Stavroula Tsiara

Influence of smoking on predictors of vascular disease.

Beyond the already well-established strong causative relationship with cancer, smoking increases the risk for vascular disease. Smoking may act directly or adversely influence risk factors contributing to the development of vascular disease. Smoking causes endothelial dysfunction, dyslipidemia (decreased high-density lipoprotein cholesterol levels, hypertri glyceridemia and increased oxidation of low-density lipoprotein cholesterol) and platelet acti vation leading to a prothrombotic state. Smoking increases emerging risk factors (eg, fibrinogen, homocysteine, and high-sensitivity C-reactive protein) and increases insulin resis tance and the risk of developing type 2 diabetes mellitus. The beneficial effects of statins and antioxidants (eg, vitamins C and E, β-carotene) are counteracted by smoking. Smoking-induced alterations in growth factors, adhesion molecules, and even in genes can accelerate the progression of atherosclerosis. The aim of this review is to consider the adverse consequences of smoking on the factors predisposing to vascular disease and to emphasize the beneficial effects of smoking cessation.

CpG methylation analysis of the MEG3 and SNRPN imprinted genes in acute myeloid leukemia and myelodysplastic syndromes

Methylation is now established as a fundamental regulator of gene transcription. To investigate this in haematologic malignancies, we evaluated the aberrant promoter methylation of two imprinted genes (MEG3 and SNRPN) in 43 MDS and 42 AML patients. MEG3 hypermethylation occurred in 15 MDS patients (34.9%), and in 20 AML patients (47.6%). SNRPN hypermethylation was observed in 15 MDS patients (34.9%), and in 21 AML patients (50%). There were no significant correlations between WHO subtype, WPSS score, karyotype, haemoglobin levels, white blood cell count, platelet count and CpG methylation of any gene. MEG3 hypermethylation was associated with significantly reduced overall survival in individuals with AML (HR=1.98, p=0.04), while SNRPN CpG methylation was not associated with survival (HR=0.94, p=0.87). In addition, no association between survival and aberrant MEG3 (HR=2.15, p=0.072) or SNRPN methylation (HR=1.08, p=0.85) was observed in patients MDS. Our findings suggest that these genes are abnormally methylated in AML and MDS patients, and methylation of MEG3 confers worse overall prognosis. The MEG3 methylation status may serve as a useful biomarker in leukemia.

Acute phase proteins and interleukins in steady state sickle cell disease.

Abstract: To identify a possible acute phase response during the steady state of sickle cell disease, we estimated the serum alterations of acute phase proteins, β2‐microglobulin (β2M), κ and λ light chains, interleukins (ILs) and tumor necrosis factor‐α (TNFα) in 21 patients. Increased concentrations of C‐reactive protein (CRP) were found in 5 patients, alpha‐1‐acid‐glycoprotein (AGP) in 3, alpha‐1‐antitrypsin (AAT) in 8, ceruloplasmin (CER) in 2, alpha‐2‐macrogiobulin (AMG) in 14 and decreased haptoglobin (HPT) and transferrin (TFR) in 11 and 9, respectively. Increased β2M was found in 10 patients and κ and λ light chains in 11. IL‐1β, IL‐2, IL‐4, IL‐10 and TNFα were not detected in any of the patients. However, significantly increased values of IL‐6 and sIL‐2r were found. This study has demonstrated increased serum levels of some of the acute phase proteins in patients during the steady state of sickle cell disease. This may be a result of a subclinical vaso‐occlusion which in turn leads to a covert inflammatory response. Cytokines, and in particular IL‐6, produced after this response, seem to be responsible for the high levels of acute phase proteins in the steady state of this disease.

