Levent Undar

Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group.

The combination of melphalan–prednisone–thalidomide (MPT) has been investigated in several clinical studies that differed significantly with regard to patient characteristics and treatment schedules. This prospective trial differs from previous melphalan–prednisone (MP) vs. MPT trials by treatment dosing, duration, routine anticoagulation, and permission for a crossover. Newly diagnosed patients with multiple myeloma (MM) (n = 122) aged greater than 55 yr, not eligible for transplantation were randomized to receive 8 cycles of M (9 mg/m2/d) and P (60 mg/m2/d) for 4 d every 6 wk (n = 62) or MP and thalidomide (100 mg/d) continuously (n = 60). Primary endpoint was treatment response and toxicities following 4 and 8 cycles of therapy. Secondary endpoints were disease‐free (DFS) and overall survival (OS). Overall, MPT‐treated patients were younger (median 69 yr vs. 72 yr; P = 0.016) and had a higher incidence of renal impairment (RI, 19% vs. 7%, respectively; P = 0.057). After 4 cycles of treatment (n = 115), there were more partial responses or better in the MPT arm than in the MP arm (57.9% vs. 37.5%; P = 0.030). However, DFS and OS were not significantly different between the arms after a median of 23 months follow‐up (median OS 26.0 vs. 28.0 months, P = 0.655; DFS 21.0 vs. 14.0 months, P = 0.342, respectively). Crossover to MPT was required in 11 patients, 57% of whom responded to treatment. A higher rate of grade 3–4 infections was observed in the MPT arm compared with the MP arm (22.4% vs. 7.0%; P = 0.033). However, none of these infections were associated with febrile neutropenia. Death within the first 3 months was observed more frequently in the MP arm (n = 8, 14.0%) than in the MPT arm (n = 2, 3.4%; P = 0.053). Long‐term discontinuation and dose reduction rates were also analyzed (MPT: 15.5% vs. MP: 5.3%; P = 0.072). Although patients treated with MPT were relatively younger and had more frequent RI, better responses and less early mortality were observed in all age groups despite more frequent discontinuation. This study is registered at http://www.clinicaltrials.gov as #NCT00934154.

Effect of iron supplementation on oxidative stress and antioxidant status in iron-deficiency anemia

This study was designed to measure the effect of iron supplementation on antioxidant status in iron-deficient anemia, including the time for hemoglobin normalization and at the time of filling of iron body stores. The extent of plasma lipid peroxidation was evaluated by measuring the levels of malondialdehyde and glutathione peroxidase (GSH-Px), and the activities of superoxide dismutase (SOD) and catalase in 63 patients with iron-deficiency anemia before and after 6 wk of iron supplementation and at the time when body iron stores are saturated. After 6 wk of iron supplementation, a significant decrease of oxidative stress was observed in the treated subjects relative to controls (p<0.05). No significant differences existed between treated patients at 6 wk and at the end of the study. The erythrocyte levels of catalase, SOD, and GSH-Px were significantly lower in treated patients relative to controls (p<0.05). These levels increased after 6 wk of supplementation (p<0.05) and showed no significant differences with those at the end of the study.

Tuberculosis-associated haemophagocytic syndrome: a report of two cases and a review of the literature.

The haemophagocytic syndrome (HS) is an uncommon reactive proliferation of mature histiocytes, and is more frequently but not exclusively associated with infections in individuals with pre-existing immunologic abnormalities. As far as we know, only 13 cases of tuberculosis-associated HS have previously been reported. We present here two cases of disseminated tuberculosis-associated HS. Both of the cases recovered with antituberculosis therapy. High-dose methylprednisolone and intravenous immunoglobulin were added in one case because of the extremely severe clinical presentation. This therapy seemed to contribute to the favourable outcome of the patient. The similarities in HLA phenotypes of this patient and others reported in the literature may provide evidence for an underlying immune dysregulation in some cases of infection-associated HS.

Activity of neutrophil NADPH oxidase in iron-deficient anemia.

This study was designed to measure the effects of iron supplementation on respiratory burst in iron-deficient anemia. The performance of neutrophils was evaluated by measuring the activity of NADPH oxidase in 18 patients with iron-deficient anemia before and after body iron stores are saturated. The activity of NADPH oxidase was significantly lower in pretreatment patients relative to controls (p<0.05). The activity increased after iron supplementation to levels that had no significant differences relative to controls.

