Biological Characteristics of AC133 Antigen-Positive Acute Leukemia

Background : AC133 antigen is a cell surface antigen which is selectively expressed on hematopoietc stem and progenitor cells. It has been reported that AC133 antigen is expressed on the subsets of CD34+ acute leukemia, and occasionally on CD34-acute leukemia. We investigated the clinical and biological characteristics of AC133 antigen-positive acute leukemia. Method: Thirty-six adult acute leukemia patients were analyzed using a cut-off criterion of 20% or more gated leukemic blasts expressing the AC133 antigen for AC133+ leukemia. The biological characteristics focused on apoptosis were examined using multicolor flow cytometry and Western blot analysis. Results: AC133 antigen was expressed in 12 cases (33.3%). Eleven of 21 (52.4%) acute myelogenous leukemia (AML) patients and 1 of 15 (6.7%) acute lymphoblastic leukemia patients were positive for AC133 antigen, and the difference was significant. None of the clinical prognostic markers were singificantly different between AC133+ and AC133- AML. Median disease free and overall survival time were not significantly different between AC133+ and AC133- AML. The expression rate of CD34 was significantly higher in AC133+ AML patients compared to those of AC133- AML (P=0.045). Among the apoptosis-related proteins, the Fas expression on the leukemic blasts was higher in the AC133+ AML(P=0.048), but Fas ligand, Bcl-2, caspase-3 expression rates were not significantly different between AC133+ and AC133 -AML. The apoptosis rate was signigicantly lower in the Ara-C treated AC133 + AML (P=0.049), but the apoptosis rates to other apoptosis-inducing agents (dox-orubicin, TNF-α) were not different between AC133+ and AC133-AML cells. We thought that there were some associations between a trend toward higher caspase-3 expression rates and lower Ara-C induced apoptosis rates in the AC133+ AML. Conclusion : There was no significant correlation between AC133 antigen expression and various clinical characteristics of acute leukemia, but the AC133 antigen might provide different biological characteristics including apoptosis from other immature cell surface markers. However, to verify the prognostic usefulness of AC133 antigen and the basis of the biological characteristics of AC133 antigen-positive acute leukemia, further study is needed.ope

Cytoplasmic Mislocalization of p27Kip1 Protein Is Associated with Constitutive Phosphorylation of Akt or Protein Kinase B and Poor Prognosis in Acute Myelogenous Leukemia

Cyclin-dependent kinase inhibitor p27Kip1 functions at the nuclear level by binding to cyclin E/cyclin-dependent kinase-2. It was shown that Akt or protein kinase B (Akt/PKB)-dependent phosphorylation of p27Kip1 led to the cytoplasmic mislocalization of p27Kip1, suggesting the potential abrogation of its activity. Here, we evaluated the localization of p27Kip1 protein in leukemic blasts in relation to Akt/PKB phosphorylation and clinical outcomes in acute myelogenous leukemia (AML). Western blot analysis of the nuclear and cytoplasmic fractions revealed a heterogenous localization pattern of p27Kip1 in AML. Cytoplasmic mislocalization of p27Kip1 was significantly associated with the constitutive serine473 Akt/PKB phosphorylation in AML cells (P < 0.05). Transfection of U937 cells with an expression construct encoding the constitutively active form of Akt/PKB resulted in a remarkable increase in the levels of cytoplasmic p27Kip1. Whereas the transfection of U937 cells with a construct encoding dominant-negative Akt/PKB resulted in a recovery of nuclear localization of p27Kip1. Both the disease-free survival and overall survival are significantly shorter in AML cases with high cytoplasmic to nuclear ratio of p27Kip1 localization compared with the cases with low cytoplasmic to nuclear ratio (P = 0.0353, P = 0.0023, respectively). Multivariate analysis indicated that the cytoplasmic to nuclear ratio of p27Kip1 localization was an independent prognostic variable for both disease-free survival and overall survival (P = 0.043, P = 0.008, respectively). These findings additionally extend our understanding of the role of p27Kip1 in AML, and buttress the case of p27Kip1 mislocalization as a prognostic indicator and Akt/PKB/p27Kip1 pathway as a ready target for antileukemia therapy.ope