Recombinant Human Erythropoietin for the Treatment of Anaemia in Patients with Chronic Idiopathic Myelofibrosis

Background: Patients with chronic idiopathic myelofibrosis (CIMF) usually present with anaemia. Treatment is often palliative and the majority of patients receive regular red blood cell (RBC) transfusions. Although recombinant human erythropoietin (rhu-EPO) has been proved effective for the treatment of anaemia in several chronic diseases, including haematological malignancies, its role in the treatment of the anaemia in CIMF is not well established. We report the beneficial effect of rhu-EPO administration in 20 patients with CIMF and discuss the parameters predicting favourable response. Patients: Twenty patients with CIMF (9 women and 11 men) regularly treated with supportive RBC transfusions were included in the study. The median age was 70 years (range 45–81 years). Rhu-EPO, 10,000 U, was given subcutaneously 3 times a week. The median duration of therapy was 83 months, ranging from 13 to 87 months. Results: Treatment was considered effective if haemoglobin levels increased over 2 g/dl within 12 weeks after enrolment or the RBC transfusion requirements were reduced by 50% within the same interval. Twelve patients (60%) responded to therapy. Responders were mainly female, had smaller spleen size (p = 0.024), low RBC transfusion requirements (≤1–2 units per month), and significantly lower endogenous serum erythropoietin (EPO) and β2-microglobulin (β2-M) levels when compared with non-responders (p < 0.0001 and 0.00001, respectively). Treatment was well tolerated and none of the patients was withdrawn from the treatment protocol because of side effects. Conclusions: Rhu-EPO administration is an effective, safe and well-tolerated treatment for patients with CIMF and anaemia leading to a significant reduction in RBC transfusion requirements. Factors predicting favourable response are low endogenous EPO and β2-M serum levels and slight to moderate splenomegaly.

Treatment of plasma cell leukemia with vincristine, liposomal doxorubicin and dexamethasone

Abstract: Primary plasma cell (PCL) leukemia is a rare lymphoproliferative disorder characterized by a malignant proliferation of plasma cells in the bone marrow and peripheral blood. Survival with standard therapy using melphalan is very poor. Doxorubicin encapsulated with liposomes has less cardiotoxicity, is at least as efficient and has fewer side effects than conventional doxorubicin. Two female patients (69 and 54 yr old) with primary PCL are described in this study. They both received a modified form of VAD (vincristine, doxorubicin and dexamethasone), a regimen which includes liposomal doxorubicin (40 mg/m2 for 1 d), vincristine (2 mg for 1 d) and dexamethasone 40 mg per os on days 1–4, 9–12 and 17–20.

Administration of a modified chemotherapeutic regimen containing vincristine, liposomal doxorubicin and dexamethasone to multiple myeloma patients: preliminary data.

Abstract: For elderly patients with multiple myeloma (MM), conventional melphalan and prednisone (MP) therapy has been the treatment of choice; the vincristine, doxorubicin and dexamethasone (VAD) regimen is preferred for younger patients who also receive high‐dose melphalan in combination with autologous or allogeneic bone marrow transplantation (BMT). Although survival time is similar in both the MP and VAD regimens, the continuous infusion of doxorubicin which the latter treatment entails constitutes a disadvantage along with the 4‐day hospitalization required. Doxorubicin also induces cardiotoxicity, particularly in the elderly. A modified form of VAD therapy includes liposomal doxorubicin (Caelyx®) (40 mg/kg for 1 d), oncovin (2 mg for 1 d) and dexamethasone 40 mg for 4 d per os. Doxorubicin encapsulated with liposomes has less cardiotoxicity, is more efficient and has fewer side effects than conventional doxorubicin, and it can be administered on an outpatient basis: dexamethasone can be given orally and vincristine in bolus infusion. In order to estimate its efficacy and tolerability, we administered this regimen to 12 patients (first‐line treatment in 6 patients, salvage therapy in 6 patients). All patients exhibited good tolerance to liposomal doxorubicin with no severe side effects. Eight patients achieved complete hematological remission and three partial response. One patient died before completing the treatment.

Combination Therapy with Recombinant Human Erythropoietin, Interferon-α-2b and Granulocyte- Macrophage Colony-Stimulating Factor in Idiopathic Myelofibrosis

