[Inhibition of NF-kB Activation Decreases Resistance in Acute Myeloid Leukemia Cells to TRAIL-induced Apoptosis in Multicellular Aggregates].

Suppression of resistance in acute myeloid leukemia cells to TRAIL-induced apoptosis in multicellular aggregates, was studied using small molecule inhibitors of the activation of the transcription factor NF-kB - NF-k9 Activation Inhibitor IV and JSH-23 at non-toxic concentrations. NF-kB Activation Inhibitor IV and JSH-23 reduced resistance in the acute myeloid leukemia cells in multicellular aggregates to cytotoxic action of recombinant protein izTRAIL. It is shown that the use of these inhibitors decreased the phosphorylation of the RelA (p65) as a main marker activation of the transcription factor NF-kB. We discuss a possible reason for increasing resistance in acute myeloid leukemia cells to TRAIL-induced apoptosis in multicellular aggregates.

[Gene expression of vascular endothelial growth factors and their receptors in different variants of the course of multiple myeloma].

AIM: To determine the significance of the angiogenic activity estimated from the gene expression of the vascular endothelial growth factors (VEGFs) VEGF-A, VEGF-C, and VEGF-D and their receptors VEGFR1, VEGFRls, VEGFR2, and VEGFR3 in the mononuclear cell fraction of bone marrow (BM) aspirates with tumor plasma cells predominating in different variants of the course of multiple myeloma (MM). MATERIALS AND METHODS: The gene expression of VEGF-A, VEGF-C, and VEGF-D and their receptors VEGFRI, VEGFRls, VEGFR2, and VEGFR3 was determined by reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: VEGF-A, VEGF-C, VEGF-D, as well as VEGFR1, VEGFRls, VEGFR2, and VEGFR3 were expressed showing different intensities in the mononuclear cell fraction of BM aspirates with a predominance of tumor plasma cells in the patients with MM, which allowed patient groups to be identified. In the group of high gene expression of VEGFs and their receptors, the number of clusters of plasma cells and vascular endothelium in the BM aspirates and the degree of osteolysis in the skeletal bones of patients with MM were significantly higher than those in the group of low or absent gene expression. The survival in the latter group was significantly higher. CONCLUSION: The investigation could provide an estimate of angiogenic processes in MM and establish their association with clinical manifestations and cytological characteristics.

[Effectiveness of bortezomib and bortezomib-containing programs for the treatment of recurrent and resistant multiple myeloma].

AIM: To evaluate the effectiveness of bortezomib and bortezomib-containing treatment programs in the therapy of resistant and recurrent multiple myeloma (MM) within a large unicenter study in real clinical practice conditions. SUBJECTS AND METHODS: The study enrolled 101 patients (48 men and 53 women aged 34 to 77 years, mean age 54 years) with resistant and recurrent MM. According to the types of paraprotein (PIg), the authors revealed the usual distribution: G, 60.7%; A, 23.8%; BJ, 13%; M, 1.15%; D, 1.15%. The PIg kappa/lambda light chain ratio was 1.7. The complicated course of the disease was noted in 50.4% of the patients. The patients were randomized into 4 treatment groups: V1--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 of a 21-day cycle; V2--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, melphalan 20 mg orally on day 2 of a 28-day cycle; V3--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, melphalan 9 mg/m2 orally for 4 days, prednisolone 60 mg/m2 orally for 4 days of a 42-day cycle; V4--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, melphalan 9 mg/m2 orally for 4 days, prednisolone 60 mg/m2 orally for 4 days, cyclophosphanum, 250 mg/m2 intravenously dropwise on days 1 to 7 of a 60-day cycle. An average of 6.5 induction treatment cycles was performed. RESULTS: Amongst the 27 patients receiving bortezomib therapy (V1), an objective response to therapy was obtained in 70.3%, including a complete response (CR) in 18.5%, a near-complete response (NCR) in 14.8%, and a partial response (PR) in 37%. When a combination of melphalan and bortezomib (VM; V2) was used, 22 patients achieved CR, NCR, and PR, which were equal to 9, 13, and 45.4%, respectively. In the group of 20 patients on the triple combination (VMP; V3), the amount of CR and PR was 90%. The use of the quadruple combination regimen (V4; VMCP) yielded an objective response (CR + NCR + PR) in 63.2% of the 32 patients, which did not virtually differ from other programs other than V3. However, the amount of CR +NCR (43.6%) was more than that in other groups. When all these programs were implemented, clinically significant myelotoxicity and grades 3 and 4 polyneuropathy were not seen. When the bortezomib-containing programs were applied, the median overall survival from the moment of diagnosis was 103 months. CONCLUSION: Bortezomib in the monotherapy and multidrug therapy for resistant and recurrent MM shows immediate and long-term benefits and a low toxicity.

