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1.
Cells ; 10(9)2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34572110

RESUMO

The ATP-binding cassette (ABC) transporter superfamily consists of several proteins with a wide repertoire of functions. Under physiological conditions, ABC transporters are involved in cellular trafficking of hormones, lipids, ions, xenobiotics, and several other molecules, including a broad spectrum of chemical substrates and chemotherapeutic drugs. In cancers, ABC transporters have been intensely studied over the past decades, mostly for their involvement in the multidrug resistance (MDR) phenotype. This review provides an overview of ABC transporters, both related and unrelated to MDR, which have been studied in osteosarcoma and Ewing's sarcoma. Since different backbone drugs used in first-line or rescue chemotherapy for these two rare bone sarcomas are substrates of ABC transporters, this review particularly focused on studies that have provided findings that have been either translated to clinical practice or have indicated new candidate therapeutic targets; however, findings obtained from ABC transporters that were not directly involved in drug resistance were also discussed, in order to provide a more complete overview of the biological impacts of these molecules in osteosarcoma and Ewing's sarcoma. Finally, therapeutic strategies and agents aimed to circumvent ABC-mediated chemoresistance were discussed to provide future perspectives about possible treatment improvements of these neoplasms.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Osteossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Humanos , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologia
2.
Cells ; 10(8)2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34440851

RESUMO

Ewing sarcoma (EwS) is an aggressive pediatric cancer of bone and soft tissues characterized by scant T cell infiltration and predominance of immunosuppressive myeloid cells. Given the important roles of extracellular vesicles (EVs) in cancer-host crosstalk, we hypothesized that EVs secreted by EwS tumors target myeloid cells and promote immunosuppressive phenotypes. Here, EVs were purified from EwS and fibroblast cell lines and exhibited characteristics of small EVs, including size (100-170 nm) and exosome markers CD63, CD81, and TSG101. Treatment of healthy donor-derived CD33+ and CD14+ myeloid cells with EwS EVs but not with fibroblast EVs induced pro-inflammatory cytokine release, including IL-6, IL-8, and TNF. Furthermore, EwS EVs impaired differentiation of these cells towards monocytic-derived dendritic cells (moDCs), as evidenced by reduced expression of co-stimulatory molecules CD80, CD86 and HLA-DR. Whole transcriptome analysis revealed activation of gene expression programs associated with immunosuppressive phenotypes and pro-inflammatory responses. Functionally, moDCs differentiated in the presence of EwS EVs inhibited CD4+ and CD8+ T cell proliferation as well as IFNγ release, while inducing secretion of IL-10 and IL-6. Therefore, EwS EVs may promote a local and systemic pro-inflammatory environment and weaken adaptive immunity by impairing the differentiation and function of antigen-presenting cells.


Assuntos
Células Dendríticas/metabolismo , Vesículas Extracelulares/metabolismo , Imunidade Adaptativa , Antígeno B7-1/metabolismo , Diferenciação Celular , Linhagem Celular , Células Dendríticas/citologia , Células Dendríticas/imunologia , Vesículas Extracelulares/transplante , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Ativação Linfocitária , Monócitos/citologia , Monócitos/metabolismo , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologia , Linfócitos T/citologia , Linfócitos T/imunologia , Transcriptoma , Microambiente Tumoral
5.
J Plast Reconstr Aesthet Surg ; 74(10): 2504-2511, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33931323

RESUMO

BACKGROUND: Pediatric sarcomas are the most common malignancies of bones in childhood. With advances in adjuvant treatment, limb salvage surgery has become common, increasing the demand of skeletal reconstruction. Traditional practice included bone grafting and transport. Recently, microsurgical tissue transfer in pediatric patients has become a well-accepted practice, with the fibula as an ideal biologic construct for long bone reconstruction. We aim to assess the success rate of this operation, including flap survival, bony union, weight-bearing ambulation, and complications. METHODS: We identified 10 pediatric patients who underwent reconstruction of long bones (femur, humerus, or tibia) with a free fibula flap from January 2015 to January 2020. All patients received neoadjuvant chemotherapy 4 weeks prior to the surgical procedure followed by adjuvant chemotherapy. RESULTS: The average follow-up time was 15 months. We had no partial or total flap loss. Three of our patients passed away in the first post-operative year due to metastatic disease. In the remaining 7 patients, we had two long-term complications. The fibula of one patient did not exhibit hypertrophy, yet weight-bearing ambulation was achieved. The other patient had nonunion proximally that required bone grafting at 8 months post-operatively. After that, the same patient fractured her fibula and required surgical fixation. She was eventually able to achieve weight-bearing ambulation. CONCLUSION: The vascularized fibula flap is a reliable tool for reconstruction in children. Flap survival is similar to that of adults. Complication rate is low compared to that for other forms of reconstruction.


