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1.
J Cancer Res Ther ; 16(4): 713-717, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930108

RESUMO

Background and Objectives: Currently, one of the most useful prognostic indicators in Ewing sarcomas (ES) is the presence of metastatic disease at diagnosis. According to various clinical guidelines, the assessment of bone marrow (BM) metastases, using light microscopy examination of bone marrow aspirates and biopsies (BMAB) is mandatory. However, the prognostic value of BM positivity is discussed controversially. Therefore, the primary aim of this study was to retrospectively review BM samples from patients with ES. Materials and Methods: This retrospective single centre study included 31 patients that were newly diagnosed with ES between 2000 and 2014. Twenty-seven patients had skeletal ES and in 4 patients the tumour was localized in the soft tissue only. Metastases at diagnosis were present in 5 out of 31 patients. BM samples were morphologically and immunohistochemically searched and screened for the presence or absence of BM metastases. Furthermore, in 15 of the 31 patients BM samples were still available and were reanalysed, using nested-polymerase chain reaction. Results: All BM samples of our 31 ES patients, including the 5 metastatic patients, were, morphologically and immunohistochemically tested negative for tumour cell appearance. The nested-PCR results were also negative in all of our 15 retested patients, including two patients with metastatic disease. Conclusions: Based on our results and on the contradictory results reported in the literature we recommend a re-evaluation of the necessity and the prognostic value of BMAB in the initial staging process of newly diagnosed ES patients.


Assuntos
Neoplasias Ósseas/patologia , Sarcoma de Ewing/patologia , Adolescente , Adulto , Biópsia por Agulha Fina , Exame de Medula Óssea/métodos , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Punção Espinal , Adulto Jovem
2.
J Cancer Res Clin Oncol ; 146(11): 2871-2883, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32770382

RESUMO

PURPOSE: Polo-like kinase 4 (PLK4) inhibitors, such as CFI-400945 and centrinone, are emerging as promising antineoplastic agents. However, their effectiveness against Ewing's sarcoma, a highly aggressive childhood cancer, remains to be established. METHODS: CFI-400945 and centrinone were tested in three Ewing's sarcoma cell lines with different TP53 status. Effects were assessed by flow-cytometric analyses of cell death, dissipation of the mitochondrial transmembrane potential and cell cycle distribution, by cell viability assay as well as by caspase 3/7 activity measurement, by immunoblotting and by immunofluorescence microscopy. RESULTS: CFI-400945 and centrinone elicited cell death in p53 wild-type and mutant Ewing's sarcoma cells. Both agents induced mitochondrial membrane depolarisation, caspase 3/7 activation, PARP1 cleavage and DNA fragmentation, indicating an apoptotic form of cell death. In addition, the PLK4 inhibitors induced a G2/M cell cycle arrest, particularly when cell killing was attenuated by the pan-caspase inhibitor z-VAD-fmk. Moreover, CFI-400945 treatment produced polyploidy. CONCLUSION: Our findings show that PLK4 inhibitors were effective against Ewing's sarcoma cells in vitro and thus provide a rationale for their evaluation in vivo.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Sarcoma de Ewing/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Indazóis/farmacologia , Indóis/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pirimidinas/farmacologia , Sulfonas/farmacologia
3.
Nature ; 585(7824): 298-302, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32669707

RESUMO

Proteins are manufactured by ribosomes-macromolecular complexes of protein and RNA molecules that are assembled within major nuclear compartments called nucleoli1,2. Existing models suggest that RNA polymerases I and III (Pol I and Pol III) are the only enzymes that directly mediate the expression of the ribosomal RNA (rRNA) components of ribosomes. Here we show, however, that RNA polymerase II (Pol II) inside human nucleoli operates near genes encoding rRNAs to drive their expression. Pol II, assisted by the neurodegeneration-associated enzyme senataxin, generates a shield comprising triplex nucleic acid structures known as R-loops at intergenic spacers flanking nucleolar rRNA genes. The shield prevents Pol I from producing sense intergenic noncoding RNAs (sincRNAs) that can disrupt nucleolar organization and rRNA expression. These disruptive sincRNAs can be unleashed by Pol II inhibition, senataxin loss, Ewing sarcoma or locus-associated R-loop repression through an experimental system involving the proteins RNaseH1, eGFP and dCas9 (which we refer to as 'red laser'). We reveal a nucleolar Pol-II-dependent mechanism that drives ribosome biogenesis, identify disease-associated disruption of nucleoli by noncoding RNAs, and establish locus-targeted R-loop modulation. Our findings revise theories of labour division between the major RNA polymerases, and identify nucleolar Pol II as a major factor in protein synthesis and nuclear organization, with potential implications for health and disease.


