Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients.

Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA). Patients and methods: Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone. Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33-45] versus 55% (95% CI: 49-61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513). Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.

Flow cytometric determination of RBC survival in autoimmune hemolytic anemia.

BACKGROUND: In cases of warm autoimmune hemolytic anemia (WAIHA), crossmatch incompatible RBCs are most often used for transfusion. The determination of the in vivo survival of transfused and autologous RBCs in WAIHA is helpful in the assessment of the efficacy of transfusion and other therapeutic interventions. CASE REPORT: A 38-year-old man presented with acute WAIHA, thrombocytopenia, and neutropenia. Steroids and IVIG therapy were ineffective, and the patient received RBCS: Because of increasing hemolysis and persisting thrombocytopenia, splenectomy was performed, resulting in partial remission. Further improvement was achieved by immunosuppressive therapy. MATERIALS AND METHODS AND RESULTS: Survival of transfused and autologous RBCs was determined, using a flow cytometric method based on the determination of different blood group antigens of patient and donor RBCS: The survival of autologous and transfused RBCs before splenectomy was determined on two consecutive days. The life span of autologous RBCs remained rather stable at 69 and 64 hours on Days 10 and 11, respectively, whereas the life span of transfused RBCs decreased from 186 hours to 25 hours. After splenectomy, the life span of transfused RBCs almost normalized: 43 days at postsplenectomy Day 3 and 87 days at postsplenectomy Day 69. CONCLUSION: Flow cytometry was successfully used to determine changing hemolytic activity during the clinical course of WAIHA. Additionally, the survival of transfused RBCs could be measured, which may be helpful to judge for the compatibility of allogeneic RBCS: Thus, we were able to show the therapeutic inefficacy of steroids and immunoglobulins, and quick improvement after splenectomy.

Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells.

Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is a mitogen and chemotactic factor for endothelial cells in vitro and an angiogenesis and vascular permeability factor in vivo. Due to its properties, VEGF is a candidate for both angiogenesis and vascular permeability/oedema induction which typically occur in glioblastomas. In this study we test the hypothesis that the antioedema effect of dexamethasone is mediated by downregulation of VEGF or VEGF receptor expression. VEGF mRNA and protein levels of two rat glioma cells lines, C6 and GS-9L, were determined after incubation with dexamethasone under normoxic and hypoxic conditions. In normoxic C6 and GS9L cells, we observed 50-60% downregulation of VEGF mRNA by dexamethasone (P=0.015 and P=0. 01, respectively). This effect was dependent on glucocorticoid-receptor (GR) function. The inhibitory effect of dexamethasone on VEGF gene expression by tumour cells was markedly reduced by hypoxia which suggests that the upregulation of VEGF driven by hypoxia overcomes the effect of the dexamethasone. Dexamethasone did not alter VEGFR-2 mRNA levels in human umbilical endothelial cells. In a subcutaneous glioma tumour model, we observed only a 15% decrease in VEGF mRNA expression in dexamethasone treated animals (n = 12) compared with controls animals (P = 0.24). We conclude that dexamethasone may decrease brain tumour-associated oedema by reduction of VEGF expression in tumour cells. However, the highly reduced activity on hypoxic tumour cells suggests that dexamethasone efficacy may be limited by hypoxia in rapidly growing tumours.

Vascular endothelial growth factor expression, vascular volume, and, capillary permeability in human brain tumors.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and a potent inducer of vascular permeability. In this study, we determined whether expression of VEGF is correlated with in vivo measurements of the capillary permeability and vascular volume of primary human brain tumors. METHODS: Tumor samples (seven glioblastomas, one anaplastic astrocytoma, two low-grade astrocytomas, one pilocytic astrocytoma, and three primary cerebral lymphomas) were stereotactically obtained from 14 patients. A semiquantitative polymerase chain reaction was used to quantify the relative expression of VEGF messenger ribonucleic acid in the tumors. VEGF protein was demonstrated in tissue sections by immunohistochemical techniques. A two-compartment dynamic computed tomographic method was used to quantitatively measure the aforementioned parameters in the regions from which the biopsies were obtained. RESULTS: In glial tumors, there was significant correlation of VEGF messenger ribonucleic acid levels with capillary permeability (P < 0.05) and vascular volume (P < 0.01). Although all primary cerebral lymphomas showed considerable increases in capillary permeability and vascular volume, VEGF expression was only slightly upregulated in these tumors. CONCLUSION: Our findings are consistent with the hypothesis that VEGF may be responsible for endothelial cell proliferation and vascular permeability in glial tumors. This relationship has implications for clinical applications, i.e., assessment of delivery of water-soluble drugs, treatment of edema, and antiangiogenesis therapy based on inhibition of VEGF function.

Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney.

Vascular endothelial growth factor (VEGF) may modulate vascular permeability, chemotaxis for monocytes, and protease activity. In addition, VEGF may play a role in embryonic and tumor angiogenesis. In fetal mouse kidney, VEGF mRNA and protein expression have been demonstrated. This finding led to the hypothesis that VEGF might be involved in renal growth and development. To further elucidate the role of VEGF in human kidney, expression of VEGF and its receptors, the specific tyrosine kinase receptors, fit-1 and KDR, were studied. In fetal (6-24 gestational wk; mesonephros and metanephros) and adult kidney, VEGF mRNA and protein could be colocalized in glomerular epithelia and collecting duct cells by in situ hybridization and immunohistology. By reverse transcription-polymerase chain reaction, mRNA of three VEGF isoforms, VEGF121, VEGF165, and VEGF189, were found in fetal kidney and cortex, isolated glomeruli, and medulla of adult human kidney. KDR and flt-1 mRNA were coexpressed in endothelia of glomeruli and in peritubular capillaries in fetal and adult kidney. These data support the assumption that VEGF and its receptors may influence renal ontogenesis. We speculate that the constitutive expression of VEGF in adult kidney may be required for the function of VEGF receptor positive-fenestrated endothelia in glomeruli and postglomerular vessels. The expression of VEGF in collecting duct and of its receptors in medullary capillaries may in addition be relevant for maintaining medullary osmolality.