Assuntos
Neoplasias Ósseas , Fíbula/transplante , Retalhos de Tecido Biológico , Efeitos Adversos de Longa Duração , Complicações Pós-Operatórias , Procedimentos Cirúrgicos Reconstrutivos , Sarcoma de Ewing , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Transplante Ósseo/efeitos adversos , Transplante Ósseo/métodos , Criança , Extremidades/patologia , Extremidades/cirurgia , Feminino , Retalhos de Tecido Biológico/efeitos adversos , Retalhos de Tecido Biológico/transplante , Humanos , Líbano/epidemiologia , Salvamento de Membro/métodos , Efeitos Adversos de Longa Duração/diagnóstico , Efeitos Adversos de Longa Duração/epidemiologia , Efeitos Adversos de Longa Duração/etiologia , Masculino , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Osteossarcoma/cirurgia , Avaliação de Processos e Resultados em Cuidados de Saúde , Pediatria/métodos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos Reconstrutivos/efeitos adversos , Procedimentos Cirúrgicos Reconstrutivos/métodos , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/patologia , Sarcoma de Ewing/cirurgia
6.
Nat Commun ; 12(1): 3230, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34050156

RESUMO

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Ósseas/diagnóstico , DNA Tumoral Circulante/sangue , Sarcoma de Ewing/diagnóstico , Adolescente , Adulto , Biomarcadores Tumorais/genética , Neoplasias Ósseas/sangue , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , DNA Tumoral Circulante/genética , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Biópsia Líquida/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Sarcoma de Ewing/sangue , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Sequenciamento Completo do Genoma , Adulto Jovem
7.
Pediatr Blood Cancer ; 68 Suppl 2: e28355, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33818887

RESUMO

Ewing sarcoma is a rare tumor that requires complex multidisciplinary management. This report describes the general management and standard radiotherapy guidelines in both North America (Children's Oncology Group) and Europe (International Society of Pediatric Oncology). Standard treatment involves multiagent induction chemotherapy followed by local treatment with surgery, definitive radiation, or a combination of surgery and radiation followed by additional chemotherapy and consolidation local treatment to metastatic sites. The data supporting the role of chemotherapy, surgery, and radiation and specific radiation therapy guidelines are presented.


Assuntos
Neoplasias Ósseas/terapia , Sarcoma de Ewing/terapia , Neoplasias Ósseas/patologia , Criança , Terapia Combinada , Humanos , Prognóstico , Sarcoma de Ewing/patologia , Taxa de Sobrevida
8.
Expert Opin Investig Drugs ; 30(6): 653-663, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33870845

RESUMO

INTRODUCTION: Over the last decades, multi-institutional clinical trials have resulted in significant improvements in the outcomes of patients with localized Ewing sarcoma; however, those with metastatic and recurrent diseases continue to fare poorly. More recently, advancements made in understanding the biology of the disease and mechanisms of response to therapy have opened the door for the incorporation of targeted therapies. Here we review the current state of treatment for Ewing sarcoma and the most recent preclinical advancements that have the potential to translate to improved care. AREAS COVERED: This review provides a general overview of the most recent clinical trials completed in Ewing sarcoma, as well as the preclinical and translational data that has the potential to be incorporated into clinical trials. A PubMed review as well as a review of published meeting abstracts was used to compose this review. EXPERT OPINION: While dose-intenstifying strategies have failed to lead to improvements in outcomes for patients with the highest-risk disease, recent preclinical advancements have shed light on potential new targeted strategies. The lack of early-phase clinical trial responses should not deter us from further developing these agents, but instead should guide us in designing novel combination strategies.


