Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics.

PURPOSE: Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.     

Treatment of Allergic Bronchopulmonary Aspergillosis with Fluconazole and Itraconazole

Treatment of allergic bronchopulmonary aspergillosis (ABPA) has remained both problematic as well as controversial. Although the sheet anchor in treatment of ABPA still remains steroids, various workers have tried oral antifungals (fluconazole and itraconazole) with encouraging results. This study evaluates the effect of fluconazole or itraconazole in the treatment of ABPA patients and compares them with the patients who had received palliative therapy other than antifungals. Case records of 44 proven cases of ABPA treated at our referral service hospital during February 1998 to April 2001 were analyzed. In addition to oral and inhaled bronchodilators, 16 patients received fluconazole 150 mg OD and 13 patients itraconazole 200 mg OD for six months. Response to therapy was assessed clinically, radiologically and by spirometry every 3 months. Patients who did not receive antifungals had chronic course characterized by airway obstruction, recurrent pulmonary consolidation and obstructive defect on pulmonary function test (PFT). Patients treated with itraconazole had better control of asthma symptoms, less requirement of reliever inhalers, steroids and lesser exacerbations of asthma during follow-up even after stopping antifungal. Fluconazole group had better control of symptoms but improvement in other parameters was not statistically significant. From this study it was evident that itraconazole improved the symptoms of airway obstruction, pulmonary functions, pulmonary opacities and decreased exacerbations during follow up.Key Words: Allergic bronchopulmonary aspergillosis, Fluconazole, Itraconazole     

Imaging features of multicentric Castleman's disease in HIV infection

AIM: To describe the computed tomography (CT) features of human immunodeficiency virus (HIV)-associated Castleman's disease. MATERIALS AND METHODS: Nine HIV-positive patients with biopsy-proven Castleman's disease were studied. Clinical and demographic data, CD4 count, histological diagnosis and human herpes type 8 (HHV8) serology or immunostaining results were recorded. CT images were reviewed independently by two radiologists. RESULTS: CT findings included splenomegaly (n=7) and peripheral lymph node enlargement (axillary n=8, inguinal n=4). All nodes displayed mild to avid enhancement after intravenous administration of contrast material. Hepatomegaly was evident in seven patients. Other features included abdominal (n=6) and mediastinal (n=5) lymph node enlargement and pulmonary abnormalities (n=4). Patterns of parenchymal abnormality included bronchovascular nodularity (n=2) consolidation (n=1) and pleural effusion (n=2). On histological examination eight patients (spleen n=3, lymph node n=9, lung n=1, bone marrow n=1) had the plasma cell variant and one had mixed hyaline-vascular/plasma cell variant. The majority had either positive immunostaining for HHV8 or positive serology (n=8). CONCLUSION: Common imaging features of multicentric Castleman's disease in HIV infection are hepatosplenomegaly and peripheral lymph node enlargement. Although these imaging features may suggest the diagnosis in the appropriate clinical context, they lack specificity and so biopsy is needed for diagnosis. In distinction from multicentric Castleman's disease in other populations the plasma cell variant is most commonly encountered, splenomegaly is a universal feature and there is a strong association with Kaposi's sarcoma.     

Re-infused autologous graft natural killer cells correlates with absolute lymphocyte count recovery after autologous stem cell transplantation

Early absolute lymphocyte count (ALC) has been reported to be a powerful prognostic indicator of survival after autologous stem cell transplantation (ASCT). One possible source affecting ALC recovery includes the re-infused autologous graft lymphocytes (AGL). To assess if the re-infused AGL correlate with ALC recovery post-ASCT, we conducted a pilot study to identify which of the re-infused AGL subsets is most associated with day 15 ALC recovery in three patients with multiple myeloma and four patients with non-Hodgkin's lymphoma. Using the Spearman rank correlation coefficient analysis ( r ), we compared absolute numbers of CD3, CD4, CD8, CD19, and CD16+/CD56+ cells/kg of body weight from the apheresis product with ALC (cells/ μl) at day 15 post-ASCT. The main lymphocyte subsets identified in the apheresis product were T cells and NK cells. There was no strong correlation between T or B cells from the apheresis product compared with the ALC at day 15 post-ASCT (CD3, r =0.21; CD4, r =0.32; CD8, r =0.39; and CD19, r =0.14 ). However, there was good correlation between NK cells from the apheresis product compared with ALC at day 15 post-ASCT (CD16+/CD56+/CD3 -, r =0.77 ). These data provide preliminary evidence that the number of re-infused autologous graft NK cells in the apheresis product significantly affect ALC recovery early post-ASCT. However, given the small sample size, our results are primarily hypothesis generating and subject of further research.     

