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Hollenbach J.A.,Childrens Hospital Oakland Research Institute | Augusto D.G.,Federal University of Parana | Alaez C.,Institute Diagnostico y Referencia Epidemiologicos InDRE | Bubnova L.,Russian Research Institute of Hematology and Transfusiology | And 15 more authors.
International Journal of Immunogenetics | Year: 2013

In the last fifteen years, published reports have described KIR gene-content frequency distributions in more than 120 populations worldwide. However, there have been limited studies examining these data in aggregate to detect overall patterns of variation at regional and global levels. Here, we present a summary of the collection of KIR gene-content data for 105 worldwide populations collected as part of the 15th and 16th International Histocompatibility and Immunogenetics Workshops, and preliminary results for data analysis. © 2012 Blackwell Publishing Ltd.

Moreau P.,University of Nantes | Karamanesht I.I.,Kiev Center | Domnikova N.,State Novosibirsk Regional Clinical Hospital | Kyselyova M.Y.,Crimean Republic Clinical Oncology Dispensary | And 14 more authors.
Clinical Pharmacokinetics | Year: 2012

Background and Objectives: The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma (MM) and, in the US, for the treatment of mantle cell lymphoma following at least one prior therapy; the recommended dose and schedule is 1.3 mg/m2 on days 1, 4, 8 and 11 of 21-day cycles, and the approved routes of administration in the US prescribing information are by intravenous and, following a recent update, subcutaneous injection. Findings from a phase III study demonstrated that subcutaneous administration of bortezomib, using the same dose and schedule, resulted in similar efficacy with an improved systemic safety profile (including significantly lower rates of peripheral neuropathy) versus intravenous bortezomib in patients with relapsed MM. The objectives of this report were to present a comprehensive analysis of the pharmacokinetics and pharmacodynamics of subcutaneous versus intravenous bortezomib, and to evaluate the impact of the subcutaneous administration site, subcutaneous injection concentration and demographic characteristics on bortezomib pharmacokinetics and pharmacodynamics. Patients and Methods: Data were analysed from the pharmacokinetic substudy of the randomized phase III MMY-3021 study and the phase I CAN-1004 study of subcutaneous versus intravenous bortezomib in patients aged ≥18 (MMY-3021) or ≤75 (CAN-1004) years with symptomatic relapsed or refractory MM after 1-3 (MMY-3021) or ≥1 (CAN-1004) prior therapies. Patients received up to eight 21-day cycles of subcutaneous or intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11. Pharmacokinetic and pharmacodynamic (20S proteasome inhibition) parameters of bortezomib following subcutaneous or intravenous administration were evaluated on day 11, cycle 1. Results: Bortezomib systemic exposure was equivalent with subcutaneous versus intravenous administration in MMY-3021 [mean area under the plasma concentration-time curve from time zero to the last quantifiable timepoint (AUClast): 155 vs. 151 ng·h/mL; geometric mean ratio 0.992 (90 % CI 80.18, 122.80)] and comparable in CAN-1004 (mean AUC last: 195 vs. 241 ng·h/mL); maximum (peak) plasma drug concentration (Cmax) was lower with subcutaneous administration in both MMY-3021 (mean 20.4 vs. 223 ng/mL) and CAN-1004 (mean 22.5 vs. 162 ng/mL), and time to Cmax (tmax) was longer with subcutaneous administration in both studies (median 30 vs. 2 min). Blood 20S proteasome inhibition pharmacodynamic parameters were also similar with subcutaneous versus intravenous bortezomib: mean maximum effect (Emax) was 63.7 versus 69.3 % in MMY-3021 and 57.0 versus 68.8 % in CAN-1004, and mean area under the effect-time curve from time zero to 72 h was 1,714 versus 1,383 %·h in MMY-3021 and 1,619 versus 1,283 %·h in CAN-1004. Time to Emax was longer with subcutaneous administration in MMY-3021 (median 120 vs. 5 min) and CAN-1004 (median 120 vs. 3 min). Concentration of the subcutaneous injected solution had no appreciable effect on pharmacokinetic or pharmacodynamic parameters. There were no apparent differences in bortezomib pharmacokinetic and pharmacodynamic parameters between subcutaneous administration in the thigh or abdomen. There were also no apparent differences in bortezomib exposure related to body mass index, body surface area or age. Conclusion: Subcutaneous administration results in equivalent bortezomib plasma exposure to intravenous administration, together with comparable blood 20S proteasome inhibition pharmacodynamic effects. These findings, together with the non-inferior efficacy of subcutaneous versus intravenous bortezomib demonstrated in MMY-3021, support the use of bortezomib via the subcutaneous route across the settings of clinical use in which the safety and efficacy of intravenous bortezomib has been established. © 2012 Springer International Publishing Switzerland.

