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Tumor cells in chronic lymphocytic leukemia (CLL) are more prone to apoptosis when cultured ex vivo, because they lack prosurvival signals furnished in vivo via B-cell receptor (BCR)-dependent and -independent pathways. This study compared the susceptibility of unmutated (UM) and mutated (M) CLL B cells to spontaneous apoptosis and prosurvival signals. UM CLL B cells showed a significantly higher rate of spontaneous apoptosis than M CLL B cells. Nuclear factor-kB (NF-kB) was rapidly inactivated, and B-cell leukemia/lymphoma 2 (Bcl-2) expression progressively down-regulated in the UM CLL B cells. CD40-Ligand, interleukin-4 and stromal cells significantly improved their viability and partially recovered Bcl-2, but not NF-kB expression. Peripheral blood mononuclear cells also offered protection of UM CLL B cells, and recovered both NF-kB and Bcl-2 expression. T cells, rather than nurse-like cells, were responsible for protecting UM CLL B cells by means of cell-to-cell contact and soluble factors. Despite their more aggressive features, UM CLL B cells are more susceptible to spontaneous apoptosis and depend from environmental prosurvival signals. This vulnerability of UM CLL B cells can be exploited as a selective target of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Telomere length (TL) has been associated with outcome in chronic lymphocytic leukemia (CLL). The aim of this extensive analysis carried out on 401 CLL patients was to assess TL conclusively as a prognostic biomarker. Our study included two cohorts used as learning (191 patients) and blinded validation series (210 patients). A TL cutoff of 5000 bp was chosen by receiver operating characteristic (ROC) analysis and Youden's index in the learning series. In this series, TL5000 bp was independently associated to a worse outcome for both overall survival (OS; 105.5 vs 281 months, P<0.001) and treatment-free survival (TFS; 24.6 vs 73 months, P<0.001). In the blinded validation series, TL5000 bp was confirmed as an independent outcome predictor for OS (79.8 vs not reached, P<0.001) and TFS (15.2 vs 130.8 months, P<0.001). Moreover, TL5000 bp independently predicted the risk of Richter's syndrome (5-year risk: 18.9 vs 6.4%, P=0.016). Within CLL subsets defined by biological predictors, TL consistently identified patient subgroups harboring unfavorable prognosis. These results demonstrate that TL is a powerful independent predictor of multiple outcomes in CLL, and contributes to refine the prognostic assessment of this disease when utilized in combination with other prognostic markers. We thus believe that this prognostic biomarker has the potential for a more widespread use in CLL.Leukemia (2009) 23, 1062–1072; doi:10.1038/leu.2008.399; published online 2 April 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVES AND METHODS: We investigated the association of serum dehydroepiandrosterone sulfate (DHEA-S) levels with dementia of Alzheimer's type (DAT) and impairment in selected cognitive domains (memory, language, attention and working memory) in 158 patients (75.5 +/- 6.7 years, 46 men) with first-diagnosed probable DAT and in 158 age- and sex-matched controls. As secondary goal, we evaluated whether DHEA-S baseline levels were associated with cumulative 6-year mortality. RESULTS: A negative correlation between DHEA-S levels and age was observed (R = -0.25, p < 0.001). Age-stratified analysis did not show significant differences of DHEA-S levels between DAT patients and controls. No significant association was found between DHEA-S levels and impairment in selected cognitive domains. Cox regression analysis showed that baseline DHEA-S levels were not associated with cumulative 6-year mortality. CONCLUSIONS: In a sample of newly-diagnosed DAT patients, we did not find significant association between presence of DAT or impairment in cognitive domains and DHEA-S levels; baseline DHEA-S levels are not associated with cumulative mortality in patients and controls. Copyright (c) 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the in vitro immunomodulatory effects of zoledronic acid (Zol) on peripheral blood V?9/Vd2 (?d) T cells of normal donors and multiple myeloma (MM) patients.?dT cells were stimulated with Zol and low doses of interleukin-2 (IL-2), and then analyzed for proliferation, cytokine production, and generation of effector activity against myeloma cell lines and primary myeloma cells. Proliferation of?dT cells was observed in 100%of normal donors and 50%of MM patients.?dT cells produced IFN-?, surface mobilized the CD107a and CD107b antigens, and exerted direct cell-to-cell antimyeloma activity irrespective of the ability to proliferate to Zol and IL-2. The memory phenotype was predominant in the MM?dT cells that proliferated in response to Zol (responders), whereas effector cells were predominant in those that did not (nonresponders). Zol induced antimyeloma activity through the monocyte-dependent activation of?dT cells and by enhancing the immunosensitivity of myeloma cells to?dT cells. Mevastatin, a specific inhibitor of hydroxy-methylglutaryl-CoA reductase, completely abrogated this antimyeloma activity.Leukemia (2005) 19, 664-670. doi:10.1038/sj.leu.2403693 Published online 3 March 2005 [ABSTRACT FROM AUTHOR]

