X Yataganas

Imperial College London, London, ENG, United Kingdom

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Publications (101)276.12 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In elderly patients with secondary leukemia, poor therapeutic response and low overall survival have been attributed mainly to age and to the primary resistance of leukemic cells to chemotherapy. Modulation of resistance has been attempted in different studies, but the results have been contradictory. We conducted an open, randomized multicenter clinical trial involving patients more than 60 years old with secondary leukemia preceded by a myelodysplastic syndrome. The induction chemotherapy regimen included idarubicin, cytarabine, and etoposide (group A); randomization involved simultaneous administration of cyclosporin-A per os (group B). Fifty-five patients were evaluated, 26 in group A and 29 in group B. Overall complete remission was achieved in 40% of the patients, 27% vs 52% in groups A and B, respectively (p=0.01). Leukemia-free survival was more favorable in patients who received cyclosporin-A, 12 vs 7 months for groups B and A, respectively (p=0.03). In a follow up period of 30 months, 7 out of 55 patients (13%) were alive, 4 of whom were in complete remission. Five out of the 7 alive patients were randomized in group B and had received cyclosporin-A. Treatment failure was higher in group A [19 of 26 patients (73%)] than in group B with CsA [14 of 29 patients (48%)] (p<0.0001). Treatment-related toxicity/mortality was 13%. Modulation of drug resistance by CsA in elderly people suffering from secondary acute leukemia may improve the outcome of chemotherapy without increasing drug toxicity and treatment-related mortality.
    Annals of Hematology 05/2006; 85(4):250-6. · 2.87 Impact Factor
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    ABSTRACT: Analysis of the rearranged immunoglobulin variable region gene hypermutation has provided important information concerning the clonal history and ontogenetic origin of various B-cell lymphoproliferative disorders. Under the selective pressure of antigen, mutational events in immunoglobulin genes will fine tune survival of B-cell clones bearing immunoglobulin with high affinity for antigen. Our studies aimed at analyzing neoplastic disorders originating from germinal and post-germinal center B-cells: follicular lymphoma and multiple myeloma. respectively. Despite the already acknowledged evidence for a selectable distribution of mutations within the clonal immunoglobulin variable heavy chain genes, very little is known about the contribution of light chains in the process of antigen selection. In follicular lymphoma. a more limited pattern of somatic mutation with less evidence of antigen selection was observed in variable K light chain genes (40%) than in their partner heavy chain genes (80%). In myeloma, hypermutation of variable light chain genes, with a distribution suggestive of antigen selection, was frequently observed. Based on these data and recent reports it appears that the light chain expressed by the clonogenic myeloma B-cells plays a pivotal role in the antigen selection process. Additionally, abortive K light chain variable region genes in X-expressing myeloma carried a significant number of somatic mutations indicating that the cell of origin is open to the hypermutation machinery at that particular developmental stage irrespective of antigen selection.
    Immunological Reviews 04/2006; 162(1):281 - 292. · 12.16 Impact Factor
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    ABSTRACT: Activating mutations of the FLT3 receptor tyrosine kinase are common in acute promyelocytic leukemia (APL) but have uncertain prognostic significance. Information regarding FLT3 expression levels in APL without FLT3 mutations is lacking. Using RT-PCR, mutation analysis of the FLT3 gene, regarding internal tandem duplications (ITDs) and codon 835-836 point mutations, was performed and real-time PCR was carried out to determine the level of FLT3 expression in 11 APL patients at diagnosis and 5 in haematological remission with molecularly detectable disease. High levels of FLT3 transcript, at least a 10-fold increase compared to the normal controls, were found at diagnosis in all 3 mutated cases and in 2 patients without detectable FLT3 mutations. FLT3 overexpression can be documented in patients without FLT3 mutations. These patients might benefit from treatment using specific FLT3 tyrosine kinase inhibitors. Larger studies are needed to evaluate the clinical and biological significance of FLT3 overexpression in the absence of FLT3 mutations.
