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Journal URL: http://carcin.oxfordjournals.org/

Journal URL: http://carcin.oxfordjournals.org/

Journal URL: http://cancerres.aacrjournals.org/

Waldenstrom’s macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the presence in patients’ serum of an I-M monoclonal component. We report on our experience with 60 WM patients, focusing on their clinical findings, response to treatment, and the possible identification of prognostic factors. Of these patients, 70% presented with fatigue, and lymphadenopathy was observed in 22%, splenomegaly in 18%, hepatomegaly in 13%, and extranodal site of involvement in 6%. Bleeding tendency was seen in 17%, infections in 17%, hyperviscosity syndrome in 12%, and cardiac failure in 25% of the patients. The median of IgM levels was 30 g/l with hypoalbuminemia in 20% of cases, hypogammaglobulinemia in 27%, polyclonal hypergammaglobulinemia in 15%, kappa light-chain restriction in 78%, and Bence-Jones proteinuria in 54%. Anemia was frequent (85%), followed by leukocytosis (18%), lymphocytosis (12%), leukopenia (10%), and thrombocytopenia (10%). Cryoglobulinemia and autoimmune hemolytic anemia were encountered in 5%. In all cases but two, bone marrow was involved. Of 50 patients initially treated with intermittent oral chlorambucil, 46 (92%) responded. Median overall survival was 108 months. Factors associated with adverse prognosis were age greater than or equal to65 years (p=0.06), presence of lymphadenopathy (p=0.06), bone marrow infiltration greater than or equal to50% (p=0.007), international prognostic index (IPI) greater than or equal to3 (p=0.0001), and Morel’s scoring system (p=0.04). Concluding, we found in this series of WM patients that chlorambucil is an effective treatment and that the parameters of age, lymphadenopathy, percentage of bone marrow infiltration, IPI, and Morel’s scoring system carry prognostic significance.

The clinical reaction and the immunological response to influenza virus vaccine were studied in 43 B-cell chronic lymphocytic leukaemia patients. The Vaxigrip vaccine was administered containing the antigens A/Ghizhou/54/89, A/Singapore/6/86, and B/Yamagata/16/88. The side-effects observed were minimal and well tolerated. Antibody production with titres > 1:20 on day 15 was observed at least for one antigen in 35 patients (81%). In 23 of them (63%) this response was retained on days 30 and 60. Patients with IgG levels (< 700 mg/dl) responded less well as compared to those having normal IgG levels (> 700 mg/dl).

The effect of recombinant interferon alfa-2b on platelet count, thrombocytosis-associated symptoms and marrow fibrosis was studied in 18 patients with myeloproliferative diseases and associated thrombocytosis (nine with essential thrombocythaemia, three with polycythaemia vera, three with myelofibrosis and three with chronic myelogenous leukaemia). A reduction of the platelet count below 600 x 10(9)/L was achieved in 94%, and below 400 x 10(9)/L in 77% of the patients within 8 to 330 days of treatment. The selective thrombocytosis-reducing effect of alpha interferon was maintained for long periods of time in most patients without serious side effects. Thrombocytosis-associated symptoms were relieved once the number of platelets was reduced to near normal levels. Marrow reticulin content was found to be reduced after treatment in two of the seven patients studied. Side effects of alpha interferon were flu-like symptoms, which usually subsided within 7 days of treatment.

Blood leukocyte DNA obtained from 11 Hodgkin’s disease patients undergoing ABVD chemotherapy was analysed for the presence of the precarcinogenic adduct O6-methyl-guanine (O6-meG) at various times (1-2 h up to 49 h) after i.v. treatment with the methylating drug dacarbazine. Adduct formation was detected in all but one of the patients examined at levels ranging up to 0.45 fmol/mu-g DNA (7.2 x 10(-7) mol/mol guanine). The levels of the adduct decreased by approximately 30% over the 24 h following exposure and were usually not detectable 49 h after exposure. In five out of seven individuals examined after more than one treatment, consistent methylation responses were noted, while in the remaining two cases the responses were mixed. No correlation between the extent of adduct formation and lymphocyte levels of the repair enzyme O6-alkylguanine - DNA alkyltransferase was observed. The average extent of O6-meG formation 1 h after dacarbazine treatment was (4.3 +/- 3.1) x 10(-2) fmol/mu-g DNA per mg/kg dose [(1.2 +/- 0.8) x 10(-3 fmol/mu-g DNA per mg/m2 dose)]. Following exposure of rats to similar doses of dacarbazine, the corresponding levels of adduct in blood leukocyte DNA were 1.1 x 10(-2) fmol/mu-g DNA per mg/kg dose (2.6 x 10(-3) fmol/mu-g DNA per mg/m2 dose).

Stimulation through the B-cell antigen receptor (BCR) is believed to be involved in the natural history of chronic lymphocytic leukemia (CLL). Some cases respond to the in vitro cross-linking of surface immunoglobulin (sIg) with effective activation. In contrast, the remaining cases do not respond to such stimulation, thereby resembling B cells anergized after antigen encounter in vivo. However the biochemical differences between the 2 groups are ill defined, and in humans the term B-cell anergy lacks a molecular definition. We examined the expression and activation of key molecules involved in signaling pathways originating from the BCR, and we report that a proportion of CLL patients (a) expresses constitutively phosphorylated extracellular signal-regulated kinase (ERK)1/2 in the absence of AKT activation; (b) displays constitutive phosphorylation of MEK1/2 and increased nuclear factor of activated T cells (NF-AT) transactivation; and (c) is characterized by cellular unresponsiveness to sIg ligation. This molecular profile recapitulates the signaling pattern of anergic murine B cells. Our data indicate that constitutive activation of mitogen activated protein (MAP) kinase signaling pathway along with NF-AT transactivation in the absence of AKT activation may also represent the molecular signature of anergic human B lymphocytes. CLL cases with this signature may be taken as a human model of anergic B cells aberrantly expanded.