Assuntos
Neoplasias Ósseas/terapia , Terapia de Alvo Molecular , Sarcoma de Ewing/terapia , Animais , Antineoplásicos/administração & dosagem , Neoplasias Ósseas/patologia , Terapia Combinada , Humanos , Sarcoma de Ewing/patologia , Terapias em Estudo/métodos
9.
Medicine (Baltimore) ; 100(11): e25074, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33725983

RESUMO

RATIONALE: The Ewing sarcoma family of malignant tumors is a group of tumors characterized by morphologically similar round-cell neoplasms and by the presence of a common chromosomal translocation; Ewing sarcoma family of tumors typically occur in children and young adults between 4 to 15 years of age. The primary tumor usually originates in the bone, extraskeletal localization is rare. PATIENT CONCERN: We present a case report concerning a 32-year-old male patient with a primary involvement of the penis. DIAGNOSIS: The histopathology from the first penile biopsy showed a small-cell neuroendocrine carcinoma; however, that result was based on a sample obtained at a different facility than the Sarcoma Center, where the investigating pathologist did not have the adequate expertise. The patient then underwent a radical penectomy and a second reading of the histology was demanded after a radical penile amputation when Ewing sarcoma with R1 resection was confirmed. INTERVENTIONS: The patient was referred to the national Sarcoma Center, where - using a multidisciplinary approach - the treatment was started with curative intent. However, it was preceded by a non-standard initiation of the therapy due to the poor primary diagnosis. OUTCOMES: The non-standard therapy at the onset of the disease caused a poor prognosis of an otherwise curable diagnosis. Despite all that, the patient survived for a relatively long time. LESSONS: The treatment of sarcomas with atypical localizations should be conducted by an experienced multidisciplinary team in a center with experience in sarcoma treatment.


Assuntos
Neoplasias Penianas/patologia , Sarcoma de Ewing/patologia , Adulto , Humanos , Masculino , Pênis/patologia
10.
Clin Orthop Relat Res ; 479(8): 1768-1779, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33635285

