[Recurrences of acute promyelocytic leukemia in children: experience with arsenic trioxide therapy and autologous hematopoietic cell transplantation].

AIM: To analyze the specific features of recurrences of acute promyelocytic leukemia (APL) in children after standard therapy with daunorubicin, cytosine arabinoside (Ara-C), all-trans retinoic acid (ATRA) and to develop further programmed treatment policy. SUBJECTS AND METHODS: The study included 9 patients with recurrent APL. The recurrences developed significantly more frequently in a very high-risk group (patients with minimal residual disease being preserved after the intensive therapy phase). Induction used arsenic trioxide (ATO) and/or standard chemotherapy + ATRA; ATO monotherapy was in consolidation. CD34+ cells were mobilized until molecular remission was achieved with high-dose Ara-C and granulocyte colony-stimulating factor. Pretransplantation conditioning involved melfalan as a basic drug in combination with high-dose AraC (5 pts), treosulfan (1 pt) or bisulfan (1 pt). Six patients received gemtusumab ozogamicin, 3-9 mg/m2, at different stages of therapy. RESULTS: Before therapy one patient died; 8 patients achieved the second molecular remission; CD34+ cell mobilization and sampling were effective in 7 cases. Five patients were in long-term molecular remission after autologous hemopoietic stem cell transplantation (autoHSCT). Follow-up was 23-40 months. One patient is being prepared for transplantation. Following autoHSCT, another patient with a developed repeat recurrence died from complications due to related partially compatible transplantation. Visceral, including cardiological, toxicity of therapy was insignificant. In the APL-2003 protocol, overall and event-free survival rates were 93 +/- 3 and 76 +/- 6%, respectively. CONCLUSION; The application of ATO and autoHSCT in recurrent APL makes it possible to achieve and preserve the second molecular remission in case of insignificant extrahematological toxicity. Russian clinics should have access to ATO.

[Efficiency of the ALL-MB-2002 protocol in children with acute lymphoblastic leukemia].

AIM: To evaluate the efficiency of the original ALL-MB-2002 protocol within the multicenter study of treatment of acute lymphoblastic leukemia (ALL) in children. SUBJECTS AND METHODS: A total of 1873 primary patients with ALL aged 1 to 18 years, of whom 1544 patients were enrolled in this study, were notified at 36 clinics of Russia and Belarus from April 15, 2002, to January 1, 2008. RESULTS: With the median observation of 4.12 years, 7-year event-free survival (EFS) was 73 +/- 13%; overall survival (OS) 78 +/- 2%; relapse-free survival 82 +/- 1%. The rates of EFS and OS were equal and amounted to 76 +/- 2 and 80 +/- 2% in the standard-risk group (SRG) and intermediate-risk group (ImRG), respectively. In the high-risk group (HRG) patients, EFS and OS were as high as 30 +/- 6 and 37 +/- 6%, respectively. The frequency of relapses with central nervous system lesion was as much as 4.7% in all the patients, 6-year cumulative risk for isolated neurorecurrences being 2.5% in the SRG patients. Adolescents, patients with the baseline leukocytosis (more than 100 x 10(9)/l), and those with a splenic size of over 4 cm or more from the costal arch margin had substantially worse survival rates. A poor early response to therapy (on induction days 8 and 15) was also associated with its lower efficiency. CONCLUSION: Despite a considerable rise in the number of centers and a slight increase in the intensity of therapy, the results of the new ALL-MB-2002 protocol are as minimum equivalents obtained in the use of the previous ALL-MB-91 protocol. A significant improvement in the overall results of therapy and a reduction in the cumulative risk for isolated neurorecurrences were noted in the ImRG patients.

[Assessment of rate of infection with agents of bacterial infections in ticks captured on one of the Moscow park terrains].

