The -137G/C Polymorphism in Interleukin-18 Gene Promoter Contributes to Chronic Lymphocytic and Chronic Myelogenous Leukemia Risk in Turkish Patients.

OBJECTIVE: Interleukin-18 (IL-18) is a cytokine that belongs to the IL-1 superfamily and is secreted by various immune and nonimmune cells. Evidence has shown that IL-18 has both anticancer and procancer effects. The aim of this study was to evaluate the relationship between IL-18 gene polymorphisms and susceptibility to chronic lymphocytic leukemias (CLL) and chronic myelogenous leukemias (CML) in Turkish patients. MATERIALS AND METHODS: The frequencies of polymorphisms (rs61667799(G/T), rs5744227(C/G), rs5744228(A/G), and rs187238(G/C)) were studied in 20 CLL patients, 30 CML patients, and 30 healthy individuals. The genotyping was performed by polymerase chain reaction and DNA sequencing analysis. RESULTS: Significant associations were detected between the IL-18 rs187238(G/C) polymorphism and chronic leukemia. A higher prevalence of the C allele was found in CML cases with respect to controls. The GC heterozygous and CC homozygous genotypes were associated with risk of CML when compared with controls. However, prevalence of the C allele was not significantly high in CLL cases with respect to controls. There was only a significant difference between the homozygous CC genotype of CLL patients and the control group; thus, it can be concluded that the CC genotype may be associated with the risk of CLL. Based on our data, there were no significant associations between the IL-18 rs61667799(G/T), rs5744227(C/G), or rs5744228(A/G) polymorphisms and CLL or CML. CONCLUSIONS: IL-18 gene promoter rs187238(G/C) polymorphism is associated with chronic leukemia in the Turkish population. However, due to the limited number of studied patients, these are preliminary results that show the association between -137G/C polymorphism and patients (CLL and CML). Further large-scale studies combined with haplotype and expression analysis are required to validate the current findings.

Plasmapheresis in a patient with "refractory" urticarial vasculitis.

Immune complexes are found in the circulation of 30%-75% of patients with urticarial vasculitis and much evidence supports the role of these immune complexes in the pathogenesis of urticarial vasculitis. Plasmapheresis is effective for removing these immune complexes; however, there are few reports on the use of plasmapheresis in the treatment of urticarial vasculitis. We describe a case of "refractory" urticarial vasculitis in which the symptoms improved after plasmapheresis treatment. We suggest that plasmapheresis be considered as an option in patients with severe or treatment-resistant urticarial vasculitis.

The clinical significance of tumor cells in bone marrow or apheresis product and the efficacy of CD34+ selection and high-dose chemotherapy in patients with Stage III breast cancer.

The purpose of this study is to determine the presence of disseminated tumor cells in bone marrow or apheresis product, and also to evaluate the clinical significance of contaminated products and the efficacy of CD34(+) selection and high-dose chemotherapy in patients with Stage III breast cancer. Fifty-five patients were enrolled in this prospective cohort study. Whereas CD34(+) positive selection was not carried out in the first group (unselected group, n:31), CD34(+) positive selection was performed in the second group (CD34 selected group, n:24). Tumor cells were detected with anticytokeratin monoclonal antibody in the bone marrow, apheresis product and positive fraction. Tumor cells were found in six (19.3%) patients in unselected group and four patients (16.6%) in CD34 selected group (P = 0.76). The percentages of distant metastases were found higher in unselected group (51.6% vs. 25%, P < 0.01). Although there were no differences between the two groups for disease free survival (DFS; 44% vs. 74%, P = 0.24) or overall survival (54% vs. 68%, P = 0.84), DFS was significantly lower in patients with tumor cells than in patients without tumor cells (21% vs. 62%, P = 0.02). In conclusion, the presence of tumor cells in bone marrow or apheresis product decreases DFS in patients with Stage III breast cancer who underwent high-dose chemotherapy. CD34(+) selection does not change survivals, but it may decrease the distant metastases.

