Incidence of Myelofibrosis in Chronic Myeloid Leukemia, Multiple Myeloma, and Chronic Lymphoid Leukemia during Various Phases of Diseases.

Pathomorphological study of trephinobiopsy specimens from 129 patients with lymphoproliferative and myeloproliferative diseases was carried out over the course of chemotherapy. Combinations of initial and manifest myelofibrosis (loose network of reticulin fibers and extensive network of reticulin and collagen fibers, respectively) predominated at the debut of chronic myeloid leukemia, chronic lymphoid leukemia, and multiple myeloma. Manifest myelofibrosis was detected in patients with chronic myeloid leukemia without hematological response (failure of normalization of hematological values) and in patients with progressing and relapsing multiple myeloma. Combinations of foci of initial and manifest myelofibrosis were most incident in patients with progressing and relapsing chronic lymphoid leukemia. The incidence of myelofibrosis was higher in patients with multiple myeloma and chronic lymphoid leukemia progression and relapses and in patients with chronic myeloid leukemia without hematological response than at the disease debut and in case of response to chemotherapy. The response to chemotherapy in patients with chronic myeloid leukemia and chronic lymphoid leukemia was associated with a decrease in the incidence of myelofibrosis. In patients with multiple myeloma responding to chemotherapy, the incidence of myelofibrosis did not change in comparison with the disease debut.

Clinical Morphological Studies of Myelofibrosis with Different Types of Bone Marrow Involvement in Patients with Chronic Lymphocytic Leukemia.

Clinical-morphological study of myelofibrosis was carried out in patients with chronic lymphocytic leukemia at the debut of the disease. Trephinobiopsy specimens of the ileac bone, aspirated specimens of the bone marrow, and peripheral blood smears were studied in 80 patients. Chronic lymphocytic leukemia was associated with myelofibrosis of different severity in 22.5% cases. Morphometric analysis of trephinobiopsy specimens showed that the severity (histology and dissemination) of myelofibrosis correlated with the type of tumor involvement of the bone marrow. Focal tumor involvement of the bone marrow predominated in trephinobiopsy specimens from patients without myelofibrosis, while patients with myelofibrosis developed mainly diffuse tumor infiltration, associated with the greatest dissemination of the initial and manifest myelofibrosis. No myelofibrosis was found in patients with interstitial tumor involvement of the bone marrow. The severity of the initial and manifest myelofibrosis directly correlated with the tumor involvement of the bone marrow and peripheral blood. Evaluation of the prognosis showed that initial myelofibrosis was associated with disease standing of 5.5 months, while manifest condition with a disease of 8.5 months and longer.

Blood microvesicles during chronic lymphoproliferative diseases.

The levels of CD19 (+) and CD20(+) microvesicles were estimated in the blood of patients with B-cell chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma by flow cytometry method. It was found that the number of B cell microvesicles is several times higher in patients than in volunteers. The level of CD20 (+) microvesicles directly correlated with the number of CD20(+) lymphocytes in patients with chronic lymphoproliferative diseases. Extramedullary tumors cells can be a source of CD19 (+) microvesicles.

Role of xenobiotic metabolism enzyme gene polymorphism in the formation of chemotherapy resistance in patients with chronic lymphoproliferative diseases.

Enzymes of the cytochrome P450 and GSTP1 families play a pivotal role in the metabolism of a wide variety of antitumor drugs and polymorphisms of genes encoding for metabolizing enzymes can affect drug efficacy and toxicity. We studied the associations between functionally significant gene polymorphisms CYP2C8, CYP2C9, CYP2C19, CYP3A5, and GSTP1 and clinical response to chemotherapy in patients with chronic lymphoproliferative diseases. Significant correlations with chemotherapy resistance were observed for CYP2C8 3 (OR=7.05; CI 95%=1.76-29.55) and CYP2C9 2 polymorphisms (OR=4.1; CI 95%=1.03-16.81). No significant association between chemotherapy resistance and other examined polymorphisms were found.

Spontaneous and mitogen-induced cytokine production in lymphoproliferative diseases.

The levels of spontaneous and mitogen-induced production of pro- and anti-inflammatory cytokines were studied in patients with chronic lymphoid leukemia, non-Hodgkin's lymphocytic lymphomas, and multiple myeloma during the course of chemotherapy. Cytokine concentrations varied within a great range and did not conform to the normal distribution law. The levels of granulocyte and granulocyte-macrophage CSF were high during the debut, progress, and remission of the lymphoproliferative diseases. Imbalance of a wide spectrum of pro- and anti-inflammatory cytokines was observed during the debut and progress of the lymphoproliferative diseases, more often in chronic lymphoid leukemia and non-Hodgkin's lymphocytic lymphomas than in multiple myeloma.

