Journal of internal medicine. Supplement最新文献

Re-activation of the fetal globin genes is the most realistic approach to correct the deranged pathophysiology of the haemoglobinopathies because the presence of gamma-chains can neutralize the toxic effects of the unbound alpha-globin chains in the beta-thalassaemias and inhibit the polymerization of Hb S in the sickle cell syndromes. Re-induction of fetal haemoglobin synthesis can be brought about either by direct activation of the respective promoter genes and possibly other positively acting elements, or by recruitment into proliferation and differentiation of a population of erythroid precursors which retain the gamma-chain synthesis programme but remain dormant in the bone marrow of the adult unless called up in cases of acute erythroid expansion. Examples of the first group include the butyric acid and derivatives and 5' azacytidine. The second group comprises erythropoietin and a series of cytostatics, with hydroxyurea as the main representative. The activity of most of the above agents has already been studied in cell cultures and animals and confirmed in several patients, both at the haematological and biochemical level as well as through their frank clinical improvement. However, application of these drugs at large is not yet justified because a series of questions concerning their long-term efficacy, the correct dosage and timing, their tolerance and toxicity, and the potential long-term dangers, including mutagenicity are still unresolved.

Inherent or acquired drug resistance is a major obstacle for the successful treatment of cancers. Many mechanisms of drug resistance have been described including a decreased drug uptake, an increase in DNA damage repair, enhanced drug detoxification, an altered level or mutation of the intracellular drug target or an increased drug efflux from the cell. Most of these mechanisms impinge upon the interaction of a drug with its cellular target or immediate consequences of such as interaction. For example, a decrease in the cellular levels of topoisomerase II thwarts the efficacy of certain topoisomerase II inhibitors, and enhanced levels of glutathione increase resistance to DNA alkylating agents. However, some tumours are inherently resistant to all chemotherapeutic agents, i.e. with different mechanisms of action. What is the mechanism(s) underlying this pleiotropic drug resistance? One possibility is that such drug-resistant tumour cells have an abnormally high threshold for the engagement of apoptosis (programmed cell death). The suppression of apoptosis as a mechanism for drug resistance is discussed in this article.

Diagnosis of von Willebrand's disease (vWD), particularly vWD Type 1, remains a clinical problem for several aspects. Its definitive diagnosis requires documentation of three factors: bleeding, low levels of qualitatively normal von Willebrand factor (vWF), and inheritance. In the absence of any of these factors the diagnosis may be only merely 'possible', or even unacceptable. Laboratory diagnosis of vWD includes screening tests and confirmatory tests. vWD Types 2 and 3 are relatively easy to diagnose and appear to be genetic disease of a single locus, the vWF gene. As new genetic and possibly non-genetic factors are discovered, the diagnosis of vWD Type 1 may become easier.

The haematopoietic stem cells in the bone marrow have long been considered, at least in theory, as an ideal target for gene therapy. Of the more than 250 clinical gene transfer protocols reported from around the world up to December 1996, almost one in three involves manipulation of haematopoietic cells. This includes both marketing trials and trials with a therapeutic intent. The human gene transfer trials targeting haematopoietic cells, the knowledge gained from them and their limitations are briefly summarized.

Antimicrobial prophylaxis in neutropenic patients has been practised in one form or another for several decades but the goal is no longer clear. From being initially solely an attempt at decontamination, drugs such as co-trimoxazole and later the fluoroquinolones were preferred to non-absorbable regimens because they achieve reliable protection against bacteraemia due to Gram-negative bacilli. Nevertheless, fever still invariably occurs during neutropenia leading to the initiation of traditional empirical therapy. Not only is this approach illogical but it also ignores the flexibility afforded the oral and parenteral formulations of the fluoroquinolones. Instead, it might be as effective and less costly if these agents were given orally until the end of neutropenia unless there was evidence of malabsorption or poor oral intake, in which case treatment would be continued parenterally. Should patients develop fever, an attempt would be made to complement treatment with another anti-microbial agent for microbiologically or clinically defined infection. This would be carried out at diagnosis, before any changes in the prophylactic regimen could be made. Otherwise, treatment with the prophylactic regimen would continue without modification. There is a less compelling need for prophylaxis against candidosis, herpes simplex and cytomegalovirus disease as these would be better managed pre-emptively when there is evidence of yeast carriage or re-activation of viral infection. Similarly, prophylaxis of aspergillosis is a forlorn hope and again a pre-emptive approach might serve us better once there is a screening test available and a safe and effective drug.

von Willebrand's disease (vWD) is caused by qualitative (type 2) and quantitative (types 1 and 3) abnormalities of von Willebrand factor (vWF). vWD type 3, a severe form of the disease with nearly complete deficiency of the protein in plasma, are found to be homozygous or compound heterozygous for null mutations in the vWF gene. Null mutations in both alleles of the vWF gene completely disrupt the protein synthesis resulting in a nearly complete deficiency of the vWF in the type 3 patients. The vWD type 1 patients (mild form with partial deficiency of the protein) could be heterozygous for null mutations or compound heterozygous for the mutations (null mutation + missense mutation) in the gene. The vWD type 2, divided into four variants: types 2A, 2B, 2M and 2N, are caused exclusively by missense mutations within three different domains of the protein (gain or loss of function). The majority of type 2A mutations are located in the A2 domain and the types 2B and 2M mutations are in the A1 domain, while the type 2N mutation is in the FVIII binding domain.

The author presents a brief overview of current therapy in adults of various ages with acute myelogenous leukemia, including remission induction and post-remission treatment and the use of haematopoietic growth factors.

Follicle centre lymphomas (FCLs) comprise the predominant subtype of indolent nodal lymphomas. Therapy is based on the stage of the disease and consists of extended field or total nodal irradiation in stages I and II. Patients with advanced stages III and IV may initially remain untreated and be watched until the occurrence of disease-related symptoms such as B-symptoms, haematopoietic insufficiency, lymphoma progression or bulky disease. On the occurrence of these signs a cytoreductive chemotherapy of mild to moderate intensity such as cyclophosphamide, vincristine, prednisone (COP) or mitoxantrone, chlorambucil, prednisone (MCP) should be initiated. In responding cases maintenance with interferon-alpha (IFN alpha) leads to a significant prolongation of the progression-free interval. Modifications of this approach include the upfront combination of IFN alpha with anthracycline containing combinations such as cyclophosphamide, doxorubicin, teniposide, prednisone (CHVP). New perspectives arise from the introduction of myelo-ablative radio-chemotherapy with subsequent stem-cell transplantation and antibody-based immunobiological therapies.