[Show abstract][Hide abstract] ABSTRACT: Iron metabolism has been implicated in carcinogenesis and several studies assessed the potential role of genetic variants of proteins involved in iron metabolism (HFE C282Y, TFR S142G) in different malignancies. Few reports addressed this issue with relation to chronic myeloproliferative disorders (CMPD). The aims of our study were (a) to examine the potential associations of CMPD development with genetic modifiers of iron metabolism in a large cohort of CMPD patients; (b) to examine associations of genetic variants of proteins involved in iron metabolism; and acquired JAK2 V617F mutation with clinical characteristics of CMPD. HFE C282Y was genotyped in 328 CMPD patients and 996 blood donors as controls, HFE H63D, and TFR S142G were tested in CMPD patients and 171 first time blood donors. JAK2 V617F mutation was tested in CMPD patients and in 122 repeated blood donors. Decreased C282Y allele frequency (allele frequency+/-95% confidence interval) was found in the CMPD group (1.8%+/-1.0%) compared with controls (3.4%+/-0.8%; P=0.048). TFR S142G allele frequency was reduced among V617F-negative CMPD patients (34.8%+/-7.6%) compared with controls (47.8%+/-5.4%; P=0.02). The frequency of JAK2 V617F was 75.9% (249 of 328) in the CMPD group. At presentation, elevated hemoglobin levels were found in V617F-positive patients compared with V617F-negative counterparts (P<0.000). Vascular complications (26.6% versus 15.2%; P=0.039) as well as female gender (57.4% versus 41.8%; P=0.019) were more common in V617F-positive patients. We found that HFE C282Y might be associated with a protective role against CMPD. Because chronic iron deficiency or latent anemia may trigger disease susceptibility for CMPD, HFE C282Y positivity may be a genetic factor influencing this effect.
[Show abstract][Hide abstract] ABSTRACT: The Val617Phe point mutation of Janus kinase 2 gene is believed to participate in the pathogenesis of myeloproliferative syndrome characterised by the clonal alteration of hematopoietic stem cells. According to current results, the frequency of Val617Phe activating mutation is around 80% in polycythaemia vera, 35% in essential thrombocythemia, and 50% in chronic idiopathic myelofibrosis. The diagnoses of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis were so far based on the exclusion of secondary factors as well as bone marrow biopsy histology. The goal of the present work was to establish simple molecular genetic techniques for the routine testing of Janus kinase 2 gene Val617Phe mutation, and to compare the clinical phenotypes of Val617Phe mutation positive and negative myeloproliferative syndromes. We employed the allele specific polymerase chain technique for detection of Val617Phe mutation in 252 patients with myeloproliferative syndrome. We measured Val617Phe frequency as 85,4% (117/137) in polycythemia vera, 56,6% (56/99) in essential thrombocythemia, and 87,5% (14/16) in idiopathic myelofibrosis. We found significantly elevated hemoglobin levels and white blood cell counts (measured at the time of diagnosis) in Val617Phe-positive polycythemia vera and essential thrombocythemia patient groups compared to Val617Phe-negative patients. However, the frequencies of splenomegaly and other complications (thrombosis, bleeding, transformation to acute leukemia) were not significantly different between the mutation-positive and negative groups. In conclusion, the non-invasive mutation analysis of the Janus kinase 2 Val617Phe is suitable for routine laboratory application and helps the differential diagnosis of myeloproliferative syndrome. Although the exact role of Val617Phe mutation testing has not yet been identified on the basis of a broad professional consensus, the testing is suggested in cases of erythrocytoses and thrombocytoses of unknown origin.
[Show abstract][Hide abstract] ABSTRACT: Hepatosplenic T-cell lymphoma is a rare, clinically aggressive lymphoma. Most cases represent a neoplasm of mature non-activated gammadelta T cells. Isochromosome 7q i(7)(q10) is thought to be the primary cytogenetic abnormality of this disease. In this paper, we describe a hepatosplenic gammadelta T-cell lymphoma case, with clonal ring chromosome 7 exemplifying an isochromosome 7q equivalent clonal aberration. A 62-year-old female patient presented with thrombocytopenia, isolated hepatosplenomegaly, and extremely high levels of LDH. Bone marrow work-up demonstrated a sinusoidal cytotoxic T-cell infiltrate with blastic features, while molecular studies verified monoclonal rearrangement for both TCR gamma and TCR delta genes. Cytogenetics revealed clonal abnormalities including ring chromosome 7, trisomy 8, and der(19), while FISH analysis detected 7q amplification with partial deletion of 7p in ring chromosome 7. To the best of our knowledge, this is the first reported T-cell lymphoma case with ring chromosome 7.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 11/2006; 449(4):479-83. · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that non-T, non-B cell CD4+CD56+ neoplasms with lymphoblastic morphology include clinically and immunophenotypically diverse entities. Although their cells of origin or classification are still controversial several entities clearly represent a distinct type of neoplasms that are clinically aggressive.
