Results of intensive therapy in childhood acute myeloid leukemia, incorporating high-dose melphalan and autologous bone marrow transplantation in first complete remission

Childhood acute myeloid leukemia (AML) has a poor prognosis with standard chemotherapy. Allogeneic bone marrow transplantation (BMT) in remission improves the outlook only for the one third of patients with sibling donors. Autologous BMT with a lower morbidity and mortality is available to all. In this study, maximum cytoreduction was achieved by intensive early chemotherapy. Final intensification, with autologous BMT was offered to all those remaining in first complete remission (CR). Patients received two induction and two consolidation courses of intensively scheduled chemotherapy. Cytoreduction was assessed on day 14 and remission was assessed after courses 2 and 4. Bone marrow was harvested after recovery from the second consolidation course or after the first maintenance course and separated on a discontinuous percoll gradient before cryopreservation. Twenty-eight of 31 consecutively enrolled patients achieved CR. Three relapsed early and, of the 25 eligible, 24 underwent autologous BMT. Twenty-three patients received high-dose melphalan and 1 received busulphan and cyclophosphamide before autologous BMT at a median of 113 days (range, 86 to 301) after initial CR. Trilineage engraftment occurred in all. Neutrophil recovery to greater than 0.5 x 10(9)/L occurred at a median of 46 days (range, 13 to 92) after autologous BMT. Platelet recovery was delayed, with a median time to achieve greater than 20 x 10(9)/L of 42 days (range, 18 to 215). With a minimum follow up of 25 months following autologous BMT only 3 children have relapsed. The 5-year event-free survival rate (EFS) from diagnosis is 68% (95% confidence interval, 46% to 90%). Five- year EFS following autologous BMT is 87% (95% confidence interval, 67% to 100%). Autologous BMT with high-dose melphalan administration after intensive chemotherapy has produced EFS equivalent to allogeneic BMT and is associated with a strikingly low relapse rate. High-dose melphalan appears to be a valuable agent for conditioning therapy in AML.     

Factor XI antigen and activity in human platelets

Washed platelets, contaminated with less than 0.20% plasma factor XI, were examined for the presence of factor XI antigen and activity. These platelets contained a factor-XI-like coagulant activity (0.67 +/- 0.11 U/10(11) platelets) that remained constant after successive washes. By means of indirect immunofluorescence, a monospecific antibody to factor XI showed specific staining of both normal platelets and platelets from patients deficient in plasma factor XI. Radiolabeled Triton extracts of washed platelets and labeled purified factor XI solutions were analyzed for factor XI antigen by Staph A immunoprecipitation analysis using antibody to purified plasma factor XI followed by SDS gel electrophoresis. On unreduced gels, the platelet material ran as a single band having an apparent molecular weight of 220,000 daltons, whereas purified plasma factor XI gave a single band at 160,000 daltons. On reduced gels, the platelet material analyzed as a single band at 52,000 daltons, whereas purified factor XI gave a single band of 80,000 daltons. Analysis of a partially purified factor XI preparation from platelets by immunoelectrophoresis revealed that the platelet preparation displayed a slightly lower cathodal electrophoretic mobility at pH 8.6 than did plasma factor XI and yet appeared to possess complete antigenic identity with plasma factor XI. These results indicate that platelets possess a form of factor XI that exists as a disulfide-linked 52,000-dalton tetramer in contrast to the plasma form that circulates as a 80,000-dalton disulfide-linked dimer.     