[Pharmacodynamic characteristics of velcade efficacy in resistant and recurrent multiple myeloma: determination of free light chains of blood serum immunoglobulins].

AIM: To ascertain individual sensitivity to velkeid in patients with resistant and recurrent multiple myeloma (MM) by determination of free light chains (FLC) of serum immunoglobulins. MATERIAL AND METHODS: Fourteen patients with MM stage III (Gcappa-5, Glambda-2, Acappa-3, Alambda-1, BJcappa-3) aged 52-75 years with documented resistance to treatment or recurrence received second-line monotherapy with velkeid. The drug was injected intravenously (jet) in a dose 1.3 mg/m2 on the treatment day 1, 4, 8 and 11. Free light chains concentration was examined with antibodies to their latent determinants (Binding Site, UK) on nephelometer (Hitathi-911, Japan) on velkeid treatment day 1, 2, 3, 5, 9 and 12. RESULTS: Nine patients showed lowering of FLC concentration and responded to treatment by Durie criteria. CONCLUSION: Dynamic follow-up of FLC concentration of the tumor clone in resistant and recurrent MM evaluates pharmacodynamics of the drug. The method provides prognosis of late clinical results.

[Clinical characteristics of velcade cumulative effect in resistant and recurrent multiple myeloma].

AIM: To assess efficacy of velcade monotherapy in patients with resistent and recurrent multiple myeloma (MM). MATERIAL AND METHODS: Velcade was given to 29 patients (11 males and 18 females at the age 41-73 years) with resistant and recurrent MM of stage 3. A standard scheme was used - 1.3 mg/m2 iv jet on day 1, 4, 8 and 11. The cycle was 21 days, a total of 6 cycles. All the patients were examined immunochemically for serum and urine PIg. An antitumor effect was studied. RESULTS: After, on the average, 3 courses of velcade therapy PIg reduction was 31.3%. The response was complete (CR) in 3.4%, partial (PR) in 44.6%, minor response (MR) in 17% and no response (NR) in 35% patients. After 6 cycles of velcade monotherapy given to 23 patients PIg reduction was 59%. CR, PR, MR, NR were seen in 2 (8.7%), 11 (47.8%), 4 (17.4%), 6(26.1%) patients, respectively. Progression occurred in 8.7%. After 3 cycles of velcade therapy in 29 patients an objective response occurred in 48%, after 6 cycles it increased to 56.5%. The group with poor respose (MR+NR) reduced from 52 (after 3 cycles) to 43.5% (after 6 cycles) patients. Cumulative toxicity of velcade 10 days after the end of cycles 3 and 6 was absent.

[Linear and adhesive phenotype of tumor lymphocytes and clinical course of chronic leucosis].

