28 research outputs found
Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect
Get PDFGastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastric cancer risk
<html>Prognostic impact of concurrent <i>MYC</i> and <i>BCL6</i> rearrangements and expression in <i>de novo</i> diffuse large B-cell lymphoma</html>
Get PDFDouble-hit B-cell lymphoma is a common designation for a group of tumors characterized by concurrent translocations of MYC and BCL2, BCL6, or other genes. The prognosis of concurrent MYC and BCL6 translocations is not well known. In this study, we assessed rearrangements and expression of MYC, BCL2 and BCL6 in 898 patients with de novo diffuse large B-cell lymphoma treated with standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). Neither BCL6 translocation alone (more frequent in activated B-cell like diffuse large B-cell lymphoma) nor in combination with MYC translocation (observed in 2.0% of diffuse large B-cell lymphoma) predicted poorer survival in diffuse large B-cell lymphoma patients. Diffuse large B-cell lymphoma patients with MYC/BCL6 co-expression did have significantly poorer survival, however, MYC/BCL6 co-expression had no effect on prognosis in the absence of MYC/BCL2 co-expression, and had no additive impact in MYC+/BCL2+ cases. The isolated MYC+/BCL6+/BCL2− subset, more frequent in germinal center B-cell like diffuse large B-cell lymphoma, had significantly better survival compared with the isolated MYC+/BCL2+/BCL6− subset (more frequent in activated B-cell like diffuse large B-cell lymphoma). In summary, diffuse large B-cell lymphoma patients with either MYC/BCL6 rearrangements or MYC/BCL6 co-expression did not always have poorer prognosis; MYC expression levels should be evaluated simultaneously; and double-hit B-cell lymphoma needs to be refined based on the specific genetic abnormalities present in these tumors
Erratum: Clinical and biological significance of de novo CD5+ diffuse large B-cell lymphoma in Western countries
Get PDFCD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBCL). Large-scale studies of de novo CD5+ DLBCL are lacking in Western countries. In this study by the DLBCL Rituximab-CHOP Consortium, CD5 was expressed in 5.5% of 879 DLBCL patients from Western countries. CD5+ DLBCL was associated with higher frequencies of >1 ECOG performance status, bone marrow involvement, central nervous system relapse, activated B-cell–like subtype, Bcl-2 overexpression, and STAT3 and NF-κB activation, whereas rarely expressed single-stranded DNA-binding protein 2 (SSBP2), CD30 or had MYC mutations. With standard R-CHOP chemotherapy, CD5+ DLBCL patients had significantly worse overall survival (median, 25.3 months vs. not reached, P< .0001) and progression-free survival (median, 21.3 vs. 85.8 months, P< .0001) than CD5− DLBCL patients, which was independent of Bcl-2, STAT3, NF-κB and the International Prognostic Index. Interestingly, SSBP2 expression abolished the prognostic significance of CD5 expression, suggesting a tumor-suppressor role of SSBP2 for CD5 signaling. Gene-expression profiling demonstrated that B-cell receptor signaling dysfunction and microenvironment alterations are the important mechanisms underlying the clinical impact of CD5 expression. This study shows the distinctive clinical and biological features of CD5+ DLBCL patients in Western countries and underscores important pathways with therapeutic implications
p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function
Get PDFThe role of p53 family member, p63 in oncogenesis is the subject of controversy. Limited research has been done on the clinical implications of p63 expression in diffuse large B-cell lymphoma (DLBCL). In this study, we assessed p63 expression in de novo DLBCL samples (n=795) by immunohistochemistry with a pan-p63-monoclonal antibody and correlated it with other clinicopathologic factors and clinical outcomes. p63 expression was observed in 42.5% of DLBCL, did not correlate with p53 levels, but correlated with p21, MDM2, p16INK4A, Ki-67, Bcl-6, IRF4/MUM-1 and CD30 expression, REL gains, and BCL6 translocation. p63 was an independent favorable prognostic factor in DLBCL, which was most significant in patients with International Prognostic Index (IPI) >2, and in activated-B-cell–like DLBCL patients with wide-type TP53. The prognostic impact in germinal-center-B-cell–like DLBCL was not apparent, which was likely due to the association of p63 expression with high-risk IPI, and potential presence of ∆Np63 isoform in TP63 rearranged patients (a mere speculation). Gene expression profiling suggested that p63 has both overlapping and distinct functions compared with p53, and that p63 and mutated p53 antagonize each other. In summary, p63 has p53-like and p53-independent functions and favorable prognostic impact, however this protective effect can be abolished by TP53 mutations