Assuntos
Nucléolo Celular/enzimologia , Nucléolo Celular/genética , DNA Ribossômico/genética , RNA Polimerase II/metabolismo , RNA não Traduzido/biossíntese , RNA não Traduzido/genética , Ribossomos/metabolismo , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Linhagem Celular Tumoral , Nucléolo Celular/fisiologia , DNA Helicases/metabolismo , DNA Intergênico/genética , Humanos , Enzimas Multifuncionais/metabolismo , Biossíntese de Proteínas , Estruturas R-Loop , RNA Helicases/metabolismo , RNA Polimerase I/antagonistas & inibidores , RNA Polimerase I/metabolismo , Ribonuclease H/metabolismo , Ribossomos/química , Ribossomos/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia
4.
J Vis Exp ; (160)2020 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-32658189

RESUMO

Many cancers are characterized by chromosomal translocations which result in the expression of oncogenic fusion transcription factors. Typically, these proteins contain an intrinsically disordered domain (IDD) fused with the DNA-binding domain (DBD) of another protein and orchestrate widespread transcriptional changes to promote malignancy. These fusions are often the sole recurring genomic aberration in the cancers they cause, making them attractive therapeutic targets. However, targeting oncogenic transcription factors requires a better understanding of the mechanistic role that low-complexity, IDDs play in their function. The N-terminal domain of EWSR1 is an IDD involved in a variety of oncogenic fusion transcription factors, including EWS/FLI, EWS/ATF, and EWS/WT1. Here, we use RNA-sequencing to investigate the structural features of the EWS domain important for transcriptional function of EWS/FLI in Ewing sarcoma. First shRNA-mediated depletion of the endogenous fusion from Ewing sarcoma cells paired with ectopic expression of a variety of EWS-mutant constructs is performed. Then RNA-sequencing is used to analyze the transcriptomes of cells expressing these constructs to characterize the functional deficits associated with mutations in the EWS domain. By integrating the transcriptomic analyses with previously published information about EWS/FLI DNA binding motifs, and genomic localization, as well as functional assays for transforming ability, we were able to identify structural features of EWS/FLI important for oncogenesis and define a novel set of EWS/FLI target genes critical for Ewing sarcoma. This paper demonstrates the use of RNA-sequencing as a method to map the structure-function relationship of the intrinsically disordered domain of oncogenic transcription factors.


Assuntos
Perfilação da Expressão Gênica , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/química , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/química , Proteína EWS de Ligação a RNA/metabolismo , Relação Estrutura-Atividade , Sítios de Ligação , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Humanos , Mutação , Proteínas de Fusão Oncogênica/genética , Domínios Proteicos , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologia
5.
Medicine (Baltimore) ; 99(27): e20859, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629673

RESUMO

RATIONALE: Extra osseous Ewing sarcoma (ES), an uncommon malignant neoplasm, accounts for about 15% of Ewing sarcoma, which mainly affects paravertebral region, lower extremity, chest wall, retroperitoneum, pelvis, and hip. Here is a 54-year-old woman of primary vaginal Ewing sarcoma with uterine fibroid, which has been fewly known or reported. PATIENT CONCERNS: The patient was admitted to our hospital because of vaginal pain. Her uterus showed as parallel position and enlarged as about 3 months of pregnancy size. DIAGNOSIS: Magnetic resonance imaging (MRI) and ultrasonography (US) demonstrated 2 heterogeneous masses in the vagina and uterus, respectively. Ultrasound-guided puncture biopsy revealed a malignant tumor in the right lateral vaginal wall. INTERVENTIONS: The patient was treated by hysterectomy, bilateral salpingo-oophorectomy, and tumors excision, with the subsequent treatment of chemotherapy. OUTCOMES: The patient recovered well without local recurrence for >1 year. LESSONS: Primary vaginal Ewing sarcoma is extremely rare. The treatments of uterine fibroid include uterine artery embolization and surgical options, While wide local excision followed by adjuvant chemotherapy and/or radiotherapy should be recommended for the vaginal ES.


