Journal of internal medicine. Supplement最新文献

von Willebrand's disease is the most frequent of inherited bleeding disorders (1:100 affected individuals in the general population). The aim of therapy is to correct the dual defects of haemostasis, i.e. abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by a prolonged bleeding time. There are two main options available for the management of von Willebrand's disease: desmopressin and transfusion therapy with blood products. Desmopressin is the treatment of choice in patients with Type 1 von Willebrand's disease, who account for approximately 80% of cases. The pharmacological compound raises endogenous factor VIII and von Willebrand factor and corrects the prolonged bleeding time in most patients. In Type 3 and in the majority of Type 2 patients, desmopressin is not effective and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are currently effective and quite safe, even though the bleeding time defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the bleeding time is associated with continued bleeding.

Desferrioxamine (DFX) remains the most effective and safe iron chelator for treatment of patients with transfusional iron overload. It is usually given by intermittent subcutaneous infusions for 8-12 h on 4-6 days weekly using a battery-driven pump. Disposable balloon infusers provide a suitable method of giving continuous subcutaneous infusions with improved patient compliance. For patients with cardiac abnormalities due to iron overload, continuous intravenous desferrioxamine is essential to eliminate toxic plasma non-transferrin bound iron and to reduce body iron stores. Deferiprone (L1, l-2 dimethyl-3hydroxy-pyrid-4-one) is a less effective iron chelator but has the advantage of being orally active. Long-term trials in which patients have taken 75 mg/kg/day have shown that deferiprone is capable of maintaining body iron stores at safe levels in a proportion of thalassaemia major patients but body iron stores, assessed by liver biopsy remain at high levels (> 15.0 mg/g dry weight) in a substantial number of patients. These concentrations have been associated with tissue damage. Trials of increased doses of deferiprone (up to 100 mg/kg/day) or of combined therapy with daily deferiprone and DFX or 1 or 2 days each week are being carried out in an attempt to achieve lower body iron burden in these patients. Preliminary results show that the drugs can be given safely together and urine iron excretion produced is additive, implying that the drugs chelate different body iron pools. Patients previously well chelated with serum ferritin levels less than 2500 micrograms/L have the fewest side-effects from deferiprone and usually may be kept at the same level of body iron for periods of at least 4 years, assessed by serum ferritin and urine iron excretion. The side-effects of deferiprone result in some patients discontinuing therapy. These side-effects, especially arthropathy, mainly occur in previously poorly chelated and so the most heavily iron-loaded patients. Nausea and other gastrointestinal symptoms, agranulocytosis or milder degrees of neutropenia account with arthropathy for nearly all the withdrawals from deferiprone therapy. Patients with cardiomyopathy due to iron overload should be given intravenous DFX rather than deferiprone. Deferiprone, licensed for pharmaceutical use in India, awaits official approval for widespread clinical use in Western Europe and North America. Meanwhile, attempts to find new orally active iron chelators and improved methods of administration of desferrioxamine are in progress.

Resistance to natural product-derived anti-cancer drugs, such as the anthracyclines and etoposide, contributes to the failure of chemotherapeutic treatment of leukaemia. One biological resistance mechanism of potential importance is the overexpression of the plasma membrane drug transporter proteins P-glycoprotein (Pgp) and multidrug resistance protein (MRP). Many studies have reported evidence for a correlation of Pgp/MDR1 expression with unfavourable prognostic features in acute myeloid leukaemia (AML). Failure to achieve complete remission (CR) is correlated with Pgp and the CD34+ phenotype. For MRP fewer data are available, which suggest a basal expression level in most AMLs. Another protein reported to correlate with treatment failure in AML is the lung resistance protein or major vault protein (LRP), a protein with a still unknown function. Co-expression of Pgp and LRP especially seems to define an adverse prognostic population. Further progress towards the understanding of the clinical importance of these proteins is hampered by the lack of validation of methods to determine their expression. A reliable way to measure Pgp seems to be the assessment of the active transport of fluorescent Pgp substrates, such as rhodamine 123 out of AML cells. Such functional Pgp assays can be used to validate mRNA or protein measurements and to quantify the effect of Pgp or the magnitude of the effect of a blocker of the Pgp-mediated drug efflux on the intracellular drug concentration. The prognostic value of such methods has still to be shown.