Prognostic impact of c-Rel nuclear expression and REL amplification and crosstalk between c-Rel and the p53 pathway in diffuse large B-cell lymphoma
Get PDFDysregulated NF-κB signaling is critical for lymphomagenesis. The regulation, function, and clinical relevance of c-Rel/NF-κB activation in diffuse large B-cell lymphoma (DLBCL) have not been well studied. In this study we analyzed the prognostic significance and gene-expression signature of c-Rel nuclear expression as surrogate of c-Rel activation in 460 patients with de novo DLBCL. Nuclear c-Rel expression, observed in 137 (26.3%) DLBCL patients frequently associated with extranoal origin, did not show significantly prognostic impact in the overall- or germinal center B-like-DLBCL cohort, likely due to decreased pAKT and Myc levels, up-regulation of FOXP3, FOXO3, MEG3 and other tumor suppressors coincided with c-Rel nuclear expression, as well as the complicated relationships between NF-κB members and their overlapping function. However, c-Rel nuclear expression correlated with significantly poorer survival in p63+ and BCL-2− activated B-cell-like-DLBCL, and in DLBCL patients with TP53 mutations. Multivariate analysis indicated that after adjusting clinical parameters, c-Rel positivity was a significantly adverse prognostic factor in DLBCL patients with wild type TP53. Gene expression profiling suggested dysregulations of cell cycle, metabolism, adhesion, and migration associated with c-Rel activation. In contrast, REL amplification did not correlate with c-Rel nuclear expression and patient survival, likely due to co-amplification of genes that negatively regulate NF-κB activation. These insights into the expression, prognostic impact, regulation and function of c-Rel as well as its crosstalk with the p53 pathway underscore the importance of c-Rel and have significant therapeutic implications
Age cutoff for Epstein-Barr virus-positive diffuse large B-cell lymphoma–is it necessary
Get PDFEpstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV+ DLBCL-e) is a molecularly distinct variant of DLBCL, characterized by a monoclonal B-cell proliferation that occurs in patients >50 years of age without a history or clinicopathologic evidence of immunodeficiency. However, patients with EBV+ DLBCL younger than 50-years-old also exist in Western countries. We evaluated the clinicopathologic, immunophenotypic and genetic features in Cacausian patients with EBV+ DLBCL who are ≤50 years of age and compared this patient group to patients who are >50 years. In patients who are ≤50 years, less frequent expression of BCL6 and a trend of more frequent expression of CD30 and pSTAT3 were found in patients with EBV+ DLBCL. In patients who are >50 years, common expression of CD30, p50, pSTAT3 and less frequent expression of BCL6 were observed. Older patients also more commonly had a poor performance status (ECOG≥2). Comparing EBV+ DLBCL patients in ≤50 years versus >50 years, both groups had similar clinicopathologic, immunophenotypic and genetic features. Gene expression profiling, microRNA profiling and treatment outcome of the younger patients with EBV+ DLBCL was not distinctive from tumors in older patients. Based on our data, we suggest that the arbitrary age cutoff for EBV+ DLBCL is unnecessary and should be eliminated in the WHO lymphoma classification scheme
Expression of Epidermal Growth Factors and Their Receptors in the Bronchial Epithelium of Subjects With Chronic Obstructive Pulmonary Disease
Full text linkControlo clÃnico e histopatológico da asma quando utilizada a hiperreactividade brônquica como um indicador adicional no tratamento da asma a longo prazo
Get PDFRESUMO: A Asma, é uma doençã inflamatória crónica das vÃas aéreas caracterizada por episódios recorrentes de dispneia e sibilância que se associam a obstrução variavel das vias aéreas.Estes aspectos podem ser desencadeados em laboratório, pela exposição a estimulos broncoconstritores, demonstrando a existência de hiperreactividade brônquica (HRB).A inflamação das vias aéreas acompanhante caracteriza-se par um·infiltrado especifico de mastocitos, linfocitos e eosinófilos no epitelio brônquico e lamina propria e par um espessamento da camada reticular subendotelial, mesmo em doentes com asma ligeira. Deste modo, os aulores consideram que o estadio da doença deve ser determinado com base na gravidade dos sintornas, grau de limitação do fluxo aéreo, grau de hiperreactividade