RESUMEN
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.
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Neoplasias de la Columna Vertebral , Humanos , Masculino , Femenino , Estudios Retrospectivos , Preescolar , Niño , Lactante , Adolescente , Resultado del Tratamiento , Neoplasias de la Columna Vertebral/cirugía , Neoplasias de la Columna Vertebral/complicaciones , Sarcoma de Ewing/cirugía , Sarcoma de Ewing/terapia , Sarcoma de Ewing/complicaciones , Neoplasias de la Médula Espinal/cirugía , Neoplasias de la Médula Espinal/complicaciones , Ependimoma/terapia , Ependimoma/cirugía , Ependimoma/diagnóstico , Laminectomía , Descompresión Quirúrgica/métodos , Teratoma/complicaciones , Teratoma/cirugía , Teratoma/diagnóstico , Teratoma/terapia , Procedimientos Neuroquirúrgicos/métodos , Neuroblastoma/cirugía , Neuroblastoma/complicaciones , Astrocitoma/complicaciones , Astrocitoma/cirugía , Astrocitoma/terapia , Tumor Rabdoide/terapia , Tumor Rabdoide/complicaciones , Meningioma/cirugía , Meningioma/terapia , Meningioma/complicaciones , Meningioma/diagnósticoRESUMEN
BACKGROUND: Ewing sarcoma (EwS) is a highly malignant and heterogeneous tumor. Exploring clinicopathological characteristics and genetic features of EwS is critical for prognosis and treatment regimen. METHODS: Clinicopathological characteristics and genetic features of young (≤ 30y) and senior (> 30y) EwS patients were analyzed based on histology, phenotype, and next-generation sequencing (NGS) detection. RESULTS: The young group (18/36) presented nontypical EwS histological morphology, whereas the senior group (18/36) presented typical morphology. The prognosis of the young group was found to be worse compared with the senior group for patients without metastasis at the initial diagnosis. DNA- and RNA-based NGS was conducted on 20 extraosseous EwS patients. 16/20 samples demonstrated EWSR1-FLI1 fusion and 4/20 demonstrated EWSR1-ERG fusion. However, 13/16 EWSR1-FLI1fusions were detected both in DNA- and RNA-based NGS, 1/16 was detected only at the DNA level, and 2/16 were detected only at the RNA level. An analysis of the genetic profiles of the EWSR1-FLI1 cases revealed that the young group was inclined to couple with more copy number variations (CNV), such as CCND1, CDK4 amplification, and fusion variations, such as CHEK1-EWSR1, SLIT2-EWSR1, and EWSR1-FAM76B fusion. The senior group was more likely to have SNV or Indel mutations, such as EPHA3 and STAG2 mutations. Moreover, patients with more CNV abnormalities had a worse prognosis than those with predominantly SNP variants. In addition, compared with the senior group, the young group had significantly higher CyclinD1 protein expression. CONCLUSION: Clinicopathological characteristics and genetic features in young and senior EwS patients differed significantly. Targeting cell cycle dysregulation based on age subgroup may be a potential therapeutic strategy for Ewing sarcoma.
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Neoplasias Óseas , Proteínas de Fusión Oncogénica , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Masculino , Femenino , Adulto , Adulto Joven , Adolescente , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Persona de Mediana Edad , Niño , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN/genética , Preescolar , Secuenciación de Nucleótidos de Alto Rendimiento , Pronóstico , Biomarcadores de Tumor/genética , Fenotipo , Proteína Proto-Oncogénica c-fli-1/genética , Mutación , Factores de Edad , Variaciones en el Número de Copia de ADNRESUMEN
BACKGROUND: Ewing's sarcoma (ES) is the second most common malignant primary bone tumor in children and adolescents. Peroxiredoxin 2 (PRDX2) is an antioxidant enzyme. AIMS: Here, we investigated the role and mechanism of PRDX2 in the development of ES. METHODS AND RESULTS: PRDX2 expression was knocked down in A673 and RDES cells by specific siRNA interference (si-PRDX2). Knockdown of PRDX2 strongly inhibited the proliferation, growth, migration, invasion, and MMP9 activity and induces apoptosis of A673 and RDES cells. si-PRDX2 significantly inhibited the phosphorylation of Akt and the expression of cyclin D1. The transcription factor that might regulate PRDX2 transcription was predicted with the JASPAR and UCSC databases, and analyzed using dual-luciferase and Chromatin co-immunoprecipitation experiments. SNAI1 could activate the transcription of PRDX2 by binding to predicted promoter binding site. CONCLUSION: PRDX2 may be a potential therapeutic target for ES.