    Anticancer research 01/2006; 26(2A):1201-7. · 1.71 Impact Factor
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    ABSTRACT: The clinical relevance of FLT3 activating mutations in Acute Promyelocytic Leukemia (APL) and its molecular subtype is not clear. Survivin, an inhibitor of apoptosis protein is known to be expressed in leukemic cell lines and cancer cells but not in adult tissue except thymus and placenta. It has also been proposed as a useful biological marker for circulating neoplastic cells. The aim of this study was to screen 16 bone marrow APL samples at diagnosis, all expressing L-type PML/RARa for Internal Tandem Duplications (ITDs) and Asp835 mutations of the FLT3 gene and survivin expression as well as to examine survivin expression during PML/RARa molecular remission long after completing chemotherapy in patients with full haematopoietic recovery.For FLT3 activating mutations and detection of survivin we used specific PCR assay for cDNA and digestion with EcoRV for Asp835 mutations. Sixteen patients (11 female, 5 male) with median age 52.5 (15-75) years and median follow up 37 (8-115) months were examined. Only one patient relapsed 30 months after diagnosis, who became molecular negative after treatment with arsenic trioxide, one patient died during induction therapy and for 2 patients no samples were available during follow up. Thirteen patients could be evaluated for survivin mRNA expression during molecular remission. All patients were treated according to the APL protocol of the Greek AML Study Group. In 3 out of 16 patients (18.7%) ITDs were detected but no Asp835 mutations were found. The nly patients with haematological relapse was negative for activating mutations both at diagnosis and relapse. In 4 out of 13 (33.3%) evaluatable patients in molecular remission for L-PML/RARa with median follow up of 43 (15-88) months survivin could not be detected. ITDs were detected at diagnosis, in 2 out of 4 (50%) survivin negative patients tested in molecular remission.In this group of patients with L-type PML/RARa APL, FLT3 mutstion status and detection of survivin during molecular remission had no statistically significant difference in age, gender, leukocyte number, platelet count, percentage of leukemic blasts in bone marrow and in the course of disease. At diagnosis, 3 patients who were found ITD negative had additional cytogenetic abnormalities, two involving chromosome 8 and one chromosome 10. No correlation was found with survivin expression during molecular remission, with median follow up 38 months. We conclude that the detection od survivin which cannot be detected by RT-PCR in normalbone marrows, could reflect a persistent clone with unknown significance for the clinical outcome of the patients. Futher evaluation of the abobe described needs to be carried out.
    The Hematology Journal 01/2004; 5:318. · 1.86 Impact Factor
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    ABSTRACT: Tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), a new marker reflecting osteoclast activity, and osteoprotegerin (OPG) were measured in 121 patients with multiple myeloma (MM) at diagnosis, and in 63 of them during pamidronate administration, to define their correlation with the extent of bone disease and disease activity in MM. Radiographic evaluation of the skeleton, measurement of other markers of bone remodelling, including N-terminal cross-linking telopeptide of type-I collagen (NTX), bone alkaline phosphatase and osteocalcin and of markers of disease activity (beta2-microglobulin, paraprotein, interleukin-6 (IL-6), were also performed. Levels of TRACP-5b were increased (p <.0001), while OPG was decreased in MM patients compared to controls (p <.01). TRACP-5b levels were associated with the radiographically assessed severity of bone disease (p <.0001) as well as with levels of NTX, IL-6 and beta2-microglobulin (p <.001, for each biochemical parameter, respectively). The combination of pamidronate with VAD-chemotherapy produced a reduction in TRACP-5b, NTX, IL-6, paraprotein and beta2-microglobulin levels from the 2nd month of treatment, with no effect on bone formation and OPG. A strong correlation was observed between changes in TRACP-5b and changes in NTX, IL-6 and beta2-microglobulin, while TRACP-5b predicted the disease progression in 5 patients. These findings suggest that TRACP-5b is increased in MM, reflects the extent of myeloma bone disease and may have a predictive value. TRACP-5b has also proved to be very useful for monitoring antimyeloma treatment, which had no effect on OPG levels.
    International Journal of Cancer 10/2003; 106(3):455-7. · 6.20 Impact Factor
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    ABSTRACT: Interaction between receptor activator of nuclear factor kappaB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRP), and beta2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We generated a prognostic index based on these factors that divided our patients into 3 risk groups. The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively. Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.