brônquica e inflamação das vias aéreas.De acordo com o Consenso Internacional (4), o principal objectivo do tratamento da Asma é reverter ou prevenir a inflamação das vias aéreas. A terapêutica, administrada de acordo com a gravidade da doença, baseiase apenas nos sintomas e na função pulmonar (determinação do débito expiratório máximo instantâneo-DEMI através da utilização do Peak-flow).Os autores referem que a inflamação das vias aéreas na asma, está associada com a hiperreactividade brônquica a estÃmulos broncoconstritores. Deste modo, postulam que a HRB pode serum elemento a considerar na terapêutica da asma, tendo investigado como a estratégia do tratamento baseada na HRB (estratégia HRB) em associação com as recommendações dos consensos internacionais (estratégia de referênda), conduzem a: 1) Controlo mais eficaz da asma; 2) Melhoria significativa da inflamação das vias aéreas.Para tal, os autores realizaram um ensaio randomizado, prospectivo, paralelo, envolvendo 75 adultos com asma ligeira a moderada, observados trimestralmente no perÃodo de 2 anos. Em cada visita foi avaliado o Volume Expiratório Máximo no 1° Segundo (VEMS) e realizada Prova de Provocação Inalada (PPI) com metacolina. Os doentes tinham cartões diários de registo de sintomas, de uso de β2-agonistas e determinações do DEMI.A terapêutica com corticosteróides (em 4 niveis) foi ajustada de acordo com as indicações 'em degraus' do Consenso Internacional (estratégia de refêrenda) as quais adicionaram 4 classes de gravidade da HRB (estrategia HRB): NÃvel I- HRB com metacolina - >4.0 mg/ml; NÃvel II-1.0 - 4.0 mg/ml; NÃvel III - 0.25 -1.0 mg/ml; NÃvel IV-<0.25 mg/ml.Foram obtidas biópsias por broncofibroscopia, no inÃcio e dois anos depois.Os autores veriticaram que os doentes tratados de acordo com a estratégia HRB tiveram menor incidência de exacerbações ligeiras do que os doentes do grupo de referência (0.23 e 0.43 exacerbações/ano/doente, respectivamente). O VEMS também melborou significativamente no grupo de estratégia HRB (p<0.05).As biópsias brônquicas revelaram uma maior redução na espessura da camada reticular subendotelial no grupo de estrategia HRB relativamente ao grupo de referência As alterações da HRB em ambos os grupos de estratégia correlacionaram-se com as contagens de eosinófilos nas biópstas (r=- 0.48; p=0.0003).Os autores concluem que a redução da HRB conjugada com a optimização dos sintomas e da função pulmonar conduzem a um controlo mais efectivo da Asma. bem como à melhoria da inflamação das vias aéreas. Deste modo, a monitorização da HRB poderia ser um marcador da inflamação a considerar nas estratégias de tratamento a longo prazo da asma. COMENTÃRIO: Nos últimos anos, têm-se procurado criar normas de orientarção no diagnóstico e terapêutica da Asma Brônquica, atraves da elaboração de Consensos Intenacionais (4) para o Diagnóstico e Tratamento desta doença. Desde 1992, têm sido feitas várias actualizações eo que se propõe neste trabalho, é a importância de inclusão do estudo da hiperreactividadc brônquica como critério adicional de detemrminayação da gravidade da asma e consequentemente, da terapeutica. Deste modo é obtido um melhor controlo clinico e functional, bem como a redução das alterações inflamatórias observadas em estudos biópticos (3,6).Entre nós (1), numa fase inicial do diagnóstico de asma, considerase que a avaltação funcional deve ser sempre que possÃvel completa, sendo realizados o estudo da mecânica venlilatória com estudo farmacodinâmico (prova da provocação inalatória inespecifica ou de broncodilatação se o doente estiver obstruido).Uma vez feito o diagnóstico e para monitorização da asma, é habitualmente feita espirometria. Nas situações mais graves e sempre que haja centros equipados, a repetição das Provas Funcionais Respiratórias sera realizada posteriormente, de modo a avaliar a evolução funcional em termos de grau de obstrução brônquica, insulação pulmonar e hiperreactividade brônquica.No domicÃlio a monitorização é feita através da determinação diária do DEMI (4) Para alguns autores, estas determinaçõs devem ser realizadas particularmente numa fase inicial, nos doentes com asma grave ou naqueles que menosprezam a sua sintomatologta (2).Como é referido no presente trabalho, certamente que o estudo da hiperreactividade brônquica tem interesse quer em termos de diagnóstico, quer prognóstico (5,7) e mesmo para monitorização da resposta à terapêutica. A sua inclusão como critério de gravidade nurn Consenso Internacional é contudo um pouco mais complexa, pela dispartdade de meios técnicos e humanos existentes nos diferentes paÃses e mesmo nas diferentes regiões de um mesmo paÃs