Reduced dose of lenograstim is as efficacious as standard dose of filgrastim for peripheral blood stem cell mobilization and transplantation: a randomized study in patients undergoing autologous peripheral stem cell transplantation.

In vitro studies have demonstrated a 27% increased efficacy of lenograstim over filgrastim. However, equal doses of 10 microg/kg/day of filgrastim and lenograstim have been recommended for mobilization of CD34+ cells without associated chemotherapy. In this study, we investigated whether a 25% reduced dose of lenograstim at 7.5 microg/kg/day is equavalent to 10 microg/kg/day filgrastim for autologous peripheral blood stem cell (PBSC) mobilization and transplantation. A total of 40 consecutive patients were randomized to either filgrastim (n = 20) or lenograstim (n = 20). The two cohorts were similar in regard to disease, sex, body weight, body surface area, conditioning regimens, previous chemotherapy cycles and radiotherapy. Each growth factor was administered for 4 consecutive days. The first PBSC apheresis was done on the 5th day. In the posttransplant period, the same G-CSF was given at 5 microg/kg/day until leukocyte engraftment. Successful mobilization was achieved in 95% of patients. Successful mobilization with the first apheresis, was achieved in 10/20 (50%) patients in the filgrastim group versus 9/20 (46%) patients in the lenograstim group. No significant difference was seen in the median number of CD34+cells mobilized, as well as the median number of apheresis, median volume of apheresis, percentage of CD34+ cells, and CD34+ cell number. Leukocyte and platelet engraftments, the number of days requiring G-CSF and parenteral antibiotics, the number of transfusions were similar in both groups in the posttransplant period. Lenograstim 7.5 microg/kg/day is as efficious as filgrastim 10 microg/kg/day for autologous PBSC mobilization and transplantation.

D-dimer levels in the prediction of the degree of intestinal necrosis of etrangulated hernias in rats.

PURPOSE: The aim of this study was to investigate the time-dependent relation between plasma D-dimer levels and the degree of intestinal necrosis and to compare these parameters with leukocyte counts in an experimental etrangulated hernia model in rats. RESULTS: When the duration of intestinal ischemia was prolonged, serum D-dimer levels increased relative to the control group, with the difference being statistically significant at hour 2 (P = 0.027). In contrast, leukocyte counts in the 2- and 4-h strangulation group were higher that those of the control group, but the difference was not statistically significant (P = 0.625 and P = 0.846, respectively). However, in the 6-h strangulation group the levels of leukocytes were significantly higher that those of the control group (P = 0.015). CONCLUSION: Serum D-dimer measurements may be used as a more valuable diagnostic parameter than leukocyte count in the early diagnosis of intestinal ischemia, including strangulated hernia.

Effects of bortezomib on platelet aggregation and ATP release in human platelets, in vitro.

INTRODUCTION: Proteasome inhibitor bortezomib (PS-341) has been the first proteasome inhibitor that has entered clinical trials with its antiproliferative and proapoptotic effects in patients with multiple myeloma. Recent studies indicate that proteasome inhibitors can be useful in prevention of experimental arterial thrombosis in renovascular hypertensive rat models. The aim of the present study is to investigate the effect of bortezomib on in vitro platelet aggregation and adenosine triphosphate (ATP) release of human platelets. MATERIALS AND METHODS: For this purpose, platelet aggregation was induced in the platelet-rich plasma (PRP) using 3 microg ml(-1) collagen, 5 microM adenosine diphosphate (ADP), 10 microM epinephrine and 1 U ml(-1) thrombin and ATP release was induced by collagen. RESULTS AND CONCLUSIONS: Bortezomib showed an inhibitory effect on platelet aggregation induced by ADP in human PRP in a dose- and time-dependent manner, whereas it had no effect on collagen-, epinephrin and thrombin-induced aggregation. ATP-release reaction induced by collagen was inhibited dose- and time-dependently by bortezomib, even though collagen-induced platelet aggregation was apparently not affected in human PRP. These findings indicate that bortezomib may be an antiaggregating agent and its' effects may be related to adenine nucleotide receptor dependent regulatory proteins which are important for physiological and pathophysiological cellular processes. However, our in vitro studies suggest that this hypothesis is inadequate to explain the observations completely. This phenomenon and its clinical implication justify further clinical investigations.

