Journal of internal medicine. Supplement最新文献

In the last two decades, important advances have been made in the biology, natural history, and prognosis of B-cell chronic lymphocytic leukaemia (CLL). In addition, treatment possibilities for patients with CLL have changed as a result of the identification of prognostic factors for survival and the availability of new drugs and treatment strategies. Patients in the early clinical stages (Binet A, Rai 0) with stable disease have a probability of long survival and should not be treated unless the disease progresses. In contrast, most patients with poor prognostic features, such as an advanced clinical stage (Binet B, C; Rai III, IV), diffuse bone-marrow infiltration or rapidly increasing blood lymphocyte levels, have a median survival probability of < 5 years and require therapy. Purine analogues are highly effective. Among these, fludarabine has become the treatment of choice for patients failing standard therapies. The role of purine analogues either alone or in combination with other drugs as front-line therapy is being investigated. Certain situations (e.g. autoimmune cytopenias, hypersplenism) require special treatment approaches (e.g. corticosteroids, splenectomy). Transplants of progenitor haematopoietic cells are also increasingly performed and deserve further investigation in younger patients with poor prognostic features. As a result of these advances, symptoms palliation is no longer the only possible goal in CLL therapy; sustained remissions and even cures are likely to be obtained in the near future.

Unlabelled: The objective of this analysis were an assessment of the feasibility of a more individually tailored approach of empirical antibiotic therapy in febrile neutropenia and an exploration of the reasons to modify the initial regimen.

Design, setting and subjects: The main source was a database on febrile neutropenic cancer patients from an unblinded large trial conducted in 35 centres world-wide. This was supplemented by data from patients enrolled in a consecutive series of randomized trials at the Department of Haematology, University Hospital Nijmegen.

Interventions: Diagnostic procedures were standardized, types of possible infections defined and the reasons for modifying an empirical regimen were recorded.

Main outcome measures: Survival of the febrile neutropenic episode, development of microbiologically and clinically defined infection in relation to causative organisms, and results of modification.

Results: Monotherapy was as effective as combination therapy with an overall mortality of < or = 7%, with 21% of neutropenic episodes accompanied by a clinically defined infection proving fatal compared with only 4% of episodes without a focus. At the end of treatment the empirical regimen had been added to in 60% of cases in the multicentre trial, in contrast to 39% in our own institution, in many cases simply because of continuing fever.

Conclusion: The development of local guidelines for individually tailoring antibiotic therapy by complementing the empirical regimen is a feasible option for achieving an optimal anti-infective strategy for febrile neutropenic cancer patients.

Invasive fungal infections are one of the leading causes of morbidity and mortality in cancer patients. Amphotericin B deoxycholate is still considered the gold standard of antifungal therapy, although the new triazoles (itraconazole and, especially, fluconazole) have shown to be able to replace amphotericin B for some therapeutic indications. The new lipid formulations of amphotericin B have disclosed new therapeutic perspectives, especially in patients with severe renal failure and documented, infections. At this time, indications, contraindications and limitation of the various drugs in the antifungal armamentarium are still partially unclear. Antifungal prophylaxis with fluconazole may be indicated in high-risk patients, although the duration of such prophylaxis should be limited as much as possible, in order to prevent selection of resistant strains and acquired resistance. Empirical antifungal therapy is used extremely widely (maybe, too widely) in many cancer centres, despite being based on limited clinical data. For this indication, fluconazole may also be effective in patients not receiving fluconazole prophylaxis, in whom Aspergillus infection is unlikely.

Gene therapy of haematopoietic stem cells (HSCs) has been under investigation for 15 years. HSCs can be easily transduced with retroviral vectors (Moloney murine leukaemia virus = MMLV) in the mouse and expression of transferred genes can be achieved in long-term reconstituted mice. While human haematopoietic progenitor cells can be transduced with high efficiency using amphotropic MMLV retroviral vectors, and expression of the transferred gene is easily obtained in their progeny cells, it has proven problematic to transfer genes efficiently into the HSCs of humans in clinical trials. Efforts are now under way, in many laboratories, to increase the gene transfer efficiency of retroviral vectors, or alternatively, to develop new vectors that can transduce quiescent human HSCs with higher efficiency than is currently possible. This brief review will address the two main research areas that are being explored. Firstly, investigations in human haematopoiesis to gain understanding into the molecular and cellular mechanisms that control HSC behaviour in vitro and in vivo. Secondly, development of new vectors that can transfer genes to quiescent human HSCs.

At least two transport proteins, P-glycoprotein (Pgp) and the multidrug resistance associated protein (MRP), are believed to play a significant role in clinical resistance to cytotoxic therapy. These proteins are expressed at relatively high levels in a number of malignant diseases including various types of leukaemias. They are variably expressed on both the plasma membrane and intracellular vesicular membranes resulting in cellular drug efflux or vesicular drug sequestration, respectively. The action of MRP as a drug transporter depends on intracellular levels of glutathione. A number of strategies for circumvention of these drug resistance mechanisms have been developed and some of these are now in clinical trial.

The prevalence of hypercholesterolaemia is similar in non-insulin-dependent diabetic (NIDDM) patients and in non-diabetic subjects. The prevalence of hypertriglyceridaemia and of low high-density-lipoprotein (HDL) cholesterol is roughly double the norm in NIDDM, but the exact prevalence varies greatly from study to study. Obesity and a familial form of hypertriglyceridaemia (conditions that may alter plasma lipoprotein levels) are frequently observed in NIDDM patients. In carefully controlled NIDDM patients without concomitant primary hyperlipoproteinaemia, body weight may be more important than glycaemic control or the type of treatment plan adopted in determining lipoprotein levels. Hypertriglyceridaemia in NIDDM is a result of both increased very-low-density-lipoprotein (VLDL) synthesis and impaired VLDL catabolism. Whilst low-density-lipoprotein (LDL) levels are normal, the LDL synthesis and removal rates may be increased. Low high-density-lipoprotein (HDL) levels may be due to increased catabolism. In addition to quantitative changes in plasma lipids and lipoproteins. NIDDM patients demonstrate qualitative lipoprotein alterations. The size and density of LDL particles in NIDDM patients are greatly affected by triglyceride levels. Smaller, denser LDL particles have been observed in hypertriglyceridaemic subjects. Glycosylation of apolipoproteins may alter the metabolic properties of lipoproteins. Glycosylated and small, dense LDL have an increased susceptibility to oxidation.

The potential role of triglyceride-rich lipoproteins (TGRLP) in the pathogenesis of atherosclerosis is briefly reviewed. Structural attributes of TGRLP are related to functional cellular interactions relative to their ability to interact with macrophage receptors and produce foam cells. Unlike low-density lipoproteins (LDL), no prior modification (oxidation or acylation) is necessary with TGRLP from certain hypertriglyceridaemic subjects and certain postprandial-TGRLP before rapid, receptor-mediated lipid engorgement occurs. In addition, arguments are examined that challenge the differing views that this lipoprotein class is not important in atherogenesis.