Vol 78, No 7 (2003)


Lymphatic tumors and theprinciple of therapeutic validity

Vorobyev I.A., Kharazishvili D.V.
Terapevticheskii arkhiv. 2003;78(7):5-7
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Detection of minimal residual disease in patients with acutemyeloid leukemia

Galtseva I.V., Savchenko V.G., Kulikov S.M., Parovichnikova E.N., Miterev G.Y., Maslova E.R., Isaev V.G.


Aim. Detection of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) and the study of its correlations with duration of recurrence-free interval. Material and methods. Bone marrow samples obtained from 37 AML patients before treatment were studied at two-color flow cytometry. The panel of monoclonal antibodies to T- and B-cell, myeloid antigens was used. The residual cells were estimated in 20 patients in remission. Results. 78% cases were diagnosed to have an anomalous immunophenotype including coexpression of lymphoid and myeloid antigens, asynchronous expression of myeloid antigens. In the first remission the residual cells were detected in 20 patients due to aberrant antigen expression. The presence of MRD was stated if bone marrow contained more than 0.12% leukemic cells. The duration of the first remission and MRD correlated. 8 patients with MRD had remission for 3 to 6 months (median 4.7 months). 12 patients free of MRD were in remission for more than 6 months (for 8 to 26 months, median 19.7 months). The threshold level of the residual cells (0.12%) was confirmed statistically using the threeparameter probability model. Conclusion. This study confirms feasibility of using flow cytometry for detection of residual cells. MRD and duration of the first remission correlate. Long-term observation of large groups of AML patients will try the validity of the above statistical model.
Terapevticheskii arkhiv. 2003;78(7):8-15
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Allogenictransplantation of the bone marrow after regimens of lowintensity conditioning in therapy of patients with hemoblastoses

Demidova I.A., Savchenko V.G., Olshanskaya Y.V., Poreshina L.P., Kutyina R.M., Surin V.L., Misyurin A.V., Domracheva E.V., Parovichnikova E.N.


Aim. To investigate effectiveness of allogenic transplantation of the bone marrow (TBM) in the treatment of hemoblastosis patients from a high risk group, the course of donor bone marrow retention, tolerance and antitumor activity of this therapy. Material and methods. 11 patients received TBM in low-intensity regimen in Hematological Research Center in 1999-2001. All the patients were from a high risk group. Conditioning was based on the combination of fludarabin with busulfan. The transplanted precursor cells were taken from the bone marrow and/or peripheral donor blood. The retention was controlled by differential agglutination of erythrocytes and amplification of hypervariable sites of DNA. Minimal residual disease was controlled by standard cytogenetical tests, fluorescent in situ hybridization or reverse-transcriptase polymerase chain reaction. Results. All the patients tolerated pretransplantation conditioning well. By chimerism, signs of retention of donor bone marrow on day +30 after TBM were observed in 9 patients of 11. Acute graft versus host reaction developed in 5 patients. This reaction was treated conventionally with methylprednisone and cyclosporin A, in 4 cases with a good effect. A complete remission persists in 5 patients. Mean follow-up lasted for 241 days. Conclusion. Thus, transplantation was successful in 50% patients with an unfavourable prognosis who are still in a complete remission. This suggests efficacy of the above method of treatment.
Terapevticheskii arkhiv. 2003;78(7):15-21
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Superhigh doses of dexamethasone in the treatment of refractory forms of acute lymphoblast leukemia of adults

Parovichnikova E.N., Savchenko V.G., Isaev V.G., Sokolov A.N., Moskov V.I., Klyasova G.A., Galtseva I.V., Ustinova E.N., Gribanova E.O., Lapin V.A., Zagoskina T.P.