RESUMO

BACKGROUND: Skeletal metastases of bone sarcomas are indicators of poor prognosis. Various imaging modalities are available for their identification, which include bone scan, positron emission tomography/CT scan, MRI, and bone marrow aspiration/biopsy. However, there is considerable ambiguity regarding the best imaging modality to detect skeletal metastases. To date, we are not sure which of these investigations is best for screening of skeletal metastasis. QUESTION/PURPOSE: Which staging investigation-18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT), whole-body MRI, or 99mTc-MDP skeletal scintigraphy-is best in terms of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in detecting skeletal metastases in patients with osteosarcoma and those with Ewing sarcoma? METHODS: A prospective diagnostic study was performed among 54 of a total 66 consecutive osteosarcoma and Ewing sarcoma patients who presented between March 2018 and June 2019. The institutional review board approved the use of all three imaging modalities on each patient recruited for the study. Informed consent was obtained after thoroughly explaining the study to the patient or the patient's parent/guardian. The patients were aged between 4 and 37 years, and their diagnoses were proven by histopathology. All patients underwent 99mTc-MDP skeletal scintigraphy, 18F-FDG PET/CT, and whole-body MRI for the initial staging of skeletal metastases. The number and location of bone and bone marrow lesions diagnosed with each imaging modality were determined and compared with each other. Multidisciplinary team meetings were held to reach a consensus about the total number of metastases present in each patient, and this was considered the gold standard. The sensitivity, specificity, PPV, and NPV of each imaging modality, along with their 95% confidence intervals, were generated by the software Stata SE v 15.1. Six of 24 patients in the osteosarcoma group had skeletal metastases, as did 8 of 30 patients in the Ewing sarcoma group. The median (range) follow-up for the study was 17 months (12 to 27 months). Although seven patients died before completing the minimum follow-up, no patients who survived were lost to follow-up. RESULTS: With the number of patients available, we found no differences in terms of sensitivity, specificity, PPV, and NPV among the three staging investigations in patients with osteosarcoma and in patients with Ewing sarcoma. Sensitivities to detect bone metastases for 18F-FDG PET/CT, whole-body MRI, and 99mTc-MDP skeletal scintigraphy were 100% (6 of 6 [95% CI 54% to 100%]), 83% (5 of 6 [95% CI 36% to 100%]), and 67% (4 of 6 [95% CI 22% to 96%]) and specificities were 100% (18 of 18 [95% CI 82% to 100%]), 94% (17 of 18 [95% CI 73% to 100%]), and 78% (14 of 18 [95% CI 52% to 94%]), respectively, in patients with osteosarcoma. In patients with Ewing sarcoma, sensitivities to detect bone metastases for 18F-FDG PET/CT, whole-body MRI, and 99mTc-MDP skeletal scintigraphy were 88% (7 of 8 [95% CI 47% to 100%]), 88% (7 of 8 [95% CI 47% to 100%]), and 50% (4 of 8 [95% CI 16% to 84%]) and specificities were 100% (22 of 22 [95% CI 85% to 100%]), 95% (21 of 22 [95% CI 77% to 100%]), and 95% (21 of 22 [95% CI 77% to 100%]), respectively. Further, the PPVs for detecting bone metastases for 18F-FDG PET/CT, whole-body MRI, and 99mTc-MDP skeletal scintigraphy were 100% (6 of 6 [95% CI 54% to 100%]), 83% (5 of 6 [95% CI 36% to 100%]), and 50% (4 of 8 [95% CI 16% to 84%]) and the NPVs were 100% (18 of 18 [95% CI 82% to 100%]), 94% (17 of 18 [95% CI 73% to 100%]), and 88% (14 of 16 [95% CI 62% to 98%]), respectively, in patients with osteosarcoma. Similarly, the PPVs for detecting bone metastases for 18F-FDG PET/CT, whole-body MRI, and 99mTc-MDP skeletal scintigraphy were 100% (7 of 7 [95% CI 59% to 100%]), 88% (7 of 8 [95% CI 50% to 98%]), and 80% (4 of 5 [95% CI 28% to 100%]), and the NPVs were 96% (22 of 23 [95% CI 78% to 100%]), 95% (21 of 22 [95% CI 77% to 99%]), and 84% (21 of 25 [95% CI 64% to 96%]), respectively, in patients with Ewing sarcoma. The confidence intervals around these values overlapped with each other, thus indicating no difference between them. CONCLUSION: Based on these results, we could not demonstrate a difference in the sensitivity, specificity, PPV, and NPV between 18F-FDG PET/CT, whole-body MRI, and 99mTc-MDP skeletal scintigraphy for detecting skeletal metastases in patients with osteosarcoma and Ewing sarcoma. For proper prognostication, a thorough metastatic workup is essential, which should include a highly sensitive investigation tool to detect skeletal metastases. However, our study findings suggest that there is no difference between these three imaging tools. Since this is a small group of patients in whom it is difficult to make broad recommendations, these findings may be confirmed by larger studies in the future. LEVEL OF EVIDENCE: Level II, diagnostic study.


Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Metástase Neoplásica/diagnóstico por imagem , Estadiamento de Neoplasias/métodos , Osteossarcoma/diagnóstico por imagem , Sarcoma de Ewing/diagnóstico por imagem , Adolescente , Adulto , Neoplasias Ósseas/patologia , Criança , Pré-Escolar , Feminino , Fluordesoxiglucose F18 , Humanos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Osteossarcoma/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/estatística & dados numéricos , Valor Preditivo dos Testes , Estudos Prospectivos , Cintilografia/métodos , Cintilografia/estatística & dados numéricos , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Sarcoma de Ewing/patologia , Sensibilidade e Especificidade , Medronato de Tecnécio Tc 99m , Imagem Corporal Total/métodos , Imagem Corporal Total/estatística & dados numéricos , Adulto Jovem
11.
J Pediatr Hematol Oncol ; 43(4): e478-e480, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33625095

RESUMO

A 6-week-old female presented with gross hematuria and was diagnosed with Ewing sarcoma of the bladder through ultrasound and cystoscopic biopsies, along with a negative metastatic workup. She was treated with transurethral resection, chemotherapy consisting of with vincristine, cycolphosphamide, doxorubicin, ifosfamide and etoposide, and partial cystectomy. After completing chemotherapy, the patient has been doing well with no evidence of disease. There have been 14 other cases, 4 pediatric, of Ewing sarcoma of the bladder reported. To our knowledge, our case is the youngest patient reported with this disease.