A Case of Primary Peripheral T-cell Lymphoma of the Stomach with Cytotoxic Phenotype

Primary gastric lymphoma is the most common form of extralymphatic non-Hodgkin's lymphoma (NHL). Most cases are of B-cell origin and few cases of lymphoma of T-cell origin have been reported. Peripheral T cell lymphoma is a lymphoma of extrathymic origin. Expression of T-cell intracellular antigen (TIA)-1 can be detected in all cytotoxic cells, and the expression of this cytotoxic protein is associated with extranodal presentation. We report a case of primary peripheral T cell lymphoma of the stomach with cytotoxic T-cell phenotype in a 70-year-old male presenting with upper gastrointestinal bleeding.ope

Elevated S-phase kinase-associated protein 2 protein expression in acute myelogenous leukemia: its association with constitutive phosphorylation of phosphatase and tensin homologue protein and poor prognosis

PURPOSE: The F-box protein S-phase kinase-associated protein 2 (Skp2) positively regulates the G(1)-S phase transition by controlling the stability of several G(1) regulators, such as p27Kip1. However, the clinical significance of Skp2 in patients with acute myelogenous leukemia (AML) remains unknown. EXPERIMENTAL DESIGN: We examined the clinical and biological significance of Skp2 expression in AML and evaluated the relationship between Skp2 and p27Kip1 expression and phosphatase and tensin homologue (PTEN) phosphorylation. RESULTS: Western blot analysis showed that high Skp2 expression was observed in 57 (57.6%) cases and significantly correlated with unfavorable cytogenetics (P = 0.035) but not with age, white blood cell count, serum lactic dehydrogenase level, and the French-American-British subtype. An inverse correlation was not observed between Skp2 and p27Kip1 expression. However, p27Kip1 protein was preferentially localized to cytoplasm in the high-Skp2-expression group. The cytoplasmic to nuclear ratio of p27Kip1 expression was significantly correlated with the levels of Skp2 expression (P < 0.001). The frequency of PTEN phosphorylation was significantly higher in the high-Skp2-expression group compared with the low- Skp2-expression group (P = 0.035). The Skp2 overexpression was significantly associated with shorter disease-free survival and overall survival (P = 0.0386 and P = 0.0369, respectively). Multivariate analysis showed that Skp2 expression was an independent prognostic factor both in the disease-free survival and overall survival. CONCLUSION: These findings suggest that Skp2 expression is an independent marker for a poor prognosis in AML. The presence of a positive correlation between Skp2 and phosphorylated PTEN suggests that an aberration in the PTEN/Skp2 signaling pathway might be operating in AML.ope

A Case of Serum Amino Acid Disturbance with Hyperammonemia in Patient with Primary Amyloidosis

There have been reports that hyperammonemia and amino acid disturbance can cause loss of consciousness in patients with multiple myelomas and normal liver function. We experienced a case of a 71-years-old female patient with amyloidosis, who had shown disturbance of consciousness. At that time, the serum ammonia level was elevated; serum amino acids disturbance was also noted. In particular, the decrease in branched-chain amino acids and increase in aromatic amino acids results in a low Fisher ratio. The Fisher ratio, the ratio of branched-chain to aromatic amino acids, has been suggested as an important indicator of consciousness disturbance. We report, for the first time in Korea, a case of amyloidosis, with mental disturbance due to serum amino acid disturbance.ope

Two Cases of Acquired Hemophilia A Successfully Treated with Oral Steroid or Danazol

Acquired Hemophilia A is a rare and considerably life-threatening coagulopathy, which is caused by the development of autoantibodies against factor VIII (FVIII) in non-hemophilic adults. Acquired FVIII inhibitors can be associated with diverse conditions, such as malignant disorders, medications, autoimmune diseases, postpartum states and others. These autoantibodies inhibit normal coagulation, had results in bleeding complications, which can contribute to mortality in a high percentages of cases. Effective control of the disorder can be achieved by prompt diagnosis and appropriate managements. Generally, the managements of acquired hemophilia A are aimed at treating the acute bleeding and eliminating inhibitors by immunosuppression. Although a range of treatment options exists for patients with acquired hemophilia A, there is no consensus with regard to the optimal therapies for this disorder. Herein, two cases, an 82-year-old man and a 78-year-old man who were successfully treated by steroid or danazol, which is a relatively mild immunosuppressive agent, are reported.ope

An increase in red blood cell distribution width from baseline predicts mortality in patients with severe sepsis or septic shock.

