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Prognostic importance of angiopoietin-2 gene transcription in chronic lymphocytic leukemia.
Gradošová, Iveta ; Pecka, Miroslav (advisor) ; Smolej, Lukáš (referee)
Chronic lymphocytic leukemia (CCL) is the most common leukemia, which is characterised by a high variable progress. According to scientific evidence acquired during several last years, angiogenesis has been proven to play an important role in pathogenesis of CLL. One of the very important cytokines playing role in this process is angiopoietin-2 (Ang-2). Elevated expression of Ang-2 has been reported in several hematological malignancies; however, data regarding Ang-2 in CLL are very limited. I measured Ang-2 transcript levels in purified mononuclear cels of 24 untreated patients with CLL by quantitative real-time PCR and normalized them for differences in RNA concentration in each sample by quantitation of transcript of Abl1 housekeeping gene. Elevated Ang-2 mRNA concentrations were detected in 10 cases (Ang-2 to Abl1 expression ratio > 5x10-3). On the other hand, 14 patients had very low or undetectable levels of Ang-2 mRNA (Ang-2 to Abl1 expression ratio < 5x10-3 or Ang-2 Cp > 35). The association between Ang-2 expression and other prognostic factors, clinical stage according to Rai and clinical course of CLL was evaluated by Chi-Square method. There was a significant association between high Ang-2 mRNA levels and unmutated IgVH genes (n= 21, p = 0.012), but not with CD38 (p = 0.057), ZAP-70 expression (p...
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Current aspects of care patients with chronic lymphocytic leukemia
Šimkovič, Martin ; Smolej, Lukáš (advisor) ; Doubek, Michael (referee) ; Papajík, Tomáš (referee)
In recent years it has been an unprecedented development of knowledge of biology and treatment options of chronic lymphocytic leukemia (CLL). Survival of patients with CLL was improved by the introduction of the monoclonal antibodies (anti-CD20) and combined chemoimmunotherapy regimens. Despite this undeniable advance in the treatment of CLL and progress in knowledge of CLL biology and pathophysiology, many current aspects of care of these patients remain unresolved. In our work we focus on epidemiology of CLL, treatment of relapsing/refractory CLL patients, rituximab infusion-related adverse events and venous thromboembolism in CLL patients. Incidence of CLL in Hradec Králové district during period 1999-2013 was 8.2 patients per 100,000 persons per year. Trends in epidemiology were analyzed after splitting patients into two groups according to the period in which the diagnosis was made: n=92 in the period 1999- 2005 and n=108 in the period 2006-2013. Significant prolongation of survival (median OS not reached vs 86 months) was observed in patients treated during the period 2006-2013 in comparison to those treated in the period 1999-2005. However, the improvement of overall survival was achieved only in younger patients (≤ 70 years). Patients with refractory CLL have highly unfavourable prognosis....
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New biological markers in lymphoproliferative diseases
Špaček, Martin ; Mandys, Václav (advisor) ; Smolej, Lukáš (referee) ; Lysák, Daniel (referee)
New biological markers in lymphoproliferative diseases Summary The prognosis of patients with lymphoid neoplasms is extremely variable. Reliable prognostic markers could allow the identification of patient subsets that may benefit from alternate approaches. Epstein-Barr virus (EBV) is associated with approximately one third of Hodgkin lymphoma (HL) cases. EBV-DNA is often present in the plasma and whole blood of EBV-associated HL patients. However, the significance of EBV-DNA monitoring is debated. In a cohort of 165 adult HL patients EBV-DNA viral load was prospectively monitored. Our results suggest that assessment of plasma EBV-DNA viral load might be of value for estimation of prognosis and follow-up of patients with EBV-positive HL. The role of the TP53 gene's R72P polymorphism in NHL has been analyzed in several studies but it has not been studied in HL. We have evaluated the role of R72P in 340 NHL and 298 HL patients. Our results support the evidence that R72P is not a prognostic factor in Caucasian NHL patients, and they indicate its irrelevance for HL development or prognosis. In a study of 73 patients with chronic lymphocytic leukemia we have assessed IgVH mutational status, presence of mutation in TP53 gene and expression of CD38 and ZAP-70. Overall concordance between ZAP-70 expression and IgVH...
