Recurrence Of Non-small Cell Lung Cancer Research Articles

DNA Methylation in Tumor and Matched Normal Tissues from Non-Small Cell Lung Cancer Patients

We used MethyLight assays to analyze DNA methylation status of 27 genes on 49 paired cancerous and noncancerous tissue samples from non-small cell lung cancer (NSCLC) patients who underwent surgical resection. Seven genes (RARB, BVES, CDKN2A, KCNH5, RASSF1, CDH13, and RUNX) were found to be methylated significantly more frequently in tumor tissues than in noncancerous tissues. Only methylation of CCND2 and APC was frequently detected in both cancerous and noncancerous tissues, supporting the hypothesis that the methylation of these two genes is a preneoplastic change and may be associated with tobacco smoking exposure. Methylation of any one of eight genes (RASSF1, DAPK1, BVES, CDH13, MGMT, KCNH5, RARB, or CDH1) was present in 80% of NSCLC tissues but only in 14% of noncancerous tissues. Detection of methylation of these genes in blood might have utility in monitoring and detecting tumor recurrence in early-stage NSCLC after curative surgical resection.

Complications of Ablative Therapies in Lung Cancer

Two cases of complications secondary to the use of microwave ablation (MWA) in non–small-cell lung cancer (NSCLC) are discussed herein. The first case involves a 62-year-old man with stage IB NSCLC who declined surgery and pursued MWA. Within 7 months, he had residual disease at the MWA treatment site, and surgery was performed. The patient was found to have pleural and chest wall involvement, making complete resection impossible. The second case involves an 86-year-old woman with a second local recurrence of NSCLC and previous treatment including surgery and chemoradiation therapy. She was initially a surgical candidate but declined surgery and pursued MWA. Within 6 months, she had residual disease at the MWA treatment site. A second MWA was performed, and she developed a large cavitary abscess at the MWA site and had subsequent clinical decline. Less invasive ablation therapies and stereotactic radiosurgery are being developed for patients with inoperable lung cancer. Because these modalities have recently been developed, trials that clearly show efficacy and survival benefit are yet to be completed. Ablation procedures can result in complications, including residual disease and cavitary lesions susceptible to infection. These cases highlight the caution that should still be observed when recommending lung ablation strategies and the importance of selecting appropriate patients.

Prognostic Factors for Gefitinib-Treated Postoperative Recurrence in Non-Small Cell Lung Cancer

Background and Objectives: The association between epidermal growth factor receptor (EGFR) mutations and response to EGFR tyrosine kinase inhibitor (TKI) has been consistently confirmed in a number of studies. However, it is still unclear whether a response to TKI treatment translates into increased survival for patients with non-small cell lung cancer (NSCLC). Methods: EGFR mutations were analyzed in 169 primary lung cancer tissues by RT-PCR and sequencing of multiple clones. The association between EGFR mutation status and the clinical outcome of gefitinib treatment was investigated. For mutation-positive cases, the percentage of mutated clones from the total number of clones was calculated. This ratio was used as the quantitative index of EGFR mutations. Results: We identified mutations in 71 of 169 patients with NSCLC. 46 patients were treated with gefitinib for postoperative recurrence. Progression-free survival and overall survival after initial gefitinib were significantly longer in patients with mutation than with wild type (univariate analysis, p < 0.001 for both). Multivariate analyses identified EGFR mutations and longer disease-free intervals after surgery as significant prognostic factors for survival. By quantitative analysis of mutation-positive cases, the increased ratio of mutated EGFR transcripts significantly associated with longer survival after gefitinib. Conclusions: EGFR mutation status and disease-free interval were associated with prolonged progression-free survival and overall survival after gefitinib treatment for postoperative recurrence of NSCLC. Quantitative analysis of mutated EGFR transcripts provided additional information for the stratification of patients with mutated EGFR.

Increased expression levels of human telomerase reverse transcriptase (hTERT) mRNA correlates with poor prognosis in resected non-small cell lung cancer (NSCLC) patients

10594 Background: Telomerase adds hexameric TTAGGG nucleotide repeats onto the ends of chromosomal DNAs to compensate for losses of each cell replication. In several tumors, telomerase is expressed in a way that tumoral cell proliferates indefinitely. Correlation between telomerase level expression, clinico-pathological characteristics and survival of lung cancer is not well established in NSCLC. Methods: We studied 149 consecutive patients (140 men/9 women) with resected NSCLC: 37.6% adenocarcinoma, 59 % squamous cell, and 3.4% large cell carcinoma. Pathological stage: I (36.9%), II (32.3%) and III (30.8%). Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used for the detection hTERT expression in lung cancer tissues immediately snap-frozen in liquid nitrogen at -80 °C. Results: Median and mean values of hTERT mRNA were 18.27 and 475.29 (SE 309.76). There were no significant differences on expression according to sex, histology, smoking history and pathological stage (ANOVA). Patients with highest values of hTERT mRNA expression (percentile 95, cut-off value &gt;353) had worse median progression free survival (PFS) (p=0.024) and overall survival (OS) (p=0.020), using Kaplan-Meier method. Multivariate analysis by Cox regression yielded that hTERT level &gt; 353 independently predicted a worse PFS (HR=0.39; 95% CI 0.17–0.93, p=0.034) and OS (HR=0.32; 95% CI 0.12–0.82, p=0.017). Conclusions: A high level of telomerase expression in tumoral tissue is strongly associated with increased risk of recurrence and mortality in resected NSCLC. The level of hTERT mRNA would predict the prognosis of lung cancer patients. No significant financial relationships to disclose.

