Recombinant interferon alfa-2b (Intron A) as post-induction therapy for responding multiple myeloma patients. M84 protocol.
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Clinical Trials as Topic↗
Biomedical subjects
A Pileri
Publications and source records attributed to A Pileri.
Human myeloma: several subsets of circulating lymphocytes express plasma cell-associated antigens.
Peripheral blood lymphocytes from 9 monoclonal gammopathies of undetermined significance (MGUS) and 27 multiple myelomas (MM) were studied with a panel of monoclonal antibodies (MoAb) that recognize B and T lymphocytes and plasma cells. No difference in the percentage of B lymphocytes, identified by B1 and B4 MoAb, was observed in MGUS and MM patients versus normal controls. However, high percentages of circulating lymphocytes expressing plasma cell-associated antigens were detected in MM (HAN-PC1+ = 29.4 +/- 20.4%; TEC-T10+ = 27.8 +/- 19.2%) whereas they were in the normal range in MGUS (HAN-PC1+ = 8.8 +/- 5.8% p = 0.006; TEC-T10+ = 5.7 +/- 4.7% p less than 0.001). Almost identical results were obtained using PCA-1 MoAb in 17 of these patients. TEC-T10+ and PCA-1+ lymphocytes were sorted and re-analyzed with phycoerythrin conjugated MoAb in 3 healthy subjects, 2 MGUS, and 4 MM patients. In normal subjects and in MGUS the majority of PCA-1+ cells belonged to the B lineage (Leu 2-, Leu3-, Leu 15-, HLA-Dr+), whereas the majority of TEC-T10+ cells are represented by activated T cells and NK cells (Leu 15+). In MM an abnormal expansion of T lymphocytes was chiefly responsible for the high values of lymphocytes expressing plasma cell-associated antigens. Moreover, in MM a clinical evaluation showed a correlation between the presence of these lymphocytes and an aggressive disease. Indeed, they can be considered a useful prognostic marker.
Antibodies, Monoclonal↗
Biochemical and immunologic abnormalities in peripheral blood T lymphocytes of patients with hemophilia A.
Subset distribution, ecto-5'nucleotidase (5'NT) activity, and the generation of allospecific cytotoxic T lymphocytes (CTL) were investigated in peripheral blood T lymphocytes from 39 hemophilia A patients divided into three groups: group A and group B (HIV-patients with CD4:CD8 ratio less than 1 and greater than 1 respectively), and group C (HIV + patients). 5'NT activity was significantly decreased compared with healthy controls in groups B and C. In group B, this deficiency was attributable to expansion of CD8 + CD11 + suppressor cells. In group C, activated (HLA-DR+) CD8+ cells were also present and contributed to 5'NT deficiency. The suppressor cell expansion seemed to be mainly related to AHF infusions, whereas HLA-DR expression was related to HIV infection. CD11+ and HLA-DR+ cells were also expanded in the CD4+ subpopulation of all three groups, whereas CD4+ CD28+ lymphocytes were significantly decreased in group C only. Lastly, alloreactive cytotoxicity was decreased in group B and was normal in groups A and C.
Cytotoxicity, Immunologic↗
Emergence of activated lymphocytes in CD4 and CD8 subpopulations of multiple myeloma: correlation with the expansion of suppressor T-cells (CD8+ OKM1+) and ecto-5'nucleotidase deficiency.
This study of CD4 and CD8 lymphocyte subpopulations in MM revealed increased proportions of cells expressing OKM1, Leu7, and HLA-DR antigens. In CD8 lymphocytes, there was a direct correlation between OKM1 and HLA-DR positivity. Two-colour analysis of purified CD8 subpopulations showed that HLA-DR was preferentially expressed by OKM1+ lymphocytes (suppressor cells), but a significant proportion of OKM1-lymphocytes (cytotoxic precursor cells) were also HLA-DR+. A significant proliferative activity found in CD2 lymphocytes was directly correlated with the proportion of HLA-DR+ cells in CD8 subpopulations only. CD8 lymphocytes displayed significantly lower 5'NT activity than those of normal subjects. This enzyme deficiency was correlated with the expansion of CD8 OKM1+ and HLA-DR+ cells; the increase in suppressor cells, as well as the emergence of activated cells, are associated with CD8 5'NT deficiency. In conclusion, the immunological pattern of CD4 and CD8 subpopulations in MM is significantly different from that in normal subjects. The implications of these data for the immune dysregulation occurring in MM are discussed.