Flow Cytometric Analysis of Circadian Changes in Platelet Activation Using Anti-Gmp-140 Monoclonal Antibody

The hemostatic activity of blood shows a circadian variation with a higher frequency of acute coronary events in the morning. The thrombotic tendency of blood is influenced by many factors, including platelets. Diurnal changes of in vivo platelet activation were investigated by whole blood flow cytometry in 10 young healthy male volunteers using anti-GMP-140 (anti-alpha-granule membrane protein 140 kD) monoclonal antibody at 3h intervals from 06:00 to 24:00. We also studied circulating platelet aggregates to investigate whether there exists a similarity between the results of these methods. Results of flow cytometric analysis indicate that there is an increase in platelet activation during the period from 06:00 to 09:00. Platelet activation then decreases gradually during the period from noon to midnight. These changes are accompanied by a similar trend in circulating platelet aggregates. This suggests that GMP-140 expression on platelets is synchronized with or followed by platelet aggregate formation in vivo, and increased platelet activation may predispose individuals to thrombosis at this time.

Single automated donor plateletpheresis increases the plasma level of proinflammatory cytokine tumor necrosis factor-α which does not associate with endothelial release markers von Willebrand factor and fibronectin

The effect of plateletpheresis on endothelium, which has strong effects on blood coagulation, fibrinolysis and platelet function, is not known. Activation of leukocytes and subsequent generation of proinflammatory cytokines during the extracorporeal circulation may activate the endothelium. To test this hypothesis we measured plasma levels of tumor necrosis factor (TNF)-alpha as a prototype of the proinflammatory cytokines, and von Willebrand factor (vWF) and fibronectin as endothelial release/damage markers before and after a single plateletpheresis procedure on an intermittent-flow machine Haemonetics MCS 3p in 17 healthy donors. We found a significant increase in median plasma level of TNF-alpha following plateletpheresis (3.5 vs 26.5 pg/ml, P=0.02). Such increases in vWF and fibronectin were not observed. The increase in plasma TNF-alpha indicates that a single plateletpheresis procedure causes leukocyte activation which does not seemingly impair endothelial cell function. The relation of plateletpheresis-induced proinflammatory cytokine release to some adverse effects observed in both donors and recipients, and the effect of repeated plateletpheresis on endothelium deserve further studies.

Improvement of Zoledronic Acid-Induced Jaw Osteonecrosis with Bortezomib

month, but the painful mass on her mandible did not recover. The clinical course, CT and biopsy findings suggested that our patient had a zoledronic acid-induced jaw osteonecrosis [3, 4] . Two months after the cessation of antibiotic therapy, MM also relapsed. Bortezomib was started on days 1, 4, 8 and 11 at a dose of 1.3 mg/m 2 as monotherapy. After the first cycle of bortezomib, clinically regression of the mass and pain relief in her left jaw were observed in the absence of dexamethasone, antibiotic or any other drug treatment that could cause the improvement in osteonecrosis. This was an unexpected and surprising finding. If it were a plasmacytoma, it would reasonably respond to bortezomib therapy, but a biopsy specimen of the involved tissue did not reveal plasmacytoma. A control CT after three cycles of bortezomib also showed improvement in the soft tissue mass with a moderate callus formation and, as a result, moderately improved osteonecrosis ( fig. 1 b). In total, four cycles of bortezomib were given without bisphosphonates. The patient responded to bortezomib therapy with a significant decrease in M-protein. She is still on follow-up with no MM-related complaints, but has neuropathic pain due to bortezomib. The exact mechanism of bisphosphonate-induced jaw osteonecrosis has not been elucidated yet, however, the cumulative ischemic effect was suggested to be the causative event. It was reported that osteonecrosis induced by bisphosphonates did not improve following surgical resection or antibiotics [4, 5] . Bortezomib is the first proThe proteasome is an enzyme complex that degrades many targeted intracellular proteins. Inhibition of this enzyme complex affects the levels of various intracellular proteins that regulate the cell cycle, leading to a decrease in cell proliferation. Bortezomib is the first proteasome inhibitor to be used in cancer therapy, especially in multiple myeloma (MM) [1, 2] . However, we report a different effect of bortezomib in a patient with relapsed MM. A 58-year-old female patient was diagnosed as having IgG MM. She received three cycles of VAD (vincristine, adriamycin and dexamethasone) chemotherapy and high-dose melphalan with autologous peripheral blood stem cell support, followed by monthly zoledronic acid. One year after high-dose chemotherapy, she had a tooth extraction from the left jaw and sometime later, she was admitted with gum hyperplasia. Since no clinically associated disease was found to explain the gum hyperplasia, it was surgically resected. Histopathological examination of this material revealed normal histological findings. One year after the tooth extraction, a painful mass appeared on her left jaw and a few days later, an inflammatory material began to drain. Computerized tomography (CT) revealed osteitis and a widespread periosteal reaction in her mandible ( fig. 1 a). Biopsy of the involved bone disclosed osteonecrosis and a mixed inflammatory reaction, but there was no evidence of plasmacytoma. With a clinical suspicion of osteomyelitis, ampicillin/sulbactam therapy was given empirically and zoledronic acid was stopped. The fistula was successfully treated after 1 Received: July 4, 2007 Accepted after revision: September 6, 2007 Published online: November 9, 2007

Azacitidine versus decitabine in patients with refractory anemia with excess blast—Results of multicenter study