The ability to transfer novel genes into mammalian cells has allowed us to conceive of novel strategies towards cancer therapy. Since the initial gene-transfer clinical trial in 1989, over 300 cancer patients have been enrolled in gene therapy trials. Despite this, an NIH-sponsored panel concluded that 'clinical efficacy has not been definitively demonstrated at this time in any gene therapy protocol'. However, the first 8 years of gene therapy research have provided us with insights regarding the areas that require further scientific progress. For example, it is now clear that while in vitro assays of gene-modified haemotopoietic progenitor cells suggest high transduction efficiencies, once these cells are infused in vivo, only a small percentage of circulating transduced cells can be detected. While the initial clinical studies have demonstrated that gene transfer in patients can be safe and feasible, they have also indicated that future research is necessary towards the development of improved gene transfer techniques for these approaches to be successful.

The protein C system is an important natural anticoagulant pathway. Protein C is the key component of the system and it is activated by thrombin bound to thrombomodulin on the surface of endothelial cells. Activated protein C (APC) inhibits coagulation by cleaving and inactivating coagulation factors factor Va and factor VIIIa. Until recently, the major genetic causes of familial venous thrombophilia were inherited deficiencies of protein C, protein S or antithrombin, but together they were found in less than 5-10% of patients with thrombosis. In 1993, the situation changed drastically with the description of inherited APC-resistance as a novel risk factor for venous thrombosis. APC-resistance is characterized by a poor anticoagulant response to APC. Inherited APC-resistance is the most common genetic risk factor for this disease and it is found in 20-60% of patients. The condition is caused by a single point mutation in the gene for factor V which predicts substitution of arginine (R) at position 506 with a glutamine (Q). Mutated factor V (FVR506Q, FV:Q506 or FV Leiden) expresses normal procoagulant properties but is partially resistant to APC. The resulting hypercoagulable state confers a life long increased risk of venous but not arterial thrombosis. The FVR 506Q mutation is common in Caucasians with a prevalence of 1-15%, whereas it is not found in other human races. The FVR 506Q mutation may, due to its high prevalence, be an additional risk factor in individuals carrying other inherited defects such as deficiency of protein S, protein C or antithrombin. Such individuals have a high incidence of thrombosis and severe thrombophilia is a multigenetic disease. The high prevalence of inherited APC-resistance and the availability of easy functional and genetic tests will stimulate the development of prophylactic regimens and hopefully result in a decreased incidence of thrombosis.

There are now a number of potential candidates for inherited thrombophilia but a definite causal relationship has been established for only a proportion of these. Accepted causes of familial thrombophilia include the factor V Leiden defect and the prothrombin 20210 G > A variant, as well as deficiencies of antithrombin, protein C and protein S. Together these inherited abnormalities account for 30-50% of individuals presenting with venous thromboembolism. Factor V Leiden, which is present in up to 7% of the European population, is the most common cause of familial thrombophilia. On a worldwide basis its prevalence varies greatly with ethnic origin. In common with other types of familial thrombophilia the frequency of factor V Leiden is highly dependent on the population group studied. Venous thromboembolism, present in approximately 55% of individuals with familial coagulation inhibitor deficiencies, is the predominant clinical manifestation of familial thrombophilia. There are indications that the venous thrombotic risk is somewhat less in those with factor V Leiden. The thrombotic risk is markedly increased in those with combined defects and in those who are homozygous for factor V Leiden. Risk factors for thrombosis include pregnancy, including the puerperium, surgery, oral contraceptive usage and prolonged periods of immobilization. A substantial proportion of venous thrombotic events may occur spontaneously, i.e. without an obvious precipitating event. The management of patients with familial thrombophilia comprises counselling, thromboprophylaxis and thrombosis treatment. Although the immediate treatment of an acute thrombotic event is not significantly different from that of patients without recognised abnormalities, detailed patient management is seriously hampered by a lack of appropriate clinical trials. Prospective clinical studies, designed to ascertain individual thrombotic risk and to evaluate different therapeutic strategies are urgently required.

Acute promyelocytic leukaemia (APL) is a distinct entity of acute myeloid leukaemia characterized by blast cell morphology, severe coagulopathy and t(15;17) translocation that fuses the PML gene on chromosome 15 to the retinoic acid receptor alpha (RAR alpha) gene on chromosome 17. Past experience indicated that APL is highly sensitive to anthracycline-based chemotherapy. GIMEMA experience reported a similar complete remission (CR) rate (77% versus 69%) in APL patients treated with idarubicin alone or idarubicin plus Ara-C, respectively. At present all-trans-retinoic-acid (ATRA) represents the mainstay of APL treatment. Current available clinical trials show that combination of ATRA and anthracycline induction therapy produces approximately 90% CR rate and seems to significantly improve disease-free survival. Furthermore ATRA combined therapy reduces induction death rate since ATRA syndrome has been managed with high-dose corticosteroids. However the development of ATRA resistance could limit the use of ATRA as post-remission treatment and therefore future efforts should be addressed to the search of new retinoids with comparable clinical activity, which can overcome ATRA resistance.

