How I treat venous thromboembolism in patients with cancer

Venous thromboembolism (VTE) is a frequent complication in cancer patients and represents an important cause of morbidity and mortality. Especially in patients who have a poor life expectancy, preventing death from pulmonary embolism is the mainstay of treatment. Critically ill patients should promptly be administered thrombolytic drugs. Except for selected patients requiring aggressive therapy, the initial VTE treatment should be conducted with either adjusted-dose unfractionated heparin or fixed-dose low-molecular-weight heparin (LMWH). LMWHs have the potential to greatly simplify the initial treatment of VTE, making the treatment of suitable patients feasible in an outpatient setting. During anticoagulant therapy, cancer patients have a 2- to 4-fold higher risk of recurrent VTE and major bleeding complications when compared with noncancer patients. The long-term administration of LMWH should be considered as an alternative to anti-vitamin K drugs in patients with advanced disease and in those with conditions limiting the use of oral anticoagulants. Prolongation of anticoagulation should be considered for as long as the malignant disorder is active. The evidence of lowered cancer mortality in patients on LMWH has stimulated renewed interest in these agents as antineoplastic drugs and raises the distinct possibility that cancer and thrombosis share common mechanisms.     

Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. The presence of anti-ADAMTS13 autoantibodies is considered a factor predisposing to relapses. Despite close monitoring and intensive plasma treatment, in these patients acute episodes are still associated with substantial morbidity and mortality rates, and the optimal therapeutic option should be prevention of relapses. This study was conducted in a patient with recurrent TTP due to high titers of ADAMTS13 inhibitors, who used to have 2 relapses of TTP a year. The study compared the standard treatment plasma exchange with rituximab. Results documented that plasma exchange had only a small transient effect on ADAMTS13 activity and inhibitors; on the contrary, prophylaxis with rituximab was associated with disappearance of anti-ADAMTS13 antibodies, a progressive recovery of protease activity, and it allowed the patient to maintain a disease-free state during a more than 2-year follow-up.     

Interleukin-2-induced increased airway responsiveness and lung Th2 cytokine expression occur after antigen challenge through the leukotriene pathway

Previous studies have shown that the allergic late airway response (LR) is dependent on the leukotriene (LT) pathway in Brown Norway (BN) rats. In this same model, interleukin-2 (IL-2) has been shown to increase allergic airway responses without increasing LT production. This study examined the relationship between the upregulation of cellular immunity with IL-2 and the LT pathway in ovalbumin-sensitized BN rats. Airway responsiveness to LTD(4) was significantly increased in BN rats pretreated with IL-2 (20,000 U twice a day for 4.5 days). Treatment with montelukast, a cysteinyl LT(1) receptor antagonist, blocked IL-2's induced increase of the LR to ovalbumin challenge. When cytokine expression was assessed either by semiquantitative polymerase chain reaction or in situ hybridization, we found that montelukast decreased the amount of IL-4 mRNA expression in the lungs while increasing the amount of interferon-gamma mRNA expression 8 hours after challenge. These results indicate that upregulation of cellular immunity with IL-2 can increase the sensitivity of the airways to LTD(4) and that inhibition of the LT pathway will block the LR and modulate cytokine expression after antigen challenge.     

Quality of life in dependent older adults living at home

The purpose of medical interventions today is to favor the duration of life and to assure its quality. For a proper evaluation of the quality of life (QoL) of the elderly, it is important to assess not only the health status, but also psychological, functional and existential domains. Up to now, QoL of the dependent older living at home does not seem to have received sufficient attention. This study is a population based, cross-sectional health survey, and tries to give a picture of the QoL conditions of a group of dependent elderly living at home, using a specifically designed structured interview. In addition to this interview the Activities of Daily Living (ADL) Index and the Zung rating scale for Anxiety and Depression (AD) were administered to a total of 167 elderly (60 males and 107 females). The most interesting results of the study are the following: (1) the definition of dependence is often worsen by cultural prejudices; (2) psychopathological factors show a deep negative effect on 'attitudes towards life' of the dependent elderly; (3) QoL of the dependent elderly people in this sample is mainly negatively influenced by the degree of depression. We believe that the 'QoL-oriented' therapeutic strategy should consider more articulated and multidisciplinary geriatric and psychosocial interventions in this population.     

An underestimated combination of opposites resulting in enhanced thrombotic tendency

Heterozygous carriers of factor V (FV) Leiden who also carry FV deficiency often develop venous thromboembolism, but the thrombosis risk associated with this rare condition (pseudohomozygous activated protein C resistance) is still unclear. The thrombosis risk of genetically characterized pseudohomozygotes (n = 6) was compared with that of FV Leiden heterozygotes (n = 683) and homozygotes (n = 50) recruited within a large cohort study on familial thrombophilia. Both thrombin generation and Kaplan-Meier thrombosis-free survival analyses were performed in different FV genotype groups. FV Leiden pseudohomozygotes showed significantly higher thrombosis risk than heterozygotes. The thrombin generation test in pseudohomozygotes showed a pattern similar to homozygotes. Accordingly, early thrombotic manifestations occurred in pseudohomozygotes at a similar rate as in homozygotes. Thus, failure to recognize FV deficiency in FV Leiden heterozygotes may result in an underestimate of the thrombosis risk and inadequate management of affected patients.     