    Blood 09/2003; 102(3):1064-9. · 9.78 Impact Factor
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    ABSTRACT: Coexistence of Philadelphia chromosome-negative (Ph-) progenitors with the Ph+ clone in the early chronic phase of chronic myeloid leukemia (CML) has been documented in previous reports. A different evaluation of methods is needed to justify the clonality of the residual Ph- progenitors. Therefore, the X chromosome inactivation patterns in individual granulocyte-monocyte colony-forming unit (CFU-GM) colonies were studied with the clonality assay for the human androgen receptor gene. A prerequisite for this evaluation was the validation of T-lymphocytes and buccal cells as control cells representing the constitutional lyonization. The percentages of polyclonal CFU-GM cells were determined in 9 Ph+ women with CML and in 5 healthy women. Results of the clonal analysis of CFU-GM colonies were compared with those from reverse transcriptase-polymerase chain reaction analysis of single colonies for BCR/ABL transcripts. Both methods of CFU-GM cell analysis were in agreement regarding the presence of variable proportions (0%-94%) of normal cells in CML. Our results suggest that (a) T-cells and buccal cells have potential for use as controls for the clonal analysis of CML cases and (b) this method can evaluate the frequency of polyclonal/clonal CFU-GM cells in CML cases and is applicable to the analysis of myeloid clonal disorders that lack specific molecular markers.
    International Journal of Hematology 07/2003; 77(5):476-81. · 1.68 Impact Factor
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    ABSTRACT: Postremission therapy is critical in maintaining complete remission (CR) in patients with de novo acute myelogenous leukemia (AML). The aim of this trial was to compare allogeneic stem cell transplantation (SCT), high-dose cytarabine (ara-C; HiDAC), and autologous SCT as postremission therapy in patients with de novo AML. One hundred twenty patients age </= 60 years with previously untreated AML (non-M3) and a performance status score of </= 2 received induction therapy with 3 days of idarubicin and 7 days of ara-C (IA). Patients in CR received one course of HiDAC. Subsequently, patients age </= 50 years with available HLA-compatible donors were assigned to receive allogeneic SCT; patients with "favorable" cytogenetics received a second course of HiDAC; and all others were randomized to a second course of HiDAC or autologous SCT. The IA combination induced CR in 99 patients (82.5%). With a median follow-up of 43 months (range, 18-64 years), the 3-year survival and failure-free survival (FFS) rates were 47% and 45%, respectively. The factors associated with longer survival were those identified for CR (i.e., age and cytogenetics). Forty-nine patients (49%) received the assigned postremission therapy. Fifteen patients underwent allogeneic SCT. Nineteen patients underwent autologous SCT and 15 patients received a second course of HiDAC, after randomization. In the allogeneic SCT group, both the 3-year survival and the FFS rates were 73%. In the autologous SCT and HiDAC groups, the 3-year survival rates were 58% and 46%, respectively (P = 0.80), and the 3-year FFS rates were 42% and 33%, respectively (P = 0.83). The three postremission treatment groups had comparable survival. Allogeneic SCT is associated with a prolonged FFS.
    Cancer 04/2003; 97(7):1721-31. · 5.20 Impact Factor
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    ABSTRACT: Early lymphoid differentiation is characterized by antigen receptor gene rearrangements; the rearrangement process is governed by two lymphoid-specific genes, RAG (recombinase activating gene)-1 and -2. The available data on the incidence and prognostic significance of clonal immunoglobulin heavy chain (IgH) gene rearrangements in acute myeloid leukemia (AML) are rather contradictory. The aim of this study was to evaluate the incidence and prognostic significance of RAG-1 and -2 mRNA transcripts and clonal IgH gene rearrangements in a cohort of uniformly treated AML patients; the available literature is also reviewed. The study was performed on 76 AML patients, newly diagnosed between August 1996 and November 1999. RAG-1/-2 gene expression was analyzed by a reverse transcriptase polymerase chain reaction technique and IgH gene rearrangements were detected with variable region (VH) family-specific and consensus framework region (FWR)-2 and/or-3 primers. Statistical associations were explored between IgH monoclonality/ RAG mRNA expression and: (i) age, gender, FAB subtype, immunophenotype, cytogenetic risk groups; (ii) response variables (response/relapse incidence, survival). In total, 38/75 samples (50.6%) were RAG-1 and/or -2 positive; 30/76 samples (39.5%) carried clonal IgH genes, whereas 13/30 IgH-positive samples (43.3%) were RAG-1/2-negative. Significant associations were detected only for RAG-2 positivity and unfavorable karyotype and IgH monoclonality and FAB subtypes M4/ M5; no association was identified with response outcome and survival. Lymphoid-specific molecular markers are detected in a significant proportion of AML patients, regardless of differentiation status (assessed morphologically/ immunophenotypically); however, in our experience, they do not seem to constitute an adverse prognostic factor.