Several trials have shown the superior impact of high-dose melphalan (usually 200?mg/m2, MEL200) vs standard therapy in myeloma patients. Intermediate-dose melphalan (100?mg/m2, MEL100) is also superior to the standard dose, but has not been clinically compared with MEL200. A total of 90 patients at diagnosis were treated with two MEL100 courses. Their clinical outcome was compared with that of a control group of 90 pair mates matched for serum ß2-microglobulin levels and Durie and Salmon clinical stage. These patients were treated at diagnosis with two MEL200 courses. Patient characteristics were similar in both groups except that the median age of the MEL100 group was significantly higher (P<0.0001). Complete remission was 35% after MEL100 and 48% after MEL200 (P=0.08). Median event-free survival (EFS) was 32 months in the MEL100 group and 42 months in the MEL200 group (P<0.005), but overall survival (OS) was not different. Transplant-related mortality was not significantly different. Haematological and extra-haematological toxicity was significantly reduced after MEL100. Despite the significant age difference, tandem MEL100 was less toxic than tandem MEL200, and MEL100 was inferior to MEL200 in terms of EFS but not in terms of OS. The intensified nonmyeloablative MEL100 regimen is an effective first-line treatment.Leukemia (2004) 18, 133-138. doi:10.1038/sj.leu.2403196 Published online 30 October 2003 [ABSTRACT FROM AUTHOR]

The aim of this work was to evaluate the long-term immunological and clinical impact of idiotype (Id) vaccination in multiple myeloma (MM) patients in first remission after high-dose chemotherapy. A total of 15 patients received a series of subcutaneous (s.c.) injections of autologous Id, conjugated to keyhole limpet hemocyanin (KLH) and in association with low doses of GM-CSF. The median duration of follow-up was 110 months from diagnosis. The vaccine induced immune responses that lasted almost 2 years after the end of treatment. Antibody responses included anti-KLH IgM and IgG (90% of patients), anti-KLH IgE (30%), anti-GM-CSF IgG (20%), anti-Id IgG (20%), and anti-Id IgE (30%). Id-specific delayed type hypersensitivity skin tests were positive in 85% of tested patients. Following vaccination, a progressive recovery of T-cell receptor (TCR) diversity was observed and the loss of oligoclonality was significantly correlated with the remission duration. Although Id/KLH conjugates did not eliminate the residual tumor burden, the median progression-free survival, and overall survival were 40 and 82 months, respectively. A retrospective case-matched analysis showed similar results in patients treated with IFN-a alone or in association with steroids. This vaccine formulation can overcome Id-specific immune tolerance by inducing clinical responses that are worthy of further investigation.Leukemia (2004) 18, 139-145. doi:10.1038/sj.leu.2403181 Published online 23 October 2003 [ABSTRACT FROM AUTHOR]

The recombinant interleukin-2 (rIL-2) generation of lymphokine-activated killer (LAK) cells was investigated in peripheral blood T lymphocytes (PBT) of 16 patients with monoclonal gammopathy of undetermined significance (MGUS) and 32 patients with multiple myeloma (MM). LAK activity was significantly decreased in MM, but not in MGUS patients. and was partially recovered in MM in the remission phase. This finding was unexpected, because CD8+ CD11b+ cells. which contain LAK precursors, are significantly increased in MM. LAK activity was investigated in purified CD8+ CD11 b+ lymphocytes to discriminate between an intrinsic defect or a defective regulation by other T cell subsets. These cells were intrinsically unable to generate LAK activity fully following rIL-2 stimulation. MM showed the more pronounced LAK deficiency, while MGUS patients showed intermediate values. Phenotyping revealed significantly increased proportions of Leu7+ and HLA-DR+ cells in MM patients. These data reveal another dysregulation of T cell effector functions in patients with monoclonal gammopathies and offer further evidence of the impairment of their cell-mediated immunity. [ABSTRACT FROM AUTHOR]

The generaton of cytotoxic T lymphocytes (CTL) towards allogeneic cells was investigated in 19 patients with monoclonal gammopathy of undetermined significance (MGUS) and 31 patients with multiple myeloma (MM). This function was significantly decreased in all patients. The cytotoxic deficiency was more pronounced in MM with poor prognosis than MM with good prognosis and MGUS patients. A phenotypic analysis of PBT lymphocytes showed that poor prognosis MM also had the highest proportions of activated cells (HLA-DR+) in CD8+ subpopulations. CTL were generated after depletion of CD11+ lymphocytes (including suppressor cells) or after inhibition of suppressor function with deoxyguanosine. No increase of cytotoxicity was detected under these conditions. Exogenous supplementation of recombinant interleukin 2 (rIL-2) was also ineffective. These data indicate that MG PBT lymphocytes are unable to fully differentiate into CTL following allogeneic stimulation. This deficiency is most evident in MM patients already showing the poorest prognosis and the most altered T cell phenotype. [ABSTRACT FROM AUTHOR]