The altered autonomic nervous system activity in iron deficiency anemia.

Autonomic function is impaired in anemic patients with various etiologies such as vitamin B12 deficiency, sickle cell trait, and thalassemia major. However, there are insufficient data about autonomic functions in patients with iron deficiency anemia, the leading cause for anemia in the general population. In the present study we aimed to investigate the autonomic status in iron deficiency anemia by analyzing the heart rate variability (HRV). Age- and gender-matched 43 patients with iron deficiency anemia and 39 healthy subjects were undertaken into 24-hr Holter monitoring for assessing the HRV. We used serum levels of iron, iron binding capacity, C-reactive protein, vitamin B12, and folate to exclude other causes of anemia. While age, gender, vitamin B12 and folate levels were not different between the groups, HRV values were lower in patients with iron deficiency anemia compared to control group, which reflects parasympathetic withdrawal. Blood hemorheological factors such as decreased viscosity and/or altered red cell deformability may be responsible for this decreased parasympathetic activity. However, these components do not display remarkable contribution in iron deficiency anemia. Therefore, we speculated a probable link between anemia and the accentuated sympathetic activity that may be triggered by hypoxia sensed through carotid bodies. Despite lacking adequate convincing evidence concerning exact mechanism of carotid body activation, it is assumed as due either to hypoxia-related mitochondrial respiratory chain inhibition or potassium channel suppression that leads to intracellular calcium accumulation. In conclusion, the present study demonstrates an altered autonomic balance in patients with true iron deficiency anemia.

Cardiac autonomic functions are altered in patients with acute leukemia, assessed by heart rate variability.

Acute leukemia is one of the leading malignancies worldwide. Although neuropathy was reported as one of the complications of leukemia, there is a little data about the autonomic involvement. This study was designed to investigate the cardiac autonomic disturbances in acute leukemias by using time-domain indices of heart rate variability (HRV). Newly diagnosed 36 patients with acute leukemia (14 acute lymphoblastic leukemia and 22 acute myeloblastic leukemia) and gender- and age-matched 32 healthy subjects as controls were enrolled in this study. The diagnosis of leukemia was established by whole blood count, peripheral smears and bone marrow aspirations. In order to rule out the effect of any medication on HRV, the patients were selected from those who had not received any antineoplastic agent yet. For assessing the cardiac autonomic functions, HRV obtained from 24-hr Holter monitor recordings was used. The age, gender and serum ferritin levels were similar, while hemoglobin levels were lower in the leukemia group. The comparison of the leukemia group and control group revealed that HRV decreased in patients with acute leukemia, which reflects sympathetic dominance in acute leukemia. This is the first study that shows altered cardiac autonomic functions in patients with acute leukemias who are not on any therapeutical intervention. The altered cardiac autonomic functions may be a sign of paraneoplastic neuropathy in patients with acute leukemia.

Cognitive dysfunction in beta-thalassemia minor.

Beta-thalassemia minor is a common, hereditary, and mostly symptomless disease. Previous studies have shown that lower hemoglobin values are associated with poorer cognitive functions. We aimed to evaluate the cognitive function in patients with beta-thalassemia minor. Thirty-two male subjects with beta-thalassemia minor and 32 sex-, age-, and education status-matched healthy subjects were enrolled in the study. Blood tests and P300 potentials were carried out. P300 potential latency in all patients was significantly longer than those in the control group (337.63+/-34.89 msec and 310.66+/-14.30 msec, respectively; t 4.046, P<0.001). The amplitudes of P300 in patient group were significantly lower than those in the control group (5.19+/-3.59 microV and 9.81+/-3.33 microV, respectively; t 5.349, P<0.001). In this study, we have found that P300 potentials are adversely affected for cognitive functions in patients with beta-thalassemia minor.