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Neoplasias Óseas , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Metaloproteinasa 9 de la Matriz , Peroxirredoxinas , Sarcoma de Ewing , Humanos , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Proliferación Celular/genética , Movimiento Celular/genética , Sarcoma de Ewing/patología , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Neoplasias Óseas/patología , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Línea Celular Tumoral , Invasividad Neoplásica , Técnicas de Silenciamiento del Gen , Apoptosis , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , ARN Interferente Pequeño/genéticaRESUMEN
BACKGROUND: Pediatric patients with recurrent/metastatic Ewing sarcoma (ES) have a dismal 5-year survival. Novel therapeutic approaches are desperately needed. Natural killer (NK) cell number and function are low in ES patient tumors, in large part due to the immunosuppressive tumor microenvironment (TME). Melanoma cell adhesion molecule (MCAM) is highly expressed on ES and associated with ES metastasis. NKTR-255 is a polymer-conjugated recombinant human interleukin-15 (IL-15) agonist improving NK cell activity and persistence. Magrolimab (MAG) is a CD47 blockade that reactivates the phagocytic activity of macrophages. METHODS: Transcriptome profiling coupled with CIBERSORT analyses in both ES mouse xenografts and human patient tumors were performed to identify mechanisms of NK resistance in ES TME. A chimeric antigen receptor (CAR) NK cell targeting MCAM was engineered by CAR mRNA electroporation into ex vivo expanded NK cells. In vitro cytotoxicity assays were performed to investigate the efficacy of anti-MCAM-CAR-NK cell alone or combined with NKTR-255 against ES cells. Interferon-γ and perforin levels were measured by ELISA. The effect of MAG on macrophage phagocytosis of ES cells was evaluated by in vitro phagocytosis assays. Cell-based and patient-derived xenograft (PDX)-based xenograft mouse models of ES were used to investigate the antitumor efficacy of CAR-NK alone and combined with NKTR-255 and MAG in vivo. RESULTS: We found that NK cell infiltration and activity were negatively regulated by tumor-associated macrophages (TAM) in ES TME. Expression of anti-MCAM CAR significantly and specifically enhanced NK cytotoxic activity against MCAMhigh but not MCAM-knockout ES cells in vitro, and significantly reduced lung metastasis and extended animal survival in vivo. NKTR-255 and MAG significantly enhanced in vitro CAR-NK cytotoxicity and macrophage phagocytic activity against ES cells, respectively. By combining with NKTR-255 and MAG, the anti-MCAM-CAR-NK cell significantly decreased primary tumor growth and prolonged animal survival in both cell- and PDX-based ES xenograft mouse models. CONCLUSIONS: Our preclinical studies demonstrate that immunotherapy via the innate immune system by combining tumor-targeting CAR-NK cells with an IL-15 agonist and a CD47 blockade is a promising novel therapeutic approach to targeting MCAMhigh malignant metastatic ES.