In this study, 5'NT activity was investigated by radiochemical and cytochemical assays in T cell subpopulations of patients with multiple myeloma (MM). Cytotoxic/suppressor (CD8) and helper/inducer (CD4) lymphocytes were separated from peripheral blood by the panning technique, or sorted with a fluorescin activated cell sorter. 5'NT activity was significantly decreased in MM CD8 lymphocytes compared with the controls. By contrast, it was comparably low in CD4 subpopulations of normal controls and MM patients. The cytochemical assay indicated that a decreased number of 5'NT cells rather than a decreased activity per cell was responsible for 5'NT deficiency in MM CD8 lymphocytes. CD8 lymphocytes with the suppressor phenotype (OKM1+, granular cells) were significantly increased in MM. These data provide a phenotypic explanation for the enhanced suppressor activity displayed by T lymphocytes in MM. A significant correlation was found between the increase of suppressor cells and the decrease of 5'NT' cells. 5'NT deficiency of CD8 lymphocytes can be a biochemical marker for the expansion of suppressor T cells. [ABSTRACT FROM AUTHOR]

Four monoclonal IgGk gammopathies were studied with anti-idiotypic sera and the percentage of lymphocytes bearing such idiotypes was evaluated with a fluorescence activated cell sorter (FACS). A large percentage (10-15%) of peripheral lymphocytes bearing receptors with the same idiotypic specificities as the M component was observed in multiple myeloma (MM) und in monoclonal gammopalhy of undetermined significance (MGUS), suggesting a malignant origin for both these diseases, Capping-endocytosis and resynthesis experiments showed that these idiotypic receptors were not simply adsorbed on the cell membrane, but actually synthesized by the cells bearing them. Experiments performed after effective conventional chemotherapy showed a strong reduction of the idiotypic compartment in only one MM patient. [ABSTRACT FROM AUTHOR]

Ecto-5'nucleotidase (5'NT), adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and deoxycytidine (CdR), deoxyguanosine (GdR), deoxyadenosine (AdR) and adenosine (AR) kinases have been measured in subpopulations of peripheral blood lymphocytes of eight healthy volunteers. The separation of B, T, T helper/inducer and T suppressor/cytotoxic cells was performed by means of density gradient centrifugation, E rosetting, passage through a nylon-wool column and antibody affinity chromatography utilising OKT8 and OKT4 monoclonal antibodies. ADA was significantly higher in T lymphocytes and 5'NT in B lymphocytes. Among T cell subpopulations, 5'NT activity was significantly higher (P < 0.01) in T suppressor/cytotoxic (OKT8+) cells (32.9 units/106 cells than in T helper/inducer (OKT4+) cells (9.7 units/106 cells). Indeed, the 5'NT activity in T suppressor cells was similar to that in B cells. T helper cells tended, however, to have higher PNP and ADA activities than T suppressor cells but the differences were not statistically significant. No major differences were noted in kinase activities between any of the lymphocyte subpopulations. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article about the expression of immunoregulatory enzyme indoleamine 2, 3-dioxygenase by acute myeloid leukemia cells.

Multiple myeloma (MM) derives from malignant transformation of plasma cells (PC), which accumulate in the bone marrow (BM), where microenvironment supports tumor growth and inhibits anti-tumor immune responses. Adenosine (ADO), an immunosuppressive molecule, is produced within MM patients' BM by adenosinergic ectoenzymes, starting from ATP (CD39/CD73) or NAD+ [CD38/CD203a(PC-1)/CD73]. These ectoenzymes form a discontinuous network expressed by different BM cells. We investigated the expression and function of ectoenzymes on microvesicles (MVs) isolated from BM plasma samples of patients with MM, using asymptomatic forms of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) as controls. The percentage of MVs expressing ectoenzymes at high levels was higher when derived from MM patients than controls. BM CD138+ PC from MM patients expressed high levels of all ectoenzymes. Paired MVs samples confirmed a higher percentage of MVs with high ectoenzymes expression in MM patients than controls. Pooled MVs from MM patients or controls were tested for ADO production. The catabolism of ATP, NAD+, ADPR and AMP to ADO was higher in MVs from MM patients than in those from controls. In conclusion, our results confirmed the hypothesis that MVs in MM niche are main contributor of ADO production. The ability of MVs to reach biological fluids strongly support the view that MVs may assume diagnostic and pathogenetic roles. [ABSTRACT FROM AUTHOR]