INTRODUCTION: A potential independent association was recently demonstrated between high red blood cell distribution width (RDW) and the risk of all-cause mortality in critically ill patients, although the mechanism underlying this relationship remains unclear. Little is known about the impact changes in RDW may have on survival in critically ill patients. Therefore, we investigated the prognostic significance of changes in RDW during hospital stay in patients with severe sepsis or septic shock. METHODS: We prospectively enrolled 329 patients who were admitted to the emergency department (ED) and received a standardized resuscitation algorithm (early-goal directed therapy) for severe sepsis or septic shock. The relationship between the changes in RDW during the first 72 hours after ED admission and all-cause mortality (28-day and 90-day) were analyzed by categorizing the patients into four groups according to baseline RDW value and ΔRDW72hr-adm (RDW at 72 hours - RDW at baseline). RESULTS: The 28-day and 90-day mortality rates were 10% and 14.6%, respectively. Patients with increased RDW at baseline and ΔRDW72hr-adm >0.2% exhibited the highest risks of 28-day and 90-day mortality, whereas the patients with normal RDW level at baseline and ΔRDW72hr-adm ≤0.2% (the reference group) had the lowest mortality risks. For 90-day mortality, a significantly higher mortality risk was observed in the patients whose RDW increased within 72 hours of ED admission (normal RDW at baseline and ΔRDW72hr-adm >0.2%), compared to the reference group. These associations remained unaltered even after adjusting for age, sex, Sequential Organ Failure Assessment (SOFA) score, Charlson Comorbidity Index, renal replacement therapy, albumin, hemoglobin, lactate, C-reactive protein and infection sites in multivariable models. CONCLUSIONS: We found that an increase in RDW from baseline during the first 72 hours after hospitalization is significantly associated with adverse clinical outcomes. Therefore, a combination of baseline RDW value and an increase in RDW can be a promising independent prognostic marker in patients with severe sepsis or septic shock.ope

Diastolic dysfunction is an independent predictor of cardiovascular events in incident dialysis patients with preserved systolic function

BACKGROUND: Diastolic heart failure (HF), the prevalence of which is gradually increasing, is associated with cardiovascular (CV) morbidity and mortality in the general population and, more specifically, in patients with end-stage renal disease (ESRD). However, the impact of diastolic dysfunction on CV outcomes has not been studied in incident dialysis patients with preserved systolic function. METHODS: This prospective observational cohort study investigates the clinical consequence of diastolic dysfunction and the predictive power of diastolic echocardiographic parameters for CV events in 194 incident ESRD patients with normal or near normal systolic function, who started dialysis between July 2008 and August 2012. RESULTS: During a mean follow-up duration of 27.2 months, 57 patients (29.4%) experienced CV events. Compared to the CV event-free group, patients with CV events had a significantly higher left ventricular (LV) mass index, ratio of early mitral flow velocity (E) to early mitral annulus velocity (E') (E/E'), LA volume index (LAVI), deceleration time, and right ventricular systolic pressure, and a significantly lower LV ejection fraction and E'. In multivariate Cox proportional hazard analysis, E/E'>15 and LAVI>32 mL/m2 significantly predicted CV events (E/E'>15: hazard ratio [HR] = 5.40, 95% confidence interval [CI] = 2.73-10.70, P32 mL/m2: HR = 5.56, 95% CI = 2.28-13.59, P15 and LAVI>32 mL/m2 had the worst CV outcomes. CONCLUSION: An increase in E/E' or LAVI is a significant risk factor for CV events in incident dialysis patients with preserved LV systolic function.ope