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Inmunoterapia , Sarcoma de Ewing , Microambiente Tumoral , Humanos , Sarcoma de Ewing/inmunología , Sarcoma de Ewing/terapia , Animales , Ratones , Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Inmunidad Innata , Línea Celular Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ewing sarcoma (ES) is a small round cell malignancy, mainly in the bone tissue, followed by the soft tissue. Lung metastases (LM) and bone metastases (BM) are the most common types of metastases. From 2010 to 2018, the Surveillance, Epidemiology, and End Results database diagnosed 242 cases of ES with LM, 186 cases of ES with BM, and 74 cases of ES with LM and BM. Univariate and multivariate logistic regression analyses were used to determine the risk factors for LM and/or BM, and Kaplan-Meier curves and Cox regression analysis were used to determine the prognostic factors for LM and/or BM. Tumor size ≥50 mm, N1 stage, BM, liver metastases, and surgical treatment were significantly correlated with LM; tumor size >100 mm, brain metastases, LM, surgical treatment, and chemotherapy were significantly correlated with BM; female, N1 stage, brain metastases, liver metastases, and surgical treatment were significantly correlated with LM and BM. Older age, BM, higher T stage, no surgical treatment, and no chemotherapy were harmful to the survival of ES patients with LM; older age, female, LM, and no chemotherapy were harmful to the survival of ES patients with BM; older age and no chemotherapy were harmful to the survival of ES patients with LM and BM. Larger tumor size, N1 stages, and organ metastases were significantly associated with ES patients with LM and/or BM. Chemotherapy is effective in improving the survival.
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Neoplasias Óseas , Neoplasias Pulmonares , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/patología , Neoplasias Óseas/secundario , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/mortalidad , Masculino , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/mortalidad , Adulto , Adolescente , Adulto Joven , Programa de VERF , Niño , Persona de Mediana Edad , Estimación de Kaplan-Meier , Pronóstico , Factores de Riesgo , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Estudios Retrospectivos , Estadificación de Neoplasias , PreescolarRESUMEN
Primary bone tumors are rare but more frequently seen during childhood and with predilection for the distal femur and proximal tibia. Therapy of benign tumors-if indicated-includes surgical resection in most cases, whereas malignant bone tumors such as osteo- and Ewing's sarcomas are treated with chemotherapy, wide resection and/or radiation therapy (Ewing's sarcoma). The reconstruction of emerging bone defects is significantly influenced by surgeon-related preferences and tumor-associated factors, respectively. Double-barrel vascularized fibula grafts or extracorporeally irradiated autografts in combination with a free fibula transplant are preferred biological reconstruction techniques around the knee joint. In cases in which the knee joint cannot be preserved, reconstruction is performed using tumor endoprostheses, but potentially emerging leg length discrepancies after resection of a potent physis must be taken into account. In considerably young patients, rotationplasty might represent a viable option with promising functional results.
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Neoplasias Óseas , Humanos , Neoplasias Óseas/terapia , Neoplasias Óseas/patología , Neoplasias Óseas/cirugía , Niño , Articulación de la Rodilla/cirugía , Articulación de la Rodilla/patología , Trasplante Óseo/métodos , Procedimientos de Cirugía Plástica/métodos , Sarcoma de Ewing/terapia , Sarcoma de Ewing/cirugía , Sarcoma de Ewing/patología , Preescolar , Adolescente , Peroné/trasplante , Masculino , FemeninoRESUMEN
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.
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Sarcoma , Neoplasias de la Columna Vertebral , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Masculino , Femenino , Adulto , Sarcoma/cirugía , Sarcoma/mortalidad , Neoplasias de la Columna Vertebral/cirugía , Neoplasias de la Columna Vertebral/mortalidad , Resultado del Tratamiento , Procedimientos Neuroquirúrgicos/métodos , Anciano , Sarcoma Sinovial/cirugía , Sarcoma Sinovial/mortalidad , Condrosarcoma/cirugía , Condrosarcoma/mortalidad , Condrosarcoma/patología , Sarcoma de Ewing/cirugía , Sarcoma de Ewing/mortalidad , Complicaciones Posoperatorias/etiología , Grupo de Atención al PacienteAsunto(s)
Neoplasias Pancreáticas , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/diagnóstico por imagen , Sarcoma de Ewing/patología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/diagnóstico por imagen , Tumores Neuroectodérmicos Primitivos/patología , Tumores Neuroectodérmicos Primitivos/diagnóstico por imagen , Tumores Neuroectodérmicos Primitivos/diagnóstico , Masculino , FemeninoRESUMEN
INTRODUCTION: Ewing sarcoma is an aggressive malignancy primarily affecting children and adolescents. Limited research is available on treatment practices, clinical course, and survival in adults. METHODS: A multi-institution retrospective cohort study of all adults (>18 years) and children (≤18 years) with Ewing sarcoma treated in British Columbia, Canada between January 01, 2000 and December 31, 2018. RESULTS: One-hundred seven individuals (66 adults, 41 children) were included in the analysis. 5-year OS was 58â¯% in adults and 75â¯% in children. For individuals with local disease, 5-year OS was 74â¯% in adults and 84â¯% in children. Adult status was associated with impaired PFS (HR, 1.8; 95â¯% CI, 1.0 - 3.1, p=0.04) and OS (HR, 1.8; 95â¯% CI, 0.9 - 3.5; p=0.088). A Charlson Comorbidity Index (CCI) ≥3 was associated with impaired survival in adults and children (HR, 3.9, 95â¯% CI, 2.0 - 7.5; p=<0.001); baseline CCIs were not significantly different between groups. Most adults (61/66; 92â¯%) and all children (41/41; 100â¯%) received systemic treatment with no significant difference in mean lines of therapy, treatment modalities or agents. Most children received interval-compressed chemotherapy (35/41; 85â¯%) compared to adults (19/61; 29â¯%; p=<0.001). Interval-compression was not significantly associated with improved survival in adults with local disease (HR, 0.51; 95â¯% CI 0.1 - 2.3; p=0.373). Children more often initiated treatment within 28 days of diagnosis (31/33; 94â¯%) compared to adults (41/64; 64â¯%, p=0.001). Treatment within 28 days was associated with improved survival in the entire cohort (HR, 2.04 95â¯% CI, 1.1 - 3.9; p = 0.03). This association was preserved in subanalysis of individuals with local disease (HR, 5.4; 95â¯% CI, 1.9 - 15; p = 0.001) and only adults (HR, 5.3, 95â¯% CI, 1.7 - 17; p = 0.005). DISCUSSION: Survival for adults with Ewing sarcoma is inferior to children despite similarities in presentation, tumour characteristics and treatments. Further studies on the value of interval-compression in adults are required. Timely initation of treatment should be a priority for this disease.
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Sarcoma de Ewing , Humanos , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/terapia , Sarcoma de Ewing/patología , Sarcoma de Ewing/tratamiento farmacológico , Masculino , Femenino , Estudios Retrospectivos , Adulto , Adolescente , Niño , Adulto Joven , Persona de Mediana Edad , Colombia Británica/epidemiología , Preescolar , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/terapia , Tasa de Supervivencia , Resultado del Tratamiento , AncianoRESUMEN
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.
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Neoplasias Pulmonares , Sarcoma de Ewing , Tomografía Computarizada por Rayos X , Humanos , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/patología , Sarcoma de Ewing/diagnóstico por imagen , Masculino , Adolescente , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico por imagen , Dolor de Hombro/etiología , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/patologíaRESUMEN
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.
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Neoplasias Óseas , Progresión de la Enfermedad , Recurrencia Local de Neoplasia , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/terapia , Sarcoma de Ewing/patología , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/diagnóstico , Femenino , Masculino , Niño , Adolescente , Pronóstico , Recurrencia Local de Neoplasia/patología , Neoplasias Óseas/mortalidad , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Neoplasias Óseas/terapia , Estudios Retrospectivos , Preescolar , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Egipto/epidemiologíaRESUMEN
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.