5'-Nucleotidase↗
Activated idiotype-reactive cells in suppressor/cytotoxic subpopulations of monoclonal gammopathies: correlation with diagnosis and disease status.
The phenotypic pattern of peripheral blood T (PBT) lymphocytes was correlated with diagnosis and clinical status in 63 patients with monoclonal gammopathies (MGs). The numbers of lymphocytes expressing activation and CD11 determinants were significantly increased in suppressor/cytotoxic and helper/inducer subpopulations of patients with multiple myeloma (MM) and MG of undetermined significance (MGUS). The number of activated suppressor/cytotoxic cells was closely correlated with diagnosis and disease status. These cells were significantly higher in MM at diagnosis (160 +/- 88) than MGUS patients (61 +/- 79; P less than .01). Their number decreased to MGUS levels in MM in stable remission (58 +/- 53), but not in MM with tumor progression (172 +/- 102; P less than .001). In individual patients, part of these cells specifically adhered to dishes precoated with the related M-protein. No monoclonal T-beta gene rearrangement was detected in PBT and cytotoxic/suppressor subpopulations from two patients with a large proportion of activated cells.
Blood Proteins↗
Defective generation of alloreactive cytotoxic T lymphocytes (CTL) in human monoclonal gammopathies.
The generation 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.
Antigens, Surface↗
Trophoblast cell line conditioned medium for in vitro culture and antigenic characterization of acute myeloid leukemia clonogenic cells.
The colony-stimulating factor-containing supernatant of the human trophoblast cell line TPA-30-1 was used to stimulate in vitro growth of acute myeloid leukemia clonogenic cells from 54 patients. Prevalent colony growth (10-greater than 1000) was observed in 63% of cases. In 31% clusters and a few colonies (1-9/1 x 10(5) plated cells) were scored. Neither colonies nor clusters could be detected in the remaining 6%. The best growth was observed in subtype M5 (8 of 9 cases, 89%). Morphological examination and recloning tests suggested that the colonies originated from leukemic progenitors. TPA-30-1 supernatant stimulation can therefore be compared with that of phytohemagglutinin or phytohemagglutinin-leukocyte-conditioned medium. In addition it does not require T-lymphocyte removal and batch screening. Extension of the culture for antigenic characterization of acute myeloid leukemia clonogenic cells to more patients than in a previous study confirmed the existence of a subgroup (39%) of patients whose acute myeloid leukemia clonogenic cells constantly expressed late myeloid differentiation antigens recognized by the monoclonal antibody S4-7. Since S4-7 spares early normal hemopoietic progenitors, this subgroup (54% M2) can be considered as candidates for autologous bone marrow transplantation after in vitro purging with S4-7 monoclonal antibody and complement.
Antigens, Neoplasm↗
Absence of (-) [3H]desmethoxyverapamil binding sites on human platelets and lack of evidence for voltage-dependent calcium channels.
The two major pathways for Ca2+ entry into cells are potential-sensitive channels and receptor-operated channels. The main object of this investigation was to identify which mechanism regulates Ca2+ entry into human platelets. Platelet stimulation with thrombin, adenosine diphosphate, platelet activating factor and arachidonic acid resulted in a concentration-dependent 2.5-3-fold increase in cytoplasmic free calcium concentration over the basal levels (140 +/- 32 nM or 104 +/- 21 respectively) as measured with the fluorescent dyes Quin-2 and Fura-2. Adrenaline and collagen had no effect in promoting intracellular Ca2+ increase as measured with Quin-2 and little effect when measured with Fura-2. Incubation of Quin-2-loaded platelets with the calcium antagonists verapamil and diltiazem, which are known to inhibit Ca2+ entry from voltage-gated channels in many types of cells, over the concentration range 10(-8) - 10(-4) M did not alter significantly either the resting or the cytoplasmic free Ca2+ after stimulation of platelets by several agonists. Moreover, the calcium antagonists exhibited little or no effect on aggregation and 5-hydroxytryptamine secretion induced by platelet activating factor, adenosine diphosphate, collagen or arachidonic acid in whole blood, platelet-rich plasma or washed platelets when employed at concentration ranges as above. Similar results were obtained in washed thrombin-stimulated platelets. High doses of verapamil (but not diltiazem) inhibited platelet aggregation and secretion in response to adrenaline. Direct radioligand binding studies with (-)[3H]desmethoxyverapamil showed that platelet membranes have no receptors for this drug, suggesting that Ca2+ entry occurs in human platelets via a pathway different from potential-sensitive Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Immunologic and virologic findings in hemophiliacs do not correlate with ecto-5'nucleotidase activity of peripheral blood lymphocytes. A difference with homosexual men.