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The role of molecular genetic and cytogenetic analyses in the diagnosis and prediction of treatment response in patients with non-Hodgkin lymphomas
Berková, Adéla ; Zemanová, Zuzana (advisor) ; Goetz, Petr (referee) ; Smolej, Lukáš (referee)
Malignant lymphoproliferative disorders include highly heterogeneous entities, i.e. lymphomas (Non-Hodgkin - NHL, as well Hodgkin's lymphoma), lymphoid leukemias, multiple myeloma and others. As currently many chromosomal aberrations with diagnostic and prognostic significance are known, molecular cytogenetic analyses of tumor cell genome has become a substantial examination also in lymphoproliferative disorders. This thesis focuses primarily on chronic lymphocytic leukemia (CLL), which is one of the mature B-cell neoplasms and represents the most common type of leukemia. We analyzed four most frequently found aberrations (13q14 deletion, ATM and TP53 gene deletion, and trisomy 12) by fluorescence in situ hybridization (FISH) and also IgH gene aberrations in some patients. We compared the findings with other factors and clinical characteristics. This work shows that the conventional G-banding is analysis relatively little relevant. FISH was more effective in detecting aberrations in CLL. Although none of the four aforementioned changes is specific to CLL, the prognostic impact is significant, particularly that of TP53 deletion. Next, detection of some IgH gene translocations is essential in differential diagnosis of CLL and other NHL (follicular, mantle cell, diffuse large B cell, Burkitt's...
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Unfavourable biological prognostic factors in Multiple Myeloma
Painuly, Utkarsh ; Smolej, Lukáš (advisor) ; Pour, Luděk (referee) ; Procházka, Vít (referee)
Title I: Aurora kinase and FGFR3 inhibition results in significant apoptosis in molecular subgroups of multiple myeloma In our pre-clinical study we examined the role of Aurora kinase and FGFR3 inhibition in MM using a small molecule inhibitor A1014907 which induced aneuploidy in MM cell lines at low nanomolar doses. However, A1014907 induced more pronounced and dose dependent apoptosis in cell lines with t(4;14) translocation. Translocation t(4;14) is observed in about 15% of patients with MM leading to constitutive activation of FGFR3 in two-thirds of these patients. Further investigation of the mechanism of action of A1014907 revealed potent FGFR3 pathway inhibition only in the sensitive cell lines. Thus, our results show that aurora kinase inhibition causes cell cycle arrest and aneuploidy with minimal apoptosis whereas inhibiting both aurora kinase and FGFR3 activity induced potent apoptosis in MM cells. This study evaluates the role of simultaneous inhibition of Aurora Kinases and FGFR3 pathway which are both important deregulated pathways in MM patients; inducing potent apoptosis. Title II: Natural history of multiple myeloma with de novo del(17p) Our clinical study involved comparing the outcomes of 310 newly diagnosed MM patients with del(17p) detected by FISH to patients with high-risk...
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Current aspects of care patients with chronic lymphocytic leukemia
Šimkovič, Martin ; Smolej, Lukáš (advisor) ; Doubek, Michael (referee) ; Papajík, Tomáš (referee)
In recent years it has been an unprecedented development of knowledge of biology and treatment options of chronic lymphocytic leukemia (CLL). Survival of patients with CLL was improved by the introduction of the monoclonal antibodies (anti-CD20) and combined chemoimmunotherapy regimens. Despite this undeniable advance in the treatment of CLL and progress in knowledge of CLL biology and pathophysiology, many current aspects of care of these patients remain unresolved. In our work we focus on epidemiology of CLL, treatment of relapsing/refractory CLL patients, rituximab infusion-related adverse events and venous thromboembolism in CLL patients. Incidence of CLL in Hradec Králové district during period 1999-2013 was 8.2 patients per 100,000 persons per year. Trends in epidemiology were analyzed after splitting patients into two groups according to the period in which the diagnosis was made: n=92 in the period 1999- 2005 and n=108 in the period 2006-2013. Significant prolongation of survival (median OS not reached vs 86 months) was observed in patients treated during the period 2006-2013 in comparison to those treated in the period 1999-2005. However, the improvement of overall survival was achieved only in younger patients (≤ 70 years). Patients with refractory CLL have highly unfavourable prognosis....
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Prognostic significance of atypical leukemic cell morphology in chronic lymphocytic leukemia.
Fučíková, Nikola ; Smolej, Lukáš (advisor) ; Vrbacký, Filip (referee)
CHARLES UNIVERSITY IN PRAGUE Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Study program: Health Care Bioanalytics Candidate: Bc. Nikola Fučíková Supervisor: doc. MUDr. Lukáš Smolej, Ph.D. Title of diploma thesis: Prognostic significance of atypical leukemic cell morphology in chronic lymphocytic leukemia The aim of this thesis is to evaluate the prognostic significance of atypical cell morphology and smudge cells in patients with untreated chronic lymphocytic leukemia. We performed differential leukocytes count and classified lymphocytes as typical and atypical in a cohort of 101 patients (median age, 66 years; males, 69%, Rai III/IV stages, 18%). For atypical CLL, we used the 15% threshold and 59% of patients were classified as atypical CLL (aCLL). For smudge cells, we chose the 30% threshold and 33% of patients were classified as smudge cells positive. Patients in early clinical Rai stage (0) had significantly higher number of smudge cells (p=0.04). We didn't find a significant association between aCLL / smudge cells with modern prognostic indicators. We didn't find a relationship between aCLL and the time to first-line therapy (p=0.394). However, patients with aCLL had a significantly shorter overall survival (p=0.0397). There was a trend toward shorter...
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Immunophenotyping of mature B-cell neoplasms
Babuňková, Eva ; Jílek, Petr (advisor) ; Smolej, Lukáš (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Author: Mgr. Eva Babuňková Supervisor: PharmDr. Petr Jílek, CSc. Title of rigorous thesis: Immunophenotyping of mature B-cell neoplasms This thesis focuses on the B-lymphoproliferative diseases immunophenotype assessed by flow cytometry, which is a method currently used for the diagnosis and classification of these diseases. Apart from the diagnostic value, flow cytometry can be used for minimal residual disease monitoring after the treatment of hematological malignancies (e.g. chronic lymphocytic leukemia). A great advantage of flow cytometry is the possibility of analysing virtually any biological material. In our work we investigated peripheral blood and bone marrow. The aim of the study was to compare the expression of selected surface markers in patients suffering from different B- lymphoproliferative disorders in peripheral blood and bone marrow. We analysed 171 samples (79 peripheral blood samples and 92 bone marrow samples), which were measured on a flow cytometer BD FACS Canto II. Seventy-five women and ninety-six men we included in the study. Peripheral blood samples and bone marrow samples were sorted into the following groups: CLL, MCL, B-NHL NOS and other B...
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The role of molecular genetic and cytogenetic analyses in the diagnosis and prediction of treatment response in patients with non-Hodgkin lymphomas
Berková, Adéla ; Zemanová, Zuzana (advisor) ; Goetz, Petr (referee) ; Smolej, Lukáš (referee)
Malignant lymphoproliferative disorders include highly heterogeneous entities, i.e. lymphomas (Non-Hodgkin - NHL, as well Hodgkin's lymphoma), lymphoid leukemias, multiple myeloma and others. As currently many chromosomal aberrations with diagnostic and prognostic significance are known, molecular cytogenetic analyses of tumor cell genome has become a substantial examination also in lymphoproliferative disorders. This thesis focuses primarily on chronic lymphocytic leukemia (CLL), which is one of the mature B-cell neoplasms and represents the most common type of leukemia. We analyzed four most frequently found aberrations (13q14 deletion, ATM and TP53 gene deletion, and trisomy 12) by fluorescence in situ hybridization (FISH) and also IgH gene aberrations in some patients. We compared the findings with other factors and clinical characteristics. This work shows that the conventional G-banding is analysis relatively little relevant. FISH was more effective in detecting aberrations in CLL. Although none of the four aforementioned changes is specific to CLL, the prognostic impact is significant, particularly that of TP53 deletion. Next, detection of some IgH gene translocations is essential in differential diagnosis of CLL and other NHL (follicular, mantle cell, diffuse large B cell, Burkitt's...
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