    Haematologica 04/2003; 88(3):268-74. · 5.94 Impact Factor
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    ABSTRACT: Various morphometric characteristics of microvessels, highlighted by means of anti-CD34 immunohistochemical staining, were evaluated in the bone marrow of 52 patients with chronic myeloid leukemia (CML) in chronic phase, in relation to several clinicopathologic parameters. Twenty control bone marrows and 15 cases of CML in blastic phase were also studied. Microvessel density (MVD), total vascular area (TVA) and several size- and shape-related parameters were quantitated in the region of most intense vascularization using image analysis. Overall, the group of chronic phase CML had higher MVD and size-related parameters and more branching microvessels than controls. Blastic phase was characterized by increased numbers of microvessels with a rounder shape and smaller caliber than chronic phase. A positive correlation emerged between marrow fibrosis and MVD as well as between white blood cell counts and rounder vessel sections. No relationship existed between microvascular parameters and Hasford or Sokal prognostic scores. In univariate analysis, overall and progression-free survival were adversely affected by MVD, size-related parameters, increased platelet count, age and spleen size. Multivariate analysis indicated that microvessel area was related to progression-free survival, whereas both MVD and area were significant prognosticators of overall survival, even when Hasford or Sokal scores are introduced into the model. Our data suggest that changes in angiogenic parameters may participate in the conversion of normal marrow to CML and ultimately to blastic transformation. More importantly, MVD and microvessel caliber are significant predictors of patient survival and progression.
    Leukemia 02/2003; 17(1):89-97. · 10.16 Impact Factor
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    ABSTRACT: Bisphosphonates have been found to reduce skeletal events in patients with multiple myeloma (MM). This is the first randomised trial to compare the efficacy of pamidronate and ibandronate, a third-generation aminobisphosphonate, in bone turnover and disease activity in MM patients. Patients with MM, stage II or III, were randomly assigned to receive either pamidronate 90 mg (group I: 23 patients) or ibandronate 4 mg (group II: 21 patients) as a monthly intravenous infusion in addition to conventional chemotherapy. Skeletal events, such as pathologic fractures, hypercalcaemia, and bone radiotherapy were analysed. Bone resorption markers [N-terminal cross-linking telopeptide of type-I collagen (NTX) and tartrate-resistant acid phosphatase type 5b (TRACP-5b)], bone formation markers (bone alkaline phosphatase and osteocalcin), markers of disease activity (paraprotein, CRP, beta 2-microglobulin), and interleukin-6 (IL-6) were also studied. In both groups, the combination of chemotherapy with either pamidronate or ibandronate produced a reduction in bone resorption and tumour burden as measured by NTX, IL-6, paraprotein, CRP, and beta 2-microglobulin from the second month of treatment, having no effect on bone formation. TRACP-5b also had a significant reduction in the pamidronate group from the second month of treatment and in the ibandronate group from the sixth month. However, there was a greater reduction of NTX, IL-6, and beta 2-microglobulin in group I than in group II, starting at the second month of treatment (P = 0.002, 0.001, and 0.004, respectively) and of TRACP-5b, starting at the fourth month (P = 0.014), that being continued throughout the 10-month follow-up of this study. There was no difference in skeletal events during this period. A significant correlation was observed between changes of NTX and changes of TRACP-5b, IL-6, and beta 2-microglobulin from the second month for patients of both groups. These results suggest that a monthly dose of 90 mg of pamidronate is more effective than 4 mg of ibandronate in reducing osteoclast activity, bone resorption, IL-6, and possibly tumour burden in MM. TRACP-5b has also proved to be a useful new marker for monitoring bisphosphonates treatment in MM.
