Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence.

PURPOSE: To evaluate the relationship between mutations of the epidermal growth factor receptor (EGFR) gene and the effectiveness of gefitinib treatment in patients with recurrent lung cancer after pulmonary resection. PATIENTS AND METHODS: We sequenced exons 18-21 of the EGFR gene using total RNA extracted from 59 patients with lung cancer who were treated with gefitinib for recurrent lung cancer. Gefitinib effectiveness was evaluated by both imaging studies and change in serum carcinoembryonic antigen (CEA) levels. RESULTS: EGFR mutations were found in 33 patients (56%). Of these mutations, 17 were deletions around codons 746-750 and 15 were point mutations (12 at codon 858, three at other codons), and one was an insertion. EGFR mutations were significantly more prevalent in females, adenocarcinoma, and never-smokers. Gefitinib treatment resulted in tumor shrinkage and/or CEA decrease to less than half of the baseline level in 26 patients, tumor growth and/or CEA elevation in 24 patients, and gefitinib effect was not assessable in nine patients. Female, never-smoking patients with adenocarcinoma tended to respond better to gefitinib treatment. Gefitinib was effective in 24 of 29 patients with EGFR mutations, compared with two of 21 patients without mutations (P < .0001). Of note, del746-750 might be superior to L858R mutations for prediction of gefitinib response. Patients with EGFR mutations survived for a longer period than those without the mutations after initiation of gefitinib treatment (P = .0053). CONCLUSION: EGFR mutations were a good predictor of clinical benefit of gefitinib in this setting.     

Electrophysiologic characteristics of atrial tachycardia originating from the right pulmonary veins or posterior right atrium: double potentials obtained from the posterior wall of the right atrium can be useful to predict foci of atrial tachycardia in right pulmonary veins or posterior right atrium

INTRODUCTION: The right pulmonary veins (RPVs) and posterior wall of the right atrium (PRA) are anatomically located adjacent to each other. The aim of this study was to demonstrate the electrophysiologic characteristics of atrial tachycardia (AT) originating from the PRA or RPVs. METHODS AND RESULTS: A total of 26 consecutive patients with AT originating from the RPVs or PRA underwent detailed atrial endocardial mapping and successful radiofrequency catheter ablation. Eight foci were found in the PRA and 18 foci in the RPVs. Analysis of P wave configuration showed that lead V1 was the most helpful in distinguishing the AT foci between these two sites. In all cases, double potential (DP) configurations were recorded from several electrodes of a multielectrode catheter placed in the PRA, and the first DP component (FP) was the earliest potential recorded from the right atrium during the tachycardia. The amplitude of the FP was higher than that of the second DP component (SP) for AT foci originating in the PRA, whereas the reverse occurred for those in the RPV. The activation sequence of the FP was from superior to inferior for the AT foci in the superior RPV, whereas the reverse occurred for the AT foci in the inferior RPV. CONCLUSION: P wave configuration in lead V1 is helpful in distinguishing AT foci between those originating in the PRA and RPVs. The DPs obtained from the PRA can be useful in predicting whether AT foci originate from the PRA or RPVs.     

Serial alterations of beta-adrenergic signaling in dilated cardiomyopathic hamsters: possible role of myocardial oxidative stress.

BACKGROUND: The relationship between enhanced myocardial oxidative stress and impaired beta-adrenergic signaling remains to be characterized during the development of dilated cardiomyopathy. METHODS AND RESULTS: Alterations in myocardial oxidative stress and beta-adrenergic signaling, as well as left ventricular (LV) functional and structural changes, were evaluated during the development of cardiomyopathy in TO-2 hamsters; F1B hamsters served as controls. LV dysfunction was first apparent at 8 weeks of age and deteriorated thereafter in the TO-2 hamsters. At 32 weeks, the animals exhibited heart failure with an increased plasma norepinephrine concentration. Cardiac myolysis, as demonstrated by elevated plasma concentration of cardiac troponin T, peaked at 8 weeks. The glutathione redox ratio revealed increased oxidative stress in the LV myocardium in TO-2 hamsters even at 4 weeks and became manifest after 8 weeks. The hearts of TO-2 hamsters had significantly reduced superoxide dismutase activity from 8 weeks onward compared with control hamsters. However, glutathione peroxidase activity was unchanged at any time point. The LV functional response to isoproterenol was markedly reduced at 8 weeks, without any apparent changes in the amount of beta-adrenergic signaling molecules, and it deteriorated thereafter. Adenylyl cyclase activity was significantly decreased, despite increased amounts of both G(s) alpha mRNA and protein, in the LV myocardium at 18 weeks. CONCLUSIONS: Myocardial oxidative stress is actually enhanced in the initial development of LV dysfunction. Both activation of myocardial oxidative stress and impairment of beta-adrenergic signaling become prominent at the stage of severe LV dysfunction. Myocardial oxidative stress may be involved in the development of beta-adrenergic desensitization.     

Prognostic value of pacing-induced mechanical alternans in patients with mild-to-moderate idiopathic dilated cardiomyopathy in sinus rhythm.

OBJECTIVES: The relation between the occurrence of pacing-induced mechanical alternans and prognosis in patients with mild-to-moderate idiopathic dilated cardiomyopathy (IDCM) in sinus rhythm was investigated prospectively. The myocardial expression of genes for Ca2+-handling proteins in such patients was also examined. BACKGROUND: Mechanical alternans occurs in some patients with severe heart failure, but the relation between the occurrence of mechanical alternans and prognosis in patients with IDCM has remained unknown. METHODS: Left ventricular (LV) pressure was measured during atrial pacing, and LV endomyocardial biopsy specimens were collected in 36 IDCM patients and 8 controls. Idiopathic dilated cardiomyopathy patients were divided into two groups consisting of 22 individuals who did not develop mechanical alternans at heart rates up to 140 beats/min (group A) and of 14 individuals who did (group B). The patients were followed up for a mean of 3.7 years. RESULTS: There was no significant difference in LV ejection fraction or the plasma concentration of brain natriuretic peptide between groups A and B. The myocardial abundance of ryanodine receptor 2 messenger ribonucleic acid (mRNA) was significantly lower in groups A and B than in controls, whereas that of sarcoplasmic reticulum Ca2+-ATPase mRNA was significantly lower in group B than in group A or controls. Stepwise multivariate analysis identified pacing-induced mechanical alternans as the strongest predictor of cardiac events. Event-free survival in group A was significantly greater than that in group B. CONCLUSIONS: The occurrence of pacing-induced mechanical alternans is a potentially useful indicator of poor prognosis in patients with mild-to-moderate IDCM in sinus rhythm.     

Myocardial perfusion imaging using adenosine triphosphate stress multi-slice spiral computed tomography: alternative to stress myocardial perfusion scintigraphy.

BACKGROUND: The present study was designed to: (i) detect myocardial ischemia in contrast enhanced multi-slice spiral computed tomography (CE-MSCT) using adenosine triphosphate (ATP) pharmacological stress test; and (ii) evaluate the potential of ATP stress CE-MSCT in a clinical setting. METHODS AND RESULTS: Twelve patients underwent ATP stress CE-MSCT and stress thallium-201 myocardial perfusion scintigraphy (MPS) and 9 of the patients received conventional coronary angiography (CAG). Dual CE-MSCT scans were performed for stress and rest images, with and without intravenous infusion of ATP (0.16 mg.kg-1.min-1) at intervals of 20 min. Myocardial perfusion and coronary artery were visually evaluated using MSCT and compared the results obtained from MPS and CAG. Of 36 territories, stress images of CE-MSCT described 26 hypo-perfusion areas and MPS described 22 redistributions. The agreement between MSCT and MPS was 83% (30/36, p<0.05). In 141 coronary artery segments of 9 patients undergoing CAG, rest images of CE-MSCT, which had significantly higher assessability than stress images (89% vs 48%, p<0.05), described 76% (13/17) of culprit coronary stenoses. CONCLUSIONS: Although CT-angiography should be currently assessed using rest images, ATP stress CE-MSCT can describe both ATP-induced myocardial ischemia and coronary artery stenoses in patients with coronary artery disease.     

Noninvasive detection of coronary artery bypass graft patency by intravenous electron beam computed tomographic angiography

This study evaluates the usefullness of intravenous electron beam computed tomographic angiography (EBA) for the detection of coronary artery bypass graft patency in 43 patients (33 men and 10 women, mean age, 65 years) who had coronary artery bypass graft surgery. EBA was performed a few days before selective bypass graft angiography (SGA). Forty axial cross-sections of angiographic images of the heart were acquired consecutively by an electrocardiographic trigger signal at 40% of the RR interval, which corresponds to the end-systolic phase. EBA data were reconstructed as a three-dimensional shaded surface display of the heart and bypass grafts. Detectability of the patency of bypass gratis was evaluated, taking selective angiographic images of the bypass grafts as a gold standard. One hundred and nine grafts (96%) out of 114 grafts were subjected to evaluation: 37 grafts were left internal mammary artery grafts (LIMA), 7 were right internal mammary artery grafts (RIMA), 6 were gastroepiploic artery grafts (GEA), 7 were free gastroepiploic artery grafts with venous drainage (free-GEA), 7 were radial artery grafts (RAG), and 45 were saphenous vein gratis (SVG). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBA were 98%, 100%, 100%, 91%, and 98%, respectively. EBA sampled at the end-systolic period was determined to be useful for the detection of coronary artery bypass graft patency and occlusion.     

过量服用蛋氨酸所致高同型半胱氨酸血症对缺血性血管新生的抑制作用

高同型半胱氨酸血症是引起动脉粥样硬化的一种独立危险因素。过量服用蛋氨酸会导致血清中同型半胱氨酸浓度增高、内皮功能受损、血管舒缩功能减弱。本研究使用过量服用蛋氨酸导致高同型半胱氨酸血症大鼠，与对照组比较，观察缺血下肢血管新生的情况，判断高同型半胱氨酸血症对缺血性血管新生的影响。将36只雄性Sprague-Dawley大鼠分为两组：对照组和高同型半胱氨酸血症组。对照组始终给予自来水；高同型半胱氨酸血症组则给予含有0．5％蛋氨酸的饮水。两组动物分别按上述方法给予不同饮水2周后，手术切除左侧股动、静脉，观察缺血28d内缺血区域血管新生和侧枝血管形成的情况。过量服用蛋氨酸导致的高同型半胱氨酸血症减弱了大鼠下肢慢性缺血性血管新生和侧枝血管的建立，这可能与高同型半胱氨酸血症减弱内皮源性一氧化氮生物活性有关。