Changes in bone marrow and peripheral compartments of the erythron under the effect of tumor cells in indolent non-Hodgkin lymphomas and multiple myeloma.

Here we present the results of pathomorphological study of erythron cells from patients with indolent non-Hodgkin lymphomas and multiple myeloma. The revealed associations suggest that tumor cells can modulate the bone marrow and peripheral compartment of the erythron in lymphoproliferative diseases leading to quantitative and morphological changes in bone marrow erythrokaryocytes and peripheral blood erythrocytes. Clinical and pathomorphological markers of dyshemopoiesis associated with the presence of anemia were identified in indolent non-Hodgkin lymphomas. In multiple myeloma, a correlation between the parameters of bone marrow and peripheral compartments of the erythron and structural modifications of myeloma cells infiltrating the bone marrow was revealed.

Morphometric study of trephine biopsy specimens in aggressive and indolent non-Hodgkin's lymphomas.

Morphometric study of the erythroid stem was performed in aggressive and indolent non-Hodgkin's lymphomas vs. other cells and tissues of the bone marrow (including the tumor tissue) before chemotherapy. Hypoplasia and abnormal maturation of the erythroid stem were particularly pronounced in diffuse infiltration of the bone marrow, which did not depend on lymphoma aggressiveness. Hypoplasia of the erythroid stem was often observed during focal infiltration of the bone marrow with lymphoma cells (despite a smaller area of tumor tissue in aggressive lymphomas than in indolent lymphomas). A decrease in the relative area of adipose tissue, smooth resorption of bone tissue, and myelofibrosis are the major changes in the bone marrow microenvironment.

Morphological characteristics of the central compartment of the erythron in aggressive and indolent non-Hodgkin's lymphomas.

Structural changes in cells of the central compartment of the erythron depended on tumor infiltration of the bone marrow. Cytostatic therapy was shown to improve quantitative indexes, but had no effect on morphological characteristics of the erythron. Examination of trepanobiopsy specimens from the iliac crest during chemotherapy revealed the existence of specific relationships between the erythron, other cells and tissues of the bone marrow, and tumor. Significant changes in the erythron were found during diffuse tumor infiltration and treatment with anthracycline antibiotics.

[Toxicity of different treatment protocols for acute myeloid leukemias in adults: the results of four Russian multicenter studies].

AIM: To comparatively analyze the toxicity of 4 treatment protocols in patients with acute myeloid leukemia (AML), which were used in the Russian multicenter center in 1992 to 2009. MATERIALS AND METHODS: The information obtained in 4 Russian multicenter studies conducted in 33 hematology departments of 26 cities and towns of the Russian Federation in 1992 to 2009 was analyzed. Randomization was made in 243 patients with AML (median age 38 years) in 1992-1995, 396 patients (median age 39 years) in 1995-1999, 392 patients (median age 39 years) in 2001-2006, and 137 patients (median age 40 years) in 2006-2009. The analysis excluded patients with acute promyelocytic leukemias who were recruited in the AML-92 and AML-95 studies. These patients' statutory forms adequately filled in were 60-70% therefore toxicity was analyzed on the basis of the data of 631 patients. RESULTS: The baseline clinical and laboratory parameters in the patients enrolled in the studies in different years slightly differ in the count of leukocytes at the onset of the disease and in the level of lactate dehydrogenase (LDH): the recent studies revealed a larger number of high-risk group patients (leukocytes more than 30 10(9)(/l; LDH more than 500 units) possibly due to the later diagnosis of AML. During the studies, the number of complete remissions remained as before (55%) after the first course and increased from 65 to 78% after the second course using cytosine arabinoside in high doses. Despite treatment intensification, mortality in the induction period remained as before (19-21%). Remission mortality decreased from 18 to 10-13%. The long-term results of using the aggressive therapy did not differ from those obtained during the standard treatment protocols. The duration of leucopenia after standard induction courses during the all studies remained equal (17-19 days); the exclusion was a HAM course as the second induction course after which the duration of neutropenia was much more than that of the standard course (17 and 10 days, respectively). During the study years, there was an increase in platelet transfusion volumes (from 20 to 53 doses during the first course and from 7 to 28 doses during the second course) and a reduction in the percentage of severe hemorrhagic complications. The incidence of pneumonias remained at the same level (40-50%) during the induction courses and that of septic complications and necrotic enteropathy considerably decreased from 40-46 to 17-19%. The incidence of invasive aspergillosis during the current programs from AML treatment was 10% (two induction courses), that of invasive candidiasis was 4.7% (two induction courses). CONCLUSION; The long-term results of treatment for AML were virtually unchanged regardless significant therapy intensification. Mortality remained high during induction treatment and in the postremission period. Its cause is severe infectious complications developing during myelotoxic agranulocytosis. The results of the analysis provide the basis for developing a new AML treatment protocol that should take into account all the merits and demerits of the previous protocols and provide a toxicity-treatment efficiency balance.

