Citations

Background— In case series, mitral regurgitation (MR) increased the risk of death after myocardial infarction (MI), yet the prevalence of MR, its incremental prognostic value over ejection fraction (EF), and its association with heart failure and death after MI in the community is not known. Methods and Results— The prevalence of MR and its association with heart failure and death were examined among 1331 patients within a geographically defined MI incidence cohort between 1988 and 1998. Echocardiography was performed within 30 days after MI in 773 patients (58%), and MR was present in 50% of cases, mild in 38%, and moderate or severe in 12%. Among patients with MR, a murmur was inconsistently detected clinically. After 4.7±3.3 years of follow-up, 109 episodes of heart failure and 335 deaths occurred. There was a graded positive association between the presence and severity of MR and heart failure or death. Moderate or severe MR was associated with a large increase in the risk of heart failure (relative risk 3.44, 95% CI 1.74 to 6.82, P <0.001) and death (relative risk 1.55, 95% CI 1.08 to 2.22, P =0.019) among 30-day survivors independent of age, gender, EF, and Killip class. Conclusions— In the community, MR is frequent and often silent after MI. It carries information to predict heart failure or death among 30-day survivors independently of age, gender, EF, and Killip class. These findings, which are applicable to a large community-based MI cohort, suggest that the assessment of MR should be included in post-MI risk stratification.

ABSTRACT Inefficient adenoviral vector (AdV)-mediated gene transfer to the ciliated respiratory epithelium has hindered gene transfer strategies for the treatment of cystic fibrosis lung disease. In part, the inefficiency is due to an absence of the coxsackie B and adenovirus type 2 and 5 receptor (CAR) from the apical membranes of polarized epithelia. In this study, using an in vitro model of human ciliated airway epithelium, we show that providing a glycosylphosphatidylinositol (GPI)-linked AdV receptor (GPI-CAR) at the apical surface did not significantly improve AdV gene transfer efficiency because the lumenal surface glycocalyx limited the access of AdV to apical GPI-CAR. The highly glycosylated tethered mucins were considered to be significant glycocalyx components that restricted AdV access because proteolytic digestion and inhibitors of O-linked glycosylation enhanced AdV gene transfer. To determine whether these in vitro observations are relevant to the in vivo situation, we generated transgenic mice expressing GPI-CAR at the surface of the airway epithelium, crossbred these mice with mice that were genetically devoid of tethered mucin type 1 (Muc1), and tested the efficiency of gene transfer to murine airways expressing apical GPI-human CAR (GPI-hCAR) in the presence and absence of Muc1. We determined that AdV gene transfer to the murine airway epithelium was inefficient even in GPI-hCAR transgenic mice but that the gene transfer efficiency improved in the absence of Muc1. However, the inability to achieve a high gene transfer efficiency, even in mice with a deletion of Muc1, suggested that other glycocalyx components, possibly other tethered mucin types, also provide a significant barrier to AdV interacting with the airway lumenal surface.

Purpose This multicenter, open-label, phase II study was undertaken to assess the antitumor activity and safety of the oral mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, CI-1040, in breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer. Patients and Methods Patients with advanced colorectal, NSCLC, breast, or pancreatic cancer received oral CI-1040 continuously at 800 mg bid. All patients had measurable disease at baseline, a performance status of 2 or less, and adequate bone marrow, liver, and renal function. Expression of pERK, pAkt, and Ki-67 was assessed in archived tumor specimens by quantitative immunohistochemistry. Results Sixty-seven patients with breast (n = 14), colon (n = 20), NSCLC (n = 18), and pancreatic (n = 15) cancer received a total of 194 courses of treatment (median, 2.0 courses; range, one to 14 courses). No complete or partial responses were observed. Stable disease (SD) lasting a median of 4.4 months (range, 4 to 18 months) was confirmed in eight patients (one breast, two colon, two pancreas, and three NSCLC patients). Treatment was well tolerated, with 81% of patients experiencing toxicities of grade 2 or less severity. Most common toxicities included diarrhea, nausea, asthenia, and rash. A mild association (P < .055) between baseline pERK expression in archived tumor specimens and SD was observed. Conclusion CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.