AIM: To study the rate of infection of ticks captured one of the Moscow park terrains with bacteria (agents of tick borreliosis and anaplasmosis). MATERIALS AND METHODS: Rates of infection of dried ticks with agents of main tick-borne bacterial infections (tick borreliosis and anaplasmosis) were determined by nested PCR. RESULTS: In May-June 2006, 76 ticks (40 adult females, 36 adult, males) belonged to Ixodes ricinus species were captured by the method "on flag". Number of ticks on the chosen terrain was 1.77 ticks per km2. 22.4% of ticks (12 females and 5 males) were positive for the agent of tick borreliosis--spirochete Borrelia burgdorferi sensu lato which is pathogenic for humans. The main detected pathogen was Euro-Asian genovariant of B. garinii--7 female and 5 male ticks (70.6% from total number of infected ticks) were infected with it. Five female ticks were infected with genovariant of B. afzelii. One female tick (1.2%) was infected with B. valaisiana. CONCLUSION: Anaplasma A. phagocytophilum causing human granulocytic anaplasmosis was not detected in captured adult ticks.

[On the issue of methods of assessment of quality of life conditioned by health].

The results of the study of 444 schoolchildren from 8-10 degrees and aged from 13 to 16 years studying in the general education schools of Moscow and Vologda are discussed. It is proved that the questionnaire TACQOL can be applied among adolescents for quantitative evaluation of their quality of life conditioned by health and to get reliable, replicable and comparative results. The range of variation of indicators is established for all scales in norm and it permits to reveal children with lower quality of life on the background of medical social problems.

[Umbilical blood is a source of hemopoietic stem cells for transplantation].

AIM: To develop and introduce into practice scientifically validated methods of collection, testing and storage of hemopoietic stem cells of umbilical blood (UB) for non-relative transplantations. MATERIAL AND METHODS: UB and UB concentrate of 1004 mature newborns were studied with morphological, immunocytometric and cultural methods. RESULTS: The established reference values of the number of leukocytes and hemopoietic stem cells (HSC) are essential for examination whether UB is useable for production of the transplantation material. Obtained with the procedure of UB concentration based on sedimentation of erythrocytes due to hydroxyethylstarch, transplantation material has volume 20.0 ml, contains 39.0 +/- 0.48 x 10(6)/ml leucocytes and 1.37 +/- 0.029% CD34+cells and does not differ from umbilical blood by percentage of basic subpopulations of leucocytes and HSC. Assessment of efficacy of leucoconcentration procedure in different pregnancy courses, delivery and technological stages of UB collection gives grounds to consider the methods optimal for use in UB bank, while testing is thought adequate for examination of the material for transplantation fitness. CONCLUSION: Introduction of the study results into practice optimizes the work of stem cell banks and allows production of effective transplantation material.

[Long-term results of combined treatment of acute promyelocytic leukemia in children and adolescents with gene therapy].

AIM: To analyse the results of treatment of children and adolescents with acute promyelocytic leukemia (APL) including polychemotherapy and ATRA (protocols APL 93, 98 and 2003). MATERIAL AND METHODS: The course of the disease, modification of the treatment protocols with reduction of anthracyclines and ATRA doses, results of molecular monitoring of PML/RARalpha transcript have been analysed for 107 APL patients. RESULTS: For prognosis of the disease important are initial characteristics of the patient and the time of the tumor regress assessed by molecular methods--establishment of molecular remission and molecular recurrence. CONCLUSIONS: In APL it is necessary to conduct molecular monitoring especially in patients at high risk and with poor prognosis in a decrease of treatment intensity for toxicity relief. Detection of molecular recurrence is indication for treatment. To raise efficacy of APL recurrence therapy it is necessary to design a special updated protocol.

[The results of a multicenter trial of acute lymphoblastic leukemia treatment on ALL-MB 91/ALL-BFM 90m in children: analysis of efficacy and toxicity].