Aim. Assessment of high-dose dexamethasone efficacy in combination with standard drugs (adriablatin, vincristin, a-asparaginase) in patients with refractory acute lymphoblastic leukemia (ALE). Material and methods. A pilot multicenter trial with participation of hematological departments of Hematological Research Center (Moscow), municipal hospital N 1 (Krasnoyarsk), municipal hospital N\8 (Yaroslavl), Research Institute of Hematology and Blood Transfusion (Kirov) included 34 patients (jtQ patients with late recurrences, 24 - with primary resistant forms, early and secondary recurrences) Results. In patients with late ALL recurrences a complete remission (CR) was achieved in 70% cases, the median being 10 months. In patients with primary resistant ALL, early and secondary recurrences CR reached 37.5%, the median was 14 months. Conclusion. The program HiDexa is highly effective : overall complete remission rate reached 47%, median of complete remission duration was 10 months. Dexamethasone in high doses must be used only intravenously.
Terapevticheskii arkhiv. 2003;78(7):21-24
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Lymphatic system neoplasms treatment: prognostic factors

Kharazishvili D.V., Vorobyev I.A.
Terapevticheskii arkhiv. 2003;78(7):24-30
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T-cell tumors withaplastic syndromes

Vinogradova Y.E., Kamenetskaya A.M., Zamulaeva I.A., Samoilova R.S., Selivanova E.I., Vodinskaya L.A., Tsvetaeva N.V., Vinogradova O.Y., Kaplanskaya I.B., Tikhomirova L.Y., Vorobyev A.I.


Aim. To detect and verify the existence of a specific form of T-cell tumor accompanied by isolated lesions of bone marrow and aplastic syndromes. Material and methods. Four patients with aplastic syndromes were examined using clinical, histological, cytological, cytogenetic, and immunophenotypic methods. Results. Four cases of T-cell tumors of bone marrow with clinical and morphological manifestations of aplastic syndrome and scanty proliferation activity in bone marrow alone were diagnosed. The proliferation activity in bone marrow was observed as formation of small clusters composed of small-size lymphoid cells with dense nucleus. Dynamic monitoring of two patients revealed a trend toward an increase in the lymphoproliferation base against the remaining clinical picture of aplastic syndrome. The T-cell immunophenotype characterized by disappearance of some markers or decrease in their density, was observed only in some blood and bone marrow lymphocytes. The most significant changes of immunophenotype were observed in one of the patients (CD2+CD3-CD4-CD5-CD7-CD8-CD16-CD56-CD45RO++). The same patient had pronounced cytogenetic changes (47XY+Y[8J, 47, XY, del(l)(pl0) [23], 46 XY [3]) and resistance to routine therapy, including cyclosporin. In one patient the process transformed into lymphosarcoma. Conclusion. The results obtained in four patients allow their clinicomorphological characteristics to be regarded as particular forms of T-cell tumors accompanied by bone marrow damage and aplastic syndrome.
Terapevticheskii arkhiv. 2003;78(7):30-34
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Morphological, morphometrical andimmunophenotyping characteristics of primary mediastinalB-cell lymphosarcoma

Dzhumabaeva В.Т., Vorobyev I.A., Kaplanskaya I.B., Sam- oilova R.S., Kharazishvili D.V., Tikhonova L.Y., Prank G.A., Vorobyev A.I.


Aim. To define histological, cytological, computer-morphometric and immunophenotypical features of primary mediastinal B-cell lymphosarcoma. Material and method. The study enrolled 43 patients with primary mediastinal B-cell lymphosarcoma (PMBCL) treated in Hematological Research Center from 1994 to 2002. The examination included morphological and immunophenotypical tests, computer morphometry of the cells by histological sections. Results. PMBCL is represented by a composite population of cells of a giant, large and small size (nuclear areas 76.24 ± 19.99, 37.77 ± 8.0 and 17.12 ± 4.34 mem2. Three types were identified: giantcell, large-cell and small-cell. A giant-cell type is represented by large and giant cells comprising, on the average, 44 and 31% of overall number of lymphoid cells. A large-cell type is primarily represented by large lymphoid cells (62% of the lymphoid population). Small-size type is represented by small cells (72% of cells). Frequent histological signs are diffuse sclerosis and focal necrosis. Tumor cells have B-cell nature. In the giant and large cell type more than 70% cells express PCNA, in the small cell type - less than 30%. Expression of activation marker CD30 is observed in 18% cases in the giant and large cell types. Conclusion. PMBCL is a morphologically heterogenous disease represented by combination of giant, large and small cells with immunophenotypically B-cell nature characterized in a giant cell and large cell type by prominent but in a small cell and large cell type by insignificant proliferative activity. CD30 expression is observed only in giant cell and large cell types.
Terapevticheskii arkhiv. 2003;78(7):34-38
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Factors of an unfavourable prognosis in patients withB-cell chronic lymphoid leukemia: a retrospective analysisof 206 cases