Determination of chronic lymphatic leukemia immunological phenotype, performed by the authors, was based upon the study of quantitative expression of membrane differentiation antigens on peripheral blood lymphocytes. The research included study of co-expression of adhesion molecules, belonging to the following families: beta 2 integrins (CD 11 beta, CD 18), immunoglobulins (CD 50), and CD 38 on tumor blood B-lymphocytes of various CD-types and T-lymphocytes in chronic leucosis. The authors developed a functional model of trans-endothelial migration of peripheral blood lymphocytes in chronic chronic lymphatic leukemia, taking into account their membrane adhesive characteristics and serum level of CD 50. The researchers determined clinical importance of the expression of linear and adhesive antigens on peripheral blood lymphocytes, and soluble HLA-1 (sHLA-1) serum levels in patients with chronic lymphatic leukemia.

Human immunoglobulin light chains lambda form amyloid fibrils and granular aggregates in solution.

Myeloma nephropathy is a disorder characterized by deposition of monoclonal immunoglobulin light chains in the kidneys. The chains deposited form either amyloid fibrils or granular (amorphous) aggregates. Distinct molecular mechanisms leading to the formation of different aggregate types in kidney of patients with multiple myeloma are poorly understood. Here we describe the self-association kinetics of human monoclonal immunoglobulin light chains lambda (GRY) isolated from urine of a patient with multiple myeloma. Under physiological conditions, the isolated light chain exists predominantly in a form of covalent dimer with apparent molecular mass of 50.1 kD. Spectral probe binding, analytical gel filtration, Western blot analysis, and electron microscopy indicate that GRY dimer aggregation occurs via two different pathways producing either amyloid fibrils or amorphous aggregates depending on microenvironment. Incubation of GRY (25 microM) for 4-14 days at 37 degrees C in phosphate buffered saline (PBS), pH 7.0, or in PBS containing urea (0.8 M), pH 6.5, leads to amyloid fibril formation. Under electron microscopy, the fibrils show unbranched thread-like structures, approximately 60-80 x 1000 A in size, which can bind thioflavin T and Congo Red. GRY maintained in acetate buffer, pH 3.5, forms granular aggregates. The structure of GRY oligomers formed during the early stage of amyloid fibril formation (1-4 days) has been examined by means of protein cross-linking with homobifunctional reagents. These oligomers are predominantly trimers and tetramers.

[Characteristics of drug resistance of tumor plasmocytes in vitro in patients with multiple myeloma differently responsive to chemotherapy]. / Kharakteristika lekarstvennoi ustoichivosti opukholevykh plazmotsitov in vitro u bol'nykh mnozhestvennoi mielomoi s razlichnym otvetom na khimioterapiiu.

AIM: To determine sensitivity of tumor plasmocytes in vitro to cytostatic drugs (prednisolone, alkeran belustin, vincristine, rubomycin, doxorubicin, cytarabin, methotrexate, cysplatin, etoposide). MATERIAL AND METHODS: The sensitivity was measured with DISC method in 12 patients with multiple myeloma (MM) in two groups: resistant and responsive to induction polychemotherapy (PCT). RESULTS: The groups appeared significantly different by lowering of pathological paraprotein concentration (PIg): by 7.4 +/- 2.5% and 32.5 +/- 3.7%, respectively (p < 0.05). The resistance to the drugs was higher in the resistant patients than in the responders (0.7 +/- 0.28 versus 0.4 +/- 0.02, p < 0.05). PCT schemes of resistant patients contained 65.0 +/- 2.3% of ineffective drugs. In the responders the percentage was 35.7 +/- 5.3% (p < 0.05). CONCLUSION: The relationship exists between resistance of tumor plasmocytes to drugs in vitro and clinical findings.

[Dental care for patients with hematological diseases]. / Stomatologicheskaia pomoshch' bol'nym s gematologicheskimi zabolevaniiami.

Clinical and cytological studies in 41 hematological patients aged 19-70 years showed appreciable shifts in the immune status and nonspecific reactivity virtually in all examinees. Layers of cellular epithelium of late (V-VI) and early (III-IV) stages were more often detected in smears impressions than individual cells. Cells of stages I-II were scarce and never formed layers. In patients with leukemia, signs of dissociation of epitheliocyte nucleus and cytoplasm maturation were observed ("mature" cytoplasm and "young" nuclei). These specific shifts should be borne in mind when rendering dental care to hematological patients.

