Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies

PURPOSE: To describe the considerations leading to marketing approval of ixabepilone in combination with capecitabine and as monotherapy for the treatment of advanced breast cancer that is refractory to other chemotherapies. EXPERIMENTAL DESIGN: Data from one randomized multicenter trial comparing combination therapy with ixabepilone and capecitabine to capecitabine alone were analyzed for support of the combination therapy indication. For monotherapy, a single-arm trial of ixabepilone was analyzed. Supporting data came from an additional single-arm combination therapy study and two single-arm monotherapy studies. RESULTS: In patients with metastatic or locally advanced breast cancer who had disease progression on or following an anthracycline and a taxane, ixabepilone plus capecitabine showed an improvement in progression-free survival compared with capecitabine alone {median progression-free survival, 5.7 [95% confidence interval (95% CI), 4.8-6.7] versus 4.1 (95% CI, 3.1-4.3) months, stratified log-rank P < 0.0001; hazard ratio, 0.69 (95% CI, 0.58-0.83)}. As monotherapy for patients who had disease progression on or following an anthracycline, a taxane, and capecitabine, ixabepilone as monotherapy showed a 12% objective response rate by independent blinded review and 18% by investigator assessment. The major toxicities from ixabepilone therapy were peripheral neuropathy and myelosuppression, particularly neutropenia. CONCLUSIONS: On October 16, 2007, the Food and Drug Administration approved ixabepilone for injection in combination with capecitabine or as monotherapy for the treatment of patients with advanced breast cancer who have experienced disease progression on previous chemotherapies.     

An evaluation of cardiac function in malnourished children by non-invasive methods

Forty-six malnourished children between 3-48 mo with varying grades of malnutrition (PEM) were evaluated for left ventricular function by echocardiography. None of these children had any pre-existing cardiac disease, chronic illness or significant anemia. Children with Grades III and IV PEM had significantly smaller cardiac chamber size and ventricular wall thickness as compared to normally nourished children. Cardiac output as well as other indices of left ventricular function (percentage fractional shortening, mean rate of circumferential fibre shortening and ejection fraction) were also significantly decreased in severe PEM. The atrophic PEM heart does appear to show left ventricular dysfunction in moderately severe malnutrition.     

Non-invasive assessment of endothelial function by brachial artery flow mediated vasodilatation and its association with coronary artery disease: an Indian perspective

Endothelial dysfunction is the final common pathway through which various coronary risk factors culminate into atherosclerosis and subsequent coronary artery disease (CAD). Endothelial function can be reliably assessed by flow mediated vasodilatation (FMD) in the brachial artery using high-resolution ultrasonography and has been shown to be an excellent surrogate marker for the presence of CAD. Two hundred and forty-one individuals comprising of 101 patients with CAD (angiographically proven, or with history of documented myocardial infarction) and 140 individuals without CAD were included in the study. All subjects underwent clinical evaluation, fasting lipid profile, treadmill test and FMD assessment. Selected individuals underwent coronary angiography too. Brachial artery diameter and Doppler indices (systolic and diastolic velocity time integrals) were recorded using high resolution ultrasonography at baseline, immediately after and at one minute after release of cuff (occlusion time 5 minutes). FMD was calculated as percentage increase in brachial artery diameter at one minute. FMD index was calculated as the ratio of FMD and percentage increase in flow during reactive hyperaemia. Mean FMD was significantly higher in non-CAD group (8.71+/-4.77%) than in CAD group (3.77+/-2.03%; p < 0.0001). The FMD index was also significantly higher in the non-CAD group (0.031 ) than in CAD group (0.021; p=0.0117). On multiple regression analysis, FMD index was found to be significantly associated with presence of CAD (p=0.0015), independent of conventional cardiovascular risk factors. Endothelial function as assessed by FMD is significantly depressed in patients with established CAD and this association is independent of presence of conventional cardiovascular risk factors.     

Hepatitis B virus infection in Haemodialysis Centres from Santa Catarina State, Southern Brazil. Predictive risk factors for infection and molecular epidemiology

Background

Patients under haemodialysis are considered at high risk to acquire hepatitis B virus (HBV) infection. Since few data are reported from Brazil, our aim was to assess the frequency and risk factors for HBV infection in haemodialysis patients from 22 Dialysis Centres from Santa Catarina State, south of Brazil.

Methods

This study includes 813 patients, 149 haemodialysis workers and 772 healthy controls matched by sex and age. Serum samples were assayed for HBV markers and viraemia was detected by nested PCR. HBV was genotyped by partial S gene sequencing. Univariate and multivariate statistical analyses with stepwise logistic regression analysis were carried out to analyse the relationship between HBV infection and the characteristics of patients and their Dialysis Units.

Results

Frequency of HBV infection was 10.0%, 2.7% and 2.7% among patients, haemodialysis workers and controls, respectively. Amidst patients, the most frequent HBV genotypes were A (30.6%), D (57.1%) and F (12.2%). Univariate analysis showed association between HBV infection and total time in haemodialysis, type of dialysis equipment, hygiene and sterilization of equipment, number of times reusing the dialysis lines and filters, number of patients per care-worker and current HCV infection. The logistic regression model showed that total time in haemodialysis, number of times of reusing the dialysis lines and filters, and number of patients per worker were significantly related to HBV infection.

Conclusions

Frequency of HBV infection among haemodialysis patients at Santa Catarina state is very high. The most frequent HBV genotypes were A, D and F. The risk for a patient to become HBV positive increase 1.47 times each month of haemodialysis; 1.96 times if the dialysis unit reuses the lines and filters ≥ 10 times compared with haemodialysis units which reuse < 10 times; 3.42 times if the number of patients per worker is more than five. Sequence similarity among the HBV S gene from isolates of different patients pointed out to nosocomial transmission.     

ENDOTHELIAL CELL CULTURE AND SEEDING OF PROSTHETIC VASCULAR GRAFTS: AN EXPERIMENTAL STUDY

Current synthetic vascular prostheses do not acquire lining of vascular endothelium in humans or dogs. Endothelial seeding of vascular grafts has been proposed as a means of reducing the thrombogenicity of these grafts. We examined feasibility of cultivating endothelial cells (EC) by tissue culture technique and their subsequent seeding onto small diameter polytetra fluoroethylene (PTFE) grafts. Twenty adult dogs underwent common carotid artery interposition with 4 mm PTFE grafts. Ten dogs received seeded and the remaining ten received unseeded grafts. Grafts were removed at 4 and 12 weeks and their gross/morphological features compared. Cumulative patency rates for seeded grafts were 70% as compared to unseeded ones 30%. Seeded grafts were completely surfaced with a mono-layer of endothelium by 4 weeks. Small graft patency appears to be related to the establishment of an endothelial surface, the development of which is clearly facilitated by seeding with autogenous endothelium.KEY WORDS: Endothelial cell seeding, Vascular grafts