The present study aimed to compare the efficacy and safety of azacitidine and decitabine in patients with myelodysplastic syndrome (MDS). A total of 88 patients diagnosed with refractory anemia with excess blast (RAEB) treated with azacitidine (n=57) or decitabine (n=31) were evaluated. Comparisons between azacitidine and decitabine groups were performed in the whole cohort, and in a 1:1 propensity score-matched cohort in order to reduce the simple selection bias. Patients who received azacitidine or decitabine had comparable overall response rates in both the unmatched (49.1% vs. 64.5%, p=0.166) and the propensity-matched cohorts (52% vs. 68%, p=0.248). The cumulative incidence of AML transformation at one year was comparable between azacitidine and decitabine in the unmatched (24.0% vs. 31.3%, p=0.26) and in the propensity-matched cohorts (18.7% vs. 31.5%, p=0.11). There was no difference in terms of transfusion requirement, febrile neutropenia episodes or the need for antifungal use during the treatment cycles in the propensity-matched cohort. The median overall survival was 20.4 months for azacitidine and 16.8 months for decitabine (p=0.59). Finally, we found that at least a four-cycle treatment with any HMA was a favorable factor. In conclusion, both azacitidine and decitabine have similar efficacy and toxicity profiles in the treatment of MDS-RAEB.

Glycemic Control and Coagulation Inhibitors in Diabetic Patients

Objective: To investigate the plasma antigenic levels and functional activities of coagulation inhibitors in poorly controlled diabetic patients and the possible effect of good glycemic control on these parameters. Research Design and Methods: Both functional activities and plasma antigenic levels of coagulation inhibitors (antithrombin III, heparin cofactor II, protein C, and protein S) and plasma levels of C4b-binding protein were measured in 28 diabetic patients (13 males, 15 females; 2 IDDM, 26 NIDDM; median age 56.5 years; median duration of diabetes 5.5 years) with poor glycemic control (median HbA1c 11.8%). Twenty-three healthy subjects were enrolled as controls. Following a 3-month intensification of antihyperglycemic therapy, good glycemic control (HbA1c <8%) was achieved in 17 patients, and the plasma levels of the same parameters during this period were compared with baseline values. Results: Functional activities and plasma antigenic levels of coagulation inhibitors were comparable in poorly controlled diabetic patients and healthy subjects. In patients achieving good control after 3 months, there was a significant reduction in plasma antigenic levels of protein S (p = 0.005) and C4b-binding protein (p = 0.03); however, no difference could be observed in other parameters. HbA1c did not show any correlation with plasma antigenic levels or functional activities of coagulation inhibitors either at baseline or at 3 months of good glycemic control. Conclusions: Our findings suggest that in poorly controlled diabetic patients, coagulation inhibitors are not different from healthy controls. Short-term good glycemic control may not exert a profound effect on coagulation inhibitors except protein S and its binding protein, C4b-binding protein.

rHuG-CSF increases the platelet-neutrophil complex formation and neutrophil adhesion molecule expression in volunteer granulocyte and stem cell apheresis donors.

Abstract:  Several reports have shown that granulocyte colony‐stimulating factor (G‐CSF) administration induces a transient, mild hypercoagulable state, which might predispose certain donors to thrombotic complications. In the present study, changes in the expression of neutrophil adhesion molecules (CD11b/CD18, CD62L) and platelet‐neutrophil complex formation following rHuG‐CSF administration were investigated in normal granulocyte and stem cell donors. For granulocyte apheresis (N = 10), rHuG‐CSF (5 µg/kg) was given subcutaneously every 12 h three times and apheresis was carried out two hours after the last dose. For stem cell apheresis (N = 8), rHuG‐CSF (10 µg/kg/day) was given subcutaneously for 5 days and apheresis was carried out when peripheral CD34+ cell counts exceeded 20 cell/µL. Expression of neutrophil adhesion molecules (CD11b/CD18, CD62L) and platelet‐neutrophil complex formation following rHuG‐CSF administration were investigated in donors by a flow cytometric method. A significant increase in neutrophil counts (P < 0.001), and decreases in platelet counts (P < 0.01) and hemoglobin levels (P < 0.01) occurred following G‐CSF administration. The expression of CD11b/CD18 significantly increased (P < 0.001) over pretreatment values with G‐CSF administration and returned to baseline 1 week after stopping the drug. In contrast, CD62L expression was decreased (P < 0.01) with G‐CSF and returned to normal after cessation of the drug. rHuG‐CSF caused more than a two‐fold increase (from 0.3 to 7.0 × 109/L) in circulating platelet‐neutrophil complexes (P < 0.01), which returned to normal after 1 week. Although clinical significance of these laboratory changes is not clear, the occurrence of neutrophil activation and increased platelet‐neutrophil complex formation might predispose certain donors or patients to thrombotic complications following G‐CSF administration.