In the last 30 years the treatment of acute lymphoblastic leukaemia has radically changed and intensified and has resulted in improvements in the chances of cure in children to up to 70% but in adults only 30% will achieve long-term disease-free survival. Data from large therapeutic trials have determined good and poor prognostic risk factors which have been of use in planning risk-directed treatment protocols and can influence the chance of cure. However intensification of treatment has also been associated with increased toxicity and significant late effects, particularly in children. In the future it will be necessary for more international collaboration and a more uniform approach to treatment in order to achieve continued improvements in the survival from this disease. In children it will be necessary to focus efforts on improving treatment of relapsed patients: chemotherapy protocols in those with a first remission of > 36 months, or for the high-risk patients with a shorter first remission, new transplantation approaches directed towards enhancing the graft-versus-leukaemia effect are going to be of increasing importance. In adults, continued efforts will be directed towards improving first remission rates with the use of increasingly intensive chemotherapeutic protocols and growth factors. The use of unrelated donor transplantation is also likely to increase, particularly in patients with 'poor-risk' disease.

For all patients with a histocompatibility antigen (HLA) identical donor we are actually using two protocols to whom the patients is assigned. This is based on which class the patients belongs to at the time of bone-marrow transplant and is independent from the patient's age. For 116 patients in Class 1 and for 271 patients in Class 2 prepared for the transplant with busulfan 14 mg/kg, cyclophosphamide 200 mg/kg and cyclosporin alone, the probabilities of survival and of event-free survival are 95% and 90% for Class 1 and 85% and 81% for Class 2. For 125 Class 3 patients prepared for the transplant with busulfan 14 mg/kg, cyclophosphamide reduced to 120-160 mg/kg, cyclosporin and 'short' methotrexate, the probabilities of survival and of event-free survival are 78% and 54%. For 108 adult patients aged between 17 and 35 years, who underwent the transplant after preparation with the same protocol used for the Class 2 or Class 3 patients, the probabilities of survival are 67% and of event-free survival are 63%. Bone marrow transplantation remains the only form of radical treatment of thalassaemia in those patients with an HLA identical donor.

Because a reduction in bone density often correlates to an increased risk of fracture, bone density is usually measured in an attempt to establish the risk of fracture. The results from bone density measurement are intended to provide a potential basis for treating osteoporosis. When assessing the value of bone density measurement, the key issues concern the reliability of the various methods (i.e., how accurately they reflect bone density) and whether bone density treatment can actually prevent fracture. OSTEOPOROSIS: Humans begin to lose bone tissue as they become older. In most cases, this process is slow and gradual. Bone tissue begins to disappear when people are aged between 30 and 40 years and continues throughout life. However, bone loss varies greatly among individuals, and some elderly people show no sign of bone loss. Several factors influence both the loss of bone mass as people age and the formation of bone mass in the growing individual. The single most important factor associated with reduced bone mass is the loss of the female sex hormone (oestrogen). Tobacco smoking, lack of exercise, and low calcium levels in the diet also reduce bone density. Reduced bone density may lead to osteoporosis, which increases the risk of fracture, often affecting the vertebrae, hips and wrists. The most common direct cause of fracture, mainly among the elderly, involves falling or stumbling. Contributing factors here include diseases or medications that affect the sight, muscle strength, and balance. Osteoporosis is one of many risk factors for fractures resulting from falls. Fracture is a large and growing health problem. Each year, approximately 60,000 people in Sweden suffer some type of fracture. With an increasing percentage of elderly people in the Swedish population, it is estimated that every second woman over 50 years of age will experience fracture at some time during their remaining life. The risk in men is lower. It is essential to prevent, as far as possible, the onset of osteoporosis and other risk factors for fracture. Preventive approaches include, increased physical activity during youth when people develop their bone mass, sufficient intake of calcium in the diet among the young and old alike, and smoking cessation (or preventing people from starting to smoke). It is particularly important to treat osteoporosis effectively, or prevent osteoporosis from developing into a serious condition. This requires further research into strategies for treating osteoporosis. The various methods for measuring bone density represent an important component in such research. MEASURING BONE DENSITY: Bone density may be measured either to establish a diagnosis or to monitor changes, e.g. follow-up treatment for osteoporosis. Bone density can be estimated roughly by simply measuring height, weight, and age, but this approach has limited value for establishing the level of bone density in individuals. To a certain extent, x-ray examination can als