Skuteczne leczenie ibrutynibem chorego na przewlekłą białaczką limfocytową z obecnością delecji 17p – opis przypadku

W pracy przedstawiono przypadek 62-letniego chorego na PBL z obecnością delecji 17p, u którego zastosowanie immunochemioterapii nie przyniosło oczekiwanego efektu. Dopiero leczenie ibrutynibem doprowadziło do remisji częściowej choroby (zmniejszenia limfadenopatii, normalizacji obrazu morfologii krwi)

Assessment of Red Blood Cell Distribution Width as a Prognostic Marker in Chronic Lymphocytic Leukemia

Red blood cell distribution width (RDW) is a quantitative measure of the variability in size of circulating erythrocytes. It was recently reported that RDW is a prognostic factor for infection diseases, cardiovascular and pulmonary diseases, as well as some neoplasms. Moreover, RDW is remarkably strong predictor of longevity, including all causes of death, for adults aged 45 years and older. To explain this occurrence it was proposed that persistent IGFs/mTOR signaling is one of the factors that play a role in affecting the RDW and mortality.The above observations induced us to analyze the prognostic role of RDW in chronic lymphocytic leukemia (CLL) being the most frequent type of adult leukemia in Western countries. The obtained results have shown that RDW may be considered as a potential CLL prognostic marker. Elevated RDW level at the moment of diagnosis was associated with advanced disease and presence of other poor prognostic factors. It is also connected with overall survival indicating shorter time in patients with elevated RDW. It is possible that the presently observed correlation between mortality and RDW of the CLL patients is affected by their metabolic (IGF-1/mTOR driven)- rather than chronological- aging. The patients with high level of RDW are expected to have an increased persistent level of IGF-1/mTOR signaling. Within the framework of personalized therapy, these CLL patients therefore would be expected to be more sensitive to the treatment with mTOR inhibitors

Assessment of the pathway of apoptosis involving PAR-4, DAXX and ZIPK proteins in CLL patients and its relationship with the principal prognostic factors

Par-4 (prostate apoptosis response-4) protein was originally found upregulated in prostate tumor cells undergoing apoptosis. Then it was further identified as a proapoptotic protein upregulated both in normal and leukemic lymphocytes. The aim of our study was to assess PAR-4 protein expression in the B cells of CLL patients and to examine its relationship with the expression of other proteins involved in the apoptosis process, such as DAXX, ZIPK and BCL-2. We found a positive relationship between PAR-4 and BCL-2 protein expression. Additionally, there was a positive correlation between PAR-4 and both DAXX and ZIPK protein expression. The results of our research were also analyzed in association with the principal CLL prognostic factors. There was a positive correlation between the expression of PAR-4 protein and the lactate dehydrogenase (LDH) serum concentration (p < 0.005). The expression of PAR-4 protein in B cells correlated positively with the percentage of CD38+ cells (p < 0.05), as well as with CD38+/ZAP-70+ cells (p < 0.05). Moreover, we found a close relationship between LPL protein expression or LPL/ADAM29 MFI ratio and PAR-4 protein expression. Our results confirm the significance of apoptosis deregulation in CLL, and suggest a possible relationship between PAR-4 expression and the clinical course of the disease. This however requires further investigation. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 1, pp. 98&#8211;103

JAK2 mutation status, hemostatic risk factors and thrombophilic factors in essential thrombocythemia (ET) patients

The recently discovered JAK2 V617F point mutation, found in 50&#8211;60% of ET patients, has been reported to be associated with a higher risk of thrombotic events. In this study, we explored if JAK2 V617F mutation, or coexisting thrombophilic and hemostatic risk factors, contributed to these complications. We examined 32 patients with ET, and looked for pathogenetic JAK2 V617F mutation and prothrombotic genes mutations: factor V Leiden, prothrombin and MTHFR. We also evaluated plasma levels of fibrinogen, factors VIII and XII, AT, protein C, protein S and serum level of homocysteine. Urokinase concentration was assessed in patients&#8217; plasma as well as platelet lysates. There was no difference in the number of thrombotic complications between ET patients with and without JAK2 mutation. However, we found a number of thrombophilic and hemostatic risk factors that could contribute to thrombotic complications in ET patients. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 2, pp. 267&#8211;271