Donor cell leukemia in a patient developing 11 months after an allogeneic bone marrow transplantation for chronic myeloid leukemia.

A 38-year-old female with chronic myeloid leukemia underwent an allogeneic bone marrow transplantation from her full-matched brother. Eleven months later, she readmitted with an acute leukemia that was shown to be of donor origin. The patient never achieved a remission even after chemotherapies with cytarabine and mitoxantrone, donor lymphocyte infusion, and second allogeneic peripheral blood stem cell transplantation. Donor cell leukemia (DCL) is sometimes misdiagnosed as relapse by clinicians and the real incidence may be higher than expected. Cytogenetic and molecular techniques may be helpful to clarify the issue of the leukemia. The current case is another case of DCL reported in the literature after an allogeneic transplant for a kind of leukemia.

Lipid profile and anticardiolipin antibodies in Behcet's disease.

BACKGROUND: Behcet's disease (BD) is a multisystem disorder characterized by a relapsing inflammatory process of unknown etiology. It is well known that atherothrombosis in systemic inflammatory disorders is closely related to coagulation and lipid metabolism abnormalities. The purpose of this study was to investigate some parameters of lipid metabolism, lipoprotein (a) [Lp(a)] and anticardiolipin antibody (ACA) levels and the relationship of these parameters with the clinical activity of BD. METHODS: Thirty three patients with BD (15 active, 18 inactive cases) and 20 healthy controls participated in the study. After performing a detailed physical exam, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), apoprotein A and B (apo-A, apo-B), Lp(a), and ACA levels (ACA-IgG and IgM) were measured in all participants. RESULTS: Patients with active BD had higher ESR, CRP and Lp(a) levels, and lower apo-A and HDL-C levels compared with the patients with inactive BD and healthy controls. ACA-IgG and IgM levels were higher in patients with active BD than healthy controls but not higher than patients with inactive BD. On the other hand, ACA-IgG level was higher in active and inactive cases with vascular involvement than in those of active and inactive cases without vascular involvement. In the analyses of correlation, in active BD patients we found a positive correlation between CRP and Lp(a) levels. CONCLUSIONS: Our findings suggest that Lp(a) behaves as an acute phase reactant and ACA levels are increased in patients with active BD. Data from patients with active BD may be compatible with the serum profile, which is accepted as a risk for the development of atherothrombosis.

Leucopenia and thrombocytopenia possibly associated with lamotrigine use in a patient.

Haematological side effects are rather exceptional with lamotrigine. We report the case of a 25-year-old woman with epilepsy who developed combined leucopenia and thrombocytopenia eight weeks after starting lamotrigine. Within weeks after lamotrigine was discontinued, all of the haematopoietic abnormalities had disappeared. To our knowledge, this is the first report of combined leucopenia and thrombocytopenia associated with lamotrigine treatment suggesting, in our patient, a causal reaction.

The excessive numbers of total nucleated cells does not affect the performance of the CliniMACS.