Concurrent comparison of the Cobe Spectra and Fenwal CS3000 for the collection of peripheral blood mononuclear cells for autologous peripheral stem cell transplantation.

Hematopoietic stem cells, collected by leukapheresis from peripheral blood, can be used as an alternative to autologous bone marrow transplantation following high-dose chemotherapy as treatment of several malignancies. We compared the ability of the Cobe Spectra and the Fenwal CS3000 to collect peripheral blood mononuclear cells (MNC) for autologous peripheral blood stem cell transplantation. Ten patients experienced repeated leukapheresis (10 L blood processed per procedure) using both instruments. Procedures were alternated between the two until a total of 7 x 10(8) MNC/kg was collected. Data from 61 Spectra and 50 CS3000 collections were analyzed. The yield (mean per procedure) of nucleated cells (NC) and MNC was higher (P less than .005) with the Spectra (0.77 x 10(10) NC and 0.54 x 10(10) MNC) than with the CS3000 (0.59 x 10(10) NC and 0.40 x 10(10) MNC). However, colony forming units (CFU-GM) were not different (P greater than .05) for Spectra (0.92 x 10(4)) and Fenwal (0.65 x 10(4) collections. Platelet contamination was lower (P less than .001) with the Spectra (2.2 x 10(11)) than the CS3000 (5.0 x 10(11)). This correlated with a higher patient blood platelet count immediately following Spectra collections (117 x 10(9)/L) versus the CS3000 (86 x 10(9)/L). Using the methods described, the Spectra product contained greater yields of NC and MNC with less platelet contamination than did the CS3000.     

Accuracy of fetal echocardiography

The reliability of prenatal ultrasound (US) for the detection of structural heart defects was investigated in a consecutive population of patients referred for prenatal US. Twenty-eight of 49 fetuses (57%) shown to have one or more heart defects with physical examination or autopsy were found to have congenital heart disease with prenatal US. There were 66 cardiac defects in 49 fetuses, 33 of which were entirely or partly identified (50%). Defects correctly diagnosed included hypoplasia of either ventricle, common atrioventricular canal, tetralogy of Fallot, transposition of the great vessels, and Ebstein anomaly. Defects rarely diagnosed correctly included semilunar valve stenosis, total anomalous pulmonary venous drainage, coarctation of the aorta, pulmonic atresia, atrioseptal defect, and ventricular septal defect. Many types of heart defects can be diagnosed accurately with prenatal US in a general population of patients not at high risk for congenital heart disease. Some lesions, however, were difficult to detect.     

Comparison of 64-slice cardiac computed tomography with myocardial perfusion scintigraphy for assessment of global and regional myocardial function and infarction in patients with low to intermediate likelihood of coronary artery disease

Background. Cardiac computed tomography (CCT) has the potential to assess both coronary anatomy and ventricular function in a single study. We examined the agreement between CCT and myocardial perfusion scintigraphy (MPS) for the assessment of global and regional ventricular function. Methods and Results. Research CCT was performed in 52 patients with a low to intermediate likelihood of coronary artery disease referred for MPS. Left ventricular enddiastolic volume, left ventricular end-systolic volume, left ventricular ejection fraction (LVEF), and myocardial wall motion and thickening were compared between techniques. In addition, myocardial contrast attenuation on CCT was compared with radiotracer uptake on MPS. LVEF values agreed well (mean difference, 4.1%; SD, 15.13%), but CCT left ventricular end-diastolic volume was greater compared with MPS (mean difference, 46.0 mL; SD, 33.34 mL) (P<.001). There was moderate agreement for segmental myocardial motion and thickening, with κ values of 0.57 (95% confidence interval, 0.51–0.63) and 0.47 (95% confidence interval, 0.41–0.53), respectively. Seventeen patients had hypoattenuation in at least 1 myocardial segment on CCT. Three of four patients with concomitant abnormalities of wall motion and thickening on CCT had infarction in the same territory on MPS. Conclusions. There was good agreement for LVEF between CCT and MPS but myocardial volumes differed, and these modalities cannot be used interchangeably. Mild abnormalities of regional function are detected more commonly by CCT than by MPS. Myocardial hypoattenuation on CCT is highly specific for myocardial infarction when associated with reduction of systolic wall thickening and regional wall motion abnormality. Dr Nicol received a grant from the Defence Postgraduate Medical Deanery.