Association of p53 gene mutation and telomerase activity in resectable non-small cell lung cancer.

PURPOSE: Mutation of the p53 gene and deregulation of telomerase may be essential for canceration in some malignant diseases. However, relationships between these occurrences have not yet been clarified. We examined the roles of p53 gene mutation and telomerase activity relative to the clinical and pathologic features of non-small cell lung carcinoma (NSCLC). METHODS: Frozen sections of 40 surgically resected NSCLC specimens were used. DNA extracted from fresh tumor specimens was analyzed with polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) method, to screen alterations in the p53 gene. Exons showing aberrant band shifts on SSCP were reamplified, and the PCR products were directly sequenced. In addition, the telomerase activity of the same specimens was analyzed quantitatively with the fluorescence-based telomeric repeat amplification protocol assay, and the total product generated (TPG) method. Clinical and pathologic parameters were evaluated using a statistical analysis system. RESULTS: Mutations of the p53 gene relevant to an altered protein were confirmed in 19 of 40 specimens (47.5%). The TPG of 40 specimens was 75.24 +/- 15.55 (mean +/- SE). The TPG of the 19 specimens positive for p53 gene mutation was significantly higher than that of the 21 specimens negative for p53 gene mutation. Furthermore, the degree of cell differentiation was significantly correlated with both p53 gene mutation and high telomerase activity. CONCLUSIONS: p53 gene mutation and high telomerase activity cooperate to induce tumorigenesis and low-grade differentiation in NSCLC. Simultaneous occurrence of p53 gene mutation and high telomerase activity may be relevant to the grade of malignancy in NSCLC.

Analysis of mutant p53 and telomerase activity in non-small cell lung cancer.

The number of mutant p53 protein-positive tumor cells in primary non-small cell lung carcinoma (NSCLC) cases were quantitated by flow cytometry (FCM) and the relationships of these data to various factors were evaluated. Furthermore, the method of quantitating telomerase activity was investigated. Forty patients with primary lung carcinoma encountered between December 1995 and December 1997 were investigated. Among these cases, telomerase activity was measured. Using PAb421, cells were reacted with fluorescent antibody and fluorescence was quantitated by FCM. Fluorescence index (FI) was estimated in relation to the positivity rates of negative controls and were quantitatively evaluated. FI values of normal lung tissue were obtained from normal lung tissue excised from young patients with pulmonary bulla. Values that were 2SD or more above the mean value of normal lung tissue (> 2.19) were regarded as mutant p53-positive, and 14 (35.0%) of 40 lung carcinoma cases were positive by this criterion. Of 13 poorly differentiated carcinoma cases, seven cases (53.8%) were positive, which was significantly high. Furthermore, the telomerase activity was converted to numerical values in 40 cases using the telomelic repeat amplication protocol (TRAP) method as well as the total product generated (TPG) method. The mean TPG value of the 40 cases was 75.21 +/- 15.63. Among these cases, the mean value of fourteen p53-positive cases was 124.49 +/- 37.19, which was higher than that of 26 negative cases, 48.68 +/- 10.88, showing a significant difference. The method used in this study was considered a useful method that allows accurate and objective evaluation of mutant p53 expression. It was suggested that mutant p53 expression may affect the degree of tumor cell differentiation. Consequently, it was confirmed in this study that mutant p53 expression and telomerase activity were closely associated in lung cancer.

An availability of video-assisted thoracic surgery for the resection of pulmonary metastases.

We report the use of video-assisted thoracic surgery (VATS) as a treatment for pulmonary metastases. Eight patients with metastatic lung cancer were treated with VATS techniques. These patients included 5 males and 3 females whose ages ranged from 34 to 61 years (average: 47.4). Their primary diseases were seminoma (n = 3), renal cell carcinoma (n = 2), colon carcinoma (n = 1), mammary carcinoma (n = 1) and choriocarcinoma (n = 1). Computed tomography (CT) scans with current generation scanners were performed preoperatively and revealed one metastatic lesion in each of five cases and two lesions in each of the other three cases. In one case, one lesion was located in each of the lungs. Tumor size ranged from 5 to 30 mm in diameter, and all lesions were in the peripheral field of the lung. VATS was carried out with three surgical ports for three cases, two surgical ports for one case, and only one port for two cases. For all cases, an endo-stapler was utilized. In two cases, the preoperative point-marking technique for tumors was employed under the guidance of CT imaging. All patients were discharged from the hospital with no complications, and were followed up with no evidence of lung recurrence. Our criteria in selecting patients for the VATS removal of metastatic lung tumors are as follows: 1) tumors are less than 30 mm in diameter in the peripheral lung, 2) the number of tumors detected by CT scan, etc., is one or two. We conclude that VATS is a good candidate for the resection of lung metastases in the selected cases. Long term outcome remains to be solved in the future.

Vascular endothelial growth factor increased by pulmonary surgery accelerates the growth of micrometastases in metastatic lung cancer.

BACKGROUND: The use of surgery for metastatic lung cancer has been established recently and the indications have been extended to multiple and bilateral lung metastases. However, in some patients, secondary lung metastasis appears soon after the first pulmonary surgery, making curative treatment very difficult. Postoperative weakness of tumor angiogenesis suppression mechanisms seems to play an important role in the recurrence of lung metastases. To verify this hypothesis, we performed a clinical and an experimental study. RESULTS AND CONCLUSION: The clinical study revealed that serum vascular endothelial growth factor (VEGF), also known as vascular permeability factor, increased after pulmonary surgery. The experimental study showed that VEGF played an important role in the rapid growth of dormant micrometastases of the lung. These results suggested that the postoperative increase of VEGF disrupted angiogenesis suppression and induced the growth of dormant micrometastases early in the postoperative period. It was also demonstrated that this effect of VEGF on micrometastases was abolished by AGM-1470, an angiogenesis inhibitor. In conclusion, postoperative treatment with AGM-1470 might inhibit the early recurrence of malignant tumors.

The prognostic factor of the surgically treated metastatic lung cancer.

Surgical treatment for metastatic lung tumor has also been aggressively performed to treat multiple or bilateral lesions recently. However, in some patients, metastatic pulmonary foci have recurred after surgery for metastatic lung tumor. These foci could not be controlled even after performing thoracotomy several times in some patients. In this study, we examined prognostic factors in patients undergoing surgery for metastatic lung tumor with respect to early relapse of metastatic pulmonary foci after surgery, and discussed strategies for improving long-term results. This study included 120 patients who underwent surgery for metastatic lung tumor in our department between November 1975 and November 1997. Overall, the 5-year survival rate was 37.1%. When results were compared among groups, there were no significant differences related to age, gender, primary organ, DFI, number of metastatic foci or surgical technique. However, the prognosis was significantly poorer in patients with recurrent metastatic pulmonary foci after surgery. Especially in patients with early relapse within 6 months after resection of the lung, the prognosis was markedly poor. Early relapse was an important factor involved in unfavorable surgical outcomes. The mechanism involved in the early relapse of metastatic pulmonary foci after surgery for metastatic lung tumor may be associated with the presence of several micrometastases that could not be recognized during surgery for metastatic lung tumor, that is, dormancy, in the lung. Surgical outcomes in patients with metastatic lung tumor will be improved if a method of controlling this increase in dormant metastases is established.