The threonine-to-methionine substitution at amino acid position 790 (T790M) of the epidermal growth factor receptor (EGFR) gene has been reported in progressing lesions after gefitinib treatment in non-small cell lung cancer (NSCLC) that causes sensitive tumors to become resistant to gefitinib. Alternatively, the EGFR T790M mutation might be present in small fractions of tumor cells before drug treatment, and the tumor cells harboring the T790M mutation might be enriched during the proliferation after drug treatment. We developed a mutant-enriched PCR assay to detect small fractions of cells with T790M mutation and used this technique to detect mutations in 280 NSCLCs, including gefitinib-treated 95 cases. Although the direct sequencing detected only 1 T790M mutant case, the mutant-enriched PCR (confirmed to enrich one mutant out of 1 Â 10 3 wild-type alleles) detected 9 additional cases among 280 cases. As linkage to clinicopathologic factors, the T790M mutation showed no bias for sex, smoking status, or histology but was significantly more frequent in advanced tumors (9 of 111 cases) than in early-stage tumors (1 of 169 cases; P = 0.0013). Among gefitinib-treated cases, gefitinib-sensitive mutations were found in 30 cases. The T790M mutation was present in 3 of 7 no-responders with the gefitinib-sensitive mutation and was not present in 19 responders (P = 0.014). Our results indicate that the T790M mutation is sometimes present in a minor population of tumor cells during the development of NSCLC and suggest that the detection of small fractions of T790M mutant alleles may be useful for predicting gefitinib resistance of NSCLCs with sensitive EGFR mutations. (Cancer Res 2006; 66(16): 7854-8)
Purpose: Mutation of epidermal growth factor receptor (EGFR) gene has been reported to be present in non^small cell lung cancer (NSCLC) and significantly associated with female sex and never-smoking status. In this study, we extensively investigated the impact of sex and smoking on the EGFR mutation. Experimental Design: We examined EGFR exons 18 to 21 status in 1,467 NSCLC patients by direct sequencing to study the impact of sex and smoking status on the EGFR mutational spectrum. Results: Among 1,467 patients, 197 mutations were found at exon 19, 176 at exon 21, 21 at exon 18, and 24 at exon 20.To examine the independent effect of sex and smoking, the mutational status of each exon was compared between smokers and never smokers in each sex and between males and females stratified by smoking status. In females, exon 19 (P = 0.001) and exon 21 (P < 0.001) mutations were significantly less frequent in ever smokers compared with never smokers. In males, exon 19 (P < 0.001), exon 21 (P < 0.001), and exon 18 (P = 0.003) mutations were significantly less frequent in ever smokers compared with never smokers. In analysis stratified by smoking, there was no difference in sex among never smokers. However, exon 19 mutations were significantly less frequent in males compared with females among ever smokers (P = 0.003). In addition, the interactive effect of male sex and ever smoking status significantly decreased the frequency of exon19 mutations (P = 0.047) when female never smoker was set as a reference. Conclusion: Both sex and smoking status could influence the EGFR mutational spectrum. Our findings suggest that individual EGFR exons may have differing susceptibilities for mutagenesis.The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) that is frequently overexpressed in malignant tumors, and its signal transduction cascade leads to a multitude of effects, including cell proliferation, cell differentiation, angiogenesis, metastasis, and antiapoptosis (1, 2). Recent findings have shown that EGFR mutations are exclusively present in lung cancer and showed significant association with sensitivity of EGFR TK inhibitor (EGFR-TKI), including gefitinib and erlotinib (3 -6). Several clinicopathologic factors were identified to be related to the frequency of EGFR mutations, including adenocarcinoma histology, female sex, and never-smoking status and East Asian ethnicity (6). Most mutations involved nucleotides of exons 18 to 21 in the TK domain, especially deletions in exon 19 and the L858R point mutation in exon 21. We previously reported that exon 19 deletions and exon 21 point mutations were frequent in never smoker compared with ever smoker and in female sex compared with male sex, but there was no bias for sex and smoking status in exon 20 insertion mutation (7). More recently, we found the lack of sex effect for the EGFR-TKI resistance related EGFR T790M mutation located in exon 20 in a minor clone of the tumor (8). These findings suggest the sex, smoking status, or their interactions in...
Although visit-to-visit variability in systolic blood pressure (SBP) has recently been demonstrated to be a strong predictor of stroke, there are no data about relationships between SBP variability and cardiac damage in hypertensive patients. We compared relationships between visit-to-visit variability in SBP and left ventricular (LV) diastolic dysfunction with the relationships between the mean SBP value and cardiac parameters in treated patients. Forty treated hypertensive patients (69±9 years of age) had their blood pressure measured at outpatient clinics every 1 or 2 months over a 1-year period. The standard deviation (s.d.) of SBP and the difference between the maximum and minimum SBPs during this year were calculated to assess visit-to-visit variability. The mean SBP during the year was also calculated. LV diastolic function was assessed by the ratio (E/A) of early (E) and late (A) diastolic transmitral flows, early diastolic mitral annular velocity (e¢) and the ratio (E/e¢) of E to e¢ using Doppler echocardiography. E/A only correlated with the s.d. of SBP (r¼À0.327, P¼0.040), whereas e¢ correlated with s.d. of SBP (r¼À0.496, P¼0.001) and maximum-minimum SBP difference (r¼À0.490, P¼0.001). E/e¢ correlated with s.d. of SBP (r¼0.384, P¼0.014), maximum-minimum SBP difference (r¼0.410, P¼0.009), and the mean value of SBP (r¼0.349, P¼0.028). Multiple regression analysis demonstrated only the maximum-minimum SBP difference independently associated with E/e¢ (b¼0.410, P¼0.009). Thus, the visit-to-visit variability of SBP showed better correlation with LV diastolic dysfunction than mean values of SBP. High visit-to-visit variability of SBP was associated with LV diastolic dysfunction and may constitute a high risk for diastolic heart failure in hypertensive patients.
The diameter of the inferior vena cava (IVC) measured with echocardiography is clinically used as a parameter to estimate right atrial pressure, which reflects dehydration or overhydration. Because elderly patients fall easily into dehydration, normal values for IVC diameters in elderly patients may be helpful for geriatric medicine. However, normal values of IVC diameter in relation to age have not been investigated. The purpose of this study was to elucidate age-related changes in IVC diameter using echocardiography. Enrolled in the study were 200 patients (67 ± 15 yrs: range 17-94 yrs) with cardiovascular risk factors but no overt cardiac diseases. IVC diameters throughout the respiratory cycle were measured as maximum and minimum IVC diameters (IVC max , IVC min ) using M-mode echocardiography. To assess IVC collapsibility, the respirophasic variation of IVC diameter was calculated as (IVC max -IVC min )/(IVC max ) × 100. Maximum IVC diameter was decreased with advancing age (r = -0.221, p = 0.002). The respirophasic variation of the IVC diameter was increased with advancing age (r = 0.244, p = 0.001). Stepwise multiple regression analysis showed that age was an independent determinant for both maximum IVC diameter (ß coefficient = -0.249, p < 0.001) and respirophasic variation of the IVC diameter (ß coefficient = 0.268, p < 0.001).Age-related decrease in maximum IVC diameter and increase in the respirophasic IVC collapsibility may indicate the decrease in right atrial pressure in some elderly patients. Therefore, elderly patients with decreased maximum IVC and increased respirophasic IVC collapsibility may need prevention for dehydration.
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