AIM: A comparative analysis of efficacy and toxicity of two chemotherapy regimens: standard German protocol ALL-BFM 90m and less intensive original test protocol ALL-MB 91 in a multicenter trial of acute lymphoblastic leukemia (ALL) in children. MATERIAL AND METHODS: In 1995-2002 a total of 834 patients with newly diagnosed ALL aged 0-18 years were admitted to 10 clinics of Russia. Of them, 713 were randomized in two groups: treatment program ALL-BFM 90m (n = 355) and ALL-MB 91 program (n = 358). RESULTS: In 7-year follow-up median, 10-year event-free survival (EFS) and overall survival (OS) did not differ significantly between the groups and was 67 +/- 3 and 68 +/- 3% (ALL-MB 91) and 74 +/- 2, 71 +/- 3% (ALL-BFM 90m), respectively. Though the rate of isolated recurrences in CNS in patients on the protocol ALL-MB 91 was 2.8%, they developed only in 0.8% patients of the standard risk group. Anemia, thrombocytopenia and agranulocytosis developed less frequently, hospital stay was significantly shorter on the test protocol vs the control one (p < 0.01). CONCLUSION: EFS and OS on the test (ALL-MB 91) and control (ALL-BFM 90m) protocols were equivalent in lower toxicity and cost of therapy.

Fludarabine, low-dose busulfan and antithymocyte globulin as conditioning for Fanconi anemia patients receiving bone marrow transplantation from HLA-compatible related donors.

Allogeneic hematopoietic stem cell transplantation (SCT) from unaffected donors remains the only modality for the correction of hematological abnormalities in Fanconi anemia (FA) patients. We performed four HLA-matched related donor SCT using a novel irradiation and cyclophosphamide-free conditioning regimen. The protocol included fludarabine 150 mg/m(2), busulfan 4 mg/kg, and antithymocyte globulin 90 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A, MTX, and daclizumab. The engraftment and occurrence of full stable donor hemopoiesis was rapid in all cases with minimal short-term toxic complications. There were no infections or febrile episodes during the inpatient phase. Three patients developed acute GVHD grade I-II involving gut and skin and one patient progressed to extensive chronic GVHD. The preparative conditioning regimen is safe and associated with low organ toxicity and effective immunosupression for the stable engraftment in FA patients undergoing SCT with matched related donors.

[Dynamics of antihemagglutinine (inhibitors and antibodies) to influenza virus in children with acute leukemia concurrently with influenza]. / Dinamika antigemaggliutininov (ingibitorov i antitel) k virusu grippa u detei s ostrym leikozom pri grippoznoi infektsii.

The study on the dynamics of some aspects of humoral immunity to influenza in children with acute leukosis in the presence of intercurrent influenza infection revealed two kinds of changes: a decline of a comparatively high initial level of antibody and inhibitors, and a rise in their titres when the initial level was lower. Both kinds of changes are characteristic both of the acute stage and the remission of acute leukosis. The chemotherapeutic treatment exerted no visible effect either on the level of the dynamics curve or on the pattern of serological shifts after influenza infection. These results suggest that in children with acute leukosis the response to influenza infection, being no different in nature from that in subjects not suffering from leukosis, is still poor quantitatively.

[The role of free oxygen radicals in the pathogenesis of Fanconi's anemia]. / Rol' svobodnykh radikalov kisloroda v patogeneze anemii Fankoni.

The authors describe the results of a study into antioxidants (superoxide dismutase and catalase) and production of the active forms of oxygen (superoxide anion radical, hydrogen peroxide, hydroxyl radical, and singlet oxygen) by blood and bone marrow leukocytes from patients with Fanconi's anemia. The generation of the active forms of oxygen was induced by silica particles while the formation of radical products was recorded by means of luminol-dependent chemiluminescence. Unbalanced excessive production of oxygen radicals such as hydroxyl radicals combined with a decrease in the activity of antioxidant defence enzymes was discovered. It is believed that it is this circumstance that causes the derangement of the membranous structures and multiple breakdowns in the hereditary apparatus. It is suggested that antiradical preparations may be applied to correcting therapy of patients with Fanconi's anemia.