    European Journal Of Haematology 02/2003; 70(1):34-42. · 2.55 Impact Factor
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    ABSTRACT: Conventional cytogenetic analysis (CCA) is the standard method for monitoring of the Philadelphia (Ph) chromosome in chronic myeloid leukemia (CML). Evaluation of breakpoint cluster region/abelson murine leukemia (BCR/ABL) fusion using interphase fluorescence in situ hybridization on peripheral blood smears (PB-FISH) might be another approach allowing more frequent and less invasive follow-up investigations. Herein, BCR/ABL fusion gene was assessed on 21 PB smears from 16 CML patients in chronic phase. Results of PB-FISH were compared with those of CCA and interphase FISH on bone marrow aspirates (BM-FISH). PB-FISH analysis was combined with CD3 immunophenotyping that allowed simultaneous investigation of the leukemic status of CD3(+) T lymphocytes and scoring CD3(-) cells for BCR/ABL fusion gene. Moreover, the frequency of BCR/ABL fusion in nonlymphoid PB cells was estimated according to the differential leukocyte counts. The incidence of BCR/ABL(+) fusion signals in CD3(+) T cells of CML patients was 5.3% (SD +/- 1.9) and did not exceed the normal cut-off value of 8%. A significant correlation (P < 0.001) was found between results of PB-FISH and methods of BM analysis (CCA or BM-FISH). Correction of PB-FISH results to include only nonlymphoid or CD3(-) cells reduced the mean of differences and improved agreement between PB-FISH and CCA or BM-FISH methods. The best agreement was noted between CCA and PB-FISH on nonlymphoid cells. On the other hand, results of BM-FISH agreed well with those of PB-FISH on CD3(-) cells. These findings imply that PB-FISH on nonlymphoid or CD3(-) cells is reliable and may replace BM analysis for monitoring of response to treatment in CML patients.
    Clinical & Laboratory Haematology 01/2003; 24(6):361-7. · 1.11 Impact Factor
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    ABSTRACT: Interaction between receptor activator of nuclear factor kB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodelling markers in121 newly diagnosed MM patients to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The ratio sRANKL/OPG was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The ratio sRANKL/OPG, CRP and b2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We have generated a prognostic index based on these factors, which divides our patients into three risk groups. The low-risk group had a 96% probability of survival at five years while the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0% respectively. Not only do these results confirm for the first time in humans the importance of the sRANKL/OPG in the development of bone disease but they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.
    The Hematology Journal 01/2003; 4:256. · 1.86 Impact Factor
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    ABSTRACT: Bone disease is a major cause of morbidity in multiple myeloma (MM). Through the interactions between myeloma and stromal cells, osteoclasts are activated resulting in an increased resorptive activity, which is illustrated by the elevated levels of N-telopeptide of type-I collagen (NTX), and of tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), an enzyme which is produced only by activated osteoclasts. The receptor activator of nuclear factor-kB ligand (RANKL) and osteoprotegerin (OPG) pathway has been found to be the dominant mediator of osteoclastogenesis and possibly promotes growth of myeloma cells. The aim of this study was to evaluate the role of soluble RANKL (sRANKL), OPG and markers of bone remodelling [NTX, TRACP-5b, bone-alkaline phosphatase (bALP), and osteocalcin (OC)] in bone disease and survival in MM. A total of 121 newly diagnosed patients (61M/60F; median age: 68 years) with MM were studied. Ten patients had no lytic lesions or osteoporosis only; 28 patients had 1-3 osteolytic lesions, while 83 patients had >3 osteolytic lesions and/or a pathological fracture. The above markers were also measured in 46, age and sex matched, healthy controls. Patients with MM had elevated mean sRANKL, TRACP-5b and NTX values and decreased levels of OPG, OC and bALP compared with controls. The ratio of sRANKL/OPG was also significantly higher in MM patients. There was a strong correlation between the ratio sRANKL/OPG and the extent of bone disease (p<0.001), stage of MM (p<0.0001), levels of TRACP-5b (p<0.0001), NTX (p<0.0001), IL-6 (p<0.0001), and beta2-microglobulin (p<0.0001). The median overall survival for the 121 patients was 56.9 months. Eighty-two patients had received only conventional chemotherapy, while 39 patients had undergone autologous stem cell transplantation. The multivariate analysis revealed that only the ratio of sRANKL/OPG, and the levels of beta2-microglobulin and CRP were independent prognostic factors for survival. Based on these 3 factors, we created a risk score (Hammersmith Prognostic Index): sRANKL/OPG ratio of <1 and beta2-microglobulin levels of 3 mg/l was given a score of 1 point; sRANKL/OPG ratio of between 1-3 and CRP levels of 10 mg/l had 2 points; 3 points were given for CRP levels of >10 mg/l and beta2-microglobulin of >3 mg/l, and 4 points for sRANKL/OPG ratio of >3. This system has subdivided our patients into three groups. The low-risk group included 26 patients (score <6), the intermediate group 55 patients (score 6-8), and the high-risk group 40 patients (score >8). The 5-year probability of survival for each group is illustrated in the Figure. We compared this scoring system with that proposed by Bataille et al using beta2-microglobulin and CRP as prognostic values. Our risk score appears to be more discriminating in identifying a very good risk group, and a superior intermediate risk group. Not only do these results confirm for the first time in humans the importance of the RANKL/OPG system in the development of bone disease but they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.
