11q23 Aberration is an additional chromosomal change in de novo acute leukemia after treatment with etoposide and mitoxantrone

We report on 2 patients with acute leukemia who had an 11q23 chromosomal aberration as an additional change after treatment with etoposide and mitoxantrone, agents that affect topoisomerase II (Topo II). One patient with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (L2) received chemotherapy, including 1,000 mg of etoposide and 75 mg of mitoxantrone. She relapsed 10 months later. Analysis at time of relapse showed a chromosomal aberration of del(11)(q23) as an additional cytogenetic change. The other patient was diagnosed with acute monoblastic leukemia (M5a) and received two autologous peripheral blood stem-cell transplantations. Her cumulative doses of etoposide and mitoxantrone were 6,000 mg and 42 mg, respectively. She also relapsed, and analysis at that time revealed del(11)(q23) as an additional chromosomal aberration. The mixed lineage leukemia/(myeloid-lymphoid leukemia (MLL) gene was not rearranged in either case, making these cases distinct from previously described therapy-related leukemias caused by Topo II Inhibitors. Based on these two cases, it may be that Topo II inhibitors can cause clonal evolution affecting chromosome band 11q23. © 1996 Wiley-Liss, Inc.     

Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia

Recently, somatic mutations of the nucleophosmin gene (NPM1), which alter the subcellular localization of the product, have been reported in acute myeloid leukemia (AML). We analyzed the clinical significance of NPM1 mutations in comparison with cytogenetics, FLT3, NRAS, and TP53 mutations, and a partial tandem duplication of the MLL gene (MLL-TD) in 257 patients with AML. We found NPM1 mutations, including 4 novel sequence variants, in 64 of 257 (24.9%) patients. NPM1 mutations were associated with normal karyotype and with internal tandem duplication (ITD) and D835 mutations in FLT3, but not with other mutations. In 190 patients without the M3 French-American-British (FAB) subtype who were treated with the protocol of the Japan Adult Leukemia Study Group, multivariate analyses showed that the NPM1 mutation was a favorable factor for achieving complete remission but was associated with a high relapse rate. Sequential analysis using 39 paired samples obtained at diagnosis and relapse showed that NPM1 mutations were lost at relapse in 2 of the 17 patients who had NPM1 mutations at diagnosis. These results suggest that the NPM1 mutation is not necessarily an early event during leukemogenesis or that leukemia clones with NPM1 mutations are sensitive to chemotherapy.     

Off-Pump Coronary Artery Bypass Grafting in a Patient with Congenital Factor V Deficiency: Report of a Case

Congenital factor V deficiency is an uncommon bleeding disorder that necessitates hemostatic correction before surgery. We herein describe a patient with severe factor V deficiency who underwent successful off-pump coronary artery bypass grafting with a transfusion of fresh-frozen plasma.     

Perioperative control of blood glucose level in cardiac surgery

It is well recognized that poor perioperative blood glucose (BG) control can increase the risk of infection, cardiovascular accidents, and even death in patients undergoing cardiac surgery. Since it has been reported that tight BG control (80–110 mg/dL) yields better outcomes in critically ill patients, it became a standard of care to control BG using intravenous insulin infusion in ICU. However, it has been debated in terms of the optimal target range whether a strict control with intensive insulin therapy is better than liberal control. Because strict BG control can often cause hypoglycemia, which in turn increases the hospital mortality. In fact, a meta-analysis of randomized clinical trials concluded that tight BG control was not associated with significantly reduced hospital mortality but was associated with an increased risk of hypoglycemia. According to the current published guidelines, it seems to be optimal to control BG level of 140–180 mg/dL in ICU. In terms of more strict BG control (110–140 mg/dL), it may be appropriate in selected patients as long as this can be achieved without significant hypoglycemia.     