Tie-2 expressing monocytes in chronic lymphocytic leukemia

IntroductionIn peripheral blood, monocytes form a heterogeneous population of cells. One particular subset of circulating monocytes is expressing the angiopoietin receptor Tie-2 (Tie2-expressing monocyte; TEM). TEM are characterized by tumor promoting properties. However, the role of TEM in chronic lymphocytic leukemia (CLL) immunopathogenesis remains undefined.Material and MethodsHere, we evaluated the monocytes with Tie-2 expression (CD14+Tie-2+) in peripheral blood of CLL patients (n=55) and normal subjects (n=15) by flow cytometry. We investigated possible associations between TEM and poor prognostic factors such as CD38 or ZAP-70 expression, Rai stage and unfavorable cytogenetic abnormalities. Moreover, we investigated the association of TEM percentage with CD14++CD16+ monocytes and Treg percentages.ResultsWe found that CLL patients had a higher percentage of CD14+Tie-2+ monocytes compared to normal controls. The percentage of TEM was positively associated with ZAP-70 expression as well as with unfavourable cytogenetic changes: del(17p) and/or del(11q). The frequency of TEM increased with the disease stage. We showed no correlation between the percentage of TEM and CD38 expression. The percentage of TEM at diagnosis was associated with white blood cell count as well as with the percentages of CD19+CD5+ lymphocytes and Tregs. The majority of CD14+Tie-2+ cells belonged to the intermediate monocytes subset (CD14++CD16+) while fewer of them were among the classical (CD14++CD16−) or non-classical monocyte (CD14+CD16++) subsets. TEM and CD14++CD16+ monocytes have a proangiogenic activity, suppress T-cell activation and promote Treg expansion. The results suggest that monitoring of TEM number and function may provide useful information in determining disease activity

Ekspresja cytokin wewnątrzkomórkowych w limfocytach T u chorych na przewlekłą białaczkę limfocytową

Functional disorders of T lymphocytes play an essential role in abnormal immune response in patients with chronic lymphocytic leukemia. The aim of this study was to assess the profile of cytokines expressed by T cells derived from patients with CLL. We have demonstrated that the intracellular levels of IL-2, IL-4, IFN-γ, TNF, IL-6 and IL-10 were significantly higher in T cells of CLL patients than in healthy donors. Moreover, the percentages of CD4+/CD3+/TNF+, CD4+/CD3+/IFN-γ+, and CD4+/CD3+/IL-2+ cells were significantly higher in ZAP-70-positive patients compared with ZAP-70-negative ones. Likewise, significantly higher percentages of CD4+/CD3+/TNF+, CD4+/CD3+/IFN-γ+ cells were observed in CD38-positive than in CD38-negative cases. What is more, there was a significant difference in median percentage of CD3+/CD4+ cells expressing TNF, IL-4, IFN-γ, IL-2 or IL-6 between patients carrying the 11q22.3 deletion and/or the 17p13.1 deletion and patients without these genetic aberrations. Our results confirm the functional disorders of T cells in CLL and their influence on the clinical course of the disease

Analiza apoptozy ex vivo komórek B i T z krwi obwodowej i szpiku kostnego chorych na przewlekłą białaczkę limfocytową

In this study we analyzed selected parameters of apoptosis in leukemic cells from peripheral blood and bone marrow of patients with chronic lymphocytic leukemia (CLL). The percentage of apoptotic leukemic B cells (Δψmlow/CD19+) was significantly lower in peripheral blood (median: 0.99%) than in bone marrow (median: 1.41%) (pW badaniach przeprowadzono analizę wybranych parametrów apoptozy komórek białaczkowych krwi obwodowej i szpiku chorych na przewlekłą białaczkę limfocytową (PBL). Odsetek białaczkowych limfocytów B ulegających spontanicznej apoptozie ex vivo (Δψmlow/CD19+) był większy w szpiku (mediana: 1.41%) w porównaniu z krwią obwodową (mediana: 0.99%) (

