FLT3 Length Mutations as Marker for Follow-Up Studies in Acute Myeloid Leukaemia

Length mutations within the FLT3 gene (FLT3-LM) can be found in 23% of acute myeloid leukaemia (AML) and thus are the most frequent mutations in AML. FLT3-LM are highly correlated with AML with normal karyotype and other cytogenetic aberrations of the prognostically intermediate group. This group is supposed to be a mixed group of AML with differences in the underlying pathogenesis. For more individualized treatment options it would be helpful to better characterize this large AML group not only by molecular mutations but also use these markers for the definition of minimal residual disease (MRD). However, so far the cytogenetically intermediate AML has been lacking suitable markers for PCR-based MRD detection like the fusion genes in the prognostically favourable subgroups. The suitability of the FLT3-LM as a target for PCR-based MRD was discussed controversially as it seemed to be a rather unstable marker. Thus, we aimed at the evaluation of FLT3-LM as a marker for residual disease in a large cohort of AML. Paired samples of 97 patients with AML at diagnosis and at relapse were analyzed. It could be shown that in only four cases a loss of the length mutation was detected. This is in the range of other well-characterized AML relapsing with a different geno- and/or phenotype. In contrast, a change in the ratio of the mutated allele in comparison to the wild-type allele was frequently observed. In detail, the FLT3-LM showed a tendency to accumulate during disease progression and was found more frequently at relapse than at diagnosis. In addition, 45 patients were analyzed at different time points during and after therapy. Using conventional PCR it clearly could be shown that for most of the patients positive at presentation FLT3-LM is a reliable PCR marker for monitoring treatment response. Even an early detection of relapse was possible in some cases. Copyright (C) 2004 S. Karger AG, Basel

European surveillance of infections in cancer patients - ESIC

Major advances in cancer therapy result from development of multidrug chemotherapy regimens. Besides death from tumor progression, infections are currently one of the major causes of mortality and morbidity. Because of the risk of complications and mortality, the treatment for febrile neutropenia is admission to hospital and administration of broad-spectrum antibiotics. Response rates of initial antimicrobial treatment vary considerably (40-92%). Due to the heterogeneity of populations in randomized studies, comparison of efficacy and identification of risk factors is limited. This is the main reason why the European Society of Biomodulation and Chemotherapy (ESBiC) is conducting a surveillance study that concentrates more on the evaluation of risk factors than on the therapeutic outcome of prospective randomized antimicrobial regimens: European Surveillance of Infections in Cancer Patients (ESIC). The present contribution is to determine which cancer patients are at low risk for fever, and can benefit from first-line treatment with treatment options such as monotherapy as well as on an outpatient basis

The role of relatives in decisions concerning life-prolonging treatment in patients with end-stage malignant disorders: informants, advocates or surrogate decision-makers?

Background: This study examines the extent to which relatives of severely ill cancer patients are involved in the decision to limit treatment (DLT), their role in communicating patient wishes and the incidence of and reasons for disagreement with relatives. Patients and methods: This cohort study followed 70 patients with terminal cancer, for whom a limitation of life-prolonging treatment was being considered. ‘Embedded researchers' recorded patients' wishes and the relatives' roles and disagreements with DLT. Results: Although 63 out of 70 patients had relatives present during their care, only 32% of relatives were involved in DLT. Physicians were more likely to know the end-of-life (EOL) preferences for those patients who had visiting relatives than those without them (78% versus 29%, P = 0.014). Most relatives supported patients in voicing their preferences (68%), but one-third acted against the known or presumed wishes of patients (32%). Disagreements with patients' relatives occurred in 21% of cases, and predominantly when relatives held views that contradicted known patient preferences (71% versus 7%, P = 0.001). Conclusion: If relatives are to play an important part in EOL decision making, we must devise strategies to recognise their potential as patients' advocates as well as their own need