Nikitin E.A., Lorie Y.Y., Melikyan A.L., Samoilova R.S., Bulycheva T.I., Obukhova T.N., Kaplanskaya I.B., Doronin V.A., Kolosova L.Y., Goryacheva S.R., Kovaleva L.G.


Mm. To assess factors of an unfavourable prognosis in a group of intermediate risk of B-cell chronic lymphoid leukemia (BCCLL). Material and methods. 206 BCCLL patients (mean age 55.5 years, male/female = 1.66) entered the study conducted by Hematological Research Center in 1992-2000. Results. Nine patients under 35 years of age did not survive 5 years except one female who achieved a complete remission on fludarabin. The type of bone marrow infiltration (diffuse vs interstitial and nodular), the time of lymphocyte count doubling (under or over 12 months) discriminate the patients by prognosis in the group of intermediate risk: medians of overall survival 65 months vs 148 months and 72 vs 133 months, respectively (p < 0.005 for both curves, log-rank criterion). Survival medians in groups with low (< 50% cells) and high (> 50% cells) expression of CD38+ cells in the group of intermediate BCCLL risk comprise 55 and 106 months (p = 0.005). The type of bone marrow infiltration and time of doubling of lymphocyte count overlap: > 70% patients with a diffuse type of bone marrow infiltration have the time of doubling under 12 months and vice versa while expression of CD38 do not overlap with these values. Combination of two signs (type of bone marrow infiltration and CD38 expression or time og lymphocyte count doubling and CD38 expression) allows more precise identification of prognostically unfavourable groups. Medians of survival for combination of the first two signs (two positive against two negative) comprise 51 months vs 169 months (p < 0.0001), for combination of the latter two signs 55 months vs 106 months was not reached (p < 0.001). Although most patients with a tumor form of BCCLL are referred to stage II, the prognosis in this form is much worse than in stage II, survival medians are 44 and 69 months, respectively (p < 0.05). A mutation status of the genes of a variable region of immunoglobulins enable identification of the group of patients with a relatively benign course of BCCLL (survival medians 61 and 289 months, p < 0.0001). Conclusion. In patients under 35 years of age BCCLL runs unfavourably and seems to require intensive poly chemotherapy. Usage of a combination of the signs (CD38, time of doubling of lymphocyte count and type of bone marrow infiltration) is a simple and reliable method of identification of prognostically different categories of patients in the group of an intermediate BCCLL risk. Prognosis in patients with a tumor form of BCCLL is unfavourable.medians of survival in patients with a tumor form and stage III-IV are comparable. Mutational status of the genes of immunoglobulin variable region may serve a marker of a long-term prognosis.
Terapevticheskii arkhiv. 2003;78(7):38-48
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Experience in theuse of polymerase chain reaction for determining T-cellclonality

Sidorova Y.V., Nikitin E.A., Peklo M., Vlasik T.N., Samoilova R.S., Kravchenko S.K., Melikyan A.L., Vinogradova Y.E., Pivnik A.V., Sudarikov A.B.


Aim. To distinguish T-cell lymphomas and reactive T-cell proliferation it is important to confirm the ability of T-cells to be cloned. Conventional histological and immunophenotypic methods fail to determine the ability of T-cells to be cloned. An experience in the use of detection of T-cell receptor gene gamma-chain (TCRy) rearrangement for determining T-cellular clonality is described. Material and methods. Polymerase chain reaction (PCR) and single strand conformational polymorphism (SSCP) were used to determine T-cell clonality. Twenty healthy donors, 28 patients with T-lymphomas, and 26patients with various non-T-cell lymphoproliferative disorders or reactive processes were studied. Results. T-cell monoclonality was detected in 23/28 (82%) T-cell lymphoma cases, whereas in all the samples from normal subjects a polyclonal pattern of rearrangements TCRy was found. The sensitivity of the method was estimated as 2,5%, 7%, and 10% was demonstrated for bone marrow, spleen, and peripheral blood, respectively. Conclusion. PCR-SSCP for TCRy was found to be a useful supplement to routine histological and immunophenotypic methods in the diagnosis of T-cell lymphomas.
Terapevticheskii arkhiv. 2003;78(7):48-52
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Cytomegaloviral infection in patients with hemoblastoses