Relationship between biomarkers and subsequent clinical and angiographic restenosis after paclitaxel-eluting stents for treatment of STEMI: a HORIZONS-AMI substudy

Drug-eluting stents (DES) reduce the incidence of in-stent restenosis (ISR) after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). Whether the use of biomarkers might be of utility to identify patients who remain at risk for DES ISR after primary PCI has never been examined. A total of 26 biomarkers were measured at enrollment and 30 days and analyzed at a central core laboratory in 501 STEMI patients from the HORIZONS-AMI trial. All patients underwent primary PCI with the TAXUS paclitaxel-eluting stent (PES), were scheduled for routine angiographic follow-up at 13 months, and were followed for 3 years. Mean in-stent late-loss was 0.28 ± 0.57 mm, and target lesion revascularization (TLR) at 3 years occurred in 9.1 % of patients. Low levels of interleukin-6 (IL-6) and placental growth factor (PLGF) at admission were associated with both higher in-stent late loss and ischemia-driven TLR. Additionally, low admission levels of cardiotrophin-1 (CT-1) were associated with higher rates of ischemia-driven TLR. At 30-day follow-up lower values of IL-1ra (IL-1ra), matrix metalloproteinase 9 (MMP9), and myeloperoxidase (MPO), and a decline relative to admission in IL-1ra, monocyte chemotactic protein-1 (MCP-1), and MMP9 were associated with higher in-stent late loss. Low values of IL-6 at 30 days were also associated with ischemia-driven TLR. After multivariate adjustment, only MPO at 30 days and a decline of MCP-1 between admission and 30 days were associated with in-stent late loss, and only CT-1 was associated with TLR. MPO at 30 days and a decline of MCP-1 between admission and 30 days were independently associated with in-stent late loss, and CT-1 was associated with TLR. Additional studies to confirm and validate the utility of these biomarkers are warranted.     

Targeting of interleukin-13 receptor on human renal cell carcinoma cells by a recombinant chimeric protein composed of interleukin-13 and a truncated form of Pseudomonas exotoxin A (PE38QQR)

We have previously shown that human renal cell carcinoma (RCC) cells express large numbers of interleukin-13 receptors (IL-13R), a newly described hemopoietic growth factor receptor. To target tumor cells that express IL-13R, we have produced a chimeric protein composed of human IL-13 and a derivative of Pseudomonas exotoxin A, termed PE38QQR. We report here that IL13-PE38QQR is highly cytotoxic to many human RCC cell lines. IL-13R-negative cell lines or cell lines expressing low numbers of IL-13R ( < 300 sites/cell) that include human bone marrow- derived cells were not susceptible to the cytotoxic effect of IL 13- PE38QQR. The sensitivity of RCC cells to IL13-PE38QQR correlated positively with the density of IL-13R. The cytotoxic activity of IL13- PE38QQR was competed by an excess of IL-13 in a protein synthesis inhibition assay and confirmed by a clonogenic assay. Even though IL-13 and IL-4 are homologues and IL-4R and IL-13R have been proposed to share a receptor subunit, IL-4 did not compete for the cytotoxicity mediated by IL13-toxin on RCC. IL13-PE38QQR competes for [125I]-IL-13 binding sites on RCC cells, although at a lower affinity than the wild- type recombinant cytokine. Human T-cell, B-cell, and monocytic cell lines are unresponsive to the cytotoxic action of IL13-PE38QQR. Thus, our results indicate that IL13-PE38QQR is highly cytotoxic to human RCC cells, although it is not cytotoxic to a variety of normal hematopoietic cells. IL13-PE38QQR should be further investigated preclinically for the treatment of human RCCs.     

Initiation of health-behaviour change among employees participating in a web-based health risk assessment with tailored feedback

Background

Biological monitoring of healthy workers exposed to hazardous dusts lack validated screening tools. Induced sputum (IS) cellular profile was compared with bronchoalveolar lavage fluid (BALF) profile in asbestos exposed workers in order to assess its usefulness in monitoring workers exposed to asbestos for a long period of time.

Methods

IS and BALF analysis was performed in 39 workers of a car brakes and clutches factory that uses chrysotile asbestos. Selection criteria were an employment history of > 15 years and the absence of a diagnosis of pneumonoconiosis. The type of cells, the existence of dust cells, of iron laden macrophages and of asbestos bodies were assessed and compared between IS and BALF samples.

