Correlation between the status of the p53 gene and survival in patients with stage I non-small cell lung carcinoma.
The association of p53 abnormalities with the prognosis of patients with non-small cell lung carcinoma (NSCLC) has been extensively investigated to date, however, this association is still controversial. Therefore, we investigated the prognostic significance of p53 mutations through exons 2 to 11 and p53 protein expression in 103 cases of stage I NSCLC. p53 mutations were detected in 49 of 103 (48%) tumors. Two separate mutations were detected in four tumors giving a total of 53 unique mutations in 49 tumors. Ten (19%) of mutations occurred outside exons 5-8. Positive immunohistochemical staining of p53 protein was detected in 41 of 103 (40%) tumors. The concordance rate between mutations and protein overexpression was only 69%. p53 mutations, but not expression, were significantly associated with a shortened survival of patients (P<0.001). Furthermore, we investigated the correlation between the types of p53 mutations and prognosis. p53 missense mutations rather than null mutations were associated with poor prognosis (P < 0.001 in missense mutations and P=0.243 in null mutations). These results indicated that p53 mutations, in particular missense mutations, rather than p53 expression could be a useful molecular marker for the prognosis of patients with surgically resected stage I NSCLC. (+info)
Comparative efficacy of positron emission tomography with FDG and computed tomographic scanning in preoperative staging of non-small cell lung cancer.
OBJECTIVE: To determine the sensitivity, specificity, and accuracy of positron emission tomography with 2-fluorine-18-fluorodeoxyglucose (PET-FDG) in the preoperative staging (N and M staging) of patients with lung cancer. The authors wanted to compare the efficacy of PET scanning with currently used computed tomography (CT) scanning. MATERIALS AND METHODS: Results of whole-body PET-FDG imaging and CT scans were compared with histologic findings for the presence or absence of lymph node disease or metastatic sites. Sampling of mediastinal lymph nodes was performed using mediastinoscopy or thoracotomy. RESULTS: PET-FDG imaging was significantly more sensitive, specific, and accurate for detecting N disease than CT. PET changed N staging in 35% and M staging in 11% of patients. CT scans helped in accurate anatomic localization of 6/57 PET lymph node abnormalities. CONCLUSION: PET-FDG is a reliable method for preoperative staging of patients with lung cancer and would help to optimize management of these patients. Accurate lymph node staging of lung cancer may be ideally performed by simultaneous review of PET and CT scans. (+info)
Expression of tissue factor in non-small-cell lung cancers and its relationship to metastasis.
Tissue factor (TF) is an initiator of the extrinsic cascade of blood coagulation. Although recent studies have revealed a relationship between metastatic properties and TF expression in some neoplastic cells, the significance of TF in lung cancer, especially in non-small-cell lung cancer (NSCLC), is still unclear. In this study, TF was detected in NSCLC cell lines by functional study, Western blot analysis and immunocytochemical staining. TF levels in eight NSCLC cell lines were also quantitated by enzyme-linked immunosorbent assay (ELISA), and TF expression was evaluated in 55 specimens of surgically resected NSCLCs. NSCLC cell lines derived from metastatic lesions produced high levels of TF (48.3+/-23.5 ng 10(-6) cells, mean +/- s.e.m.), whereas those derived from primary lesions produced low levels of TF (0.2+/-0.1 ng 10(-6) cells). Immunohistochemical studies disclosed significantly stronger staining for TF in cells from NSCLC patients with metastasis than in those without metastasis. Among the 28 patients with metastasis, ten were strongly positive, 16 were moderately positive and two were negative for TF. In contrast, among the 27 patients without metastasis, only two were strongly positive, 18 were moderately positive and seven were negative for TF. Therefore, malignant cells from patients with lung cancer produce various levels of TF, and TF may play an important role in the metastatic process. (+info)
Novel regions of allelic deletion on chromosome 18p in tumors of the lung, brain and breast.
