Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.380
Filtrar
1.
Lancet Oncol ; 21(11): 1433-1442, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33035457

RESUMO

BACKGROUND: Activating mutations of EZH2, an epigenetic regulator, are present in approximately 20% of patients with follicular lymphoma. We investigated the activity and safety of tazemetostat, a first-in-class, oral EZH2 inhibitor, in patients with follicular lymphoma. METHODS: This study was an open-label, single-arm, phase 2 trial done at 38 clinics or hospitals in France, the UK, Australia, Canada, Poland, Italy, Ukraine, Germany, and the USA. Eligible patients were adults (≥18 years) with histologically confirmed follicular lymphoma (grade 1, 2, 3a, or 3b) that had relapsed or was refractory to two or more systemic therapies, had an Eastern Cooperative Oncology Group performance status of 0-2, and had sufficient tumour tissue for central testing of EZH2 mutation status. Patients were categorised by EZH2 status: mutant (EZH2mut) or wild-type (EZH2WT). Patients received 800 mg of tazemetostat orally twice per day in continuous 28-day cycles. The primary endpoint was objective response rate based on the 2007 International Working Group criteria for non-Hodgkin lymphoma, assessed by an independent radiology committee. Activity and safety analyses were done in patients who received one dose or more of tazemetostat. This study is registered with ClinicalTrials.gov, NCT01897571, and follow-up is ongoing. FINDINGS: Between July 9, 2015, and May 24, 2019, 99 patients (45 in the EZH2mut cohort and 54 in the EZH2WT cohort) were enrolled in the study. At data cutoff for the analysis (Aug 9, 2019), the median follow-up was 22·0 months (IQR 12·0-26·7) for the EZH2mut cohort and 35·9 months (24·9-40·5) for the EZH2WT cohort. The objective response rate was 69% (95% CI 53-82; 31 of 45 patients) in the EZH2mut cohort and 35% (23-49; 19 of 54 patients) in the EZH2WT cohort. Median duration of response was 10·9 months (95% CI 7·2-not estimable [NE]) in the EZH2mut cohort and 13·0 months (5·6-NE) in the EZH2WT cohort; median progression-free survival was 13·8 months (10·7-22·0) and 11·1 months (3·7-14·6). Among all 99 patients, treatment-related grade 3 or worse adverse events included thrombocytopenia (three [3%]), neutropenia (three [3%]), and anaemia (two [2%]). Serious treatment-related adverse events were reported in four (4%) of 99 patients. There were no treatment-related deaths. INTERPRETATION: Tazemetostat monotherapy showed clinically meaningful, durable responses and was generally well tolerated in heavily pretreated patients with relapsed or refractory follicular lymphoma. Tazemetostat is a novel treatment for patients with follicular lymphoma. FUNDING: Epizyme.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Benzamidas/administração & dosagem , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Linfoma Folicular/tratamento farmacológico , Piridonas/administração & dosagem , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Feminino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Piridonas/efeitos adversos , Resultado do Tratamento
2.
Ann Hematol ; 99(10): 2441-2443, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32808104
3.
Int J Hematol ; 112(2): 136-138, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32506320

RESUMO

Diffuse follicular lymphoma (FL) variant is a rare condition that shows distinctive clinical, morphological, immunophenotypic, and molecular features that distinguish it from classical FL. Diffuse FL variant is characterized by a predominantly diffuse growth pattern, absence of the t (14;18) IGH/BCL2 translocation, CD23 expression, and presence of 1p36 deletion. Gene mutations involving STAT6 have been reported, with nuclear expression of STAT6 and phosphorylated STAT6 detected by immunohistochemistry. Patients frequently present with inguinal node involvement and low clinical stage. We describe the case of an 80-year-old female diagnosed with diffuse FL variant, presented with a classic diagnostic pattern and an unusual aggressive clinical onset.


Assuntos
Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Idoso de 80 Anos ou mais , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Linfonodos/patologia , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Mutação , Fosforilação , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas c-bcl-2/genética , Doenças Raras , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Translocação Genética
4.
Cancer Cell ; 37(5): 655-673.e11, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32396861

RESUMO

Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.


Assuntos
Linfócitos B/imunologia , Transformação Celular Neoplásica/imunologia , Reprogramação Celular , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Linfoma de Células B/imunologia , Linfoma Folicular/imunologia , Mutação , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Camundongos , Camundongos Endogâmicos C57BL
5.
Cancer Cell ; 37(5): 621-622, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32396854

RESUMO

Interactions between germinal center B cells and immune cells in the microenvironment can play integral roles in transformation and growth of follicular lymphoma (FL). Three recent studies, two in this issue of Cancer Cell and one in Cell Reports, elucidate how genetic alterations in CTSS and EZH2 impact these interactions, with implications for FL immunotherapy.


Assuntos
Linfoma Folicular , Catepsinas , Centro Germinativo , Humanos , Linfoma Folicular/genética , Microambiente Tumoral/genética
6.
Diagn Pathol ; 15(1): 31, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245492

RESUMO

BACKGROUND: Reverse Variant of Follicular Lymphoma (RVFL) is one of the rare morphological variants of FL, characterized by dark staining small centrocytes in the center and pale staining large centroblasts at the periphery of the neoplastic follicles. Only rare cases of RVFL have been described to date. The histological appearance of this little known variant of FL may be misinterpreted if pathologists are unaware of its existence. The main purpose of this study is to draw pathologists' attention to such an uncommon growth pattern of FL so that this variant can be correctly recognized and the clinical significance further studied in the future. METHODS: Four cases of FL with unusual morphologic features were evaluated for the expression pattern of CD20, CD10, BCL6, BCL2, CD21, CD23, CD3, CD5, Cyclin D1, IgD and Ki67 by immunohistochemistry. Fluorescence in situ hybridization (FISH) with break-apart probes was performed to detect BCL2 gene rearrangement. RESULTS: All four cases showed distinctive morphologic pattern of RVFL; in addition, each also exemplified unique morphological features. Immunohistochemical stains confirmed the cells in both the central areas and the peripheral cuffs had the same immunophenotypic profiles, contrasting to the FL with marginal zone differentiation in which only the center of the nodules showed expression of CD10. FISH demonstrated BCL2 gene rearrangement in all cases. CONCLUSION: The growth pattern of this rare FL variant may mimic FL with marginal-zone differentiation and other entities including but not limited to marginal zone lymphoma (MZL), progressive transformation of germinal centers (PTGC) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). Pathologists should be familiar with this unusual morphological variant to avoid diagnostic pitfalls.


Assuntos
Linfonodos/patologia , Linfoma Folicular/patologia , Adulto , Biomarcadores Tumorais/análise , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma Folicular/genética , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/genética
7.
BMC Bioinformatics ; 21(1): 144, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293247

RESUMO

BACKGROUND: The study of cancer genomics continually matures as the number of patient samples sequenced increases. As more data is generated, oncogenic drivers for specific cancer types are discovered along with their associated risks. This in turn leads to potential treatment strategies that pave the way to precision medicine. However, significant financial and analytical barriers make it infeasible to sequence the entire genome of every patient. In contrast, targeted sequencing panels give reliable information on relevant portions of the genome at a fiscally responsible cost. Therefore, we have created the Targeted Panel (TarPan) Viewer, a software tool, to investigate this type of data. RESULTS: TarPan Viewer helps investigators understand data from targeted sequencing data by displaying the information through a web browser interface. Through this interface, investigators can easily observe copy number changes, mutations, and structural events in cancer samples. The viewer runs in R Shiny with a robust SQLite backend and its input is generated from bioinformatic algorithms reliably described in the literature. Here we show the results from using TarPan Viewer on publicly available follicular lymphoma, breast cancer, and multiple myeloma data. In addition, we have tested and utilized the viewer internally, and this data has been used in high-impact peer-reviewed publications. CONCLUSIONS: We have designed a flexible, simple to setup viewer that is easily adaptable to any type of cancer targeted sequencing, and has already proven its use in a research laboratory environment. Further, we believe with deeper sequencing and/or more targeted application it could be of use in the clinic in conjunction with an appropriate targeted sequencing panel as a cost-effective diagnostic test, especially in cancers such as acute leukemia or diffuse large B-cell lymphoma that require rapid interventions.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Software , Algoritmos , Neoplasias da Mama/genética , Feminino , Dosagem de Genes , Genoma Humano , Genômica , Humanos , Linfoma Folicular/genética , Mieloma Múltiplo/genética , Mutação , Medicina de Precisão , Navegador
9.
Am J Clin Pathol ; 153(5): 672-685, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32112707