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Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica , Proteína Proto-Oncogénica c-fli-1 , Proteína EWS de Unión a ARN , Sarcoma de Ewing , Factor de Transcripción AP-1 , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patología , Sarcoma de Ewing/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Humanos , Proteína EWS de Unión a ARN/metabolismo , Proteína EWS de Unión a ARN/genética , Factor de Transcripción AP-1/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Fusión Oncogénica/genética , Línea Celular Tumoral , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética , Perfilación de la Expresión GénicaRESUMEN
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.
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Ensamble y Desensamble de Cromatina , Proteínas de Unión al ADN , Proteína EWS de Unión a ARN , Sarcoma de Ewing , Factores de Transcripción , Humanos , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patología , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Línea Celular Tumoral , Proteína EWS de Unión a ARN/metabolismo , Proteína EWS de Unión a ARN/genética , Regulación Neoplásica de la Expresión Génica , Proliferación Celular , Proteínas de Fusión Oncogénica/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Cromatina/metabolismo , Carcinogénesis/genética , Animales , Ratones , Dominios Proteicos , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Separación de FasesRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neutropenia Febril , Filgrastim , Rabdomiosarcoma , Sarcoma de Ewing , Humanos , Masculino , Femenino , Adolescente , Sarcoma de Ewing/tratamiento farmacológico , Niño , Proyectos Piloto , Estudios Prospectivos , Preescolar , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Rabdomiosarcoma/tratamiento farmacológico , Neutropenia Febril/prevención & control , Neutropenia Febril/inducido químicamente , Neutropenia Febril/etiología , Filgrastim/uso terapéutico , Filgrastim/administración & dosificación , Filgrastim/efectos adversos , Ciclofosfamida/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Dactinomicina/administración & dosificación , Dactinomicina/efectos adversos , Dactinomicina/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/administración & dosificación , LactanteRESUMEN
BACKGROUND: Adolescents and young adults (AYAs) with Ewing sarcoma have a worse prognosis than children. Population-based survival evaluations stratifying findings by important clinical factors are, however, limited. This Dutch population study comprehensively compared survival of children and AYAs with Ewing sarcoma over three decades considering diagnostic period, tissue of origin, tumor site, and disease stage. METHODS: Data on all children (0-17 years, N = 463) and AYAs (18-39 years, N = 379) diagnosed with Ewing sarcoma in the Netherlands between 1990-2018 were collected from the Netherlands Cancer Registry with follow-up until February 2023. Five-year relative survival was calculated using the cohort method. Multivariable analyses were conducted through Poisson regression. RESULTS: Children with Ewing sarcoma had a significantly higher 5-year relative survival than AYAs (65 % vs. 44 %). An increasing trend in survival was noted reaching 70 % in children and 53 % in AYAs in 2010-2018. Results were similar for Ewing bone sarcoma and extraosseous Ewing sarcoma. AYAs had a poorer prognosis than children for most tumor sites and regardless of disease stage. Survival probabilities were 60 % vs. 78 % for localized disease and 20 % vs. 33 % for metastatic disease. Multivariable-regression analysis, adjusted for follow-up time, diagnostic period, sex, disease stage, and tumor site, confirmed increased excess mortality among AYAs compared with children (excess HR: 1.7, 95 % CI: 1.3-2.1). CONCLUSIONS: Despite survival improvements since the 1990s, AYAs with Ewing sarcoma in the Netherlands continue to fare considerably worse than children. This survival disparity was present irrespective of tissue of origin, tumor site, and disease stage.