[Specific cellular immunity indices in acute leukemia in children]. / Nekotorye pokazateli spetsificheskogo kletochnogo immuniteta pri ostrom leikoze u detei.

Studies on the cell immunity in patients with acute leukemia were conducted in two functionally different tests: in cytotoxic reaction of lymphocytes and in the reaction of inhibition of leucocytes adherence which manifest accordingly the killer and antigen-reactive function of immunocompetent cells. There was found a statistically reliable enhancement of lymphocytes reactivity in patients with acute leukemia against leukemia-associated antigens compared with lymphocytes of healthy donors. The cytotoxic activity of lymphocytes was enhanced during the complete remission and before the recurrence, whereas the potential of antigen-reactive cells was reduced during the complete remission and against the background of the recurrence.

[Results of the treatment of childhood acute lymphoblastic leukemia according to the Berlin-Moscow-91 protocol in 1991-2000]. / Rezul'taty lecheniia ostrogo limfoblastnogo leikoza u detei po protokolu Moskva-Berlin-91 v 1991-2000 gg.

The report deals with the results of application of an original protocol--the Berlin-Moscow-91 (BM-91)--for the treatment of acute lymphoblastic leukemia (ALL) in children. The researchers' major concern was to improve survival and cut down side-effects incidence as well as to prevent and successfully manage occult neuroleukemia as a potential source of relapse. Patients aged 5 months-15 years received the BM-91 and ALL BFM-90m treatment first at one clinic and later at several centers. Out of 852 children with primary diagnosis of ALL admitted to Russian hematological hospitals (March 2, 1991-November 3, 2000), 687 were included into the study; 329 received the MB-91 protocol. Nine-year recurrence-free survival was 73% while overall survival--80%. Toxic side-effects after L-asparaginase were reported in 27 (7.9%). It is concluded that good results in childhood ALL treatment can be achieved without resorting to high-dosage chemotherapy and radiation in most cases.

[Treatment of acute lymphoblastic leukemia in children according to the ALL-BFM-90m protocol in the Russian Federation and the Republic of Belarus]. / Lechenie ostrogo limfoblastnogo leikoza u detei po protokolu OLL-BFM-90m v Rossiiskoi Federatsii i Respublike Belarus'.

Prognosis for children treated according to the BFM-90m protocol (Berlin-Frankfurt-Munster Group) for acute lymphoblastic leukemia (ALL) improved significantly as compared with previous modalities. Methotrexate was used in the dose of 1,000 mg/m2, 36 h. The paper presents the 10-year results for this modification. Patients aged 0-15 years were treated at hematological hospitals of Moscow, other Russian towns and in Minsk, Belarus, (July 5, 1990-November 11, 2000). BFM-90m treatment was given to 682 children out of 1,326 with primary diagnosis of ALL; a comparative trial of the MB-91 protocol hed been carried out at the same clinics since 1991. During 10 years, recurrence-free survival was 72% while overall survival--77%. Toxicity of side-effects was tolerable. The BFM-90m treatment showed significantly better results in both countries.

[Endotoxemia in crush syndrome]. / Endotoksemiia pri sindrome dlitel'nogo razdavlivaniia.

The crush syndrome developing in casualties in mass catastrophes is the cause of their high mortality rates. We examined 18 children aged from 9 to 14 years with the crush syndrome who suffered during the earthquake in Armenia. Besides other laboratory studies, the test for the titer of antibodies (TA) to endotoxin was performed. Despite the applied complex therapy, the children's condition grew worse on day 8. The TA level reduced threefold. Six patients received a single infusion of plasma with naturally increased TA titer in a dose of 10 ml/kg. On the following day after TA infusion, the condition of children in the experimental group improved, the clinical picture of endotoxemia in the control group persisted for 10-12 days.

[Characteristics of pathogenesis of acute leukemia in children]. / Osobennosti patogeneza ostrykh leikozov u detei.