Proteomics of AML1/ETO Target Proteins: AML1–ETO Targets a C/EBP–NM23 Pathway

Abstract Introduction The rational design of targeted therapies for acute myeloid leukemia (AML) requires the discovery of novel protein pathways in the systems biology of a specific AML subtype. We have shown that in the AML subtype with translocation t(8;21), the leukemic fusion protein AML1–ETO inhibits the function of transcription factors PU.1 and C/EBPα via direct protein–protein interaction. In addition, recently using proteomics, we have also shown that the AML subtypes differ in their proteome, interactome, and post-translational modifications. Methods We, therefore, hypothesized that the systematic identification of target proteins of AML1–ETO on a global proteome-wide level will lead to novel insights into the systems biology of t(8;21) AML on a post-genomic functional level. Thus, 6 h after inducible expression of AML1–ETO, protein expression changes were identified by two-dimensional gel electrophoresis and subsequent mass spectrometry analysis. Results Twenty-eight target proteins of AML1–ETO including prohibitin, NM23, HSP27, and Annexin1 were identified by MALDI-TOF mass spectrometry. AML1–ETO upregulated the differentiation inhibitory factor NM23 protein expression after 6 h, and the NM23 mRNA expression was also elevated in t(8;21) AML patient samples in comparison with normal bone marrow. AML1–ETO inhibited the ability of C/EBP transcription factors to downregulate the NM23 promoter. These data suggest a model in which AML1–ETO inhibits the C/EBP-induced downregulation of the NM23 promoter and thereby increases the protein level of differentiation inhibitory factor NM23. Conclusions Proteomic pathway discovery can identify novel functional pathways in AML, such as the AML1–ETO–C/EBP–NM23 pathway, as the main step towards a systems biology and therapy of AML. </jats:sec

A scheme with two large extra dimensions confronted with neutrino physics

We investigate a particle physics model in a six-dimensional spacetime, where two extra dimensions form a torus. Particles with Standard Model charges are confined by interactions with a scalar field to four four-dimensional branes, two vortices accommodating ordinary type fermions and two antivortices accommodating mirror fermions. We investigate the phenomenological implications of this multibrane structure by confronting the model with neutrino physics data.Comment: LATEX, 24 pages, 9 figures, minor changes in the tex

A 4-gene expression score associated with high levels of Wilms Tumor-1 (WT1) expression is an adverse prognostic factor in acute myeloid leukaemia

Wilms Tumor-1 (WT1) expression level is implicated in the prognosis of acute myeloid leukaemia (AML). We hypothesized that a gene expression profile associated with WT1 expression levels might be a good surrogate marker. We identified high WT1 gene sets by comparing the gene expression profiles in the highest and lowest quartiles of WT1 expression in two large AML studies. Two high WT1 gene sets were found to be highly correlated in terms of the altered genes and expression profiles. We identified a 17-probe set signature of the high WT1 set as the optimal prognostic predictor in the first AML set, and showed that it was able to predict prognosis in the second AML series after adjustment for Europe

Evaluating a patient's request for life-prolonging treatment: an ethical framework

Contrary to the widespread concern about over-treatment at the end of life, today, patient preferences for palliative care at the end of life are frequently respected. However, ethically challenging situations in the current healthcare climate are, instead, situations in which a competent patient requests active treatment with the goal of life-prolongation while the physician suggests best supportive care only. The argument of futility has often been used to justify unilateral decisions made by physicians to withhold or withdraw life-sustaining treatment. However, we argue that neither the concept of futility nor that of patient autonomy alone is apt for resolving situations in which physicians are confronted with patients' requests for active treatment. Instead, we integrate the relevant arguments that have been put forward in the academic discussion about 'futile' treatment into an ethical algorithm with five guiding questions: (1) Is there a chance that medical intervention will be effective in achieving the patient's treatment goal? (2) How does the physician evaluate the expected benefit and the potential harm of the treatment? (3) Does the patient understand his or her medical situation? (4) Does the patient prefer receiving treatment after evaluating the benefit-harm ratio and the costs? (5) Does the treatment require many resources? This algorithm shall facilitate approaching patients' requests for treatments deemed futile by the physician in a systematic way, and responding to these requests in an ethically appropriate manner. It thereby adds substantive considerations to the current procedural approaches of conflict resolution in order to improve decision making among physicians, patients and families

Treatment of Older Patients with Mantle-Cell Lymphoma

BACKGROUND: The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission. METHODS: We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression. RESULTS: Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P=0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P=0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P=0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P=0.005). CONCLUSIONS: R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphom