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São Paulo, Brazil

Vivona D.,University of Sao Paulo | Bueno C.T.,University of Sao Paulo | Lima L.T.,University of Sao Paulo | Hirata R.D.C.,University of Sao Paulo | And 5 more authors.
Blood Cells, Molecules, and Diseases | Year: 2012

Background: Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor used for treating chronic myeloid leukemia (CML). IM has high efficacy, however some individuals develop a resistance due to impaired bioavailability. Polymorphisms in genes encoding membrane transporters such as ABCB1 have been associated with differences in protein expression and function that influence the response to several drugs. Aim: To investigate the relationship of ABCB1 polymorphisms with markers of response to IM in patients with CML. Methods: One hundred eighteen CML patients initially treated with a standard dose of IM (400. mg/day) for 18. months were selected at two health centers in Sao Paulo City, Brazil. The response criteria were based on the European LeukemiaNet recommendations. ABCB1 polymorphisms c.1236C. >. T (rs1128503), c.3435C. >. T (rs1045642) and c.2677G. >. T/A (rs2032582) were evaluated by PCR-RFLP. Results: ABCB1 polymorphisms were not related with a risk for CML in this sample population (p. <. 0.05). In the CML group, frequencies of ABCB1 SNPs were similar between responder and non-responder patients (p. >. 0.05). In the responder group, the frequency of ABCB11236CT/2677GT/3435CT haplotype was higher in patients with major molecular response (MMR) (51.7%) than in patients without MMR (8.3%, p = 0.010). Furthermore, carriers of this haplotype had increased the probability of reaching the MMR compared with the non-carriers (OR: 11.8; 95% CI: 1.43-97.3, p = 0.022). Conclusions: The ABCB1 1236CT/2677GT/3435CT haplotype is positively associated with the major molecular response to IM in CML patients. © 2011 Elsevier Inc.. Source

Machado L.E.,Servico de Hematologia
Einstein (São Paulo, Brazil) | Year: 2012

This study describes a new method used in the clinical laboratory at Hospital Israelita Albert Einstein to detect mutations in exons 8 and 17 of the KIT gene in patients with acute myeloid leukemia. Genomic DNA extraction was performed on 54 samples of peripheral blood or bone marrow from patients with acute myeloid leukemia. The extracted DNA was amplified by polymerase chain reaction and sequenced, and the fragments were analyzed. Within the analyzed samples, we detected four mutations in exon 8, two mutations in exon 17, and mutations or a double mutation in one sample. The tests detecting mutations in exon 8 and 17 on the KIT gene were successfully standardized. The test is now included among the routine diagnostics employed for patients at Hospital Israelita Albert Einstein clinical laboratory. Source

Vasconcelos F.C.,Instituto Nacional Of Cancer Inca | Silva K.L.,Instituto Nacional Of Cancer Inca | Souza P.S.D.,Instituto Nacional Of Cancer Inca | Silva L.F.R.,Instituto Nacional Of Cancer Inca | And 3 more authors.
Cytometry Part B - Clinical Cytometry | Year: 2011

The involvement of the multidrug resistance (MDR) mediated by ABC transporter proteins P-glycoprotein (Pgp) and multidrug resistance-associated protein-1 (MRP1) overexpressions in patients with chronic myeloid leukemia (CML) are not completely understood. Pgp and MRP1 expressions and activity were analyzed in samples from 158 patients with chronic myeloid leukemia (CML). Using flow cytometry, Pgp expression was more frequently observed in early chronic (P = 0.00) and in advanced (P = 0.02) CML phases when it was compared to MRP1 expression. Variation of MDR expression and activity were observed during the CML evolution in patients previously treated with interferon and imatinib. In the K562-Lucena cell line, Pgp positive, imatinib caused an enhancing in Pgp expression at protein and mRNA levels, whereas in the Pgp negative cell line, this drug was capable of decreasing MDR1/Pgp mRNA levels. Our result emphasizes the importance of understanding the different aspects of MDR status in patients with CML when they are under investigation in determining imatinib resistance. © 2010 International Clinical Cytometry Society. Source