Sipol A.A.,Saint Petersburg State University | Babenko E.V.,Saint Petersburg State University | Borisov V.I.,Alexion Pharma | Naumova E.V.,Moscow Medical Academy | And 9 more authors.
Hematology | Year: 2015

Objectives: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal stem cell disorder characterized by partial or absolute deficiency of glycophosphatidyl-inositol (GPI) anchor-linked surface proteins on blood cells. A lack of precise diagnostic standards for flow cytometry has hampered useful comparisons of data between laboratories. We report data from the first study evaluating the reproducibility of high-sensitivity flow cytometry for PNH in Russia.Methods: PNH clone sizes were determined at diagnosis in PNH patients at a central laboratory and compared with follow-up measurements in six laboratories across the country. Analyses in each laboratory were performed according to recommendations from the International Clinical Cytometry Society (ICCS) and the more recent ‘practical guidelines’. Follow-up measurements were compared with each other and with the values determined at diagnosis.Results: PNH clone size measurements were determined in seven diagnosed PNH patients (five females, two males: mean age 37 years); five had a history of aplastic anemia and three (one with and two without aplastic anemia) had severe hemolytic PNH and elevated plasma lactate dehydrogenase. PNH clone sizes at diagnosis were low in patients with less severe clinical symptoms (0.41–9.7% of granulocytes) and high in patients with severe symptoms (58–99%). There were only minimal differences in the follow-up clone size measurement for each patient between the six laboratories, particularly in those with high values at diagnosis.Conclusions: The ICCS-recommended high-sensitivity flow cytometry protocol was effective for detecting major and minor PNH clones in Russian PNH patients, and showed high reproducibility between laboratories. © 2015 W. S. Maney & Son Ltd.

Selivanov E.A.,Russian Research Institute of Hematology and Transfusiology | Rugal V.I.,Russian Research Institute of Hematology and Transfusiology
Cellular Transplantation and Tissue Engineering | Year: 2011

The regulation development of haemopoietic stem cells by rabbit anti-human CD34 + stem cells immune globulin has been established. It was showed by experimental investigation on rats with cytostatic haemo-immunosuppression and in culture human CD34 + stem cells. Thus, in animals which received anti-CD34 + immune globulin the recovery of blood and immunity values occurred earlier than in the control animals. The experimental animals recovered haemolymphocytopoiesis after one month while control group normalized haemopoietic function after two months. In vitro colony-forming ability human haemopoietic stem cells are increased in 30 per cent by the addition specific CD34 + immune globulin in counditioned medium. Our preliminary date suggest that rabbit anti-human mesenchymal stem cells immune globulin can stimulate the differentiation of mesenchymal cells in osteoblasts and endotheliocytis the cells that form haemopoietic niche.

Gritsaev S.V.,Russian Research Institute of Hematology and Transfusiology | Martynkevich I.S.,Russian Research Institute of Hematology and Transfusiology | Ivanova M.P.,Russian Research Institute of Hematology and Transfusiology | Moskalenko M.V.,Russian Research Institute of Hematology and Transfusiology | And 3 more authors.
Voprosy Onkologii | Year: 2010

Two FLT3-ITD mutations, one FLT3-TKD) and five NPM1 mutations were detected in 7 patients with de novo myelodysplastic syndrome (MDS) out of 44 cases of MDS and MDS/mixed myeloid diseases. Expression of one of the three investigated mutations was identified: 4 in gene NPM1(9.1%) and 2 - FLT3-ITD (4.5%); simultaneous FLT3-ITD and NPM1 mutation - 1 (2.3%); no progression in NPM1 within 9-20 months - 3, although with chromosome 7 damage - 2. It was suggested that NPM1 mutation without complex karyotype may serve as marker of relatively favorable course.

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