Infiltrative Rash Secondary to Leukemic-Phase Diffuse Large B-Cell Lymphoma With t(14;18), CDKN2A and MLL Deletion.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous and highly aggressive subtype of non-Hodgkin's lymphoma. It commonly presents as rapidly-growing, painless lymphadenopathy (LAD). DLBCL presenting in leukemic-phase is rare, with fewer than 40 cases published. Chemotherapy remains the standard approach, although selecting the correct regimen has become more perplexing in patients with CDKN2A mutations. Patients with MLL- and CDKN2A-positive DLBCL may benefit from therapy with a dose-adjusted regimen of rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) compared to traditional rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). Herein, we report a case of leukemic-phase DLBCL presenting as a cutaneous eruption of the bilateral lower extremities, which has not been previously reported in the literature.

Isotype-specific inhibition of the phosphatidylinositol-3-kinase pathway in hematologic malignancies.

In the last decade, the advent of biological targeted therapies has revolutionized the management of several types of cancer, especially in the realm of hematologic malignancies. One of these pathways, and the center of this review, is the phosphatidylinositol-3-kinase (PI3K) pathway. The PI3K pathway seems to play an important role in the pathogenesis and survival advantage in hematologic malignancies, such as leukemia, lymphoma, and myeloma. The objectives of the present review, hence, are to describe the current knowledge on the PI3K pathway and its isoforms, and to summarize preclinical and clinical studies using PI3K inhibitors, focusing on the advances made in hematologic malignancies.

Viral lymphomagenesis: from pathophysiology to the rationale for novel therapies.

The association between viruses and lymphomas has long been recognized; however, the pathophysiological phenomena behind this relationship are unclear, and have been the object of intense research. Although our understanding of such mechanisms is slowly improving, much is still left to learn. With the recent advances in cancer biology, a diversity of biological pathways and novel targets and agents have been described in patients with haematological malignancies and successfully put into clinical practice. Clear examples are rituximab and brentuximab vedotin in patients with B cell lymphomas and Hodgkin lymphoma respectively. The main purpose of this review is not only to succinctly summarize what we know regarding the pathogenesis and pathophysiology of virally induced lymphomas and to describe the current practices in terms of diagnosis of treatment of such lymphomas, but also to provide a scientific rationale for the use of novel therapies that are likely to improve the outcomes of patients with these conditions.

Epidemiology and survival outcomes of ocular and mucosal melanomas: a population-based analysis.

Extracutaneous melanomas are poorly characterized tumors that include ocular (OM), mucosal (MM) and leptomeningeal melanomas, often lacking standardized staging and treatment guidelines. We analyzed cases of cutaneous melanoma (CM, N = 219,890), OM (N = 7,069) and MM (N = 2,755) of different anatomical origins, diagnosed between 1988 and 2010, recorded in the Surveillance Epidemiology and End Results (SEER) database. Relative survival was studied in patients grouped by summary stage classification (localized, regional or distant disease) and in multivariate models adjusting for varying distribution of baseline factors. Unlike in CM, the incidence rate in MM increased exponentially with age. Five-year relative survival was significantly worse for OM (78%) and for most mucosal sites (aggregate 34%, range 3-69%) compared with CM (89%). The differences between primary sites were particularly pronounced in localized disease, with a hazard ratio of 5.7 for OM, 4.3-9.0 for external genital or oral cavity MM and 19.8-90.4 for other mucosal locations. Melanomas of the pharynx, gastrointestinal, urinary tract and vagina had poor outcomes regardless of clinical stage. In contrast to CM, there was no evidence of improved survival in OM and MM during the study period. A substantial proportion of patients with operable OM or MM underwent radical organ resections (13-88% depending on site and stage) or perioperative radiotherapy (0-66%). In conclusion, extracutaneous melanomas have a markedly worse survival than CM and aggressive locoregional management appears to be insufficient for their control. Because of poor outcomes in MM, studies of systemic therapy are warranted regardless of the extent of disease at presentation.