A point mutation in the MET oncogene abrogates metastasis without affecting transformation

The MET oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF), known to stimulate invasive growth of epithelial cells. MET is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis. To investigate whether this oncogene is directly responsible for the acquisition of the metastatic phenotype, we exploited a single-hit oncogenic version of MET, able to transform and to confer invasive and metastatic properties to nontumorigenic cells, both in vitro and in nude mice. We mutagenized the signal transducer docking site of Met (Y¹³⁴⁹VHVX₃Y¹³⁵⁶VNV), which has the uncommon property of binding and activating multiple src homology region 2 (SH2)-containing intracellular effectors. Notably, a point mutation (H¹³⁵¹ → N) increased the transforming ability of the oncogene but abolished its metastatic potential. This mutation duplicates the Grb2 binding site, super-activating the Ras pathway and preventing the binding of the other intracellular transducers. Complementation in trans with another nonmetastatic mutant (N¹³⁵⁸ → H), recruiting all the transducers downstream to Met except Grb2, rescued the invasive–metastatic phenotype. It is concluded that the metastatic potential of the MET oncogene relies on the properties of its multifunctional docking site, and that a single point mutation affecting signal transduction can dissociate neoplastic transformation from metastasis.     

Felodipine (once daily) versus nifedipine (four times daily) for Prinzmetal''s angina pectoris

In 30 consecutive patients with Prinzmetal's angina pectoris, the antiischemic effect of felodipine, a new long-acting vasoselective calcium antagonist, administered at doses of 10 and 20 mg once daily was compared with that of the wellestablished therapeutic regimen with nifedipine administered at a dose of 20 mg 4 times daily. Twenty-four-hour Holter monitoring was performed during a 2-day placebo run-in and at the end of each of 3 consecutive 6-day periods during which the 3 active treatments were administered in randomized sequence. Three patients withdrew, whereas 27 completed the study. The therapeutic regimens tested proved to be similarly effective; primary end points (ischemic episodes recorded by Holter monitoring, and anginal attacks reported on diary cards) occurred in 5 patients (19%) during nifedipine treatment, and in 7 (26%) and 3 (11%) during felodipine treatment with 10 and 20 mg, respectively (p = not significant). The distribution of residual ischemic episodes demonstrated that treatment with felodipine once daily provides 24-hour antiischemic protection. Twenty-six patients were followed up with 20 mg of felodipine once daily for a mean of 6 ± 5 months, and 21 of them (81%) remained free of symptoms and Holter-recorded ischemic attacks. It is concluded that for Prinzmetal's angina pectoris, 24-hour antiischemic protection may be achieved with administration of felodipine once daily. The availability of a simplified therapeutic approach may constitute a real advantage in terms of patient compliance and improving the quality of life.     

Favorable cardiovascular risk profile and 10-year coronary heart disease incidence in women and men: results from the Progetto CUORE.

BACKGROUND: Cardiovascular risk factor research has recently broadened its focus based on new data indicating the benefits of low risk, i.e. favorable levels of all major risk factors. The aims of this study were to assess further the relation of low risk to coronary heart disease risk, and implications for prevention. DESIGN: We conducted a prospective population-based Italian study, of 7438 men and 13 009 women aged 35-69 years, with a mean follow-up of 10.4 years and validated first coronary events. METHODS: Baseline coronary heart disease risk was classified into three categories: low risk; unfavorable but not high risk; and high risk. To analyze the relation of these risk profiles to coronary heart disease incidence, age-adjusted, sex-averaged coronary heart disease incidence was calculated for persons free of coronary heart disease and stroke, stratified as baseline low risk, unfavorable but not high risk or high risk. To assess the independent relationship of individual risk factors to coronary heart disease incidence, multivariate proportional hazards models were computed for combinations of risk factors. RESULTS: Only 2.7% of participants met low risk criteria; 81.4% were high risk. Age-adjusted coronary heart disease incidence for the whole cohort was 37.1 out of 10000 person-years (men 59.0; women 15.3). No coronary heart disease events occurred in low-risk men, only two in low-risk women. For women and men who were not high risk, the age-sex standardized coronary heart disease rate was 62% lower than for high-risk participants. Blood pressure, need for antihypertensive medication, smoking, hyperglycemia, diabetes, total and high-density lipoprotein cholesterol were independently related to coronary heart disease risk. CONCLUSIONS: Favorable levels of all modifiable readily measured risk factors - rare among Italian adults - assure minimal coronary heart disease risk. Population-wide prevention is needed, especially improved lifestyles, to increase the proportion of the population at low risk.