Publications (299) View all
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Article: The microenvironment of AIDS-related diffuse large-B-cell lymphoma provides insight into the pathophysiology and indicates possible therapeutic strategies.
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ABSTRACT: Despite the use of highly active antiretroviral therapy (HAART), AIDS-related lymphoma remains common. We investigated the tumor, microenvironment, and viral components in 41 AIDS-related diffuse large-B-cell lymphoma (AR-DLBCL) in the pre and post-HAART era. The outcome has improved and the frequency of the prognostically unfavorable immunoblastic histology has decreased after HAART. Compared with sporadic cases, AR-DLBCL demonstrated increased hyperproliferation (P<0.001) and c-Myc rearrangements, reduced CD4(+) (P<0.001) and FOXP3(+) T-cells (P<0.001), increased activated cytotoxic T-cells (P<0.001), but no significant difference in tumor-associated macrophages. HIV-infected patients with few tumor-associated macrophages had very poor outcome. Our analysis showed that AR-DLBCL is highly angiogenic with higher blood-vessel density than sporadic cases (P<0.001) and highlighted the role of EBV in angiogenesis. We recognized viral profiles in biopsies and as a second step examined the reactive cytotoxic-cell infiltrates. Our observation of markedly higher numbers of cytotoxic cells in AR-DLBCL with LMP1 and/or p24 compared to cases lacking viral antigens (P<0.001) has important clinical implications, implicitly linked to the immunosurveillance theory. Whereas early initiation of HAART should improve immunosurveillance and reduce the incidence of LMP1-positive AR-DLBCL, cases without viral antigens appear able to avoid immunologic reaction and likely require additional strategies to improve surveillance.Blood 05/2013; · 9.90 Impact Factor -
Article: Understanding the immunodeficiency in chronic lymphocytic leukemia: potential clinical implications.
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ABSTRACT: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Although significant advances have been made in the treatment of CLL in the last decade, it remains incurable. Treatments may be too toxic for some elderly patients, who constitute most of the individuals with this disease, and there remain subgroups of patients for which this therapy has minimal activity. This article summarizes the current understanding of the immune defects in CLL. It also examines the potential clinical implications of these findings.Hematology/oncology clinics of North America 04/2013; 27(2):207-35. · 2.05 Impact Factor -
Article: Another look at follicular lymphoma: immunophenotypic and molecular analyses identify distinct follicular lymphoma subgroups.
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ABSTRACT: AIMS: The aim of this study was to analyse the immunophenotypic and molecular features of a large series of follicular lymphomas, focusing in particular on atypical cases that fail to express CD10 and/or bcl-2. Such cases present diagnostic pitfalls, especially with regard to the differential diagnosis from follicular hyperplasia and marginal zone B-cell lymphoma. Therefore, we also included an immunohistochemical evaluation of stathmin, which is strongly expressed by germinal centre B cells, as a putative new marker for follicular lymphomas, particularly those with an atypical phenotype. METHODS AND RESULTS: Two hundred and five follicular lymphomas were investigated with immunohistochemistry and fluorescence in-situ hybridization (FISH). The use of three distinct anti-bcl-2 antibodies together with CD10 expression data and FISH analysis for bcl-2 and bcl-6 rearrangements allowed subclassification of follicular lymphoma into four distinct subgroups: (i) CD10-positive/bcl-2-positive, (ii) CD10-positive/bcl-2-negative, (iii) CD10-negative/bcl-2-positive, and (iv) CD10-negative/bcl-2-negative. All cases were bcl-6-positive. STMN1 (stathmin) was shown to be helpful in diagnosing bcl-2-negative and/or CD10-negative follicular lymphomas, and in their distinction from marginal zone B-cell lymphoma. CONCLUSIONS: Combined immunohistological and molecular analyses reveal that follicular lymphomas showing an atypical immunophenotypic and molecular profile exist, and we demonstrate that STMN1 represents a novel useful diagnostic marker for these.Histopathology 03/2013; · 3.08 Impact Factor -
Article: Chronic lymphocytic leukemia cells induce defective LFA-1-directed T cell motility by altering Rho GTPase signaling that is reversible with lenalidomide.
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ABSTRACT: T lymphocytes have an essential role in adaptive immunity and rely on the activation of integrin lymphocyte function-associated antigen-1 (LFA-1) to mediate cell arrest and migration. In cancer, malignant cells modify the immune microenvironment to block effective host anti-tumor responses. Here we show for the first time that CD4 and CD8 T cells from patients with chronic lymphocytic leukemia (CLL) exhibit globally impaired LFA-1-mediated migration and that this defect is mediated by direct tumor cell contact. We show that following coculture of previously healthy T cells with CLL cells, subsequent LFA-1 engagement leads to altered Rho GTPase activation signaling by down-regulating RhoA and Rac1, while up-regulating Cdc42. Of clinical relevance, repair of this T cell defect was demonstrated using the immunomodulatory drug lenalidomide that completely rescued adhesion and motility function by restoring normal Rho GTPase activation signaling. Our report identifies a novel cancer immune evasion mechanism whereby tumor cells induce Rho GTPase signaling defects in T cells that prevent appropriate LFA-1 activation and motility. We believe these findings identify important biomarkers and highlight the clinical utility of immunotherapy to rescue normal T cell function in CLL that are likely to have relevance in other cancers.Blood 01/2013; · 9.90 Impact Factor -
Article: A shot in the arm for radiotherapy.
Blood 01/2013; 121(2):246-8. · 9.90 Impact Factor
