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Virchows Arch ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31975037


Mantle cell lymphoma (MCL) shows a clinical aggressiveness that varies from patient to patient. Despite major advances in outcomes with current immunochemotherapy, the future development of therapies requires risk stratification to tailor therapy intensity. Within the group of reference pathologists for the ongoing trials of the European MCL Network, we performed a round robin test on a tissue microarray to evaluate the reproducibility in assessing the biomarkers of outcome in MCL. Cytological subtype, Ki67-index and expression of p53 and SOX11 were evaluated on 20 diagnostic tumour samples by eight participating labs independently. We demonstrate that the assessment of the proliferation index by counting the Ki67 positive cells as well as assessment of SOX11 and p53 expression status is reproducible between labs. For the most established prognostic biomarker, Ki67, the intra-class correlation coefficient was very good when assessed as a continuous parameter (0.87). The agreement was lower when the values were analysed in a dichotomized way applying the commonly used cutoff of 30% (kappa = 0.65, complete concordance of all labs in 13/20 (65%)). Cases with discrepant results between labs in the dichotomized analysis showed mean values close to the cutoff of 30%. Centralised scoring and digital image analysis revealed results in line with the scores from individual labs. All cases in our cohort were additionally assessed for gene expression signatures and of TP53 gene alterations. Given the good reproducibility when guidelines of assessment are applied, the biomarker studied in this inter-laboratory test presents potential candidates to be enhanced for risk-stratification in the future clinical trials.

Histopathology ; 75(5): 704-714, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31173643


AIMS: Mantle cell lymphoma (MCL) is a heterogeneous disease with an aggressive behaviour in most cases, which is associated with expression of sex determining region-Y-box11 (SOX11). Experimental studies have shown that SOX11 expression is associated with an angiogenic switch characterised by increased expression of angiogenic-related signatures and vascularisation of murine tumours. However, the relationship between angiogenesis and SOX11 expression in primary tumours is not well understood. Therefore, the aim of this study was to evaluate the development of microvascular angiogenesis in primary MCL in relation to SOX11 expression and its potential prognostic value. METHODS AND RESULTS: Fifty-six patients diagnosed with MCL, 38 SOX11-positive and 18 SOX11-negative, were studied. The relative intratumoral microvascular area (MVA) and microvessel density (MVD) (number of intratumoral microvessels/µm2 ) were measured on CD34-stained slides using a computerised image analysis system. SOX11-positive MCL showed a significant higher microvascular development than negative tumours (median MVA = 14.5 × 10-3 versus 5.0 × 10-3 P < 0.001; median MVD = 18.6/µm2 versus 14.2/µm2 , P = 0.021). Analysing the MVA and MVD as continuous variables, a high MVD was associated with shorter overall survival (P = 0.004), and a similar tendency was observed for high MVA (P = 0.064). The microvascular development was not related to the Ki-67 proliferative index or 17p/TP53, 9p or 11q alterations. CONCLUSIONS: These findings suggest that SOX11 promotes an angiogenic phenotype in primary MCL, which may contribute to the more aggressive behaviour of these tumours.

Histopathology ; 75(6): 799-812, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30861172


AIMS: The clinical implications of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in patients with post-transplant lymphoproliferative disorders are largely unknown, and its association with Epstein-Barr virus (EBV) status and PD-L1 copy number alterations (CNAs) has not been thoroughly studied. METHODS AND RESULTS: PD1/PD-L1 expression was studied in 50 adult post-transplant lymphoproliferative disorders, and the correlations with PD-L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty-seven (74%) cases were classified as diffuse large B-cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty-four cases were EBV-positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD-L1 expression in tumour cells and tumour-associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD-L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non-germinal centre type DLBCL (P < 0.001). Cases with PD-L1-positive tumour cells showed a higher number of PD-L1 CNAs than PD-L1-negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD-L1 expression showed the worst overall survival (P < 0.001). CONCLUSIONS: The PD1/PD-L1 axis is deregulated in post-transplant lymphoproliferative disorders, with frequent PD-L1 expression and PD1 negativity. PD-L1 expression is associated with EBV latency II or III and PD-L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD-L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches.

Blood ; 133(9): 940-951, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30538135


Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1- MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1-/D2- MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1-/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1- MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1- MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1- MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1-/D2-/D3- MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1- MCL.

Ciclina D2/genética , Ciclina D3/genética , Elementos Facilitadores Genéticos , Rearranjo Gênico , Cadeias Leves de Imunoglobulina/genética , Linfoma de Célula do Manto/genética , Idoso , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição SOXC/genética , Translocação Genética
Salud UNINORTE ; 24(1): 10-22, jun. 2008. tab, mapas
Artigo em Espanhol | LILACS | ID: lil-562487


Objetivos: Describir las características de la transmisión hereditaria de la enfermedad en familias de la ciudad de Cartagena (Colombia) y analizar algunos factores medioambientales del núcleo familiar de los pacientes que pudieran influir en la evolución y/o severidad de la patología. Materiales y métodos: Se estudiaron 22 pacientes, distribuidos en 16 familias, del “Programa de atención integral a pacientes con fibrosis quística” de la Universidad de Cartagena. Se recopiló información acerca de las condiciones de vivienda del grupo familiar y se evaluaron aspectos fenotípicos hereditarios, y se construyeron genealogías para esta enfermedad. Resultados: El análisis de pedigríes reveló lo siguiente: en ocho familias (67%), los individuos afectados presentan rasgos caucásicos; en cinco familias (42%) se reconoce existencia de ancestros europeos; en dos familias (17%) existe consaguinidad. En relación con el aspecto ambiental, se encontró que 33% de las familias estudiadas habitan viviendas en malas condiciones. Conclusiones: Entre las familias de los pacientes con fibrosis quística de la ciudad de Cartagena detectados en este estudio se verifica la transmisión hereditaria autosómica recesiva, se confirma el mestizaje de nuestras poblaciones. La reincidencia de enfermos y la consanguinidad en varias familias denota la falta de asesoramiento genético y el desconocimiento de la evolución de la enfermedad por su grupo familiar. Estos resultados pueden ser el punto de partida de estudios más amplios que sirvan de fundamento para la implementación de políticas tendientes a reducir la frecuencia y severidad de la enfermedad a nivel local y nacional...

Objective: Describe characteristics of hereditary transmissión diseases in families in Cartagena (Colombia) also analysing some environmental factors that might affect the evolution and or severity of this diseases. Materials and methods: Twenty-two patients distributed into 16 families attending to the Universidad de Cartagena's Integral attention program for CF families were studied. Information about family house conditions was collected; some inherited phenotype aspects were evaluated, and genealogy trees were constructed for this disease. Results: Our pedigree analysis reveals the next issues: first, caucasian traits in affected individuals are present in eight families (67%); second, european ancestors are reported in five families (42%); third, inbreeding was detected in two families (17%). Thirty three percent of these families are living in bad housing conditions. Conclusions: Between relatives of cystic fibrosis patients from Cartagena it is verified the autosomal recessive hereditary transmission, it is confirmed the crossbreeding inside our population. The relapse of patients and the blood relationship in several families reveal the lack of genetic counseling and inadequate knowledge about the evolution of the disease between the members of the families. These results could be the starting point of larger studies that serve as a foundation of politics tending to reduce the frequency and severity of the disease in a local and national level...

Fibrose Cística , Alteração Ambiental , Hereditariedade