In this work we present the immunophenotypic and genotypic features of bone marrow (BM), peripheral blood (PB), lymph node and skin lymphocytes from a patient diagnosed as plasmacytoid dendritic cell leukemia involving the skin, BM, PB, lymph nodes, liver and spleen. For determination of immunophenotypic characteristics of malignant plasmacytoid dendritic cells 73 monoclonal antibodies detecting lineage markers, chemokine receptors, cytokine receptors, activation, and co-stimulatory molecules were used.
The malignant cells proved to express CD4+, CD56+ lineage negative leukemia phenotype characteristically positive for CD36, CD38, CD40, CD45, CD45RA, CD68, CD123, CD184, HLA-DR, BDCA2, and granzyme-B corresponding to the preplasmacytoid dendritic cell developmental stage. The presence of CD11a/CD18, CD84, CD91, CD95, alphavbeta5, CDw197, and the absence of CD52 and CD133 in this case can be regarded as additional features of malignant cells. Completing the immunophenotypes with multidrug resistance function can provide additional information for characterizing pDC leukemia.
European Journal Of Haematology 11/2005; 75(4):346-51. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment outcome in patients with acute myeloid leukemia are determined by prognostic factors.
Between January 1996 and December 2001 160 patients were treated with newly diagnosed acute myeloid leukemia. Treatment results were analysed according to the age and cytogenetics. Different types of induction and postremission protocols were applied. The median age was 42.2 +/- 12.8 (16-60) years.
Complete remission was reached in 113 (70.6%) patients. 25/160 (15.6%) individuals were refractory to treatment, 22/160 (13.8%) patients died within one month. One hundred and ten out of 113 who went into remission were given postremission therapy. Twelve out of 50 relapsed patients achieved a second complete remission. The complete remission rate and cumulative survival of patients below the age of forty years were significantly higher than of those above the age of 40 years. Four fifths of refractory patients as well as nearly all patients with secondary leukemia were older than 40 years. Similarly to studies published in the literature, the expected survival was the best in patients who had a favourable cytogenetics. In contrast, all patients who fell into the unfavourable cytogenetic group died within three years. Intensification of the postremission treatment resulted in an improved survival.
Classification of acute myeloid leukemia and careful determination of prognostic factors are necessary at the time of diagnosis. This predicts outcome, as well as provides means for application of individualized therapy.
[Show abstract][Hide abstract] ABSTRACT: An unusual case of hepatosplenic gamma delta T-cell lymphoma with leukemic phase in a 39-year-old woman is reported. At the first presentation she had splenomegaly and pancytopenia diagnosed as hypersplenia treated by splenectomy. Subsequently, she developed hepatomegaly and progressive neoplastic lymphocytosis. The bone marrow showed a sinusoidal infiltrate of medium-sized cells. Flowcytometric analysis of peripheral blood mononuclear cells demonstrated expression of CD3, CD7, CD16, CD56 antigens and T-cell receptor gamma delta. A monoclonal TCR gamma- and beta-chain gene rearrangement were detected by polymerase chain reaction. The patient was treated by traditional chemotherapy and alpha-interferon, unsuccessfully. Therefore, 2-chlorodeoxyadenosine was introduced resulting in a complete remission for 6 months. The reported case demonstrates the usefulness of 2-chlorodeoxyadenosine in treatment of hepatosplenic gamma delta T-cell lymphoma.
[Show abstract][Hide abstract] ABSTRACT: Chimerism is an exceptional immunogenetic state, characterized by the survival and collaboration of cell populations originated from two different individuals. The prerequisites to induce chimerism are immunosuppression, myeloablation or severe immunodeficiency of the recipients on one side and donor originated immuno-hematopoietic cells in the graft on the other. Special immunogenetic conditions to establish chimerism are combined with bone marrow transplantation, transfusion and various kinds of solid organ grafting. There are various methods to detect the type of chimera state depending on the immunogenetic differences between the donor and recipient. The chimera state seems to be one of the leading factors to influence the course of the post-transplant period, the frequency and severity of graft-versus-host disease (GVHD), and the rate of relapse. However, the most important contribution of the chimeric state is the development of graft versus leukemia (GVL) effect. A new conditioning protocol (DBM/Ara-C/Cy) for allogeneic BMT in CML patients and its consequence on chimera state and GVL effect is demonstrated.