It has been recently demonstrated that ecto-5'nucleotidase (5'NT) activity is significantly decreased in the peripheral blood lymphocytes (PBL) of homosexual men. This paper reports a study of PBL 5'NT activity in 38 hemophiliacs at risk for the acquired immunodeficiency syndrome (AIDS). The enzyme activity was correlated to the immunologic and virologic data. T-cell subset distribution was unbalanced and directly correlated with the cumulative amount of AHF infused. PBL 5'NT activity, however, was similar to that of healthy controls. 6 patients displayed serum antibodies to the human immunodeficiency virus (HIV) but no decrease in PBL 5'NT activity. In conclusion, these data indicate that both heavily treated and seropositive as well as untreated hemophiliacs have normal PBL 5'NT activity. This striking dissimilarity between homosexual men and hemophiliacs suggests that some immunologic alterations leading to 5'NT deficiency occur in the former only.
5'-Nucleotidase↗
Cytobiological studies in multiple myeloma.
Multiple myeloma (MM) is a heterogeneous disease in which the median survival time varies from a few months to more than 10 years. Clinical, kinetic, and immunological studies reflected such a heterogeneity. In clinical studies beta 2-microglobulin (beta 2-M), which is a well-known prognostic factor, was evaluated as an expression of tumor burden: a linear increase has been observed from stage I to stage III. No clear cutoff was detected between monoclonal gammopathy of undetermined significance (MGUS) and stage I MM. Kinetic studies have been performed by 3[H]thymidine or 5-bromo-2-deoxyuridine incorporation in bone marrow plasma cells. An analysis has been carried out between beta 2-M and the labeling index (LI). No correlation has been observed between these 2 parameters which identify different subgroups of poor prognosis patients. MGUS always showed an LI less than 1% allowing a clear distinction from stage I MM. A reduced survival time has been observed in patients with an LI greater than 2%. A subgroup of MM patients characterized by an LI greater than 2% and a decrease of M component greater than 50% within 3 months (early responders) has been identified. These patients showed a median survival time of about 10 months. Immunological studies identified a sharp decrease of 5' nucleotidase (5'NT) enzymatic activity in peripheral blood lymphocytes. This enzymatic defect is the biochemical marker of the expansion of a T subpopulation expressing low levels of 5'NT. This subpopulation was characterized by monoclonal antibodies and is represented by activated suppressor cells (OKM1+, DR+). Such an unbalancement in the T cell subpopulation was evident in poor prognosis patients. Clinical, kinetic and immunological studies identified new prognostic parameters that will be useful in the future therapeutic strategy of MM.
5'-Nucleotidase↗
Multiple myeloma: ecto-5' nucleotidase deficiency of suppressor/cytotoxic (CD8) lymphocytes is a marker for the expansion of suppressor T cells.
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 fluorescein 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 (OKMI+, 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.
5'-Nucleotidase↗
Biochemical evidence for the presence of abnormal B lymphocytes in the peripheral blood of multiple myeloma patients.
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5'-Nucleotidase↗
Cell kinetics of multiple myeloma.
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Cell Cycle↗
Differential expression of ecto-5' nucleotidase activity by functionally and phenotypically distinct subpopulations of human Leu-2+/T8+ lymphocytes.
Subsets of Leu-2+/T8+ cytotoxic/suppressor T lymphocytes were isolated by using various methods of purification and were investigated for expression of ecto-5' nucleotidase (5'NT) enzyme activity by radiochemical, cytochemical, and ultrastructural techniques. By using both the radiochemical and the cytochemical methods. T4-OKM1- cells displayed higher 5'NT activity in comparison with the entire T4- subpopulation. Analyses of the subpopulations of T4- (and predominantly Leu-2+) cells defined by the Leu-15 or Lyt-1 (9.3) monoclonal antibodies demonstrated that T4-Leu-15- and T4-Lyt-1+ cells displayed high 5'NT activity, whereas virtually no activity was present in T4-Leu-15+ and T4-Lyt-1-cells. At the ultrastructural level, the 5'NT reaction product was detected on the plasma membrane of a proportion of nongranular Leu-2+/T8+ lymphocytes, but no activity was found on cells with a granular lymphocyte (GL) morphology. 5'NT activity was also analyzed in peripheral blood mononuclear cells from one patient with expanded numbers of GL and two patients with GL leukemia. The enzymatic activity was significantly lower in these patients than in normal controls. This study provides new cytochemical evidence demonstrating the heterogeneity of Leu-2+/T8+ cells, and indicates that the population with the suppressor phenotype and function (Leu-15+/Lyt-1-, GL morphology) displays low or absent 5'NT activity, whereas the population composed of cytotoxic cell precursors (Leu-15-/Lyt-1+, nongranular morphology) has high 5'NT activity. Implications of these data for the interpretation of low 5'NT activity described in several immunodeficiency states and lymphoproliferative disorders are discussed.