Assuntos
Leiomioma/complicações , Sarcoma de Ewing/complicações , Sarcoma de Ewing/diagnóstico , Neoplasias Vaginais/complicações , Neoplasias Vaginais/diagnóstico , Feminino , Humanos , Leiomioma/diagnóstico , Pessoa de Meia-Idade , Sarcoma de Ewing/patologia , Neoplasias Vaginais/patologia
6.
Br J Radiol ; 93(1115): 20200257, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32706980

RESUMO

OBJECTIVE: To evaluate the multiparametric MRI in predicting chemotherapy response in pathologically proven cases of osteosarcoma and Ewing's sarcoma. Correlation between the tumor size changes and internal breakdown using RECIST 1.1, modified RECIST, quantitative apparent diffusion coefficient (ADC) and tumor volume as well as dynamic contrast-enhanced MRI (DCE-MRI). METHODS: The study included 104 patients pathologically proved osteosarcoma (53) and Ewing`s sarcoma (51) underwent MRI examinations; before and after chemotherapy. All patients were assessed using the RECIST 1.1 criteria, m-RECIST, quantitative ADC, and tumor volume evaluation. 21 patients underwent DCE-MRI curve type with quantitative parameters. Correlation between the different evaluations was carried out. Results were correlated with the post-operative pathology in 42 patients who underwent surgery and for statistical evaluation, Those patients were classified into responders (≥90% necrosis) and non-responders (<90% necrosis). RESULTS: The initial mean ADC of 104 patients of osteosarcoma and Ewing's sarcoma (0.90 ± 0.29) and (0.71 ± 0.16) respectively, differed significantly from that after treatment (1.62 ± 0.46) and (1.6 ± 0.39) respectively with (p<0.001).ADC variations (ADC%) in the non-progressive group were higher than those of the progressive group (128.3 ± 63.49 vs 36.34 ± 78.7) % with (p<0.001).ADC values and ADC variations were inversely correlated with morphologic changes, regardless of the effectiveness of chemotherapy expressed as changes in tumor size based on (RECIST 1.1, RECIST, and 3D volume). Linear regression analysis revealed a Pearson correlation coefficient of r=-0.427, -0.498 and -0.408, respectively with (p<0.001).An increase in the ADC value was not always associated with a reduction in tumor volume. The disease control rate (defined as the percentage of CR+PR+SD patients) was 89.4% and 93.9% according to RECIST 1.1 and m-RECIST respectively.42 out of the 104 patients had postsurgical histological evaluation as regards the chemotherapeutic response divided into two groups. ADC values showed a statistically significant difference between Group A and Group B being more evident with minimum ADC% (p<0.001). CONCLUSION: Quantitative diffusion-weighted imaging with ADC mapping and ADC % after chemotherapy allows a detailed analysis of the treatment response in osteosarcoma and Ewing's sarcoma. The therapeutic response can be underestimated using RECIST 1.1, so the modified RECIST should be also considered. ADVANCES IN KNOWLEDGE: Quantitative ADC especially ADC% provided an accurate non-invasive tool in the assessment of post-therapeutic cases of osteosarcoma and Ewing's sarcoma.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Imagem de Difusão por Ressonância Magnética , Imageamento por Ressonância Magnética Multiparamétrica , Osteossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Área Sob a Curva , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Criança , Pré-Escolar , Meios de Contraste , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/patologia , Osteossarcoma/cirurgia , Estudos Prospectivos , Curva ROC , Critérios de Avaliação de Resposta em Tumores Sólidos , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/patologia , Sarcoma de Ewing/cirurgia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Adulto Jovem
7.
Arch Bronconeumol ; 56(10): 674-676, 2020 10.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32586699

Assuntos
Adenocarcinoma/diagnóstico por imagem , Betacoronavirus , Neoplasias Ósseas/diagnóstico por imagem , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Biópsia Guiada por Imagem/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pandemias , Pneumonia Viral/diagnóstico , Sarcoma de Ewing/diagnóstico por imagem , Adenocarcinoma/complicações , Adenocarcinoma/patologia , Idoso , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Neoplasias Ósseas/complicações , Neoplasias Ósseas/patologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/epidemiologia , Gerenciamento Clínico , Feminino , Humanos , Achados Incidentais , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Masculino , Invasividade Neoplásica , Equipamento de Proteção Individual , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/secundário , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/epidemiologia , RNA Viral/sangue , Reação em Cadeia da Polimerase em Tempo Real , Caixa Torácica/diagnóstico por imagem , Sarcoma de Ewing/complicações , Sarcoma de Ewing/patologia , Canal Vertebral/diagnóstico por imagem , Canal Vertebral/patologia , Telecomunicações , Adulto Jovem
8.
PLoS One ; 15(6): e0234243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502203