Savchenko V.G., Troitskaya V.V., Misyurin A.V., Parovichnikova E.N., Isaev V.G., Mendeleeva L.P., Lyubimova L.S., Demidova I.A., Aksenova E.V., Filatov F.P., Garanzha T.A., Ustinova E.N., Gribanova E.O., Galstyan G.M.


Aim. To estimate the incidence of cytomegaloviral (CMV) infection and CMV disease in patients with acute leukemia at different stages of chemotherapy and in patients after transplantation of hemopoietic cells. Material and methods. The trial was carried out in 33 patients with acute leukemia at different stages of chemotherapy, 20 patients subjected to transplantation of autologic hemopoietic cells and 21 patients who had received transplantation of allogenic hemopoietic cells. To study the dynamics of the CMV infection markers, enzyme immunoassay of the titer of the specific immunoglobulins M and G was made, detection of the viral antigen in immunofluorescence reaction and cultivation with fibroblast cell culture and determination of the cytomegalovirus DNA by polymerase chain reaction (PCR). Results. Before chemotherapy, up to 90% patients with acute leukemia were infected with cytomegalovirus (similar rate of infection was observed in healthy donors of hemopoietic cells). By the time of transplantation all the patients were infected with cytomegalovirus. During chemotherapy of acute leukemia, the primary infection and reactivation of latent infection occurred in 30% patients, whereas CMV disease developed in 18% patients. In case of transplantation of autologic hemopoietic cells the rate of reactivation of CMV infection (15%) was one-half of that value in patients with acute leukemia (30%). Similar trend was observed in case of development of CMV disease (5% and 18%, respectively). In case of transplantation of allogenic hemopoietic cells the incidence of reactivation of CMV infection was three times higher than in case of transplantation of autologic hemopoietic cells (47.6% and 15%, respectively, p = 0.02). The incidence of development of CMV disease in case of transplantation of allogenic hemopoietic cells was also significantly higher than in case of transplantation of autologic hemopoietic cells (28.6% and 5%, respectively, p - 0.05). Conclusion. Cytomegalovirus is an infection agent responsible for severe complications of chemotherapy of acute leukemia and transplantation of hemopoietic cells in patients with hemoblastoses. Among hematological patients, the group of the highest risk of development of this complication includes recipients of transplantation of allogenic hemopoietic cells, particularly from seronegative donors.
Terapevticheskii arkhiv. 2003;78(7):52-58
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Prevalence ofmycelial fungi in a hematological hospital

Petrova N.A., Klyasova G.A., Funygina L.P.


Aim. To study prevalence, quantity and species of mycelial fungi in the air of a hematological hospital. Material and methods. Air samples in the hematological departments were taken monthly by PU- IB device in the volume 250 l/min. Seeding and identification of mycelial fungi were made on the Chapeck medium. Results. Tests for mycelial fungi in the air was 95%. Dominating species were the following: Penicillium spp., Cladosporium spp., Aspergillus spp. The fungal contamination was seasonal. Maximal isolation of Penicillium spp was seen in winter and autumn. Aspergillus spp. is represented with 13 species of which most frequent were A.versicolor, A. niger, A. fumigatus, A. ochraceus, A. flavus. Pathological material from 19 patients contained Aspergillus spp.: A. fumigatus, A. flavus, A. niger. The isolation peak was in autumn-winter and coincided with maximal isolation of fungal spores from the air. The analysis of air samples taken in the wards where patients had Aspergillus spp. In biomaterials showed that concentration of spores Aspergillus spp. was higher than in nearby wards and corridor: 45.6 CPU/M3 vs 18.8 CFU/m3 and 24.7 CFU/M3, respectively. However, morphologically identical strains (patient-air) were recognized only in 4 cases from the nearby wards and corridor. None of the air samples taken in the ward of the patient contained identical species. Minimal amount of the spores of micromycetes was registered in the wards furnished with ventilation with laminar airflow. Most contaminated was the air of 4 bed wards in the old building. Conclusion. Mycological monitoring of the air in hematological departments determined the structure of mycelial fungi complexes. Though ambient air in the wards is full of fungi, detection of morphologically identical strains causing invasive mycosis in immunocompromised patients is rare. Further studies are necessary.
Terapevticheskii arkhiv. 2003;78(7):58-63
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Invasive aspergillesis in immunocompromised patients

Klyasova G.A., Petrova N.A., Galstyan G.M., Gotman L.N., Vishnevskaya E.S., Sysoeva E.P., Khoroshko N.D., Mikhailova E.A., Parovichnikova E.N., Isaev V.G., Ustinova E.N., Kremenetskaya A.M., Kravchenko S.K., Glasko E.N., Kaplanskaya I.В., Vernyuk M.A., Krasnova E.O., Shavlokhov S.V., Ryzhko V.V., Savchenko V.G.


Aim. To analyse results of treatment of invasive aspergillesis in immunocompromised patients for 2000-2002. Material and methods. The study was made of patients who, when treated with antibiotics, exhibited foci in the lungs typical for invasive aspergillesis. Aspergillus were detected in the sputum, bronchoalveolar lavage, bronchial wash-ups, aspergilla antigen (galactomannan) was detected in the blood. Results. Invasive aspergillesis was diagnosed in 25 patients. 13 (52%) patients were treated with adjuvant glucocorticoids. 19 (76%) patients had neutropenia. All the patients had fever. Foci in the lungs were in 24 patients. Aspergillus were detected in 15 patients, a positive antigen galactomannan in 7 patients. A. Fumigatus, A flavus, A. Niger occurred in 67, 26.5 and 6.5% patients, respectively. All the patients received amphotericin В (median of the treatment reached 38 days, total dose 880-3500 mg). In 5 patients amphotericin В was replaced for liposomal amphotericin В because of high creatinine. 7 patients continued with itraconasol in a dose 400-600mg/day. The foci were removed in 3 patients. The cure was achieved in 12 patients, 13 patients died (cause of death - respiratory insufficiency). Conclusion. Lethality in invasive aspergillesis in immunocompromised patients remains high - 52%. Cultural detection of mycelial fungi was, as a rule, delayed. Early diagnosis of the disease requires monitoring of the aspergilla antigen in the blood and computer tomography of the chest especially in fever persisting in the treatment of wide-spectrum antibiotics.
Terapevticheskii arkhiv. 2003;78(7):63-68
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Clinical manifestations of porphyrin metabolism disorders

Pustovoit Y.S., Karpova I.V., Pivnik A.V., Surin V.L., Lukyanenko A.V., Luchinina Y.A.


Aim. To characterize patients -with various nosological unities ыо/porphyria in accordance with their age, clinical symptoms, provoking factors, therapy and outcome. Material and methods. Patients with acute intermittent porphyria (43), hereditary coproporphyria (8), variegate porphyria (3), porphyria cutanea tarda (7), hepatoerythropoietic porphyria (1), and hereditary erythropoietic porphyria (2) were studied. One patient was suspected of porphyria caused by deficiency of delta-aminolevulenic acid dehydrogenase. Results. The patients were from the CIS. The overwhelming majority of them were young and middleaged subjects. Rapid development of the disease and severe neurological symptoms were predominantly observed in patients with acute forms of porphyria. Conclusion. Early diagnosis of porphyrin metabolism disorders makes it possible to decrease abruptly the number of cases leading to severe complications, disability, and fatal outcome. The use of inexpensive methods of screening of porphyrin metabolism disorders provides a promising approach to solving this problem. These methods should be used in municipal hospitals. In addition, asymptomatic carriers of defective gene should be revealed at the preclinical stage using various methods of molecular genetic assay
Terapevticheskii arkhiv. 2003;78(7):68-73
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Computer multimedia case history as a present-day tool of keepingrecords

Shklovsky-Kordi N.Е., Zingerman В.V., Goldberg S.V., Velichko S.A., Gudilina Y.Y., Kaplanov K.D., Klimenko S.V., Kravchenko S.K., Kremenetskaya A.M., Kobelyatsky V.F., Kostochkina S.V., Margolin O.V., Rivkind N.В., Freidin Y.L., Erlikh L., Vorobyev A.I.