5'-Nucleotidase↗
Multiple myeloma plasma cell kinetics: rapid and reliable evaluation using 5-bromo-2-deoxyuridine (BrdUrd) DNA incorporation detected by an anti-BrdUrd monoclonal antibody.
In 19 patients with monoclonal gammopathy, plasma cell proliferative activity was evaluated using 5-bromo-2-deoxyuridine (BrdUrd) incorporation, as revealed by an anti-BrdUrd monoclonal antibody. A simultaneous standard labelled thymidine incorporation was carried out in all patients as reference test. The BrdUrd method was confirmed as a reliable test and is recommended for routine clinical application in monoclonal gammopathies.
Antibodies, Monoclonal↗
Antigenic phenotype of myelomonocytic progenitors (CFU-GM) in chronic myeloproliferative disorders.
The antigenic phenotype of myelomonocytic progenitors [colony-forming unit granulocyte-macrophage (CFU-GM)] from 33 patients with chronic myeloproliferative disorders was investigated using four cytotoxic monoclonal antibodies. Monoclonal antibodies S3-13, S8-6, and S16-144 which recognize normal hemopoietic progenitors of different lineages reacted with almost all CFU-GM. R1B-19 monoclonal antibody identified two subpopulations of myelomonocytic progenitors (type 1 and 2 CFU-GM), as reported previously in normal subjects. In 3 of 11 patients with chronic myelogenous leukemia, in 1 of 2 patients with chronic myelomonocytic leukemia, and in 2 of 4 patients with polycythemia vera, a higher proportion of the more immature CFU-GM (type 1) was detected in bone marrow cells. The more differentiated CFU-GM (type 2) is not detectable in normal peripheral blood. By contrast, in 14 of 15 chronic myelogenous leukemia patients, in 1 of 2 chronic myelomonocytic leukemia patients and in 3 of 8 patients with idiopathic myelofibrosis, it was present in high to very high proportions. It is clear from these findings that the antigens present on normal CFU-GM are expressed in chronic myeloproliferative disorders. The proportion and distribution of type 1 and 2 CFU-GM, on the other hand, are very different from those observed in the normal subjects.
Adult↗
Cytokinetic studies in human myeloma.
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Autoradiography↗
Treatment of multiple myeloma: a randomized study of three different regimens.
The results of an Italian multicentric trial for treatment of symptomatic Multiple Myeloma (MM) are reported. One hundred and thirty-three previously untreated patients were singled out at random for three different chemotherapy schedules: Melphalan plus Prednisone (M.P.) X 6 monthly cycles; Vincristine plus Melphalan plus Cyclophosphamide plus Prednisone (VMCP) X 6 monthly cycles; Peptichemio, Cyclophosphamide, BCNU. Drugs in this latter schedule were administered sequentially, for a period of six months. Criteria for response, progression and relapse were those of the Southwestern Oncology Group. Fifteen patients in MP chemotherapy (35%) and 20 patients in VCMP chemotherapy (46%) achieved an objective response (decrease of at least 50% in the synthesis index of Monoclonal Component (M.C.], while only 3 out of the other 21 patients assigned to the third schedule responded to treatment. No significant differences were noted in the survival curves in either of the three treatment groups. The 38 responding patients did not receive maintenance therapy; no significant difference was found in remission duration between patients in MP and VCMP arms, with a median duration of 16 months for the whole group. No statistical difference was observed between survival and remission curves of patients with a 'response' (M. spike reduction greater than 75%) and those with 'improvement' (M. spike reduction between 75 and 50%). The authors conclude that the inclusion of Vintristine in a combination chemotherapy does not produce clear survival benefits; a longer induction period (12 cycles) could allow a better differentiation between MP and VMCP regimens.
Antineoplastic Combined Chemotherapy Protocols↗