This prospective study was carried out in healthy donors and patients. The performance of the CliniMACS was evaluated with the comparison of the numbers of total nucleated cell (TNC) within and over the capacity of the normal scale column. In addition, large vs. normal scale column and manual vs. automated washing systems were also compared. A total of 44 selections were done. Eighteen normal scale selections were done with initial TNC numbers over 6 x 10(10) and 14 selections were performed below this number. None of the cases had CD34+ cell numbers over the capacity. Flow cytometry was used to check each separation performance for purity and recovery of CD34+ cells along with T- and B-cell depletion level parameters. All healthy donors had significantly better mean purity and recovery of CD34+ cells, and T- and B-cell depletion status than that of patients with values 95 vs. 85%, P: 0.006; 77 vs. 58%, P: 0.004; 4.55 log vs. 4.06 log, P: 0.004; 3.19 log vs. 2.63 log, P: 0.01, respectively. However, the performance of the system was not dependent on using the normal or large-scale column; automated or manual washing systems; and initial TNC numbers above (>6 x 10(10), range: 7.05-21.84 x 10(10), mean: 12.32 x 10(10)) or within (<6 x 10(10), range: 0.86-5.89 x 10(10), mean: 4.15 x 10(10)) the column capacity. In conclusion, the performance of the CliniMACS is more efficient in healthy donors than in patients. However, the performance of the system did not change as long as the numbers of CD34+ cells (range: 0.34-5.87 x 10(8)) were not exceeding the column capacity despite that more than 6 x 10(10) TNCs were used.

Outer hair cell activity of the cochlea in patients with iron deficiency anemia.

OBJECTIVE: Iron deficiency anemia is a common disorder, which has been reported to affect the auditory system. However, there are some conflicting points related with the pattern of hearing impairment. The aim of this study is to analyze the outer hair cell activity of the cochlea in patients with iron deficiency anemia. METHOD: Pure-tone audiometry (PTA) (250-6000 Hz) and distortion product otoacoustic emission (DPOAE) results of 42 patients with iron deficiency anemia and 22 healthy, age and sex matched subjects for the control group were compared. Cubic DPOAEs (2f1-f2) were obtained at 65 and 55 dB sound pressure level (SPL). DP grams were plotted as a function of f2 and signal-to-noise ratio (SNR) was specified as the difference in decibels SPL between DPOAE amplitude and the ambient noise level at a given f2. In DP grams, DP amplitudes and noise levels obtained from the baseline measurements were presented as the upper and lower limits of DP amplitude and noise level that were the 10th and 90th percentiles calculated by adding and subtracting standard deviations and from mean baseline DP amplitude and noise level. Independent-samples t-test is used for comparison of the groups. RESULTS: Pure-tone audiometry was normal in patients with iron deficiency anemia and control subjects and there was no significant difference in comparison of DPOAE in both groups and both sides and the results were between two percentiles (P > 0.05). CONCLUSION: The results of the present study did not support a casual relationship between the iron deficiency anemia and the auditory dysfunction on the basis of DPOAE.

Renal tubular dysfunction in beta-thalassemia minor.

BACKGROUND: Persons with beta-thalassemia minor usually are symptomless. However, we previously reported renal tubular dysfunction in a patient with beta-thalassemia minor. The aim of this study is to investigate renal function in patients with beta-thalassemia minor. METHODS: Forty-one subjects with beta-thalassemia minor and 20 sex- and age-matched healthy subjects were enrolled in the study. For analysis, patients were divided into 2 groups: group A, all patients with anemia (n = 19), and group B, patients without anemia (n = 22). Blood and 24-hour urine samples were obtained for hematologic and biochemical analysis. RESULTS: Anemic patients had increased urinary zinc excretion (U(zinc)) and fractional excretion of sodium (FE(Na)) and uric acid (FE(UA)) compared with both controls and patients without anemia. Hemoglobin levels correlated significantly in a negative manner with U(zinc), FE(Na), and FE(UA) in patients with beta-thalassemia minor. However, serum lactate dehydrogenase levels correlated significantly in a positive manner with the same parameters. In addition, 6 of 41 patients (14.6%) with beta-thalassemia minor showed significant signs of renal tubulopathy, such as hypercalciuria, decreased tubular reabsorption of phosphorus with hypophosphatemia, hypomagnesemia with renal magnesium wasting, hypouricemia with renal uric acid wasting, and tubular proteinuria. CONCLUSION: Proximal renal tubular dysfunction is not rare in patients with beta-thalassemia minor.