Aim. To design the program of computer multimedia case history (MCH) for collection, storage and analysis of information about the patient including diagnostic images; to test MCH for application in telemedical consulting and control over valid conduction of the treatment protocol. Material and methods. Brief representation of information is reached by integrated multilevel placement of the data on common time axis. Dynamics of the selected parameters is represented as normalized diagrams in the same system axes. Electron tables arefdled either by hand or import of the data from individual electron file of all the information about the patient. Diagnostic images and conclusions are obtained from local computer bases of the diagnostic units. Inexpensive commonly used computers allows one to input digital micro- and macrophotos, x-ray images, etc. Monitor information is available from the universal computer net directly from the monitors Geolink-M. Results. MCH was tested in the Hematological Research Center of RAMS. In cooperation with Bryansk diagnostic center N 1 telemedical consulting and some data bases were perfected. The MCH system joints routine activity of the clinic without any problems raising quality of the patients management, facilitating the access to therapeutic and diagnostic information and its analysis. On-line breaking the limits of the controlled parameters and protocols is detected automatically. These events are emphasized by "blocking questions" which must be worked out by the user. The information on the patient can be fully stored on CD-ROM in line with the MCH program providing organization of the data. Conclusion. The system is introduced which collects medical information from various sourses and builds up comprehensive representation of the data on the same time axis. The system provides control over implimintation of the protocols of the patients' management, gives a convenient access to medical information, ensures its reliable storage and availability in case of the patients transfer to other medical institutions, facilitates analysis of clinical cases, conduction of medical consulting.
Terapevticheskii arkhiv. 2003;78(7):73-76
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Meningitis caused by Listeria monocytogenes in a patientwith multiple myeloma

Pokrovskaya О.S., Mendeleeva L.P., Gribanova E.О., Usiinova E.N., Klyasova G.A., Sharikova O.A., Galstyan G.M., Yatskov K.V., Varlamova E.Y., Kaplanskaya I.В., Fedorova S.Y., Drozdova A.G., Savchenko V.G.
Terapevticheskii arkhiv. 2003;78(7):76-78
pages 76-78 views

Hemolytic anemia due to anomalous unstable hemoglobin BuenosAires

Rumyantseva Y.V., Surin V.L., Smetanina N.S., Plyasunova S.A., Blokhina L.V., Kolodei S.V., Zhirkova L.V.
Terapevticheskii arkhiv. 2003;78(7):78-81
pages 78-81 views

Several malignant tumors in one patient for 16 years

Mitish N.E., Mendeleeva L.P., Lyubimova L.S., Momotyuk K.S., Parovichnikova E.N., Isaev V.G., Demidova I.A., Gribanova E.О., Ustinova E.N., Kaplanskaya I.B., Kutyina R.M., Poreshina L.P., Shpakova A.P., Tikhonova L.Y., Domracheva E.V., Savchenko V.G.
Terapevticheskii arkhiv. 2003;78(7):81-82
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Iron deficiency anemia inpregnant women and its management with gino-tardiferon

Sokolova M.Y., Nikonov A.P.
Terapevticheskii arkhiv. 2003;78(7):87-89
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Transplantation of allogenic bone marrow inacute leukemias and chronic myeloid leukemia

Mendeleeva L.P.
Terapevticheskii arkhiv. 2003;78(7):89-94
pages 89-94 views

Valentina Aleksandrovna Nasonova (the 80th anniversary ofbirth)

- -.
Terapevticheskii arkhiv. 2003;78(7):95-96
pages 95-96 views

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