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.     

急性白血病细胞SHIP基因的突变分析

目的　评价SHIP基因突变在白血病发病中的作用。方法　利用逆转录 聚合酶链反应(RT PCR)、单链构象多态性 (SSCP)及DNA序列分析技术检测了 4 1例急性白血病患者、5 0名正常人的骨髓或外周血标本、8株白血病细胞系SHIP基因表达及突变情况。结果　RT PCR显示所有标本中都有SHIP基因表达 ,发现 32例急性髓系白血病 (AML)患者中有 7例 (2 2 % )和 9例急性淋巴细胞白血病 (ALL)患者中有 1例 (12 % )存在SHIP基因的突变 ,其中 1例AML患者发病时标本同时存在 2个错义突变 ,而完全缓解后消失。发病时患者的白血病细胞在体外随着IL 3的刺激其Akt磷酸化明显增加。结论　首次发现急性白血病细胞中SHIP基因突变 ,提示SHIP基因的突变可能与白血病发病有关 ,在造血细胞中 ,很可能作为一个抑癌基因通过负性调节PI3K/Akt信号通路发挥作用     

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.     

De novo CD5+ diffuse large B-cell lymphoma: a clinicopathologic study of 109 patients.

De novo CD5+ diffuse large B-cell lymphoma (CD5+ DLBCL) is known to have phenotypically and genotypically different characteristics than CD5- DLBCL and mantle cell lymphoma (MCL). To further characterize CD5+ DLBCL, 109 patients with CD5+ DLBCL were reviewed, and the results were compared with those of 384 CD5- DLBCL and 128 cyclin D1+ MCL patients. Patients with CD5+ DLBCL showed a higher age distribution (median, 66 years; P =.0083) and a female predominance (male-female ratio, 49:60, P =.011) compared with those with CD5- DLBCL. CD5+ DLBCL was more closely associated with many aggressive clinical features or parameters than CD5- DLBCL: 69% older than 60 years (P =.039), 34% with performance status greater than 1 (P =.0016), 69% with serum lactate dehydrogenase level higher than normal (P <.0001), 62% with stage III/IV disease at diagnosis (P =.0023), 35% with more than one extranodal site (P =.023), and 40% with B symptoms (P =.0031). The overall International Prognostic Index score was thus significantly higher for the patients with CD5+ DLBCL than for those with CD5- DLBCL (P =.00005). The most frequent site of extranodal involvement was bone marrow (28%), a higher frequency than that for CD5- DLBCL (P <.0001) but lower than that for cyclin D1+ MCL (P =.0015). Histopathologically, CD5+ DLBCL showed centroblastic morphology except for 3 patients with immunoblastic disease, and interfollicular growth pattern (7%) and intravascular or intrasinusoidal infiltration (19%) were observed. Immunophenotypically, CD5+ DLBCL was characterized by a CD5+CD10-CD19+CD20+CD21-CD23- cyclin D1- phenotype and a predominance of surface IgMkappa. Of particular interest is that CD5+ DLBCL was characterized by a survival curve significantly inferior to that for patients with CD5- DLBCL (P =.0026). These findings suggest that CD5+ DLBCL may constitute a unique subgroup of DLBCL.