RESUMO

OBJECTIVES: To better characterize the clinicopathologic presentation and outcomes of follicular lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit and triple-hit follicular lymphoma), we present three cases from our institution and perform a literature review of 37 published cases. METHODS: Cases were identified using institutional SoftPath software and the MEDLINE database via the PubMed search engine. Clinical and pathologic data were collected with subsequent stratification by histologic grade and treatment for comparison. RESULTS: Similar to classic follicular lymphoma, patients presented most often with low-grade (1-2) but high-stage (III-IV) disease with absence of B symptoms; however, overall survival was worse than that of traditional follicular lymphoma. In a small sample size, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) achieved better outcomes than a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Specific pathologic features that might prompt testing for MYC rearrangement include elevated proliferation index out of proportion to cytology and aggressive features such as angioinvasion. CONCLUSIONS: Double-hit and triple-hit follicular lymphoma may be better classified as a distinct entity from classical follicular lymphoma with a worse prognosis. Aggressive therapy with a treatment regimen used for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements might be beneficial, but more evidence is needed to justify aggressive treatment as standard of care.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Rearranjo Gênico , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Prognóstico , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêutico
10.
J Oncol Pharm Pract ; 26(4): 943-966, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31964218

RESUMO

Lymphomas are a diverse group of hematologic malignancies that arise from either T cell, B cell or the natural killer cell lineage. B cell lymphomas arise from gene mutations with critical functions during normal B cell development. Recent advances in the understanding of molecular pathogenesis demonstrate that many different recurrent genomic and molecular abnormalities and dysregulated oncogenic regulatory pathways exist for many subtypes of B cell lymphomas, both across and within histological subtypes. Pathogenetic processes such as (1) chromosomal aberrations, for example, t(14;18) in follicular lymphoma, t(11;14) in mantle cell lymphoma, t(8;14) in Burkitt lymphoma; dysregulations in signaling pathways of (2) nuclear factor- κB (NF-κB); (3) B cell receptor (BCR); (4) Janus kinase/signal transducers and transcription activators (JAK-STAT); (5) impaired apoptosis/cell cycle regulation due to mutated, rearranged or amplified MYC, BCL-2, BCL-6 proto-oncogenes; (6) epigenetic aberrations may contribute to pathogenesis. More studies are under way to elucidate the molecular heterogeneity underlying many types of lymphomas that account for variable responses to treatment, generation of subclones and treatment resistance. Although significant research is still needed, targeted therapy promises to provide new options for the treatment of patients with lymphomas. This article provides a non-exhaustive overview on the current understanding on the genetics of pathogenesis of B cell lymphomas and their therapeutic implications.


Assuntos
Biomarcadores Tumorais/genética , Linfoma de Células B/genética , Linfoma de Células B/terapia , Medicina de Precisão/métodos , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/tendências , Marcação de Genes/métodos , Marcação de Genes/tendências , Humanos , Linfoma de Células B/metabolismo , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Folicular/terapia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/terapia , Mutação/efeitos dos fármacos , Mutação/fisiologia , Medicina de Precisão/tendências , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
11.
Blood ; 135(3): 181-190, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31697802

RESUMO

The genetic background of follicular lymphomas (FLs) diagnosed in advanced clinical stages III/IV, and which are frequently characterized by t(14;18), has been substantially unraveled. Molecular features, as exemplified in the clinicogenetic risk model m7FLIPI, are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), which accounts for ∼20% of newly diagnosed FL in which the detection rate of t(14;18) is only ∼50%. To investigate the genetic background of localized-stage FL, patient cohorts with advanced-stage FL or localized-stage FL, uniformly treated within phase 3 trials of the German Low-Grade Lymphoma Study Group, were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL patients. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (area under the curve, 0.98) by penalized logistic regression. Of note, 3% of samples harboring an "advanced-stage signature" in the localized-stage cohort exhibited inferior failure-free survival (hazard ratio [HR], 7.1; P = .0003). Likewise, in the advanced-stage cohort, 7% of samples with a "localized-stage signature" had prolonged failure-free survival (HR, 2.3; P = .017) and overall survival (HR, 3.4; P = .072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Linfoma Folicular/genética , Linfoma Folicular/patologia , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Linfoma Folicular/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Translocação Genética , Adulto Jovem
15.
Am J Surg Pathol ; 44(3): 329-339, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31688142

RESUMO

Follicular lymphoma (FL) is one of the most frequently diagnosed lymphomas in the United States and Europe. The definition of and basic approach to diagnosis and grading of FL is essentially unchanged in the recently updated revision of the World Health Organization (WHO) classification. FL is a biologically and histopathologically heterogeneous disease. Although there is an improved understanding of some FL variants and specific subtypes, there are cases whose recognition is particularly challenging, either because they have unusual features or represent examples of new or rare variants. Herein, we share a series of unusual and difficult to recognize FLs with the goal of increasing awareness of the expanding histopathologic variability in FL. Unusual FL discussed here include: FL with Castleman-like changes, FL with plasmacytic differentiation, and immunoglobulin G4-positive plasma cells in the setting of immunoglobulin G4-related disease, FL with marginal zone differentiation and involving mucosa-associated lymphoid tissue sites, diffuse FL variant expressing CD23 with STAT6 mutation, large B-cell lymphoma with IRF4 rearrangement, CD10-negative and MUM1-positive aggressive FL, and Epstein-Barr virus-positive FL.


