Predictors of response to immunosuppressive therapy with antithymocyte globulin and cyclosporine and prognostic factors for survival in patients with severe aplastic anemia.

BACKGROUND: Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) plus cyclosporine (CSA) is standard therapy in patients with severe aplastic anemia (SAA) who do not have an available HLA-matched sibling donor. METHODS AND PATIENTS: The current study aimed to determine the predictive factors for response to IST in patients with SAA and to identify prognostic factors following IST. A total of 62 patients diagnosed with SAA who received IST with either rabbit ATG (n = 33) or horse ATG (n = 29) plus CSA between October 1994 and December 2007 were included. RESULTS: With a median follow-up duration of 60.5 months, complete response and overall response were estimated to be 31% and 53%, respectively. The 4 yr overall survival rate was 75 + or - 6%. In terms of predicting the response to IST, neutrophil counts above 0.3 x 10(9)/L prior to IST were the only significant predictive factor (P = 0.02). Survival following IST was significantly different in favor of both the group showing high absolute reticulocyte counts (ARC) above 10.9 x 10(9)/L prior to IST (P = 0.004) and the group achieving any response following IST (P = 0.002). CONCLUSIONS: Pre-IST neutrophil counts might predict the response to IST, while absolute ARCs prior to IST and response status after IST could be prognostic factors following IST.

Prognostic factor analysis and proposed prognostic model for conventional treatment of high-grade primary gastric lymphoma.

OBJECTIVES: We conducted a clinical risk factors analysis to define a prognostic model for high-grade primary gastric lymphoma (HG-PGL). METHODS AND RESULTS: The median event-free survival and overall survival of 214 HG-PGL patients were 54 and 104.5 months, respectively, after a median follow-up duration of 60 months. According to the prognostic factor analysis, survival, advanced age, male gender, higher LDH levels and the presence of ascites were identified as independent prognostic factors for HG-PGL. We identified four groups at different risk: group 1, no adverse effect; group 2, one factor; group 3, two factors; group 4, three or four factors. The new prognostic model showed excellent prognostic capacity to differentiate subgroups according to their risk stratification. CONCLUSIONS: The proposed new prognostic model for HG-PGL demonstrated a balanced distribution of patients into four groups with good prognostic capacity.

Activation of Raf1 and the ERK pathway in response to l-ascorbic acid in acute myeloid leukemia cells.

L-ascorbic acid (LAA) shows cytotoxicity and induces apoptosis of malignant cells in vitro, but the mechanisms by which such effects occur have not been elucidated. In the present study, we provide evidence that the ERK MAP kinase pathway is activated in response to LAA (< 1 mM) in acute myeloid leukemia cell lines. LAA treatment of cells induces a dose-dependent phosphorylation of extracellular signal-regulated kinases (ERK) and results in activation of its catalytic domain. Our data also demonstrate that the small G protein Raf1 and MAPK-activated protein kinase 2 are activated by LAA as an upstream and a downstream regulator of ERK, respectively. Although the ERK pathway has been known to activate cell proliferation, pharmacologic inhibition of ERK reduces LAA-dependent apoptosis and growth inhibitory response of acute myeloid leukemia cell lines, suggesting that this signaling cascade positively regulates induction of apoptotic response by LAA.

L-ascorbic acid represses constitutive activation of NF-kappaB and COX-2 expression in human acute myeloid leukemia, HL-60.

There is increasing evidence that L-ascorbic acid (LAA) is selectively toxic to some types of cancer cells at pharmacological concentrations, functioning as a pro-oxidant rather than as an anti-oxidant. However, the molecular mechanisms by which LAA initiates cellular signaling leading to cell death are still unclear. In an effort to gain insight into these mechanisms, the effects of LAA on eukaryotic transcription nuclear factor NF-kappaB and cyclooxygenase-2 (COX-2) expression were investigated. In the present study, LAA suppressed DNA binding activity of NF-kappaB, composed of a p65/p50 heterodimer, through inhibition of degradation of inhibitory kappaB-alpha (IkappaB-alpha) and prevention of nuclear translocation of p65. The inhibitory effect of LAA on NF-kappaB activity was dependent upon glutathione levels in HL-60 cells, as well as generation of H2O2 but not superoxide anion. LAA also downregulated the expression of COX-2, which has a NF-kappaB binding site on its promoter, through repressing NF-kappaB DNA binding activity. Moreover, cotreatment of 1 microM arsenic trioxide (As2O3) with various concentrations of LAA enhanced an LAA-induced repression of NF-kappaB activity and COX-2 expression. In conclusion, our data suggest that LAA exerts its anti-tumor activity through downregulation of NF-kappaB activity and COX-2 expression, and these inhibitory effects can be enhanced by co-treatment with As2O3.