    Hematology J. 4 (suppl 1), S161, 2003. 01/2003; 4:S161.
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    ABSTRACT: The information concerning potential effects of somatic hypermutation on bcl-2 sequences translocated to the immunoglobulin heavy chain gene (IgH) locus in follicular lymphoma (FL) is rather limited. We analysed the complete open reading frame (ORF) of the bcl-2 gene for the presence of mutations in 24 bcl-2/IgH-positive diagnostic FL samples by the single strand conformation polymorphism (SSCP) technique. A prior analysis on many of these FL samples had revealed a consistent pattern of somatic hypermutation in IgH genes. Abnormally migrating bands on SSCP gels were identified only in 4/24 samples. This result provides strong support for the notion that in FL the translocated bcl-2 coding region is not targeted by somatic hypermutation.
    Leukemia and Lymphoma 01/2003; 43(12):2391-3. · 2.61 Impact Factor
  • Leukemia Research 08/2002; 26(7):699-700. · 2.76 Impact Factor
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    ABSTRACT: Treatment with recombinant human erythropoietin (rHuEpo) improves anaemia in approximately 20% of patients with myelodysplastic syndromes (MDS). We investigated the potential advantage of a prolonged administration of rHuEpo to achieve higher erythroid response rates (RR) in 281 MDS patients: 118 with refractory anaemia (RA), 77 with refractory anaemia and ringed sideroblasts (RARS), 59 with refractory anaemia with excess of blasts and blast count < 10% (RAEB-I), and 27 with RAEB and blast count between 11-20% (RAEB-II). rHuEpo was given subcutaneously at a dose of 150 U/kg thrice weekly, for a minimum of 26 weeks. Response to treatment was evaluated after 12 and 26 weeks of therapy. The overall RR was 45.1%; the RR for RA, RARS, RAEB-I and RAEB-II were 48.3%, 58.4%, 33.8% and 13% respectively. A significant increase in RR was observed at week 26 in RA, RARS and RAEB-I patients, as the response probability increased with treatment duration. The RR was higher in the good cytogenetic prognostic group and serum Epo level of > 150 U/l at baseline predicted for non-response. The median duration of response was 68 weeks and the overall risk of leukaemic transformation was 21.7%. These results suggest that prolonged administration of rHuEpo produces high and long-lasting erythroid RR in MDS patients with low blast counts, particularly in those with pretreatment serum Epo levels of < 150 U/l and good cytogenetic prognosis.
    British Journal of Haematology 07/2002; 118(1):174-80. · 4.94 Impact Factor
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    ABSTRACT: Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative diseases that carry intrinsically the potential for leukemic transformation. The aims of this study were (1) to detect involvement of N- and K-ras mutations in codons 12 and 13 in the pathogenesis of the chronic and blastic phases of PV and ET, (2) to study the occurrence of microsatellite instability (MSI) in chromosomes 5 and 7 during the chronic phase and blastic transformation of the disease, and (3) to examine the incidence of leukemia in patients treated with hydroxyurea (HU). Samples of PV and ET patients were analyzed with a polymerase chain reaction. No N- or K-ras mutations were detected. A positive score for MSI in chromosome 7 was found in 1 patient with PV during leukemic transformation. Three of 69 patients developed acute myelogenous leukemia, 2 with PV and 1 with ET. As of this report, the overall incidence of leukemic transformation is 5.7% (2/35 patients) in PV and 3.3% (1/30 patients) in ET patients treated with HU. These results indicate that (1) MSI is a genetic marker that can be detected, even in a small group of patients, at the blastic phase of the disease and (2) no increased leukemogenicity was noted in this group of patients treated with HU.