[Show abstract][Hide abstract] ABSTRACT: Chimerism is an exceptional immunogenetic state, characterized by the survival and collaboration of cell populations originated from two different individuals. The prerequisits to induce chimerism are immuno-suppression, myeloablation, or severe immunodeficiency of the recipients on the one side and donor originated immuno-hematopoietic cells in the graft on the other. The pathologic or special immunogenetic conditions to establish chimerism are combined with bone marrow transplantation, transfusion, and various kinds of solid organ grafting. Different types of chimerism are known including complete, mixed and mosaic, or split chimerism. There are various methods used to detect the type of chimera state, depending on the immunogenetic differences between the donor and recipient. The induction of complete or mixed chimerism is first determinated by the effect of myeloablative therapy. The chimera state seems to be one of the leading factors to influence the course of the post-transplant period, the frequency and severity of GVHD, and the rate of relapse. However, the most important contribution of the chimeric state is in development of graft versus leukemia effect. A new conditioning protocol (DBM/Ara-C/Cy) for allogeneic BMT in CML patients and its consequence on chimera state and GVL effect is demonstrated.
Human Immunology 03/2000; 61(2):101-10. · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Molecular genetical techniques could be developed for detection of the chimera gene of Philadelphia chromosome or that of its gene product, due to the relatively conserved structure of the chimera gene. The authors successfully analysed 123 blood/bone marrow samples from 106 patients using these molecular techniques adapted from the literature. Patients were classified by the first diagnosis, 65 CML, 7 AML, 13 ALL patients were studied. 12 patients had the diagnosis of myeloproliferative syndrome, and 9 patients were after bone marrow transplantation. 57% of the total, and by diagnosis, 74% of CML, 28% of AML, 54% of ALL, and 33% of post-transplant samples have shown the chimera gene structure characteristic for Philadelphia chromosome. All patients of myeloproliferative syndrome were negative. In some cases the authors had the opportunity to study simultaneously the peripheral blood and the bone marrow sample of the same patient and of the same date. The ratio of the positivity of the two samples varied from one to infinite. The authors could follow the effect of interferon in one case, the change of clonality of the leukemic cell line in an other case. They had the opportunity to detect two different abnormal gene structures in the sample of an AML patient.
[Show abstract][Hide abstract] ABSTRACT: Between 1984-1988, 57 adult acute leukemic patients were treated with intensive combined chemotherapy in the National Institute of Haematology and Blood Transfusion. For the evaluation of response to therapy, 4 investigations were performed in parallel: bone marrow aspirate, bone marrow biopsy, cytogenetic analysis and bone marrow culture. Nonparametric test for samples taken for the evaluation of remission status showed that bone marrow biopsy was significantly the most sensitive method for the detection of residual disease. The bone marrow culture was also on the borderline of significance, but the low CFU-GM level did not always correlate with the further clinical course. Occasionally, karyotypic abnormality was the only sign of the residual disease. It would be of great importance to quantitate the minimal residual disease in order to evaluate and compare the various intensive postinduction therapeutic strategies.
[Show abstract][Hide abstract] ABSTRACT: The authors report on two multiple myeloma sibling pairs. In the absence of a known disease-specific marker one can only speculate
on an explanation: is it because of inherited errors or is it related to the same environmental exposure, or both? In this
study HLA typing and metabolizing enzyme polymorphism studies have been carried out with the aim of finding inherited similarities
in the siblings or characteristics that might differ from the average population. Sibling pair 1 shared an HLA haplotype.
Sibling pair 2 shared only HLA-B51, DR4, DRw53, DQ3. Sibling 1/1 was GSTT1 / GSTM1 null and GSTP1 Ile105Val; sibling 1/2 was a GSTT1 / GSTM1 heterozygote and GSTP1 Ile105Val; sibling 2/1 and 2/2 were GSTT1 heterozygotes and shared GSTM1 null / GSTP1 Ile105Ile. The siblings had identical light chain or heavy chain secretion, or both. The similarities found in the inherited factors
together with the same environmental exposure in the siblings’ first 20 years of life imply that the development of the same
disease cannot be a coincidence.
Central European Journal of Medicine 4(4):501-505. · 0.26 Impact Factor