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1.
Adv Anat Pathol ; 23(4): 202-43, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27271843

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with considerable heterogeneity reflected in the 2008 World Health Organization classification. In recent years, genome-wide assessment of genetic and epigenetic alterations has shed light upon distinct molecular subsets linked to dysregulation of specific genes or pathways. Besides fostering our knowledge regarding the molecular complexity of DLBCL types, these studies have unraveled previously unappreciated genetic lesions, which may be exploited for prognostic and therapeutic purposes. Following the last World Health Organization classification, we have witnessed the emergence of new variants of specific DLBCL entities, such as CD30 DLBCL, human immunodeficiency virus-related and age-related variants of plasmablastic lymphoma, and EBV DLBCL arising in young patients. In this review, we will present an update on the clinical, pathologic, and molecular features of DLBCL incorporating recently gained information with respect to their pathobiology and prognosis. We will emphasize the distinctive features of newly described or emerging variants and highlight advances in our understanding of entities presenting a diagnostic challenge, such as T-cell/histiocyte-rich large B-cell lmphoma and unclassifiable large B-cell lymphomas. Furthermore, we will discuss recent advances in the genomic characterization of DLBCL, as they may relate to prognostication and tailored therapeutic intervention. The information presented in this review derives from English language publications appearing in PubMed throughout December 2015. For a complete outline of this paper, please visit: http://links.lww.com/PAP/A12.


Subject(s)
Lymphoma, Large B-Cell, Diffuse , Humans , Lymphoma, Large B-Cell, Diffuse/pathology
2.
Sci Rep ; 6: 21252, 2016 Feb 19.
Article in English | MEDLINE | ID: mdl-26893254

ABSTRACT

The potential role of AKT/mTOR signalling proteins and its association with the Raf-MEK-ERK pathway was investigated in hairy cell leukaemia (HCL). BRAFV600E expression and activated forms of AKT, mTOR, ERK1/2, p70S6k and 4E-BP1 were immunohistochemically assessed in 77 BM biopsies of HCL patients and correlated with clinicopathological and BM microvascular characteristics, as well as with c-Caspase-3 levels in hairy cells. Additionally, we tested rapamycin treatment response of BONNA-12 wild-type cells or transfected with BRAFV600E. Most HCL cases expressed p-p70S6K and p-4E-BP1 but not p-mTOR, being accompanied by p-ERK1/2 and p-AKT. AKT/mTOR activation was evident in BONNA-12 cells irrespective of the presence of BRAFV600E mutation and was implicated in cell proliferation enhancement. In multivariate analysis p-AKT/p-mTOR/p-4E-BP1 overexpression was an adverse prognostic factor for time to next treatment conferring earlier relapse. When p-AKT, p-mTOR and p-4E-BP1 were examined separately only p-4E-BP1 remained significant. Our findings indicate that in HCL, critical proteins up- and downstream of mTOR are activated. Moreover, the strong associations with Raf-MEK-ERK signalling imply a possible biologic interaction between these pathways. Most importantly, expression of p-4E-BP1 alone or combined with p-AKT and p-mTOR is of prognostic value in patients with HCL.


Subject(s)
Leukemia, Hairy Cell/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Biomarkers , Caspase 3/genetics , Caspase 3/metabolism , DNA Mutational Analysis , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression , Kaplan-Meier Estimate , Leukemia, Hairy Cell/genetics , Leukemia, Hairy Cell/mortality , Leukemia, Hairy Cell/pathology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Mutation , Patient Outcome Assessment , Proportional Hazards Models , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism
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