The Relationship of Initial Transferrin Saturation to Cardiovascular Parameters and Outcomes in Patients Initiating Dialysis

BACKGROUND: The prognostic importance of anemia for cardiovascular (CV) events and mortality has been extensively investigated. However, little is known about the impact of transferrin saturation (TSAT), a marker reflecting the availability of iron for erythropoiesis, on clinical outcome in dialysis patients. METHODS: A total of 879 anemic incident dialysis patients were recruited from the Clinical Research Center for End-Stage Renal Disease in Korea and were divided into 3 groups according to baseline TSAT of ≤20%, 20-40%, and >40%. RESULTS: There were no differences in hemoglobin levels and the proportion of patients on erythropoiesis-stimulating agents or iron supplements among the 3 groups. During a mean follow-up duration of 19.3 months, 51 (5.8%) patients died. CV composite (11.71 vs. 5.55 events/100 patient-years, P = 0.001) and all-cause mortality rates (5.38 vs. 2.31 events/100 patient-years, P = 0.016) were significantly higher in patients with TSAT ≤20% compared to those with TSAT 20-40% (reference group). Cox regression analysis revealed that patients with TSAT ≤20% had 1.62- and 2.19-fold higher risks for CV composite outcome (P = 0.046) and all-cause mortality (P = 0.030). Moreover, TSAT ≤20% was significantly associated with left ventricular hypertrophy [odds ratio (OR)  = 1.46], high-sensitivity C-reactive protein ≥3 mg/dL (OR = 2.09), N-terminal pro B-type natriuretic peptide ≥10000 pg/mL (OR  = 2.04), and troponin-T≥0.1 ng/mL (OR  = 2.02), on logistic regression analysis. CONCLUSIONS: Low TSAT was a significant independent risk factor for adverse clinical outcome in incident dialysis patients with anemia, which may be partly attributed to cardiac dysfunction and inflammation.ope

Changes in echocardiographic parameters according to the rate of residual renal function decline in incident peritoneal dialysis patients

Residual renal function (RRF) is associated with left ventricular (LV) hypertrophy as well as all-cause and cardiovascular (CV) mortality in patients with end-stage renal disease. However, no studies have yet examined the serial changes in echocardiographic findings according to the rate of RRF decline in incident dialysis patients. A total of 81 patients who started peritoneal dialysis (PD) between 2005 and 2012 at Yonsei University Health System, Seoul, South Korea, and who underwent baseline and follow-up echocardiography within the first year of PD were recruited. Patients were dichotomized into "faster" and "slower" RRF decline groups according to the median values of RRF decline slope (-1.60 mL/min/y/1.73 m(2)). Baseline RRF and echocardiographic parameters were comparable between the 2 groups. During the first year of PD, there were no significant changes in LV end-diastolic volume index (LVEDVI), left atrial volume index (LAVI), or LV mass index (LVMI) in the "faster" RRT decline group, while these indices decreased in the "slower" RRT decline group. The rate of RRF decline was a significant determinant of 1-year changes in LVEDVI, LAVI, and LVMI. The linear mixed model further confirmed that there were significant differences in the changes in LVEDVI, LAVI, and LVMI between the 2 groups (P = 0.047, 0.048, and 0.001, respectively). During a mean follow-up duration of 31.9 months, 4 (4.9%) patients died. Compared with the "slower" RRF decline group, CV composite (20.29/100 vs 7.18/100 patient-years [PY], P = 0.098), technique failure (18.80/100 vs 4.19/100 PY, P = 0.006), and PD peritonitis (15.73/100 vs 4.95/100 PY, P = 0.064) developed more frequently in patients with "faster" RRF decline rate. On multivariate Cox regression analysis, patients with "faster" RRF decline rate showed 4.82-, 4.44-, and 7.37-fold higher risks, respectively, for each clinical outcome. Preservation of RRF is important for conserving cardiac performance, resulting in an improvement in clinical outcomes of incident PD patients.ope