Assuntos
Linfoma Folicular/diagnóstico , Linfoma Folicular/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Masculino , Pessoa de Meia-Idade
16.
Int J Oncol ; 56(1): 7-17, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31789408

RESUMO

Although the majority of patients with follicular lymphoma (FL) harbor the t(14;18)(q32;q21) IGH/BCL2 gene rearrangement that leads to the overexpression of BCL2 protein, approximately 20% of FL cases lack t(14;18)(q32;q21). It is considered that BCL2 overexpression underscores the development of the majority of cases of FL and their transformation to more aggressive lymphoma [known as transformed FL (tFL)]. However, FL cases lacking the t(14;18)(q32;q21) translocation exhibit symptoms analogous to their t(14;18)­positive counterparts. An important goal of recent research on FL has been to clarify the distinctions between the two different forms of FL. Numerous studies have shed light onto the genetic and molecular features of t(14;18)­negative FL and the related clinical manifestations. In this review, we summarize the current knowledge of t(14;18)­negative FL occurring in the lymph nodes with an emphasis on the underlying molecular and clinical features. In addition, novel treatment directions are discussed.


Assuntos
Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 18/genética , Linfoma Folicular/genética , Linfoma Folicular/patologia , Translocação Genética , Humanos , Prognóstico
17.
Nat Rev Dis Primers ; 5(1): 83, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831752

RESUMO

Follicular lymphoma (FL) is a systemic neoplasm of the lymphoid tissue displaying germinal centre (GC) B cell differentiation. FL represents ~5% of all haematological neoplasms and ~20-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Tumorigenesis starts in precursor B cells and becomes full-blown tumour when the cells reach the GC maturation step. FL is preceded by an asymptomatic preclinical phase in which premalignant B cells carrying a t(14;18) chromosomal translocation accumulate additional genetic alterations, although not all of these cells progress to the tumour phase. FL is an indolent lymphoma with largely favourable outcomes, although a fraction of patients is at risk of disease progression and adverse outcomes. Outcomes for FL in the rituximab era are encouraging, with ~80% of patients having an overall survival of >10 years. Patients with relapsed FL have a wide range of treatment options, including several chemoimmunotherapy regimens, phosphoinositide 3-kinase inhibitors, and lenalidomide plus rituximab. Promising new treatment approaches include epigenetic therapeutics and immune approaches such as chimeric antigen receptor T cell therapy. The identification of patients at high risk who require alternative therapies to the current standard of care is a growing need that will help direct clinical trial research. This Primer discusses the epidemiology of FL, its molecular and cellular pathogenesis and its diagnosis, classification and treatment.


Assuntos
Linfoma Folicular/genética , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Linfoma Folicular/fisiopatologia , Linfoma Folicular/terapia , Recidiva , Rituximab/uso terapêutico , Resultado do Tratamento
18.
J Med Case Rep ; 13(1): 376, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31856921

RESUMO

BACKGROUND: Paragangliomas and pheochromocytomas are sympathetic or parasympathetic tumors derived from the paraganglia and the adrenal medulla, respectively. Paragangliomas and pheochromocytomas can be sporadic or familial, the latter frequently being multifocal and possibly due to succinate dehydrogenase complex genes mutations. In addition, 12% of sporadic paragangliomas are related to covered succinate dehydrogenase complex mutations. The importance of identifying succinate dehydrogenase complex mutations is related to the risk for these patients of developing multiple tumors, including non-endocrine ones, showing an aggressive clinical presentation. CASE PRESENTATION: We report the case of a 45-year-old Caucasian man with an indolent mass in his neck. Ultrasound of his neck, magnetic resonance imaging, and 1,4,7,10-tetraazacyclododecane-N(I),N(II),N(III),N(IIII)-tetraacetic acid(D)-Phe(1)-thy(3)-octreotide (68Ga-DOTATOC) positron emission tomography-computed tomography and endocrine work-up were consistent with a carotid body paraganglioma with concomitant nodal enlargement in several body regions, which turned out to be a follicular lymphoma at histology. He was found to carry a germline Succinate dehydrogenase subunit B gene (SDHB) mutation. CONCLUSION: It is crucial to look for a second malignancy in the case of a paraganglioma demonstrating succinate dehydrogenase complex germline mutations.


Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Mutação em Linhagem Germinativa/genética , Neoplasias de Cabeça e Pescoço/patologia , Linfoma Folicular/patologia , Paraganglioma/patologia , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/genética , Humanos , Linfoma Folicular/diagnóstico por imagem , Linfoma Folicular/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Paraganglioma/diagnóstico por imagem , Paraganglioma/genética , Succinato Desidrogenase , Resultado do Tratamento , Ultrassonografia
19.
J Vet Diagn Invest ; 31(6): 809-817, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31585524

RESUMO

Bcl-2, an anti-apoptotic protein, is commonly overexpressed in follicular lymphomas in humans. This is usually the result of a chromosomal translocation that transposes the Bcl-2 gene into the immunoglobulin gene locus. The immunohistochemical assessment of this overexpression can be used as a tool for the differentiation of follicular lymphoma and follicular hyperplasia. In cats, little information about the expression of Bcl-2 in follicular lymphoma exists. We investigated 18 follicular lymphomas histologically and immunohistochemically for the expression of Bcl-2, CD3, CD45R, and feline leukemia virus. Clonality was assessed by PCR for antigen receptor gene rearrangements. Although the histology resembled that of their human counterparts, diffuse expression of Bcl-2 within the follicles of the feline lymphomas, as seen in human cases, was not present. Only single cells within the follicles, comparable to the reactive controls, were positive for Bcl-2 expression. The mean survival time of 4.6 y confirmed the indolent character of the tumor. None of the clinical parameters assessed were statistically significant predictors of survival. Furthermore, a statistically significant difference in survival of animals with or without anti-neoplastic therapy was also not demonstrable.


Assuntos
Doenças do Gato/genética , Expressão Gênica , Linfoma Folicular/veterinária , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Gatos , Feminino , Linfoma Folicular/genética , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
20.
Front Immunol ; 10: 1943, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475004

RESUMO

Follicular lymphoma (FL) is the second most frequent subtype of B non-Hodgkin's lymphomas (NHL) for which the treatment is based on the use of anti-CD20 mAbs. NK cells play a crucial role in their mechanism of action and the number of these cells mediating antibody-dependent cell cycotoxicity (ADCC) in the peripheral blood of FL patients predict the outcome. However, their presence in FL biopsies, their activation and their role have been poorly investigated. Moreover, in vitro studies have not deciphered the exact signaling cascades triggered by NK cells in presence of anti-CD20 mAbs on both effector and target cells in a relevant FL model. We performed in silico analyses and ex vivo functional assays to determine the presence and the activation status of NK cells in FL biopsies. We modelized ADCC phenomenon by developing a co-culture model composed by 3D-cultured FL cells and NK cells. Thus, we investigated the biological effect of anti-CD20 mAbs by fluorescent microscopy and the phosphorylation status of survival pathways by cell bar coding phosphoflow in target cells. In parallel, we measured the status of activation of downstream FcγRIIIa signaling pathways in effector cells and their activation (CD69, perforin, granzyme B, IFNγ) by flow cytometry. We determined by in vivo experiments the effects of anti-CD20 mAbs in presence of NK cells in SCID-Beige engrafted FL mice. Here, we show that functional NK cells infiltrate FL biopsies, and that their presence tends to correlate with the survival of FL patients. Using our 3D co-culture model, we show that rituximab and GA101 are able to promote degranulation, CD69 expression, IFNγ production and activate FcγRIIIa signaling cascade in NK cells, and inhibit survival pathways and induce apoptosis in FL cells. The effect of GA101 seems to be more pronounced as observed in vivo in a xenograft FL model. This study strongly supports the role of NK cells in FL and highlights the application of the 3D co-culture model for in vitro validation.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antígenos CD20/imunologia , Células Matadoras Naturais/imunologia , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Animais , Citotoxicidade Celular Dependente de Anticorpos/genética , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Antígenos CD20/genética , Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Técnicas de Cocultura , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Células Matadoras Naturais/metabolismo , Linfoma Folicular/genética , Linfoma Folicular/imunologia , Camundongos SCID , Trastuzumab/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA