RESUMO
PURPOSE: Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS: In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS: The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION: Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Linfoma de Células B/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Recidiva Local de Neoplasia , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Progressão da Doença , Europa (Continente) , Feminino , Humanos , Linfoma de Células B/genética , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/mortalidade , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Medição de Risco , Fatores de Risco , América do Sul , Fatores de Tempo , Estados Unidos , Adulto JovemRESUMO
NUT carcinoma (NC) is a rare malignant neoplasm usually located in the midline, including the upper aerodigestive tract. NC is an aggressive and highly lethal type of carcinoma. It is defined by the rearrangement of the nuclear protein in the testis (NUT) gene on chromosome 15q14. In most cases, the NUT is involved in a balanced translocation with the BRD4 gene on chromosome 19p13.1, an event that creates a BRD4-NUT fusion gene. The relationship between the human papillomavirus (HPV), p16, and upper aerodigestive tract cancer has been long postulated. In this study, we evaluated the relationship of the p16 expression in 4 cases of NCs and its eventual association with HPV. All 4 cases presented typical histopathologic findings with nuclear positivity of the NUT protein and strong expression for p16. None of these cases, however, showed an association with HPV evaluated by polymerase chain reaction. Despite the expression of p16, this negative result for HPV indicates that HPV infection probably does not play a role in the pathogenesis of NC.
Assuntos
Carcinoma/genética , Neoplasias Pulmonares/genética , Neoplasias do Mediastino/genética , Neoplasias Nasofaríngeas/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Adulto , Carcinoma/diagnóstico , Carcinoma/patologia , Inibidor p16 de Quinase Dependente de Ciclina , Feminino , Expressão Gênica , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/patologia , PapillomaviridaeRESUMO
Angiomatoid "malignant" fibrous histiocytoma is a rare sarcoma of low malignant potential that occurs most commonly in the extremities of children and young adults. Herein, we present a case of angiomatoid malignant fibrous histiocytoma with unusual histologic features arising in the mediastinum of an 80-year-old man. The tumor exhibited a reticular growth pattern and myxoid stroma. The tumor cells expressed epithelial membrane antigen and desmin. Cytogenetic analysis revealed the translocation t(2;22)(q33;q12). Molecular genetic analysis confirmed the rearrangement of the EWSR1 locus and the presence of the EWSR1/CREB1 fusion. This report expands the clinicopathologic spectrum of angiomatoid malignant fibrous histiocytoma and underscores the value of integrating morphologic, immunophenotypic, and molecular findings in the identification of its unusual morphologic variants.
Assuntos
Histiocitoma Fibroso Maligno/patologia , Neoplasias do Mediastino/patologia , Idoso de 80 Anos ou mais , Proteínas de Ligação a Calmodulina/genética , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 22/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Análise Citogenética , Histiocitoma Fibroso Maligno/genética , Humanos , Masculino , Neoplasias do Mediastino/genética , Proteínas de Fusão Oncogênica/genética , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Translocação GenéticaRESUMO
The anterior mediastinum is a common site of tumors with abundant lymphoid elements. Flow cytometry is a useful complementary technique to analyze this type of tumors, which provides qualitative and quantitative information. A differential diagnosis can be sometimes made between thymoma and precursor T-lymphoblastic lymphoma (T-LBL). Correct identification is of utmost importance for patient treatment. A total of 38 mediastinal tumors were analyzed, and samples were separated for flow cytometry. Flow cytometry data from thymomas and normal thymic tissue were compared with 42 cases of T-LBL from other anatomical locations. Among 38 mediastinal tumors, we found 6 benign lesions, 9 diffuse large B-cell lymphomas (DLBCL), 10 Hodgkin lymphomas (HL), 11 thymomas and 2 T-LL. Flow cytometry provided positive information in 24 cases, and defined lymphoid neoplastic cells immunophenotype or the typical lymphocytes accompanying thymomas. Flow cytometry helped differentiate 10 cases of HL and 4 benign lesions from other lymphomas (DLBCL, T-LBL, etc.). CD3, CD4 and CD8 expressions were most useful for the differential diagnosis of thymomas and T-LL. To conclude, flow cytometry is a valid complementary technique, which promptly provides information on mediastinal lesions, requiring small quantities of tissue for both early diagnosis and follow up of these diseases.