Asunto(s)
Neoplasias Óseas , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/mortalidad , Adolescente , Países Bajos/epidemiología , Masculino , Femenino , Niño , Adulto Joven , Adulto , Preescolar , Lactante , Neoplasias Óseas/mortalidad , Recién Nacido , Sistema de Registros , Pronóstico , Tasa de Supervivencia , Factores de EdadRESUMEN
Ewing sarcoma (EwS) is a cancer that arises in the bones and soft tissues, typically driven by the Ewing's sarcoma breakpoint region 1-Friend leukemia virus integration 1 (EWS-FLI) oncogene. Implementation of genetically modified animal models of EwS has proved difficult largely owing to EWS-FLI's high toxicity. The EWS-FLI1FS frameshift variant that circumvents toxicity but is still able to perform key oncogenic functions provided the first study model in Drosophila. However, the quest for Drosophila lines expressing full-length, unmodified EWS-FLI remained open. Here, we show that EWS-FLI1FS's lower toxicity is owed to reduced protein levels caused by its frameshifted C-terminal peptide, and report new strategies through which we have generated Drosophila lines that express full-length, unmodified EWS-FLI. Using these lines, we have found that the upregulation of transcription from GGAA-microsatellites (GGAAµSats) presents a positive linear correlation within a wide range of EWS-FLI protein concentrations. In contrast, rather counterintuitively, GGAAµSats-independent transcriptomic dysregulation presents relatively minor differences across the same range, suggesting that GGAAµSat-dependent and -independent transcriptional upregulation present different kinetics of response with regards to changing EWS-FLI protein concentration. Our results underpin the functional relevance of varying EWS-FLI expression levels and provide experimental tools to investigate, in Drosophila, the effect of the EWS-FLI 'high' and 'low' states that have been reported and are suspected to be important for EwS in humans.
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Proteínas de Fusión Oncogénica , Proteína Proto-Oncogénica c-fli-1 , Proteína EWS de Unión a ARN , Animales , Proteína EWS de Unión a ARN/metabolismo , Proteína EWS de Unión a ARN/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína Proto-Oncogénica c-fli-1/genética , Humanos , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patología , Animales Modificados Genéticamente , Drosophila/genética , Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismoRESUMEN
OBJECTIVE: To review and analyze the clinical diagnosis and treatment of renal Ewing's sarcoma with venous tumor embolus, to follow up the survival and prognosis of the patients, and to provide help for the diagnosis and treatment of the disease. METHODS: Clinical data (including general data, surgical data and postoperative pathological data) of patients diagnosed with renal Ewing's sarcoma with venous tumor embolus in Peking University Third Hospital from June 2016 to June 2022 were collected, and the prognosis of the patients was followed up to analyze the influence of diagnosis and treatment process on the prognosis of the disease. RESULTS: There were 6 patients, including 1 male and 5 females. There were 4 cases of left renal tumor and 2 cases of right renal tumor. The median age at diagnosis was 28 years (16-52 years). The imaging findings were all exogenous tumors with internal necrotic tissue and hemorrhage. The mean maximum tumor diameter was 12.6 cm, and the mean tumor thrombus length was 7.8 cm. Four patients underwent open surgery and 2 patients underwent laparoscopic surgery. The postoperative pathological results were renal Ewing sarcoma. Immunohistochemical results showed 3 cases of CD99 (+), 2 cases of FLI-1 (+), and 1 case of CD99, FLI-1 (-). 3 patients received chemotherapy (cyclophosphamide, doxorubicin, vincristine/ifosfamide, etoposide), 1 case received chemotherapy combined with radiotherapy, and 2 cases received no adjuvant therapy. The mean overall survival (OS) of the 6 patients was 37 months, and the mean OS of the 4 patients (47 months) who received chemotherapy was significantly higher than that of the 2 patients (16 months) who did not receive chemotherapy (P=0.031). CONCLUSION: Renal Ewing's sarcoma with venous tumor embolus is rare in clinic, and it is common in young female patients. The operation is difficult and the prognosis is poor. Surgical resection, adjuvant radiotherapy and chemotherapy can improve the overall survival rate of the patients.
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Neoplasias Renales , Sarcoma de Ewing , Trombosis de la Vena , Humanos , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/terapia , Femenino , Masculino , Adolescente , Adulto , Neoplasias Renales/diagnóstico , Neoplasias Renales/terapia , Neoplasias Renales/patología , Persona de Mediana Edad , Trombosis de la Vena/diagnóstico , Adulto Joven , Pronóstico , Proteína Proto-Oncogénica c-fli-1 , Antígeno 12E7 , Células Neoplásicas Circulantes , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: While soft tissue sarcomas affect younger patients, few studies have assessed the distribution of underlying pathogenic germline variants. PATIENTS AND METHODS: We retrospectively identified all pediatric and young adult patients (0-22 years) at Haukeland University Hospital, Norway (1981-2019), through clinical and pathological records. We identified n = 46 eligible patients. From these 46 patients, adequate material representing normal tissue was available for n = 41 cases (n = 24 diagnosed with rhabdomyosarcoma, 9 with synovial sarcomas, 2 with Ewing sarcomas, and 6 without further classification), with matching tumor tissue for n = 40. Normal tissue samples were analyzed for germline pathogenic variants (PVs) by targeted sequencing of 360 cancer genes. RESULTS: Out of the 41 analyzed cases, we found PVs or likely PVs in 7 (17%). These variants were found in TP53, MUTYH, FANCC, DICER1, FANCA, MYO3A, and MYO5B. Supporting the causality of these PVs, four cases revealed loss of heterozygosity (LOH) of the wild-type allele in the tumor tissue, one patient with a PV in DICER1 had a second somatic variant in DICER1, and a patient with a PV in TP53 had the altered allele amplified in the tumor. For three out of five with available family history, a history of other cancers in relatives was recorded. Among genes with variants of uncertain significance, CHD1L was of particular interest, revealing a stop-gain and a missense variant. INTERPRETATION: A high fraction of young patients with soft tissue sarcoma harbor PVs. Among the genes affected, we substantiate a potential role of MYO5B and propose a potential role for MYO3A.
Asunto(s)
Mutación de Línea Germinal , Humanos , Masculino , Niño , Adolescente , Femenino , Adulto Joven , Estudios Retrospectivos , Preescolar , Lactante , Sarcoma/genética , Sarcoma/patología , Recién Nacido , Adulto , Noruega , Predisposición Genética a la Enfermedad , Sarcoma Sinovial/genética , Sarcoma Sinovial/patología , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , Pérdida de Heterocigocidad , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologíaRESUMEN
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).
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Sarcoma de Ewing , Malformaciones Vasculares , Humanos , Sarcoma de Ewing/patología , Sarcoma de Ewing/diagnóstico , Diagnóstico Diferencial , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/patología , Masculino , Femenino , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/diagnóstico , NiñoRESUMEN
Ewing sarcoma is a cancer of bone and soft tissue in children and young adults primarily driven by the EWS-FLI1 fusion oncoprotein, which has been undruggable. Here, we report that Ewing sarcoma depends on secreted sphingomyelin phosphodiesterase 1 (SMPD1), a ceramide-generating enzyme, and ceramide. We find that G-protein-coupled receptor 64 (GPR64)/adhesion G-protein-coupled receptor G2 (ADGRG2) responds to ceramide and mediates critical growth signaling in Ewing sarcoma. We show that ceramide induces the cleavage of the C-terminal intracellular domain of GPR64, which translocates to the nucleus and restrains the protein levels of RIF1 in a manner dependent on SPOP, a substrate adaptor of the Cullin3-RING E3 ubiquitin ligase. We demonstrate that both SMPD1 and GPR64 are transcriptional targets of EWS-FLI1, indicating that SMPD1 and GPR64 are EWS-FLI1-induced cytokine-receptor dependencies. These results reveal the SMPD1-ceramide-GPR64 pathway, which drives Ewing sarcoma growth and is amenable to therapeutic intervention.