[The results of a multicenter randomized trial on the treatment of acute myeloid leukemia of adults].

AIM: Systematization of the results of 20-year multicenter randomized trial of the efficacy of treatment of acute myeloid leukemia (AML) of adults; presentation of the design of the study of the strategy of consolidation and maintenance therapy after high-dose consolidation initiated in 2007. MATERIAL AND METHODS: Treatment outcomes on the protocol AML-01.01 are presented for 354 AML patients from 29 hematological centers located in 22 towns of Russia and 2 towns of Ukraine. The patients were randomized into 3 groups by variant of therapy: 124 patients (62 males and 62 females; age median 42 years) received 4 courses of 7+3+VP-16 and 5 courses of maintenance therapy (7+3 with thioguanin); 130 patients (65 males and 65 females, age median 41 year) received 2 courses of 7+3+VP-16, 2 courses 7+3, maintenance--5 courses 7+3 with thioguanin; 126 patients (57 males and 68 females, age median 40 years) were given 2 courses of 7+3+VP-16, 2 HAD courses, treatment discontinuation. RESULTS: A complete remission after the first course of 7+3+VP-16 was achieved in 55% patients, after the second course--in 30% after the course 7+3+VP-16 or 7+3 with mitoxantron, in 70%--after NAM. Overall and recurrence-free survival were 18 and 35%; 30 and 20%; 36 and 30%, respectively. There was no significant difference in efficacy of the treatment scheme. CONCLUSION: The multivariate analysis has shown that a leading factor having impact on treatment results was the number of randomized patients: the less patients were randomized, the worse were the results.

Hemogram and myelogram in progressing non-Hodgkin's lymphomas.

Parameters of hemogram and myelogram were studied in patients with aggressive and indolent non-Hodgkin's lymphomas: the relationships between the parameters recorded before treatment and during remission or progress 6 months after chemotherapy were studied by multifactorial analysis. The progress of indolent non-Hodgkin's lymphomas was associated with changes caused by tumor infiltration of the bone marrow; lymphocytosis in the myelogram or hemogram was associated with a relative decrease in the count of granulocytic hemopoietic stem cells. A sign associated with the absence of remission in aggressive non-Hodgkin's lymphomas was decreased level of hemoglobin and erythroid cells. Changes in myelogram attesting to anemia and suppressed erythropoiesis before chemotherapy are additional prognostic factors indicating obligatory intensification of chemotherapy for patients with aggressive non-Hodgkin's lymphomas.

[Risk factors of pseudomonas infection in hemoblastosis patients]. / Faktory riska psevdomonadnoi infektsii u patsientov s gemoblastozami.

A total of 67 patients with diseases of the blood system and infectious complications, admitted to the Hematological Department of the Novosibirsk Regional Clinical Hospital, were examined. For this study only patients with etiologically established diagnosis were taken. The study revealed that Pseudomonas sp., whose strains were susceptible to Ceftazidime in 100% of cases and resistant to Cefepime and Imipenem in 15-17% of cases, was the etiological agent of 13.6% of all cases of infectious complications in hemoblastosis patients. Infectious lesions of pulmonary parenchyma, the presence of chronic diseases of the respiratory tract in the medical history, neutropenia, artificial ventilation of the lungs were found to be adverse prognostic factors with respect to a high risk of Pseudomonas infection in such patients. Therapy with glucocorticosteroids and cytostatics, preceding antibacterial prophylaxis were not linked with the isolation of Pseudomonas from the patients exhibiting the same levels of lethality and severity of infectious complications.

[Clinical characteristics of respiratory infection in patients with hematologic malignancy and neutropenia]. / Klinicheskaia kharakteristika infektsii dykhatel'nykh putei u patsientov s gemoblastozami i neitropeniei.