    International Journal of Hematology 06/2002; 75(4):394-400. · 1.68 Impact Factor
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    ABSTRACT: Amifostine (AMF) promotes in vitro growth and survival of hematopoietic progenitors. In this study we evaluated the efficacy of AMF in the treatment of anemia in patients with low-risk myelodysplastic syndromes (MDS) and the possible predicting value for response to AMF therapy of two types of in vitro clonogenic assays. Two different doses of AMF, 300 mg/m2 (group A, 11 patients) or 400 mg/m2 (group B, 16 patients), were studied. AMF was given three times weekly for 3 weeks, i.v., followed by 2 weeks off therapy. Patients were evaluated after two cycles of treatment. Partially or nonresponding patients of group A received 400 mg/m2 AMF and were reevaluated. An increase of hemoglobin (Hb) values of more than 2 g/dl and a 100% decrease in transfusion requirements for at least 6 weeks were defined as a complete response (CR) while an increase of Hb values of 1-2 g/dl or a 50% decrease in transfusion requirements was considered as a partial response (PR). In group A, two out of 11 (18.1%) patients achieved a CR with the initial dose and one of the nine that received 400 mg/m2 AMF achieved a PR. In group B, three out of 16 (18.7%) patients achieved a PR; the overall response rate in both groups was 22.2%. In group A, bone marrow progenitor assay was performed pre- and post-amifostine treatment. Erythroid burst-forming units (BFU-E) were increased in six out of 11 (54.5%) patients, and this increase preceded the rise in Hb levels in three of them. In group B, a clonogenic assay was performed in 11 out of 16 patients before AMF treatment. In vitro results after pretreatment with 500 microM amifostine confirmed the response of two MDS patients that achieved a PR. No response in vitro was observed in all eight nonresponding patients and in one PR patient. The lack of response in the clonogenic assays predicted for nonresponse to treatment with a predictive power of 91.8%. We conclude that 300 mg/m2 is an adequate initial treatment for low-risk MDS patients and both clonogenic assays have a strong predicting value for response to treatment.
    Annals of Hematology 05/2002; 81(4):182-6. · 2.87 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by ineffective haemopoiesis, resulting in variable degrees of cytopenia and intrinsically carrying the potential of leukaemic transformation. Neither curative nor standard therapy has been available yet for the majority of patients with MDS. Young patients with matched related donors might undergo allogeneic bone marrow transplantation, while high-dose chemotherapy may lead to significant lasting improvement in a limited number of patients with high-risk MDS. Combination of growth factors, like recombinant erythropoietin and recombinant human granulocyte-colony-stimulating factor, or erythropoietin alone, with or without cyclosporine, has shown favourable response rates in subgroups of these patients [1, 2]. Interleukin-3 and interleukin-6 improve platelet count in about one third of patients with MDS but are associated with relatively important side effects [3]. Danazol, a synthetic attenuated androgen, has received special interest due to its initially demonstrated activity in idiopathic thrombocytopenic purpura and autoimmune haemolytic anaemia and some encouraging results from trials in MDS patients with thrombocytopenia [4–8]. We summarise the results of danazol therapy in 17 patients with MDS and thrombocytopenia and discuss the effect of danazol in this subgroup of MDS patients.
    Acta Haematologica 02/2002; 107(4):234-6. · 0.89 Impact Factor

Publication Stats

890 Citations
276.12 Total Impact Points

Institutions

  • 2003
    • Imperial College London
      • Faculty of Medicine
      London, ENG, United Kingdom
  • 1984–2003
    • Laiko Hospital
      • First Department of Surgery
      Athínai, Attica, Greece
  • 1995–2002
    • National and Kapodistrian University of Athens
      • • Division of Internal Medicine V
      • • Department of Medicine
      • • Department of Internal Medicine - Nursing
      Athens, Attiki, Greece
    • Athens State University
      Athens, Alabama, United States
  • 2001
    • University of Thessaly
      • Laboratory of Biology
      Lárisa, Thessalia, Greece
  • 1991
    • University Hospital of Heraklion
      • Department of Gastroenterology
      Irákleio, Attica, Greece