Lung cancer is now the number one cause of cancer death for both men and women. An age-adjusted analysis over the past 25 years shows that in women specifically, lung cancer incidence is on the rise. It is estimated that 10-20 genetic events including the alteration of oncogenes and tumor suppressor genes will have occurred by the time a lung tumor becomes clinically evident. In an effort to identify regions containing novel cancer genes, chromosome 18p11, a band not previously implicated in disease, was examined for loss of heterozygosity (LOH). In this study, 50 matched normal and NSCLC tumor samples were examined using six 18p11 and one 18q12.3 PCR-based polymorphic markers. In addition, LOH was examined in 29 glioblastoma pairs and 14 paired breast carcinomas. This analysis has revealed potentially two regions of LOH in 18p11 in up to 38% of the tumor samples examined. The regions of LOH identified included a 2 cm area between markers D18S59 and D18S476, and a more proximal, 25 cm region of intermediate frequency between D18S452 and D18S453. These results provide evidence for the presence of one or more potential tumor suppressor genes on the short arm of chromosome 18 which may be involved in NSCLC, brain tumors and possibly breast carcinomas as well. (+info)
Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer.
BACKGROUND: Conventional cytologic analysis of sputum is an insensitive test for the diagnosis of non-small-cell lung cancer (NSCLC). We have recently demonstrated that polymerase chain reaction (PCR)-based molecular methods are more sensitive than cytologic analysis in diagnosing bladder cancer. In this study, we examined whether molecular assays could identify cancer cells in bronchoalveolar lavage (BAL) fluid. METHODS: Tumor-specific oncogene mutations, CpG-island methylation status, and microsatellite alterations in the DNA of cells in BAL fluid from 50 consecutive patients with resectable (stages I through IIIa) NSCLC were assessed by use of four PCR-based techniques. RESULTS: Of 50 tumors, 28 contained a p53 mutation, and the identical mutation was detected with a plaque hybridization assay in the BAL fluid of 39% (11 of 28) of the corresponding patients. Eight of 19 adenocarcinomas contained a K-ras mutation, and the identical mutation was detected with a mutation ligation assay in the BAL fluid of 50% (four of eight) of the corresponding patients. The p16 gene was methylated in 19 of 50 tumors, and methylated p16 alleles were detected in the BAL fluid of 63% (12 of 19) of the corresponding patients. Microsatellite instability in at least one marker was detected with a panel of 15 markers frequently altered in NSCLC in 23 of 50 tumors; the identical alteration was detected in the BAL fluid of 14% (three of 22) of the corresponding patients. When all four techniques were used, mutations or microsatellite instability was detected in the paired BAL fluid of 23 (53%) of the 43 patients with tumors carrying a genetic alteration. CONCLUSION: Although still limited by sensitivity, molecular diagnostic strategies can detect the presence of neoplastic cells in the proximal airway of patients with surgically resectable NSCLC. (+info)
Trimodality therapy in stage III non-small cell lung cancer: prediction of recurrence by assessment of p185neu.
In a trimodality treatment approach for stage III non-small cell lung cancer the prognostic impact of pretherapeutic p185neu assessment was evaluated. Fifty-four patients were admitted to chemotherapy followed by twice-daily radiation with concomittant low-dose chemotherapy and subsequent surgery. Immunohistochemical assessment of p185neu expression was performed in paraffin-embedded mediastinal lymph node metastases, by mediastinoscopy biopsy prior to therapy. Paraffin-embedded biopsies of mediastinal lymph node metastases were available in 33 cases. Seven out of eight patients with positive p185neu staining developed distant metastases, in contrast to seven out of 25 negative cases. Expression of p185neu in mediastinal lymph node metastases was a significant predictor for progression-free survival (p=0.047) and resulted mainly from significant differences in metastases-free survival (p185neu-positive versus p185neu-negative: median, 11 versus 19 months; 2- and 3-yr rates, 13% and 0% versus 40% and 32%; p=0.04). On the basis of these preliminary results it was concluded that further evaluation of p185neu expression in trials on neoadjuvant and adjuvant therapy is warranted. When the prognostic impact of p185neu in such trials with larger patient numbers is confirmed, this may contribute to the identification of stratification variables for future treatment approaches of non-small cell lung cancer. (+info)
Combined modality therapy of lung cancer.
Combined modality therapy for lung cancer was first demonstrated to be successful in limited-stage small cell lung cancer. Concurrent administration of chemotherapy with chest and elective brain irradiation appears to produce the best results, with cisplatin/etoposide as the core chemotherapy. Using such programs, 2-year survival in the 40% range and 5-year survivals in excess of 20% may be expected, based on the results of multiple studies. Attempts to improve on these results through the use of altered schemes of chest irradiation or the delivery of high-dose consolidation chemotherapy are ongoing but to date have not been shown to affect survival significantly. We remain at a plateau in the effectiveness of combined modality therapy for small cell lung cancer, with little evidence that it impacts survival at all in extensive-stage disease. The incorporation of new agents in combination chemotherapy regimens, more "specific" immunotherapy directed at tumor-associated antigens, and the potential adjunctive use of broad-spectrum neuropeptide antagonists offer promise for the future. In non-small cell lung cancer, the sequential use of platinum-based chemotherapy and chest irradiation appears superior in survival to standard, daily fractionated radiation therapy used alone, with long-term survival increased from 5-10% to 15-20%. Concurrent administration of chemotherapy with cisplatin/etoposide and chest irradiation produces 2-year survival in the range of 30%, about twice that would be expected for radiation therapy alone, but has not been compared to it in the setting of a randomized trial. Low-dose cisplatin on a daily basis has been combined as a "sensitizer" with chest irradiation, producing initial results that appeared encouraging. However, these have not been reproduced in subsequent, randomized trials. Another approach to combined modalities has been to give chemotherapy or chemotherapy/radiation therapy as induction, followed by surgical resection, with or without subsequent additional treatment. Most patients (80-85%) can be resected, with encouraging survival at 2 and 3 years in the Southwest Oncology Group experience (37 and 26%, respectively). However, toxicity is greater, and such an approach is associated with an overall mortality risk in the range of 10%. A current intergroup study attempts to define the role of surgery in this setting. The major recent development that is likely to influence the future of combined modality therapy for this disease is the advent of multiple new chemotherapeutic agents, such as the taxanes, gemcitabine, vinorelbine, and the topoisomerase-I inhibitors, which have activity in stage IV disease. The immediate challenge is how to combine these agents with platinum analogues, radiation, and surgery. Aiding this process may be the use of molecular biological "markers" that may predict the chance of success or failure with a given systemic agent. The next decade is likely to see substantial improvements in the outcome of treatment for patients with stages I-III non-small cell lung cancer, based on the systemic exploration of combined modalities. (+info)
The expression of beta-catenin in non-small-cell lung cancer: a clinicopathological study.
AIMS: To investigate the expression of beta-catenin in non-small-cell lung cancer (NSCLC) and its clinical significance. METHODS: 101 patients were surgically treated for NSCLC by lobectomy or pneumectomy with systematic lymph node dissection. Follow up was available in all patients, ranging from 24 to 110 months. Immunostaining of tissue sections from primary tumours and (when present) their lymph node metastases was performed and evaluated using a monoclonal antibody against beta-catenin. Correlations were investigated between beta-catenin immunostaining in primary tumours and E-cadherin immunostaining (data available from a previous study), lymph node stage, and survival. RESULTS: There were significant correlations between scores for beta-catenin immunostaining and E-cadherin immunostaining in primary tumours (p = 0.007), and between the beta-catenin immunostaining score in primary tumours and in their lymph node metastases (p = 0.006). An inverse correlation was found between the beta-catenin immunostaining score in primary tumours and lymph node stage N0, N1, or N2 (p = 0.03). According to the Kaplan-Meier survival estimate, the level of beta-catenin expression in primary tumours was a statistically significant prognostic factor (p = 0.01). CONCLUSIONS: Reduced beta-catenin expression in surgically treated NSCLC is clearly associated with lymph node metastasis and an infavourable prognosis. The existence of a functional relation between E-cadherin and beta-catenin is supported by the results of this clinicopathological study. (+info)