Stem cell mobilization by G-CSF in solid and hematological malignancies: single daily dose is better than split dose in obese patients.

In the past, variable results were reported for single daily and two divided daily doses of granulocyte colony-stimulating factor (G-CSF) in stem cell collection where no study exists investigating the effect of body mass index (BMI) on mobilization. The numbers of CD34(+) cells collected were compared in 86 patients with solid or hematological malignancies receiving either single daily (14 mug/kg/day) G-CSF (filgrastim) as group I (n=36) or two divided doses of G-CSF daily (2 x 7 mug/kg/day) as group II (n = 50). Both groups were divided into subgroups according to their BMI as group a (BMI 25 kg/m(2)). Two groups were similar in terms of BMI, gender, and disease characteristics. All patients have received G-CSF as a single or two divided doses subcutaneously and aphereses have been done on the 5th day. No significant difference in numbers of CD34(+) cells between groups Ia and Ib, groups IIa and IIb, and groups Ia and IIa was found. On the other hand, the mean ratio and the number of CD34(+) cells in group Ib were significantly higher than those of group IIb (0.58 +/- 0.06% vs. 0.37 +/- 0.26%, P = 0.01 and 3.67 +/- 0.65 x 10(4)/kg/ml vs. 1.92 +/- 0.37 x 10(4)/kg/ml, P= 0.02). In conclusion, in patients with BMI >25 kg/m(2), once daily G-CSF compared to split dose administration induces a greater number of CD34(+) stem cell mobilization, which suggests the presence of a different pharmacokinetics in obese patients.

Effect of plateletpheresis on complete blood count values using three different cell separator systems in healthy donors.

The aim of this study is to investigate changes of CBC values after plateletpheresis in healthy and volunteer donors by using three different cell separator systems. The platelets were collected from 95 donors using the COBE Spectra, from 87 donors using the Fenwal CS-3000 Plus, and from 83 donors using the Fresenius AS-204. After plateletpheresis, white blood cells (WBC), hemoglobin (HGB), hematocrit (HCT), and platelets (PLT) were decreased significantly. When we used the COBE Spectra, the drop in the values of HGB and HCT was significantly less than for the other devices. It is recommended that hematological parameters should be monitored carefully in donors who are supposed to undergo long-term regular apheresis, and to prevent the occurrence of an artificial anemia, which is likely to happen. Selection of cell separator systems should be based on this possibility.

Itraconazole is not effective for the prophylaxis of fungal infections in patients with neutropenia.

Fungal infections are a major problem among patients with hematological malignancies. To evaluate the efficacy of itraconazole (200 mg twice daily) in the prophylaxis of fungal infections in neutropenic patients, we conducted a prospective trial. A total of 61 patients with acute leukemia (113 cytotoxic chemotherapy episodes) were enrolled in the study. One patient in the itraconazole group was excluded because itraconazole was not taken due to gastrointestinal hemorrhage. Because the duration of neutropenia (neutrophil count, <0.5 x 10(9)/l) did not reach 7 days, 3 (1 patient) and 13 (4 patients) cytotoxic chemotherapy episodes in the itraconazole and control groups, respectively, were excluded. After these exclusions, the study population consisted of 31 patients (54 cytotoxic chemotherapy episodes) who had taken itraconazole and 24 patients (43 cytotoxic chemotherapy episodes) who had not taken itraconazole. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (absolute neutrophil count, >1 x 10(9)/l) unless a systemic fungal infection was documented or suspected. Thirteen episodes (24%) in the itraconazole group and 7 episodes (16%) in the control group proceeded to intravenous amphotericin B (P > 0.05). Fungal infections occurred in 9 episodes (17%) in the itraconazole group and in 5 episodes (12%) in the control group (P > 0.05). Overall mortality was five deaths in the itraconazole group and two in the control group. These deaths were not due to clinically documented fungal infection. In our study, efficacy of itraconazole in the prophylaxis of fungal infections in neutropenic patients was not detected.