Assuntos
Antígenos CD/análise , Biomarcadores Tumorais , Citometria de Fluxo , Neoplasias do Mediastino/patologia , Timoma/patologia , Neoplasias do Timo/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo CD3/análise , Antígenos CD4/análise , Antígenos CD8/análise , Criança , Pré-Escolar , Feminino , Humanos , Hiperplasia , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/imunologia , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Linfócitos T/imunologia , Timoma/genética , Timoma/imunologia , Neoplasias do Timo/genética , Neoplasias do Timo/imunologia , Adulto JovemRESUMO
El mediastino anterior es un sitio frecuente de localización de tumores ricos en elementos linfoides. La identificación correcta de cada entidad es de importancia en el tratamiento de los pacientes. En ocasiones puede plantearse el diagnóstico diferencial entre timoma y linfoma linfoblástico con fenotipo de precursor T (LLB-T). La Citometría de Flujo (CF) es una técnica complementaria útil para estos tumores de la cual se obtiene información cualitativa y cuantitativa. Revisamos 38 tumores mediastinales que tenían estudio de CF. Además comparamos los resultados de CF de timomas y tejido tímico normal con 42 casos de LLB-T de otras localizaciones anatómicas. De los 38 tumores mediastinales 6 eran lesiones benignas, 9 linfomas difusos de células grandes con fenotipo B (LDCG-B), 10 linfomas de Hodgkin (LH), 11 timomas y 2 LLB-T. En 24 casos la CF aportó información positiva, definiendo el inmunofenotipo de las células linfoides neoplásicas, o los linfocitos característicos que acompañan a los timomas. La CF en los 10 casos de LH y en 4 lesiones benignas permitió descartar otros tipos de linfoma (LDCG-B, LLB-T, etc.). Las marcaciones para CD3, CD4 y CD8 fueron las más útiles para el diagnóstico diferencial entre timomas y LLB-T. En conclusión, la CF es una técnica complementaria de utilidad que aporta información en lesiones mediastinales de manera rápida, requiriendo cantidades pequeñas de material, tanto para el diagnóstico inicial como para el monitoreo de estas enfermedades.
The anterior mediastinum is a common site of tumors with abundant lymphoid elements. Flow cytometry is a useful complementary technique to analyze this type of tumors, which provides qualitative and quantitative information. A differential diagnosis can be sometimes made between thymoma and precursor T-lymphoblastic lymphoma (T-LBL). Correct identification is of utmost importance for patient treatment. A total of 38 mediastinal tumors were analyzed, and samples were separated for flow cytometry. Flow cytometry data from thymomas and normal thymic tissue were compared with 42 cases of T-LBL from other anatomical locations. Among 38 mediastinal tumors, we found 6 benign lesions, 9 diffuse large B-cell lymphomas (DLBCL), 10 Hodgkin lymphomas (HL), 11 thymomas and 2 T-LL. Flow cytometry provided positive information in 24 cases, and defined lymphoid neoplastic cells immunophenotype or the typical lymphocytes accompanying thymomas. Flow cytometry helped differentiate 10 cases of HL and 4 benign lesions from other lymphomas (DLBCL, T-LBL, etc.). CD3, CD4 and CD8 expressions were most useful for the differential diagnosis of thymomas and T-LL. To conclude, flow cytometry is a valid complementary technique, which promptly provides information on mediastinal lesions, requiring small quantities of tissue for both early diagnosis and follow up of these diseases.
Assuntos
Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antígenos CD/análise , Biomarcadores Tumorais , Citometria de Fluxo , Neoplasias do Mediastino/patologia , Timoma/patologia , Neoplasias do Timo/patologia , /análise , /análise , /análise , Hiperplasia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/imunologia , Fenótipo , Estudos Retrospectivos , Linfócitos T/imunologia , Timoma/genética , Timoma/imunologia , Neoplasias do Timo/genética , Neoplasias do Timo/imunologiaRESUMO
We performed chromosome analysis of 15 neuroblastomas found by mass screening using a vanillymandelic acid spot test. We found near triploid chromosome abnormalities, ranging from 60 to 77 chromosomes, in the tumor cells from 14 patients, and hyperdiploidy with the mode of 50 in cells from one. A structural abnormality was observed in only one patient. We did not find a marker chromosome 1, homogeneously staining region, or double minutes, which have been previously reported in advanced neuroblastomas or in cell lines. All of our patients were completely free of disease 4 to 32 months after diagnosis. We consider that patients with hyperdiploidy or near triploidy are different from those with marker chromosome 1, homogeneously staining region, or double minutes and may constitute a subgroup with a good prognosis in childhood neuroblastoma.