Scheiner M.A.M.,Instituto Nacional Of Cancer Inca | Da Cunha Vasconcelos F.,Instituto Nacional Of Cancer Inca | Da Matta R.R.,Instituto Nacional Of Cancer Inca | Dal Bello Figueira Jr. R.,Servico de Hematologia | Maia R.C.,Instituto Nacional Of Cancer Inca
Journal of Cancer Research and Clinical Oncology | Year: 2012

Purpose Polymorphisms in the ABCB1 gene may influence P-glycoprotein (Pgp) expression and/or activity. Because the population in Brazil is markedly heterogeneous, we analyzed the relationship between ABCB1 polymorphisms and Pgp expression/activity in Brazilian acute myeloid leukemia (AML) patients. Methods Acute myeloid leukemia samples from 109 patients were studied. ABCB1 gene variants rs1128503 (C1236T) and rs1045643 (C3435T) were analyzed by PCR-RFLP assay. Pgp expression and Pgp activity were analyzed by flow cytometry. Results There was a similar distribution of Pgp expression and activity on polymorphisms C1236T, C1236C, and T1236T for exon 12, and C3435T, C3435C, and T3435T for exon 26. An exception was observed in the lowest ratio of mean fluorescence intensity (MFI) median for Pgp expression in the TT genotype for both studied exons, and its correspondence to a low MFI median for Pgp activity. Pgp expression did not show impact on the response to remission induction therapy, but the MFI median of Pgp expression in the remission failure group was higher than that of the complete remission (CR) group of patients (p = 0.04). Overall survival (OS) was significantly influenced by CR (p = 0.0001). Better 5-year OS and 5-year event-free survival rates (p = 0.04 and p = 0.007, respectively) were achieved in patients presenting the genetic variant CC in exon 12 followed by those presenting the variant CT in exon 26 (p = 0.001). Conclusions Polymorphisms in the ABCB1 gene and the levels of Pgp expression could be useful to identify prognostic in AML patients. © Springer-Verlag 2012. Source

Sandes A.F.,Federal University of Sao Paulo | Yamamoto M.,Federal University of Sao Paulo | Matarraz S.,University of Salamanca | Chauffaille M.L.L.F.,Federal University of Sao Paulo | And 5 more authors.
Haematologica | Year: 2012

Background Multiparameter flow cytometric analysis of bone marrow and peripheral blood cells has proven to be of help in the diagnostic workup of myelodysplastic syndromes. However, the usefulness of flow cytometry for the detection of megakaryocytic and platelet dysplasia has not yet been investigated. The aim of this pilot study was to evaluate by flow cytometry the diagnostic and prognostic value of platelet dysplasia in myelodysplastic syndromes. Design and Methods We investigated the pattern of expression of distinct surface glycoproteins on peripheral blood platelets from a series of 44 myelodysplastic syndrome patients, 20 healthy subjects and 19 patients with platelet alterations associated to disease conditions other than myelodysplastic syndromes. Quantitative expression of CD31, CD34, CD36, CD41a, CD41b, CD42a, CD42b and CD61 glycoproteins together with the PAC-1, CD62-P, fibrinogen and CD63 platelet activation- associated markers and platelet light scatter properties were systematically evaluated. Results Overall, flow cytometry identified multiple immunophenotypic abnormalities on platelets of myelodysplastic syndrome patients, including altered light scatter characteristics, over- and under expression of specific platelet glycoproteins and asynchronous expression of CD34; decreased expression of CD36 (n=5), CD42a (n=1) and CD61 (n=2), together with reactivity for CD34 (n=1) were only observed among myelodysplastic syndrome cases, while other alterations were also found in other platelet disorders. Based on the overall platelet alterations detected for each patient, an immunophenotypic score was built which identified a subgroup of myelodysplastic syndrome patients with a high rate of moderate to severe alterations (score>1.5; n=16) who more frequently showed thrombocytopenia, megakaryocytic dysplasia and high-risk disease, together with a shorter overall survival. Conclusions Our results show the presence of altered phenotypes by flow cytometry on platelets from around half of the myelodysplastic syndrome patients studied. If confirmed in larger series of patients, these findings may help refine the diagnostic and prognostic assessment of this group of disorders. © 2012 Ferrata Storti Foundation. Source

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