Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia

The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to- moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.     

Interferon-alpha stimulates production of interleukin-10 in activated CD4+ T cells and monocytes

In the present study, we investigated the effect of interferon-alpha (IFN-alpha) on the expression of interleukin-10 (IL-10) mRNA and protein synthesis in human monocytes and CD4+ T cells. In mononuclear cells, IFN-alpha induced expression of IL-10 mRNA and further enhanced lipopolysaccharide (LPS)-stimulated IL-10 expression. In purified monocytes, a strong expression of IL-10 mRNA induced by LPS was not further enhanced by IFN-alpha. In highly purified CD4+ T cells, IFN- alpha upregulated IL-10 mRNA upon activation with phytohemagglutinin and phorbol myristate acetate. In purified monocytes, an effect of IFN- alpha on IL-10 protein synthesis was dependent on costimulation with LPS. Maximal stimulation of IL-10 protein by IFN-alpha was seen after prolonged incubation periods of 48 to 96 hours, whereas IFN-gamma reduced IL-10 production in the early incubation period. Similar effects of IFN-alpha were observed in CD4+ T cells activated with CD3 and CD28 monoclonal antibodies. Addition of IFN-alpha caused an increase of IL-10 in culture supernatants of activated T-helper cells of more than 100% after 96 hours of incubation. In contrast, other cytokines, including IFN-gamma and IL-4, had no influence on IL-10 secretion stimulated by CD3 and CD28 in CD4+ T cells. In serum samples of IFN-alpha-treated individuals, we failed to detect an influence of cytokine treatment on IL-10 serum levels, confirming the requirement of additional activating signals for IFN-alpha-mediated effects on IL-10 synthesis. In conclusion, IFN-alpha enhances the late induction of IL- 10, which physiologically occurs upon stimulation of monocytes and T cells. Biologically, this effect might enhance the negative-feedback mechanism ascribed to IL-10, which limits inflammatory reactions.     

WHO生存质量评估简表的等价性评价

目的评价WHO生存质量评估简表(WHOQOL-BREF)在13个国家的等价性。方法采用多组验证性因子分析方法,对世界卫生组织生存质量研究小组提供的13个国家的数据进行分析,评价WHOQOL-BREF不同国家的等价性。结果各个国家的各个领域的Cronbachα系数均大于0·7,分布在0·7至0·88之间。除了英国和挪威之外,其它国家的社会关系领域的Cronbachα系数均大于0·65。采用根据世界卫生组织生存质量研究小组研制量表时构建的四因子模型对数据分别进行拟合,拟合优度指数(CFI)均大于0·8,其中德国、西班牙和美国的拟合优度指数大于0·9。多组验证性因子分析发现模型拟合尚可,CFI等于0·88,各个国家的因子负荷不全相等,因子负荷的轮廓相似。结论WHOQOL-BREF在13个国家具有相同的因子结构,且有等价性。     

针式腹腔镜下胆囊切除术的临床应用

目的 与开腹胆囊切除术相比,腹腔镜胆囊切除术（ＬＣ）有减少术后不适和较少的创作,但仍有改进的余地。方法：为进一步减轻手术创伤,我们引进了针式腹间胆囊切除术,共２９例。结果 平均手术时间为７５分钟,１９例当天出院,１０例隔天出院,其中１例是胆总管探查。结论 针式航空 镜胆囊切除术是一种可靠的技术。     

High resolution analysis of follicular lymphoma genomes reveals somatic recurrent sites of copy‐neutral loss of heterozygosity and copy number alterations that target single genes

A multiplatform approach, including conventional cytogenetic techniques, BAC array comparative genomic hybridization, and Affymetrix 500K SNP arrays, was applied to the study of the tumor genomes of 25 follicular lymphoma biopsy samples with paired normal DNA samples to characterize balanced translocations, copy number imbalances, and copy‐neutral loss of heterozygosity (cnLOH). In addition to the t(14;18), eight unique balanced translocations were found. Commonly reported FL‐associated copy number regions were revealed including losses of 1p32‐36, 6q, and 10q, and gains of 1q, 6p, 7, 12, 18, and X. The most frequent regions affected by copy‐neutral loss of heterozygosity were 1p36.33 (28%), 6p21.3 (20%), 12q21.2‐q24.33 (16%), and 16p13.3 (24%). We also identified by SNP analysis, 45 aberrant regions that each affected one gene, including CDKN2A, CDKN2B, FHIT, KIT, PEX14, and PTPRD, which were associated with canonical pathways involved in tumor development. This study illustrates the power of using complementary high‐resolution platforms on paired tumor/normal specimens and computational analysis to provide potential insights into the significance of single‐gene somatic aberrations in FL tumorigenesis. © 2010 Wiley‐Liss,Inc.