Seven patients, 3 men and 4 women 48-72 years of age and suffering from idiopathic myelofibrosis were given a combination of recombinant human erythropoietin (r-hu-Epo), interferon-alpha-2b (IFN) and GM-CSF, in an attempt to treat their pancytopenia and marrow fibrosis. The dose of r-hu-Epo was 200 U/kg 3 times weekly, that of IFN was 3 x 10(6)/U 3 times weekly, and that of GM-CSF was 250 micrograms/m2/daily. The duration of therapy ranged from 3 to 6 months for r-hu-Epo and IFN and was 3 weeks for GM-CSF. The treatment regimen had a beneficial effect on all patients. The levels of hemoglobin increased in all patients but particularly in 5 (2 of whom had been dependent on red blood cell transfusions). Splenomegaly decreased significantly in 4 patients. Fibrosis in the bone marrow decreased in 2 patients. Three patients also had an increase in the number of white blood cells during the therapy with GM-CSF. We observed mild side effects in 6 of our patients. One patient had severe side effects from IFN and treatment was discontinued. In conclusion, the combination of r-hu-Epo, IFN and GM-CSF may improve the anemia (due to r-hu-Epo), increase the white blood cell count (due to GM-CSF) and reduce the marrow fibrosis (probably due to IFN) in patients with idiopathic myelofibrosis.

Treatment of β-Thalassemia Patients with Recombinant Human Erythropoietin: Effect on Transfusion Requirements and Soluble Adhesion Molecules

The most common single genetic disorder and a major public health issue in Greece and other Mediterranean countries is β-thalassemia. Current therapeutic approaches for homozygous β-thalassemia entail blood transfusions and iron chelation therapy with deferoxamine or deferiprone for preventing tissue hemosiderosis. Recently, much effort has focused on various inducers of fetal hemoglobin (HbF) such as recombinant human erythropoietin (rHuEPO), especially in β-thalassemia intermedia. Ten adult patients, 5 with β-thalassemia major and 5 with β-thalassemia intermedia, received 150 IU/kg rHuEPO (epoetin-α) subcutaneously three times a week. Seven patients were transfused every 14–30 days and 3 with β-thalassemia intermedia were only occasionally transfused. The minimum duration of treatment was 12 weeks in order to define if there was any response. Transfusion intervals were modified according to the rHuEPO response to maintain stable Hb values. Lower transfusion requirements were observed in 5 patients after rHuEPO treatment (p = 0.028). In the 3 non-transfused patients, Hb values increased, and the patients are still being treated and followed up for a period ranging from 14 weeks to 2 years. Two patients with thalassemia major discontinued treatment after 12 weeks, as they did not achieve any response regarding transfusion requirements or Hb values. Pretreatment serum transferrin receptor levels were higher than in controls (p < 0.001) and significantly increased following rHuEPO treatment (p = 0.027). Patients had higher serum endothelin-3, sICAM-1 and sE-selectin values before rHuEPO treatment compared to controls (p < 0.001, p < 0.001 and p = 0.016, respectively), but these values were not altered during treatment. HbF values presented a slight, non-significant increase. rHuEPO treatment has a beneficial effect in transfusion-dependent β-thalassemia patients. Although a slight increase in HbF levels was observed, other possible mechanisms are probably involved. None of our patients experienced thrombotic complications and a rise in blood pressure.

Pleural Effusion in Chronic Myelomonocytic Leukemia

Pleural effusion in 4 patients with chronic myelomonocytic leukemia (CMML) is described in this report. According to the literature, pleural effusion in CMML is a poorly understood and rare occurrence. Two of our patients presented with pleural effusion as an initial symptom while the other 2 developed it during the course of the disease. In only 1 patient was the pleural effusion due to leukemic infiltration while in the other 3 it was a reactive phenomenon. Peripheral lymphadenopathy was observed only in the former patient who died of acute leukemia. After prednisolone therapy the pleural effusions resolved in the other 3 patients.

Treatment of 34 patients with myelodysplastic syndromes with 13-CIS retinoic acid.

Abstract:  Thirty‐four patients with myelodysplastic syndromes, 23 men and 11 women, aged between 47 and 80 years, with all types of myelodysplastic syndromes were treated with 13‐cis‐retinoic acid. The dose of retinoic acid ranged between 10 and 60 mg/m2/daily and was administered in combination with vitamin E to diminish side effects. The duration of treatment was 3 months to 5 years. Partial remission was achieved in 4 patients, 1 with RA type, 2 with RAEB and 1 with CMML. Survival ranged from 1 to 5 years. Patients who received retinoic acid developed mild side effects. In conclusion, the administration of 13‐cis‐retinoic acid improves the hematological picture in a small number of MDS patients (11.7%).