Results

35 IS samples (90%) had dust cells, 34 (87%) iron laden macrophages and in 8 samples (21%) asbestos bodies were found. In most samples neutrophils were dominated. Samples with asbestos bodies (ABs) had significantly higher lymphocytes and lower neutrophils count compared with the samples without ABs. Macrophages and neutrophils in IS and BALF exhibited significant inter-relations (Spearman's rho: 0.26-0.29, p < 0.05) while IS lymphocytes count showed an inverse relation with BALF neutrophils (Spearman's rho: -0.36). Neutrophils and dust cells were highly correlated between the samples (Spearman's rho: 0.35, p < 0.05) while IS dust cells and lymphocytes were inversely related (Spearman's rho: -0.36, p < 0.05). More years of employment in the company was related with more neutrophils (Spearman's rho: 0.26) and less lymphocytes (Spearman's rho: -0.33) count. In multivariate analysis the presence of AB in IS samples was strongly related to the presence of asbestos bodies and lymphocytes count in BALF samples.

Conclusions

IS and BALF analysis showed a similar cellular profile indicating that IS sampling in exposed workers to asbestos as a less invasive and expensive method may be useful in providing an insight both for inhalation of dusts and inflammatory processes in the lung.     

Developing best practice for fungal specimen management: audit of UK microbiology laboratories

This study represents an audit of microbiology laboratories in the UK to ascertain whether they are aware of, or follow, the Health Protection Agency (HPA) National Standard Methods Standard Operating Procedure (NSM SOP) for the investigation of dermatological specimens for superficial mycoses, or use a locally adapted version. A questionnaire audit was distributed to 179 NHS microbiology laboratories throughout England, Wales, Scotland and Northern Ireland. The NSM SOP was followed by 92% of laboratories for the microscopy of dermatological samples; light microscopy/ KOH digestion was used by 63% and fluorescence microscopy/KOH digestion by 29% of laboratories. Preliminary reports post-microscopy were issued by 98% of laboratories, with 93% issuing reports within 48 hours. Adherence to the NSM SOP guidelines for culture was low; only 34% of laboratories incubated microscopy-negative specimens for the recommended 14 days, while approximately 60% incubated microscopy-positive specimens for 21 days. The culture medium recommended by the NSM SOP was used in 82% of laboratories. Comments were added to culture reports by 51% of laboratories; most were added manually and comments varied between laboratories. Nail samples were the most common sample received from primary care, followed by skin and hair. These results show no significant difference in the rate of microscopy positives versus culture positives. Microscopy and culture are the easiest and cheapest methods available to UK laboratories for the investigation of suspected superficial fungal infections. Although most laboratories included in this audit claimed to follow the NSM SOP for microscopy and culture, these results show that the techniques used vary throughout the UK. To maximise the service provided to primary care, UK laboratories should use standardise methods based on the NSM SOP.     

基因治疗与心力衰竭

目的:探讨基因治疗方案的有效性和安全性。资料来源:应用计算机检索PUBMED1980-01/2006-10和EMCC 1994-10/2006-10与心力衰竭的基因治疗相关文章,检索词“Gen Therapy,Heart Failure”,并限定文章语言种类为“English”;同时计算机检索CMCC 1994-01/2006-10的相关文章,限定文章语言种类为中文,检索词“基因治疗、心力衰竭”。资料选择:对资料进行初审,选取试验包括上述治疗组和对照组的文献,然后筛除明显不随机临床试验的研究,对剩余的文献开始查找全文,进一步判断是否为RCT。纳入标准为:①试验包含平行对照组,即一般药物治疗。②治疗组为转基因治疗。资料提炼:共收集到49篇相关的随机和未随机试验,31个试验符合纳入标准。其余的排除。资料综合:31个试验包括478例动物模型,分别对应用不同靶点的转基因或基因敲除等方案进行治疗者予以评价。31篇文章中有10篇未达到预期的治疗目标,主要是在目的基因的选择及转染载体的选择方面出现了偏差。结论:虽动物试验取得了一定的成果,但尚无人体基因治疗的文献报道,随着基因技术的进步,基因治疗有望成为治疗心力衰竭的新途径。