The aim of the study was a comparative assessment of clinical and laboratory findings characterizing the course of pneumonia or bronchitis in patients with hematological malignancy (HM) and neutropenia. The course of the respiratory infections (RI) was studied in 47 HM patients. RI in HM were found to develop in patients with a large tumor, in bone marrow involvement, in patients without a complete remission, more frequently pneumonia arises in acute leukemia, bronchitis--in patients with lymphoproliferative diseases. Among causative agents Gram-negative and Gram-positive microorganisms were detected at the same rate (44.2 and 45.9%, respectively), fungi were diagnosed in 9.8% cases. Enterobacteriaceae microorganisms were found more often in patients with pneumonia. Gram-positive agents occurred more frequently in bronchitis. Such clinical markers in neutropenic patients as dyspnea, dullness in the lung, weakened respiration, moist rales in the lungs and fever 39 degrees C and higher point to pneumonia. If the above markers are absent but there is cough, fever 38-39 degrees C, tough respiration, dry rales both pneumonia and bronchitis are possible.

Erythropoiesis in patients with aggressive and indolent non-Hodgkin's lymphomas.

Parameters of the erythroid, granulocytic, and megakaryocytic hemopoietic stems were compared in 87 patients with aggressive and indolent non-Hodgkin's lymphomas before and 6 months after the start cytostatic therapy. Before chemotherapy anemia was detected in 46% patients with aggressive and 49% patients with indolent lymphomas. Hemoglobin content, peripheral blood erythrocyte count, and total count of erythroid cells in the bone marrow increased during chemotherapy in the indolent lymphoma group. Increased count of erythroid cells in the myelogram was due to decreased count of lymphoid cells in the bone marrow, which was associated with complete or partial remission. In aggressive lymphoma chemotherapy decreased the mean level of hemoglobin and mean erythrocyte count in the peripheral blood, but the total count of erythroid cells in the bone marrow increased; no relationship was detected between lymphocyte count in the bone marrow and erythropoiesis characteristics. Lymphocytosis >50% in the myelogram before chemotherapy was less frequent in this group in comparison with indolent non-Hodgkin's lymphomas.

MDR1 Gene C1236T and C6+139T polymorphisms in the Russian population: associations with predisposition to lymphoproliferative diseases and drug resistance.

Study of MDR1 polymorphism in intron 6 and exon 12 of healthy individuals and patients with chronic lymphoproliferative diseases showed that the presence of mutant 6+139T allele is a factor determining resistance to lymphoproliferative diseases. Comparison of genotyping results in 53 patients and the data on the efficiency of drug therapy showed no significant associations of C(6+139)T and C(1236)T genotypes with drug resistance.

Possible prediction of the efficiency of chemotherapy in patients with lymphoproliferative diseases based on MDR1 gene G2677T and C3435T polymorphisms.

Study of polymorphism in MDR1 gene exons 21 and 26 revealed that T2677T and T3435T alleles are not a factor predisposing to lymphoproliferative diseases, but they determine the efficiency chemotherapy. Individuals with T2677T and T3435T haplotypes are at highest risk of drug resistance. Association between genotypes G2677T and C3435T was detected in normal subjects and in patients with lymphoproliferative diseases.

Functional activity of P-glycoprotein in lymphocytes of patients with lymphoproliferative diseases.

Functional activity of P-glycoprotein in lymphocytes of patients with lymphoproliferative diseases was studied using rhodamine 123. Functional activity of P-glycoprotein in patients receiving a course of chemotherapy was lower than in controls. P-glycoprotein activity was higher in patients receiving more aggressive therapy. Initially activity of P-glycoprotein was higher in patients who did not respond to chemotherapy in comparison with those whose clinical status improved after a course of chemotherapy.

[Prognosis of nosocomial pneumonia outcome]. / Prognozirovanie iskhoda nozokomial'noi pnevmonii.

AIM: To assess frequency of occurrence of factors registered before or in the course of nosocomial pneumonia (NP) and implications of these factors for the risk of NP lethal outcome. MATERIALS AND METHODS: 70 NP patients entered the study. They were admitted to hospital with diagnosis of chronic nonspecific pulmonary disease, severe trauma, hemoblastosis, other tumors, etc. 26 of them recovered and were discharged from hospital, 44 patients died. RESULTS: The risk of lethal outcome in NP was higher in hepatic disturbances, high levels of urea in the blood, hemorrhagic syndrome, antibiotic treatment prior to NP, administration of glucocorticosteroids. St. aureus as the etiologic agent of nosocomial pneumonia was registered more frequently in patients with a lethal outcome. CONCLUSION: Further studies are needed for more precise evaluation of pathophysiological links between NP and lesions of other organs.