The main components of acute leukemia pathogenesis have been considered from the current positions: origination of the leukemic clone, characteristics of leukemia tumor histogenesis, mechanisms of proliferation and differentiation of leukemic cells. The main pathogenetic differences of acute leukemia in children and adults have been traced. The importance of these differences for the clinical picture, prognosis and response to chemotherapy has been analyzed.

[Class I and II HLA antigens in children with acute lymphoblastic leukemia]. / HLA-antigeny I i II klassov pri ostrom limfoblastnom leikoze u detei.

Investigation of the distribution of HLA antigens in children with acute lymphoblastic leukemia demonstrated a significant increase of the B17 antigen frequency and a decrease of the frequency of DR7 antigen. A high index of the relative risk (RR-3.207) was also revealed for antigen B40 carriers. The typing of the children suffering from acute lymphoblastic leukemia should be carried out, as shown by the investigations, based on the immunocytological variant of acute lymphoblastic leukemia.

[Status of the pediatric oncohematologic service in Russia]. / Sostoianie detskoi onkogematologicheskoi sluzhby v Rossii.

In spite of the fact that official statistical data show lower cancer morbidity of pediatric population in Russia than in Europe and USA (9.7 against 13.8 and 13.6, respectively), real cancer incidence may be close to mean incidence in Europe and USA as in Moscow it is 14.8 in boys and 12.0 in girls. Lower numbers in some other regions may be attributable to low standards of cancer diagnosis and inadequate case registration. In Moscow where standards of children's hematological service are high the proportion of some malignancies is the following: hemoblastoses-48.5%, CNS tumors-19.8%, neuroblastoma-8.0%, renal tumors-6.5%, sarcomas of soft tissues and bones-2.4 and 4.6%, respectively. The efficacy of anticancer treatment of children in many regions of Russia is poor, but the situation may be changed for the best by introduction of new approaches developed in the Moscow Research Institute of Pediatric Hematology.

[ENT lesions in children with AIDS]. / Porazhenie LOR-organov pri SPIDe u detei.

The number of AIDS patients in Cambodia is on the increase. The examination for AIDS covered 50,000 children and 23,000 adults. HIV-seropositive results were obtained in 1800 and 1250 children and adults, respectively. ENT lesions in children with AIDS are characterized.

[The effect of polychemotherapy on hemopoiesis in acute lymphoblastic leukemia in children]. / Vlianie polikhimioterapii na gemopoéz pri ostrom limfoblastnom leikoze u detei.

Bone marrow granulocytic-macrophagal precursors (GMP) and fibroblastic precursors (FP) were measured in 235 children with acute lymphoblastic leukemia (ALL) receiving polychemotherapy (PCT) in progression of the disease. A total of 408 culture investigations were conducted. PCT proved to exert different effects on hemopoiesis during the first acute ALL period and remission. In the former period the target for PCT were blast cells, the course of induction therapy increased the number of GMP, FP and early granulocytic cells. In recurrent ALL the sensitivity of GMP to PCT grew, while FP remained intact. PCT performed in remission resulted in gradual suppression of granulocytopoiesis, GMP beginning from the second remission year. The treatment discontinuation on remission year 3-5 produced enhancement of granulocytosis by all parameters.

[The use of monoclonal antibodies to lipid A for the correction of the hemodynamic disorders in endotoxemia]. / Ispol'zovanie monoklonal'nykh antitel k lipidu A dlia korrektsii gemodinamicheskikh narushenii pri éndotoksemii.

Endotoxemia induced by gram-negative bacteria leads to endotoxic shock pathogenetically stemming from the integral component of the bacterial wall--lipid A. The study made to define the ability of lipid A monoclonal antibodies to correct hemodynamic disturbances due to endotoxemia in dog experiments showed the efficacy of the antibodies administration. ReLPS isolated from Salmonella Minnesota was used as an antigen. Administration of the complex monoclonal antibodies-endotoxin caused no hemodynamic impairment.