[The extratumor mechanisms of osteolysis in multiple myeloma and the means for their correction]. / Vneopukholevye mekhanizmy osteoliza pri mnozhestvennoi mielome i puti ikh korrektsii.

In 70 patients with stage III multiple myeloma (MM) the authors studied spontaneous and lipopolysaccharide-induced production of interleukin-1 (IL-1) and interleukin-6 (IL-6) by blood and bone marrow mononuclear cells, concentration of parathyroid hormone and vitamin D3 in the serum. Bone marrow density was measured at photon absorption (Gambro), in patients treated with osteoprotectors bonefos and oxidevit before and after therapy (3.5-6 month course). It is shown that in MM there is a pathogenetic association between production of osteotropic IL-1, IL-6 and bone demineralization. The cases with reduced concentration of Ca and P ions in the serum (4 and 5.7% of patients, respectively) and increased PTH concentration (7%) suggest the existence of new, extratumor mechanisms of osteolysis. It is found that biphosphonates are optimal osteoprotectors. Bonefos (chlodronat, Lieras, Finland) arrests osteolysis proved by a significant increase of bone marrow density and clinical effect.

[The clinical significance of the immunological phenotype in non-Hodgkin's lymphomas]. / Klinicheskoe znachenie immunologicheskogo fenotipa nekhodzhskinskikh limfom.

To study immunological phenotype of tumor cells in the blood and tumor tissue of 68 patients with non-Hodgkin's lymphomas, the authors have used flow cytometry of lymphocytes and enzyme immunoassay in cryostat sections of lymph nodes with application of monoclonal antibodies to differentiating antigens of human lymphocytes. Histological types of lymphoma are shown to differ immunophenotypically. Differential antigens of prognostic and diagnostic value have been determined.

[Computed tomography in the diagnosis of abdominal and retroperitoneal lymphosarcomas]. / Rol kompíuternoi tomografii v diagnostike limfosarkom briushnoi polosti i zabriushinnogo prostranstva.

Analysis of the data of 87 computer-aided tomographic examinations of patients with peritoneal and retroperitoneal lymphosarcomas permitted the authors single out a peculiar computer-tomographic "semeiotics" of this condition. Four states in computer-tomographic changes of the lymph nodes in this area were distinguished, each of them corresponding to specific clinical manifestations of the suffering. The authors came to such a conclusion as a result of detecting in the same 18 patients of a clear-cut correlation between the type of computer-tomographic semeiotics and lymphosarcoma phase in the process of therapy and after it, during remission. Not denying a high value of computer-aided tomography in the diagnosis of peritoneal and retroperitoneal lymphosarcomas, the authors confirm the well-known diagnostic potentialities of ultrasonic examination and consider that ultrasound should remain the primary diagnostic instrument in such conditions.

[Rare clinical forms of multiple myeloma]. / Redkie klinicheskie formy mnozhestvennoi mielomy.

Rare variants of multiple myeloma were revealed as a result of clinical and immunological examination of 287 multiple myeloma (MM) patients. The authors characterize clinically MM with paraproteinemia IgD and IgM as well as lymphoplasmocytic myeloma distinguished basing on immunological typing of circulating lymphocytes.

[Radiologic diagnosis of non-Hodgkin's lymphoma in abdominal and retroperitoneal sites]. / Luchevaia diagnostika nekhodzhkinskikh limfom abdominal'noi i retroperitoneal'noi lokalizatsii.

A total of 112 patients with non-Hodgkin's lymphomas of abdominal and retroperitoneal localization were examined by the ultrasonic and x-ray methods, in 83 of them x-ray computer-aided tomography was used. Angiographic examinations and puncture biopsy monitored by US or x-ray CAT were carried out if indicated. The authors discuss the problems of ultrasonic and x-ray semeiotics of the lymphomatous involvement of the lymph nodes, spleen, gastrointestinal tract. They claim that USE, permitting the specification of further plan of examination of each patient, and x-ray examination as a method to assess the gastrointestinal status are the optimal methods for the primary diagnosis of non-Hodgkin's lymphomas. US data may prompt further application of x-ray CAT, whose results will supplement the US findings. Angiographic examinations should be carried out only in the most difficult diagnostic situations, bearing in mind the invasive nature of the method and its high price.