Abstract Inhaled glucocorticosteroids (ICS) are commonly prescribed for chronic obstructive pulmonary disease. No adverse effect on bone mineral density (BMD) has been proven. In a randomized double-blind, placebo-controlled trial at seven centers in North America, we recruited 412 current smokers or recent quitters with mild to moderate chronic obstructive pulmonary disease. They used inhaled triamcinolone acetonide, 600 mcg, or placebo, twice daily. We measured femoral neck and lumbar spine BMD at baseline and after 1 and 3 years, and serum osteocalcin at baseline, 3 months, 1 year, and 3 years. After 3 years, BMD at the femoral neck decreased 1.78% more with ICS than with placebo (p &lt; 0.001). More participants in the ICS group experienced 6% or more loss of femoral neck BMD (p = 0.002). Lumbar spine BMD increased in the placebo group by 0.98% but decreased by 0.35% in the ICS group (a difference of 1.33%, p = 0.007). Changes in osteocalcin did not correlate with changes in BMD. Fractures, lost height, or osteoporosis diagnoses were not increased among ICS users compared with placebo users. In summary, the use of inhaled triamcinolone acetonide was associated with loss of BMD at the femoral neck and lumbar spine after 3 years of treatment.

Background— Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. Methods and Results— Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the β-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the β-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant ( P <0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. Conclusions— In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation β-blocker.

Abstract Learning Objectives After completing this course, the reader will be able to: Understand the treatment options for limited versus extensive small cell lung cancer. Understand the role of prophylactic cranial irradiation for small cell lung cancer. Understand second-line chemotherapy regiments for small cell lung cancer. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com In this review, we cover current therapy and promising new regimens and highlight areas where improvement is needed in the management of small cell lung cancer.

AbstractThis unit provides a set of protocols for introducing recombinant genes into normal, injured, and atherosclerotic arteries. The protocols include animal preparation, surgical techniques, and delivery systems. Protocols describe gene delivery to normal, injured, and stented porcine iliofemoral arteries, employing a double balloon infusion catheter to deliver the vector. Another basic protocol describes gene delivery to atherosclerotic arteries using a hyperlipidemic double‐injury rabbit model, and requires surgical exposure of the artery and instillation of the gene vector via a catheter. Additional protocols describe gene delivery to normal and injured murine carotid and femoral arteries. An describes a percutaneous method for arterial gene delivery. These protocols may be adapted to deliver genes to either injured or noninjured atherosclerotic arteries.

Purpose Low-dose computed tomography (CT) has been suggested for lung cancer screening. Several observational trials have published their preliminary results, and some investigators suggest that this technique will save lives. There are no mortality statistics, however, and the current study used published data from these trials to estimate the disease-specific mortality in this high-risk population. Patients and Methods Two nonrandomized CT screening trials were selected from the literature for analysis. The number of trial participants, the number of lung cancers diagnosed per year, and stage distribution of the cancers was recorded. Previously published 5-year survival data were used to calculate the number of predicted lung cancer deaths and estimate the overall lung cancer mortality per 1,000 person-years among participants screened. These statistics were then compared to the previous Mayo Lung Project, which used chest radiographs and sputum cytology for screening high-risk individuals. Results This study estimates the lung cancer mortality is 4.1 deaths per 1,000 person-years in the Mayo Clinic CT screening trial, and is 5.5 deaths per 1,000 person-years in the Early Lung Cancer Action Program trial. These data are similar to the lung cancer mortality of 4.4 deaths per 1,000 person-years in the interventional arm, and 3.9 deaths per 1,000 person-years in the usual-care arm of the previous Mayo Lung Project. Conclusion These data suggest that CT screening could produce similar outcomes to prior chest radiographic trials in this high-risk group. Results from randomized trials are required, however, before the true utility of mass screening with CT for lung cancer can be determined.