Assuntos
Neoplasias Ósseas/patologia , Sarcoma de Ewing/patologia , Neoplasias da Bexiga Urinária/secundário , Bexiga Urinária/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/terapia , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Hematúria/diagnóstico , Humanos , Ifosfamida/uso terapêutico , Lactente , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/terapia , Resultado do Tratamento , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/terapia , Vincristina/uso terapêutico
12.
Eur J Surg Oncol ; 47(7): 1778-1783, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33622576

RESUMO

AIM: The aim is to evaluate which of the existing scoring systems of histological response to neoadjuvant chemotherapy best stratifies the clinical outcome of patients with localized Ewing sarcoma of bone. METHODS: 474 patients with diagnosis of localized Ewing sarcoma of bone were included. The median follow-up was 13.5 years. RESULTS: The overall survival and the disease-free survival (DFS) were 70.8% and 63.9% at 5 years. The percentage of histological response to neoadjuvant chemotherapy ranged between 5% and 100% (mean 83%). The agreement between Bologna System and the different percentual cut-offs of histological response to neoadjuvant chemotherapy was high, with kappa statistics of 0.83 for a cut-off of ≥90%; 0.86 for a cut-off of ≥95%; 0.79 for a cut-off of ≥96% and 0.61 for a cut-off of 100%. Statistically higher DFS rates for good responders compared to poor responders were found when using each given system. Model performance indicators showed that Bologna system had a lower AIC score and a higher c-statistics to predict DFS. When the patients classified as good responders using the different percentual cut-offs of histological response to neoadjuvant chemotherapy, were instead re-classified using the Bologna system, statistical differences were noted in DFS within each specific group. CONCLUSIONS: All scoring tools to evaluate histological response to neoadjuvant chemotherapy offer good predictive value for DFS in localized Ewing's sarcoma of bone. The Bologna system better stratifies those patients with histological response to neoadjuvant chemotherapy between 90 and 99%, representing a more reliable scoring tool in this subset.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Quimioterapia Adjuvante , Sarcoma de Ewing/patologia , Sarcoma de Ewing/cirurgia , Adolescente , Adulto , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Estudos Retrospectivos , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/mortalidade , Taxa de Sobrevida
13.
Medicine (Baltimore) ; 100(4): e24484, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33530265

RESUMO

BACKGROUND: Ewing sarcoma (ES), the second most prevalent bone malignant tumor has no widely known prognostic biomarker. Earlier studies have suggested that chaperonin containing TCP1 complex 6A (CCT6A), which encodes a molecular protein chaperone, is involved in the pathogenesis of many cancers. However, there are no known reports providing clear evidence of its role in ES pathogenesis. METHODS: We performed a bioinformatic analysis of 32 ES specimens from the GSE17618 dataset concentrating on the differences in gene expression, OS, event-free survival (EFS) in the different subgroups. Immunohistochemical studies were also performed to identify the expression levels of selected genes in ES and immediate paracancerous tissues. RESULTS: After 3 screenings, CCT6A was identified to be highly correlated with ES prognosis. Our survival analysis revealed a low overall survival (OS) for high CCT6A expression (P-value = .024). Our Cox regression analysis identified CCT6A expression, lEFS, and age were strongly associated with prognosis of ES. Our multivariate Cox regression analysis shows that CCT6A (P-value = .015), age (P-value = .026), and EFS (P-value = .002) were independent poor prognostic biomarkers. Our immunohistochemical analysis showed that the expression levels of CCT6A were significantly higher in ES tissues compared to the paracancerous tissues. CONCLUSION: From the results of our study, we identified the expression levels of CCT6A to be strongly associated with prognosis of ES. Thus, the expression levels of the CCT6A gene could serve as a biomarker for the prediction of ES prognosis.