[Production of interleukin-1 and interleukin-6 in a culture of mononuclear cells of peripheral blood and bone marrow in multiple myeloma]. / Produktsiia interleikina-1 i interleikina-6 v kul'ture mononuklearnykh kletok perifericheskoi krovi i kostnogo mozga pri mielomnoi bolezni.

Constitutive and lipopolysaccharide (LPS)--induced production of interleukin (IL)-1 and IL-6 have been investigated in peripheral blood (PB) and bone marrow (BM) of patients with multiple myeloma (MM) and PB of health donors. The level of these cytokines has been higher in MM in comparison with norm. Monocytes of PB of patients with MM have been more stimulated by LPS than those of health people. When adherent and nonadherent cells have been cultured apart, there not have not been any differences in constitutive IL-6 production between compared groups. The important role of cell-cell interactions in regulation of IL-6 production is proposed. High level of IL-6 in BM of patients with MM is conditioned by mutual stimulation of adherent and nonadherent cells.

[The distribution of class-I HLA antigens in patients with multiple myeloma]. / Raspredelenie HLA-antigenov I klassa u bol'nykh mnozhestvennoi mielomoi.

HLA antigens class 1 have been investigated in Russian patients with multiple myeloma. Compared to controls, myeloma patients demonstrated more frequent occurrence of antigens A11 and B7. Antigen A11 was more common for males and subjects with early response to treatment. Antigen B7 was more frequent in females with the slow response. These correlations are significant without correction on the number of the antigens studied. Association heterogeneity in males and females, in different therapy responders gives grounds for a differential approach to myeloma pathogenesis, choice of drugs, prognosis of survival.

[The immunological phenotype and proliferative activity of the tumor lymphocytes in multiple myeloma]. / Immunologicheskii fenotip i proliferativnaia aktivnost' opukholevykh limfotsitov pri mnozhestvennoi mielome.

An immunological phenotype of blood lymphocytes and proliferative activity of tumor cells were studied using a panel of monoclonal antibodies to lymphocyte differential antigens and tracer 3H-thymidine, respectively, in 84 patients with multiple myeloma. CD-19 and CD38 antigens were identified as markers for circulating tumor lymphocytes. The count of CD38+ and CD71+lymphocytes correlated with the count of marrow plasmocytes including 3H-thymidine in the disease recurrence. Proliferative parameters of blood lymphocytes, plasmocytes and lymphocytes of the bone marrow were identical being, consequently, elements of the same tumor clone.

[Comparison of proliferative and immunoglobulin-secreting capacity of peripheral blood lymphocytes of healthy persons and patients with B-cell immunoproliferative diseases]. / Sravnenie proliferativnoi i immunoglobulin sekretiruiushchei sposobnosti limfotsitov perifericheskoi krovi zdorovykh liudei i bol'nykh s B-kletochnym immunoproliferativnym zabolevaniem.

The proliferative response and in vitro immunoglobulin production induced polyclonal activators were studied in 12 patients with multiple myeloma (MM) and in 15 healthy individuals. The spontaneous production of IgM was decreased. PWM-induced immunoglobulin production of the peripheral blood lymphocytes was the same.

[The effect of industrial and ecological factors on the hemopoietic and immune systems (a review of the literature)]. / Vliianie proizvodstvennykh i ékologicheskikh faktorov na krovetvornuiu i immunnuiu sistemy (obzor literatury).

The review provides data on the influences of different industrial and ecologic factors on the hematoplasty and immune systems in man. There were the clinico-hematologic syndromes caused by these factors.