront chemotherapy. The median greatest diameter of mass at diagnosis was 100 (67-148) mm and 51 (39-100) mm at preoperative imaging after chemotherapy. Pleural effusion (n=8), costal destruction (n=9), extension to neural foramina (n=3), pulmonary or diaphragmatic nodule (n=5) and distant bone metastasis (n=4) were present at diagnosis in some cases. More than one surgery was performed in 9 (60%) of the children in order to remove the primary tumor and metastases. Costal excision (n=11), diaphragmatic resection (n=6) and chest wall reconstruction with graft material were performed on 8 patients. All cases had radiotherapy postoperatively. Mortality occurred in 9 (60%) patients due to local recurrences or metastases. Only 3 children reached 5-year survival and were considered to be cured. The remaining 3 patients completed their first line oncologic treatments and were under surveillance without treatment. Conclusion: The EFT in the chest wall are aggressive tumors with poor prognosis despite multimodality treatment. Surgeons dealing with these patients should be familiar with complex chest wall reconstruction techniques. [ABSTRACT FROM AUTHOR]