Depletion of the programmed death-1 receptor completely reverses established clonal anergy in CD4(+) T lymphocytes via an interleukin-2-dependent mechanism.

Recent studies have implicated the cell surface receptor Programmed Death-1 (PD-1) in numerous models of T cell anergy, though the specific mechanisms by which the PD-1 signal maintains tolerance is not clear. We demonstrate that the depletion of PD-1 with siRNA results in a complete reversal of clonal anergy in the A.E7 T cell model, suggesting that the mechanism by which PD-1 maintains the anergic phenotype is a T-cell-intrinsic phenomenon, and not one dependent on other cell populations in vivo. We have also shown that the neutralization of IL-2 during restimulation abrogates the effect of PD-1 depletion, suggesting that tolerance mediated by PD-1 is wholly IL-2 dependent, and likewise intrinsic to the tolerized cells.

A regulatory CD4+ T cell subset in the BB rat model of autoimmune diabetes expresses neither CD25 nor Foxp3.

Biobreeding (BB) rats model type 1 autoimmune diabetes (T1D). BB diabetes-prone (BBDP) rats develop T1D spontaneously. BB diabetes-resistant (BBDR) rats develop T1D after immunological perturbations that include regulatory T cell (Treg) depletion plus administration of low doses of a TLR ligand, polyinosinic-polycytidylic acid. Using both models, we analyzed CD4+CD25+ and CD4+CD45RC- candidate rat Treg populations. In BBDR and control Wistar Furth rats, CD25+ T cells comprised 5-8% of CD4+ T cells. In vitro, rat CD4+CD25+ T cells were hyporesponsive and suppressed T cell proliferation in the absence of TGF-beta and IL-10, suggesting that they are natural Tregs. In contrast, CD4+CD45RC(-) T cells proliferated in vitro in response to mitogen and were not suppressive. Adoptive transfer of purified CD4+CD25+ BBDR T cells to prediabetic BBDP rats prevented diabetes in 80% of recipients. Surprisingly, CD4+CD45RC-CD25- T cells were equally protective. Quantitative studies in an adoptive cotransfer model confirmed the protective capability of both cell populations, but the latter was less potent on a per cell basis. The disease-suppressing CD4+CD45RC-CD25- population expressed PD-1 but not Foxp3, which was confined to CD4+CD25+ cells. We conclude that CD4+CD25+ cells in the BBDR rat act in vitro and in vivo as natural Tregs. In addition, another population that is CD4+CD45RC-CD25- also participates in the regulation of autoimmune diabetes.

Early growth response gene-2, a zinc-finger transcription factor, is required for full induction of clonal anergy in CD4+ T cells.

Ag-specific immune tolerance results from the induction of cellular mechanisms that limit T cell responses to selective Ags. One of these mechanisms is characterized by attenuated proliferation and decreased IL-2 production in fully stimulated CD4(+) Th cells and is denoted T cell anergy. We report the identification of the early growth response gene (Egr-2; Krox-20), a zinc-finger transcription factor, as a key protein required for induction of anergy in cultured T cells. Gene array screening revealed high Egr-2 expression distinctly persists in anergized but not proliferating murine A.E7 T cells. In contrast, Egr-1, a related family member induced upon costimulation, displays little or no expression in the anergic state. IL-2-mediated abrogation of anergy causes rapid depletion of Egr-2 protein. Full stimulation of anergic A.E7 T cells fails to enhance IL-2 and Egr-1 expression, whereas Egr-2 expression is greatly increased. Silencing Egr-2 gene expression by small interfering RNA treatment of cultured A.E7 T cells before incubation with anti-CD3 alone prevents full induction of anergy. However, small interfering RNA-mediated depletion of Egr-2 5 days after anergy induction does not appear to abrogate hyporesponsiveness to stimulation. These data indicate that sustained Egr-2 expression is necessary to induce a full anergic state through the actions of genes regulated by this transcription factor.