RESUMO

The presence of the chimeric EWSR1-FLI1 oncoprotein is the main and initiating event defining Ewing sarcoma (ES). The dysregulation of epigenomic and proteomic homeostasis induced by the oncoprotein contributes to a wide variety of events involved in oncogenesis and tumor progression. Attempts at studying the effects of EWSR1-FLI1 in non-tumor cells to understand the mechanisms underlying sarcomagenesis have been unsuccessful to date, as ectopic expression of EWSR1-FLI1 blocks cell cycle progression and induces apoptosis in the tested cell lines. Therefore, it is essential to find a permissive cell type for EWSR1-FLI1 expression that allows its endogenous molecular functions to be studied. Here we have demonstrated that HeLa cell lines are permissive to EWSR1-FLI1 ectopic expression, and that our model substantially recapitulates the endogenous activity of the EWSR1-FLI1 fusion protein. This model could contribute to better understanding ES sarcomagenesis by helping to understand the molecular mechanisms induced by the EWSR1-FLI1 oncoprotein.


Assuntos
Carcinogênese/genética , Expressão Ectópica do Gene , Proteínas de Fusão Oncogênica/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Sítios de Ligação , DNA/metabolismo , Células HeLa , Humanos , Proteínas de Fusão Oncogênica/metabolismo
9.
Pediatr Blood Cancer ; 67(7): e28370, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386107

RESUMO

BACKGROUND: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent sarcoma. Nab-paclitaxel is a taxane modified to improve drug exposure and increase intratumoral accumulation and, in combination with gemcitabine, is standard therapy for pancreatic cancer. Applying the dosages and schedule used for pancreatic cancer, we performed a phase II trial to assess the response rate of gemcitabine and nab-paclitaxel in patients with relapsed Ewing sarcoma. PROCEDURE: Using a Simon's two-stage design to identify a response rate of ≥ 35%, patients received nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 i.v. on days 1, 8, and 15 of four-week cycles. Immunohistochemical analysis of archival tissue was performed to identify possible biomarkers of response. RESULTS: Eleven patients from four institutions enrolled, with a median age of 22 years (range, 14-27). Patients were heavily pretreated (median 3 prior regimens, range, 1-7). Thirty-five cycles were administered (median 2, range, 1-8). Accrual was stopped after 11 patients, due to only one confirmed partial response. Two other patients had partial responses after two cycles, but withdrew because of adverse effects or progression before confirmation of continued response. The predominant toxicity was myelosuppression, and four (36%) patients were removed due to hematologic toxicity despite pegfilgrastim and dose reductions. Expression of secreted protein, acidic and rich in cysteine (SPARC) and CAV-1 in archival tumors was not predictive of clinical benefit in this small cohort of patients. CONCLUSIONS: In patients with heavily pretreated Ewing sarcoma, the confirmed response rate of 9% was similar to multi-institutional studies of gemcitabine and docetaxel.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Albuminas/administração & dosagem , Neoplasias Ósseas/patologia , Criança , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Prognóstico , Sarcoma de Ewing/patologia , Adulto Jovem
10.
Brain Tumor Pathol ; 37(3): 111-117, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32449046

RESUMO

The CIC-DUX4 translocation is the most common genetic alteration of small round cell sarcomas without EWSR1 rearrangement. These "Ewing-like sarcomas" usually occur in peripheral soft tissues, and rare primary central nervous system (CNS) tumors have been described. We report a rare case of primary spinal intramedullary Ewing-like sarcoma harboring CIC-DUX4 translocation. A 23-year-old man presented with weakness in the extremities. Magnetic resonance imaging revealed a large intramedullary tumor spanning C3-C5 with heterogeneous enhancement following gadolinium administration. Histologically, most of the tumor displayed dense myeloid proliferation composed of medium- to slightly small-sized primitive cells. Postoperatively, he received local adjuvant radiation therapy without tumor progression for 10 months. Target RNA sequencing analysis revealed the CIC-DUX4 fusion gene. Methylation array analysis resulted in a diagnosis of "methylation class CNS Ewing sarcoma family tumor with CIC alteration". Although this tumor lacked characteristic histological features such as lobular structures in association with desmoplastic stroma, relatively uniform nuclei with prominent nucleoli and eosinophilic cytoplasm, which are often found in CIC-rearranged sarcomas of soft tissue, were identified. Recently, many CNS and soft tissue tumors require genetic analysis for precise diagnosis. To consider certain molecular testing, careful histological examination is essential.


Assuntos
Proteínas de Fusão Oncogênica/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Neoplasias da Coluna Vertebral/genética , Neoplasias da Coluna Vertebral/patologia , Translocação Genética , Diagnóstico Diferencial , Humanos , Imagem por Ressonância Magnética , Masculino , Sarcoma de Ewing/diagnóstico por imagem , Neoplasias de Tecidos Moles , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Adulto Jovem
11.
Nat Commun ; 11(1): 2423, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415069

RESUMO

Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/metabolismo , Estresse Oxidativo , Sarcoma de Ewing/patologia , Adulto , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Criança , Condrócitos/metabolismo , Metilação de DNA , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Hidrazinas/química , Células-Tronco Mesenquimais/metabolismo , Camundongos , Repetições de Microssatélites , Mitocôndrias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Oncogenes , Interferência de RNA , Fatores de Transcrição SOXD/metabolismo , Sarcoma/genética
13.
Anticancer Res ; 40(4): 2265-2269, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234924

RESUMO

A 49-year-old male with Ewing sarcoma and bone, pleural, lung and mediastinal lymph node metastasis was treated with cabozantinib after four lines of previous systemic treatments. He responded objectively and subjectively well for 8 months. In this heavily pretreated patient, the daily starting dose of 60 mg had to be reduced to 30 mg because of adverse events. We conclude that treatment with cabozantinib administered in further-line was active in this particular patient with metastatic Ewing sarcoma. The underlying mechanism of action remains unclear. Because of a stable disease on a long-term treatment with pazopanib targeting an anti-angiogenic pathway common to both drugs previously administered in this patient, it is hypothesized that the action of cabozantinib could be ascribed to its action on the non-common receptors AXL and c-Met. The potential of cabozantinib should be further investigated more upfront in this disease either alone or in combination with other systemic treatments.


Assuntos
Anilidas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Piridinas/uso terapêutico , Sarcoma de Ewing/tratamento farmacológico , Neoplasias Ósseas/patologia , Evolução Fatal , Humanos , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Sarcoma de Ewing/patologia
15.
Pediatr Blood Cancer ; 67(7): e28284, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333633

RESUMO

BACKGROUND: VTP-50469 is a potent inhibitor of the menin-MLL1 interaction and is implicated in signaling downstream of EWSR1-FLI1. PROCEDURE: VTP-50469 was evaluated against seven Ewing sarcoma (EwS) xenograft models and in vitro against EwS cell lines. RESULTS: VTP-50469 showed limited antitumor activity, statistically significantly slowing tumor progression in four tumor models but with no evidence of tumor regression. In vitro, the IC50 concentration was 10 nM for the mixed lineage leukemia (MLL)-rearranged leukemia cell line MV4;11, but > 3 µM for EwS cell lines. CONCLUSIONS: In contrast to its high level of activity against MLL1-rearranged leukemia xenografts, VTP-50469 shows little activity against EwS models.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Histona-Lisina N-Metiltransferase/efeitos dos fármacos , Proteína de Leucina Linfoide-Mieloide/efeitos dos fármacos , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Sarcoma de Ewing/tratamento farmacológico , Animais , Antineoplásicos/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Pediatria , Proteínas Proto-Oncogênicas/metabolismo , Sarcoma de Ewing/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Pediatr Blood Cancer ; 67(6): e28222, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32207565

RESUMO

BACKGROUND: Regorafenib is a small molecule multikinase inhibitor that inhibits multiple kinases including BRAF, KIT, PDGFRB, RAF, RET, and VEGFR1-3. PROCEDURES: The in vivo anticancer effects of regorafenib were assessed in a panel of six osteosarcoma models, three rhabdomyosarcoma models, and one Ewing sarcoma model. RESULTS: Regorafenib induced modest inhibition of tumor growth in the models evaluated. CONCLUSION: The overall pattern of response to regorafenib appears similar to that of the kinase inhibitor sorafenib, with pronounced slowing of tumor growth in some models, limited to the period of agent administration, being the primary treatment effect.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Rabdomiossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Animais , Apoptose , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Proliferação de Células , Criança , Feminino , Humanos , Camundongos , Camundongos SCID , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/patologia , Sarcoma de Ewing/enzimologia , Sarcoma de Ewing/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Acta Orthop Traumatol Turc ; 54(1): 42-48, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32175896

RESUMO

OBJECTIVE: The aim of this study was to compare the results of chemotherapy or combined chemotherapy-radiation therapy with surgical intervention following neodjuvant therapy in pelvic Ewing's sarcoma patients. METHODS: The study population consisted of 39 patients with pelvic Ewing's sarcoma treated in our clinic between 1994 and 2014. Of these patients, 28 patients (11 boys and 17 girls; mean age: 19.57±6.8 years) were treated with chemotherapy and radiation therapy and the remaining 11 patients (9 boys and 2 girls; mean age: 18.64±8.1 years) patients underwent surgical intervention after neoadjuvant chemotherapy or chemotherapy plus radiation therapy. Internal hemipelvectomy was performed in 10 patients, and external hemipelvectomy was performed in one patient. Survival rates were compared between the surgical and non-surgical treatment groups. Predictive factors, such as treatment protocol (surgery, neoadjuvant chemotherapy, definitive radiotherapy), mass localisation, mass size, presence of metastasis at the time of diagnosis, and presence of late metastases were compared between the groups. The effects of each variable on survival were also examined. RESULTS: The overall 3- and 5-year survival rates of the 28 non-surgical patients were 41.4% and 26.1%, respectively, while those of the surgical patients were 53% and 35.4%, respectively (p=0.777). Large mass size, presence of metastasis at the time of diagnosis, and presence of late metastases were significantly associated with lower survival rates. CONCLUSION: The survival rates of the patients who underwent surgery were higher than those of non-surgical patients, although the difference was not statistically significant. Definitive radiation and chemotherapy would be preferable in selected cases, such as patients with sacral localisation, without surgical intervention. LEVEL OF EVIDENCE: Level III, Therapeutic Study.


Assuntos
Neoplasias Ósseas , Quimiorradioterapia/métodos , Pelve/patologia , Sarcoma de Ewing , Procedimentos Cirúrgicos Operatórios/métodos , Adolescente , Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Feminino , Humanos , Masculino , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Sarcoma de Ewing/patologia , Sarcoma de Ewing/terapia , Taxa de Sobrevida , Tempo para o Tratamento , Resultado do Tratamento , Adulto Jovem
18.
Pathologe ; 41(2): 116-122, 2020 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-32060684

RESUMO

Ewing sarcomas are highly malignant tumors that are mainly found in children and adolescents. In addition to early clinical diagnosis, correct histopathological and molecular genetic classification is the most important step. Although EWSR1-FLI1 fusion is by far the most common detectable change, there are also other representatives of the Ewing sarcoma family that cannot be distinguished histopathologically and immunohistochemically from classical Ewing sarcomas and that have different molecular genetic profiles. Although a precise molecular genetic differentiation of the various representatives of small round blue cell tumors does not yet lead to any change in the standard chemotherapy and surgical treatment applied, it does allow an estimation of the prognosis and will probably contribute in the future to an even more individualized treatment of Ewing sarcomas within the framework of personalized medicine.


Assuntos
Neoplasias Ósseas/patologia , Sarcoma de Ewing/patologia , Neoplasias Ósseas/terapia , Humanos , Prognóstico , Sarcoma de Ewing/terapia
19.
Lancet Oncol ; 21(3): 446-455, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32078813

RESUMO

BACKGROUND: Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma. METHODS: We did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m2) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605. FINDINGS: Between April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4-35·4) for patients with Ewing sarcoma and 31·1 months (24·4-31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13-42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4-26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20-50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects. INTERPRETATION: Cabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation. FUNDING: Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.


Assuntos
Anilidas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Sarcoma de Ewing/tratamento farmacológico , Adulto , Neoplasias Ósseas/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Osteossarcoma/patologia , Prognóstico , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Sarcoma de Ewing/patologia , Taxa de Sobrevida , Adulto Jovem
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