Phase I/II study of humanized anti-CD33 antibody conjugated with calicheamicin, gemtuzumab ozogamicin, in relapsed or refractory acute myeloid leukemia: final results of Japanese multicenter cooperative study

The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of gemtuzumab ozogamicin (GO) in patients with relapsed and/or refractory CD33-positive acute myeloid leukemia (AML). Patients received 2-h infusions of GO twice with an interval of approximately 14 days. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria Version 2.0. Samples for pharmacokinetics were taken on day 1 and day 8 of the first treatment cycle. The dose was increased stepwise and, in each cohort, patients were treated at the same dose. Forty patients, median age 58 years (range 28–68) were treated; 20 and 20 patients were enrolled to the phase I and II parts, respectively. In the phase I part, dose-limiting toxicities (DLTs) were hepatotoxicities, and the recommended dose was established as 9 mg/m² given as two intravenous infusions separated by approximately 14 days. The pharmacokinetic study revealed that C _max and AUC were equivalent to those of non-Japanese patients. In the phase II part, complete remission was observed in 5 patients, and one patient had complete remission without platelet recovery. Four of these 6 in remission and one in the phase I are long-term survivors (alive for at least 44 months). GO is safe and effective as a single agent among Japanese CD33-positive AML patients. Remission lasted longer in a subset of patients than in non-Japanese patients in earlier studies. Further studies of this agent are warranted to establish standard therapy. S. Furusawa: deceased.     

Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C

BACKGROUND & AIMS: Hepatitis B virus (HBV) isolates of genotype B (HBV/B) with or without the recombination with genotype C over the precore region plus core gene have been reported. METHODS: All the 41 HBV/B isolates having the recombination with genotype C (HBV/Ba) possessed the nucleotide 1838 of A in contrast to that of G in all 29 of those without the recombination (HBV/Bj). Taking advantage of this single nucleotide polymorphism, a restriction fragment length polymorphism method was developed that distinguished HBV/Ba from HBV/Bj. RESULTS: HBV/Bj was detected in 90 of the 97 (93%) carriers of HBV/B from Japan, whereas HBV/Ba occurred in all 177 carriers of HBV/B from other countries (China, 20; Hong Kong, 45; Taiwan, 32; Thailand, 30; Vietnam, 30; and the United States, 20 [all of an Asian ethnicity]). In a case-control study, hepatitis B e antigen (HBeAg) and the double mutation in the core promoter (T1762/A1764) were significantly more frequent in 80 carriers each of HBV/Ba than HBV/Bj (35% vs. 18%, P < 0.05 and 33% vs. 15%, P < 0.05, respectively). Differences in the prevalence of HBeAg were more conspicuous between the carriers of HBV/Bj and HBV/Ba older than 30 years (5 of 66 or 8% vs. 16 of 62 or 26%, P < 0.01). CONCLUSIONS: HBV/B having the recombination with genotype C is frequent in Asia, except in Japan, and HBeAg is more prevalent in carriers of HBV/Ba than HBV/Bj.     

Cyclic strain delays the expression of tissue factor induced by thrombin in human umbilical vein endothelial cells

Most studies of tissue factor (TF) expression in endothelial cells (EC) are performed under stationary culture conditions. The purpose of this study was to determine the influence of mechanical stimuli such as cyclic strain (CS) on the expression of TF in EC exposed to thrombin (Thr). Human umbilical vein endothelial cells (HUVEC) were exposed to 4 U·mL⁻¹ Thr in the presence or absence of 10% average CS at 60 cycles·min⁻¹ and then TF expression was measured. TF messenger RNA (mRNA) expression peaked at 2 hours in HUVEC exposed to Thr, but at 4 hours in HUVEC exposed to both Thr + CS. TF expression was inhibited by p38 and extracellular signal-regulated protein kinase (ERK) inhibitors. For both Thr or Thr + CS stimuli, p38 and ERK activity peaked at 5 minutes (p < 0.05). Nuclear factor-kappa B levels remained high in the Thr group but not in the Thr + CS group, while Egr-1 levels were elevated in the Thr + CS group. We demonstrated CS-delayed, Thr-induced TF mRNA expression in HUVEC, which may be modulated by p38 and ERK inhibitors.