TP53 polymorphism in plasma cell myeloma

Introduction. Significant and accessible predictive factors for bortezomib treatment in plasma cell myeloma (PCM) are still lacking. TP53 codon 72 polymorphism (P72R) results in proline (P) or arginine (R) at 72 amino acid position, which causes synthesis of proteins with distinct functions. The aims of our study were to: 1) analyze whether this polymorphism is associated with an increased risk of PCM; 2) study whether the P72R polymorphism affects overall survival (OS) among PCM patients; 3) assess the possible association of the P72R polymorphism with sensitivity to bortezomib in cell cultures derived from PCM patients. Material and methods. Genomic DNA from newly diagnosed 59 patients (without IgVH gene rearrangements and TP53 deletions) and 50 healthy blood donors were analyzed by RFLP-PCR to identify TP53 polymorphism. Chromosomal aberrations were detected by use of cIg-FISH. The lymphocyte cell cultures from a subgroup of 40 PCM patients were treated with bortezomib (1, 2 and 4 nM). Results. The P allele of the P72R polymorphism was more common than the R allele in PMC patients compared to controls (39% vs. 24%), and the difference was significant (p = 0.02). The PP and PR genotypes (in combina­tion) were more frequent among cases than in controls (65% vs. 42%, OR = 2.32, p = 0.04). At the cell culture level and 2 nM bortezomib concentration the PP genotype was associated with higher necrosis rates (10.5%) compared to the PR genotype (5.7%, p = 0.006) or the RR genotype (6.3%, p = 0.02); however, no effect of genotypes was observed at bortezomib concentrations of 1 and 4 nM. The shortest OS (12 months) was observed in patients with the PP genotype compared to patients with the PR or RR genotypes (20 months) (p = 0.04). Conclusions. The results suggest that P72R polymorphisms may be associated with an increased PCM risk and may affect OS of PCM patients. However, we saw no consistent results of the polymorphism effect on apoptosis and necrosis in cell cultures derived from PCM patients. Further studies are need in this regard

ACE Insertion/Deletion Polymorphism (rs4646994) Is Associated With the Increased Risk of Multiple Myeloma

Introduction: The insertion (I allele) deletion (D allele) polymorphism of ACE gene (rs4646994) may influence the etiopathogenesis of multiple myeloma (MM). ACE gene is expressed in bone marrow cells and encodes angiotensin converting enzyme (ACE). It converts angiotensin I to active peptide angiotensin II, which stimulates proliferation of hematopoietic stem cells. This suggests possible association of ACE I/D gene polymorphism with MM. The aim of our study was to check possible impact of this polymorphism on risk of development and outcome of MM, as well as, sensitivity to bortezomib in cell cultures derived from MM patients.Objects and Methods: Genomic DNA from 98 newly diagnosed MM patients and 100 healthy blood donors were analyzed by PCR method. Chromosomal aberrations were detected by use of cIg-FISH. In a subgroup of 40 MM patients nucleated bone marrow cells were treated with bortezomib in vitro.Results: The Hardy-Weinberg equilibrium test showed that genotypic frequencies diverged significantly from the equilibrium. The differences between I and D allele frequencies in control and study population were significant (p = 0.046). We observed the association between DD genotype and more than 2-fold risk of MM - OR = 2.69; p &lt; 0.0001. We did not detect any significant differences among studied genotypes regarding clinical and laboratory parameters. Moreover, we did not observe the association between survival of MM patients and I/D genotypes. Bortezomib increased number of apoptotic and necrotic cells, but the only statistically significant differences were observed in the number of viable cells at 1 nM between ID and DD genotypes (p = 0.026).Conclusion: Presented results confirmed the significant relationship between ACE (I/D) polymorphism and risk of MM development. We did not observe the association of ACE I/D polymorphism with disease outcome and bortezomib in vitro sensitivity

Secondary malignancy in patients with essential thrombocythemia – case reports

Nadpłytkowość samoistna (ET; essential thrombocythemia) należy do przewlekłych chorób mieloproliferacyjnych i ma na ogół mało agresywny przebieg, jednak czas przeżycia chorych jest krótszy w porównaniu z ogólną populacją. Do niedawna za główne przyczyny skrócenia czasu życia chorych uznawano zaawansowany wiek i przebyte epizody zakrzepowe. Obecnie coraz więcej uwagi zwraca się na inny powód, jakim jest rozwój u tych chorych wtórnych nowotworów niehematologicznych.ET is a relatively indolent disease, but a shorter survival of patients has been observed. Previously the main risk factors for reduced survival time were advanced age and the history of thrombotic complications. Recently the other cause of reduced survival is put on – secondary nonhematological neoplasms