Assuntos
Neoplasias Ósseas/genética , Chaperonina com TCP-1/metabolismo , Sarcoma de Ewing/genética , Adolescente , Fatores Etários , Biomarcadores Tumorais/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Criança , Bases de Dados Genéticas , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/patologia , Adulto Jovem
14.
Am J Surg Pathol ; 45(4): 523-530, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33538423

RESUMO

Ewing sarcoma (ES) is a highly malignant tumor that rarely occurs in the uterine cervix. Herein, we report 8 cases with ES arising primarily in the uterine cervix by focusing on clinicopathologic and molecular cytogenetic features and differential diagnoses. Eight cases of cervical ES were diagnosed between February, 2012, and September, 2018. The age of patients ranged from 13 to 47 years. Abnormal vaginal bleeding and lower abdominal pain were the most common symptoms. Histologically, the tumor was composed of uniform, round, and oval cells with a narrow rim of eosinophilic cytoplasm. Fibrous septa were observed between tumor cell nests. The tumors showed brisk mitotic activity and areas of coagulative necrosis. According to immunohistochemical studies, 50% (4/8) of the cases were positive for cytokeratin (AE1/AE3), and 87.5% (7/8) were positive for synaptophysin, which resulted in a diagnostic confusion with small cell carcinoma, primarily when dealing with small cervical biopsies. Molecular testing demonstrated the rearrangement of the EWSR1 gene in all of the 8 cases, which confirmed the diagnosis of ES. Although rare, ES should be considered as indicators of cervical small round cell neoplasms. Molecular analysis may greatly contribute to the final diagnosis of ES occurring in this unusual location.


Assuntos
Biomarcadores Tumorais , Sarcoma de Ewing , Neoplasias Uterinas , Adolescente , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Queratinas/análise , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/química , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Neoplasias Uterinas/química , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Adulto Jovem
15.
Clin Nucl Med ; 46(7): e391-e392, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33630799

RESUMO

ABSTRACT: Ewing sarcoma is the second most common primary malignant bone tumor that usually affects diaphysis of long bones during the second decade of life. Isolated unilateral orbital metastasis from this tumor presenting as proptosis is extremely rare. Here we report a case of 11-year-old boy where whole-body FDG PET/CT scan detected primary an Ewing sarcoma site in the left femur and isolated orbital metastasis in the left eye. Follow-up PET/CT scan after 6 cycles of chemotherapy showed resolution of the previously seen lesions.


Assuntos
Neoplasias Ósseas/patologia , Fluordesoxiglucose F18 , Neoplasias Orbitárias/diagnóstico por imagem , Neoplasias Orbitárias/secundário , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Sarcoma de Ewing/patologia , Criança , Fêmur/diagnóstico por imagem , Humanos , Masculino , Imagem Corporal Total
16.
Clin Nucl Med ; 46(5): 422-423, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33630793

RESUMO

ABSTRACT: Ewing sarcoma is an aggressive malignancy that most often presents as an undifferentiated primary bone tumor; less commonly, it arises in extraosseous soft tissues of mesenchymal cell origin. Primary extraosseous involvement of seminal vesicle is rarely reported. Herein, we describe FDG PET/CT and MRI findings of a 55-year-old man who presented with a pelvic mass, which was confirmed to be primary Ewing sarcoma/primitive neuroectodermal tumor arising from seminal vesicle by histopathologic findings.


Assuntos
Neoplasias Ósseas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Sarcoma de Ewing/diagnóstico por imagem , Glândulas Seminais/diagnóstico por imagem , Neoplasias Ósseas/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Sarcoma de Ewing/patologia
17.
Taiwan J Obstet Gynecol ; 60(1): 142-144, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33494989

RESUMO

OBJECTIVE: Ewing sarcoma is a type of neuroectodermal tumors (Ewing family of tumors-EFT) that mostly affect the bone or soft tissue. Primary uterine Ewing sarcoma is extremely rare. CASE REPORT: We report a case of a primary uterine Ewing sarcoma in a 46-year-old patient, treated with total abdominal hysterectomy, and bilateral salpingo-oophorectomy and following adjuvant chemotherapy with 6 cycles of vincristine, doxorubicin, and cyclophosphamide, achieving complete remission for one year. CONCLUSION: Complete resection for EFT is the first choice of treatment, regardless of their origins. Adjuvant chemotherapy or radiotherapy is mandatory if needed. Due to rarity of the disease, this report re-emphasizes the accurate diagnosis and appropriate treatment for these unusual tumor types occurred in female genital organs.


Assuntos
Tumores Neuroectodérmicos Primitivos Periféricos/terapia , Sarcoma de Ewing/terapia , Neoplasias Uterinas/terapia , Quimioterapia Adjuvante , Feminino , Humanos , Histerectomia , Ilustração Médica , Pessoa de Meia-Idade , Tumores Neuroectodérmicos Primitivos Periféricos/patologia , Sarcoma de Ewing/patologia , Neoplasias Uterinas/patologia , Útero/patologia
18.
Oncogene ; 40(6): 1176-1190, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33414491

RESUMO

Ewing sarcoma (ES) is the second most common bone tumor in children and young adults. Unfortunately, there have been minimal recent advancements in improving patient outcomes, especially in metastatic and recurrent diseases. In this study, we investigated the biological role of p21-activated kinases (PAKs) in ES, and the ability to therapeutically target them in high-risk disease. Via informatics analysis, we established the inverse association of PAK1 and PAK4 expression with clinical stage and outcome in ES patients. Through expression knockdown and small-molecule inhibition of PAKs, utilizing FRAX-597, KPT-9274, and PF-3758309 in multiple ES cell lines and patient-derived xenograft models, we further explored the role of PAKs in ES tumor growth and metastatic capabilities. In vitro studies in several ES cell lines indicated that diminishing PAK1 and PAK4 expression reduces tumor cell viability, migratory, and invasive properties. In vivo studies using PAK4 inhibitors, KPT-9274 and PF-3758309 demonstrated significant inhibition of primary and metastatic tumor formation, while transcriptomic analysis of PAK4-inhibitor-treated tumors identified concomitant suppression of Notch, ß-catenin, and hypoxia-mediated signatures. In addition, the analysis showed enrichment of anti-tumor immune regulatory mechanisms, including interferon (IFN)-É£ and IFN-α responses. Altogether, our molecular and pre-clinical studies are the first to establish a critical role for PAKs in ES development and progression, and consequently as viable therapeutic targets for the treatment of high-risk ES in the near future.


Assuntos
Sarcoma de Ewing/tratamento farmacológico , Quinases Ativadas por p21/genética , Acrilamidas/farmacologia , Aminopiridinas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interferon-alfa/genética , Interferon gama/genética , Pirazóis/farmacologia , Pirróis/farmacologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases Ativadas por p21/antagonistas & inibidores
20.
Medicine (Baltimore) ; 100(2): e24038, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33466151

RESUMO

RATIONALE: Prostatic sarcoma (PS) is a very rare malignant tumor that accounts for <0.1% of prostate malignancies, and Ewing's sarcoma is an extremely rare form of PS. PATIENT CONCERNS: We reported on a 64-year-old patient with PS and a 36-year-old patient with Ewing's sarcoma, both of whom were examined by contrast-enhanced ultrasonography (CEUS) before surgery. DIAGNOSES: The 2 cases were proven to be prostatic stromal sarcoma, which was confirmed by imaging manifestations and histopathological findings. INTERVENTIONS: The 64-year-old patient underwent radical prostatectomy, and the 36-year-old patient underwent chemotherapy combined with local radiotherapy. OUTCOMES: PS showed diffuse enlargement of the prostate on sonography, and the necrotic liquefying area within the large vessels could be clearly displayed by CEUS. CEUS can be advocated as a valuable noninvasive and safe imaging diagnosis method for PS.


Assuntos
Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Sarcoma/diagnóstico por imagem , Sarcoma/patologia , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Prostatectomia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/cirurgia , Sarcoma/diagnóstico , Sarcoma/cirurgia , Sarcoma de Ewing/patologia , Sarcoma de Ewing/cirurgia , Ultrassonografia
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