Results of surgical resection for tracheobronchial cancer involving the tracheal carina

Carinal resection is a technically demanding procedure that is associated with significant morbidity and mortality. We review our experience of carinal resection and analyze its surgical results. Between 1987 and 2004 a total of 35 patients underwent carinal resection for carcinoma involving tracheal carina. Surgical indications are primary non-small-cell lung cancer (NSCLC) in 29 patients, recurrence of NSCLC in 5, and tracheal cancer in 1. Operative procedures were divided into two groups: a reconstruction group (modified montage method in 14, one-stoma type in 2, montage type in 1); and a pneumonectomy group (tracheal sleeve in 10, wedge pneumonectomy in 8). Postoperative complications and survival of the two groups were evaluated. Three patients died postoperatively (8.5%). Major complications were noted in eight patients (22.8%), including three anastomotic stenoses, two pneumonias with respiratory failure, one dehiscence, one cardiac herniation, and one empyema. Six of these eight patients were in the reconstruction group. The overall survival was 42.5% at 2 years and 28.3% at 5 years. In patients with primary NSCLC, 7 of 16 patients with NO disease survived more than 5 years, but all 13 patients with N1 or N2 disease died within 3 years. In the pneumonectomy group, 9 of 13 patients died within 2 years. Carinal resection for tracheobronchial carcinoma is feasible with acceptable morbidity and mortality. Nodal involvement can be a potential contraindication for carinal resection. Careful selection of patients is crucial, especially when pneumonectomy is required.

Is surgical resection indicated for a solitary non–small cell lung cancer recurrence?

Some investigators have reported long-term survival after surgical resection of a solitary non-small cell lung cancer recurrence in various sites. However, the role and indications of the second operation remain unclear. We reviewed 28 patients with a solitary recurrence after successful initial resection of primary non-small cell lung cancer who underwent resection of the recurrent lesion. The clinicopathologic factors associated with outcome were analyzed. There were 17 men and 11 women. Recurrence resection was performed for the following sites: 16 in the lung, 5 in the brain, 2 in the adrenal gland, and 1 each in the chest wall, stomach, skin, pelvic lymph node, and malar bone. The median survival time was 25 months, and the 1-, 2-, and 5-year survival rates after recurrence were 89%, 59%, and 32%, respectively. Advanced p-stage (p-stage II and III, n = 14) of the primary tumor was the significant negative prognostic factor. Patients with p-stage II or III had survival equivalent to that of those who had multiple recurrences or were unfit for further surgical intervention. Resection of a solitary non-small cell lung cancer recurrence might provide long-term survival in highly selected patients. However, surgical resection might be contraindicated if the primary tumor is stage II or III.

Increased Expression of Myosin Light Chain Kinase mRNA Is Related to Metastasis in Non-Small Cell Lung Cancer

Background: The invasiveness of tumor cells depends in large part on their motility, which in turn depends on cytoskeletal function. A major cytoskeletal component involved in cell motility is myosin II, the classical form of myosin first identified in muscle but also expressed in nonmuscle cells. Myosin II is activated by myosin light chain kinase (MLCK), which phosphorylates it on its regulatory light chain. In this context, the contribution made by MLCK to tumor cell motility and invasiveness has been investigated extensively in vitro, but clinical evidence of such a contribution has been lacking. In the present study, therefore, we examined the role of MLCK in the metastasis of non-small cell lung cancer (NSCLC) in a clinical setting. Methods: We measured MLCK mRNA expression in tumor samples from 39 NSCLC patients using real-time semiquantitative reverse transcription polymerase chain reaction carried out in a LightCycler. We then correlated MLCK mRNA expression with known clinicopathological factors. Results: We found that levels of MLCK mRNA expression were higher in patients who showed disease recurrence and distant metastasis than in those who did not. Moreover, the 3-year disease-free survival rate among patients showing lower levels of MLCK mRNA expression [log₁₀(MLCK/GAPDH) <1.4] was significantly greater than among those showing higher MLCK mRNA expression [log₁₀(MLCK/GAPDH) ≧1.4] (87.5 vs. 50.0%; log-rank test, p = 0.021). Conclusion: These findings are the first clinical evidence that expression of MLCK is correlated with disease recurrence and distant metastasis in NSCLC.

Accurate Molecular Detection of Non-small Cell Lung Cancer Metastases in Mediastinal Lymph Nodes Sampled by Endoscopic Ultrasound-Guided Needle Aspiration

The recurrence of disease after the complete resection of early stage non-small cell lung cancer (NSCLC) indicates that undetected metastases were present at the time of surgery. Quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) is a highly sensitive technique for detecting rare gene transcripts that may indicate the presence of cancer cells, and endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is a minimally invasive technique for the nonoperative sampling of mediastinal lymph nodes. The aim of this study was to determine whether these two techniques could enhance the preoperative detection of occult metastases. Patients with NSCLC were evaluated with chest CT and positron emission tomography scans. Those patients without evidence of metastases (87 patients) underwent EUS-guided FNA. Lymph nodes from levels 2, 4, 5, 7, 8, and 9 were sampled and evaluated by standard cytopathology and real-time RT-PCR. Normal control FNA specimens were obtained from patients without cancer who were undergoing EUS for benign disease (17 control specimens). For each sample, messenger RNA was extracted and real-time RT-PCR was used to quantitate the expression of six lung cancer-associated genes (ie, CEA, CK19, KS1/4, lunx, muc1, and PDEF) relative to the expression of an internal control gene (beta(2)-microglobulin). Clinical thresholds of marker positivity were set at 100% specificity, as determined by the receiver operating characteristic curve analysis. Of the cytology-positive lymph nodes (27 lymph nodes), the expression of the KS1/4 gene was above its respective clinical threshold in 25 of 27 samples (93%), making this the most sensitive marker for the detection of metastatic NSCLC. At least one of the six lung cancer-associated genes was overexpressed in 18 of 61 cytology-negative patients (30%), of which KS1/4 was overexpressed in 15 of 61 patients (25%). Based on the high accuracy of EUS-guided FNA/RT-PCR, we predict that some of the patients in the cytology-negative/marker-positive category will have high NSCLC recurrence rates. Among the genes used in our marker panel, KS1/4 appears particularly useful for the detection of overt or occult metastatic disease.

Decreased T cell infiltration and lymphocyte/dendritic cell/monocyte gene expression as well as increased Cyp3A5 mRNA predicts early recurrence of non-small cell lung cancer (NSCLC) following surgical resection

7141 BackgroundRecent phase III data (T. Le Chevalier et al., Proc Am Soc Clin Oncol, 2003) indicate a potential benefit of adjuvant chemotherapy in NSCLC, following surgical resection. Thus, we examined whether cDNA microarray analysis could be used to identify markers that correlate with early recurrence of NSCLC in patients treated with surgery alone. Methods An observational protocol to assay NSCLC tissue banked at resection from patients with stage Ia-IIIb tumors was implemented, using a longitudinal database. The patients were stratified into two groups: Group A (n=15) exhibited no recurrence at two years following surgery and Group B (n=11) exhibited recurrence, documented by tissue diagnosis. Group A was 73% stage I, 20% stage II and 7% stage III. Group B was 36% stage I, 9% stage II and 55% stage III. All evaluable patients were included in the analysis. RNA was isolated from whole tumor tissue and individual tumors were compared using U133 Affymetrix chips. Results A set of 35 T and B cell, dendritic cell and monocyte mRNA species was significantly increased in Group A compared to Group B (F test P<0.0043). Group A tumors exhibited intraepithelial tumor infiltrating T cells (TIL) in 80% (12/15) of cases, by CD2 IHC, compared to 27% (3/11) of Group B (P=0.022). Cyp3A5 mRNA was increased 18.7-fold in Group B (P=0.0001), Notch3 1.7-fold (P=0.002) and collagen 18A1 2.2-fold (P=0.005). Conclusions A set of 35 gene expression markers from lymphocytes/dendritic cells/monocytes negatively associated with early relapse of NSCLC has been identified. Intraepithelial T cell tumor infiltration is confirmed to be negatively associated with relapse. These results suggest that infiltration by specific lymphocyte, dendritic, and monocyte cell types inhibits NSCLC recurrence. Increased Cyp3A5, Notch3 and collagen 18A1 mRNA also correlates with recurrence. These markers may help determine which NSCLC patients may benefit from adjuvant chemotherapy. This work was supported by NIH Grant P20-GM66402–02 and the Thoracic Oncology Program at Indiana University. No significant financial relationships to disclose.

Decreased T cell infiltration and lymphocyte/dendritic cell/monocyte gene expression as well as increased Cyp3A5 mRNA predicts early recurrence of non-small cell lung cancer (NSCLC) following surgical resection

7141 BackgroundRecent phase III data (T. Le Chevalier et al., Proc Am Soc Clin Oncol, 2003) indicate a potential benefit of adjuvant chemotherapy in NSCLC, following surgical resection. Thus, we examined whether cDNA microarray analysis could be used to identify markers that correlate with early recurrence of NSCLC in patients treated with surgery alone. Methods An observational protocol to assay NSCLC tissue banked at resection from patients with stage Ia-IIIb tumors was implemented, using a longitudinal database. The patients were stratified into two groups: Group A (n=15) exhibited no recurrence at two years following surgery and Group B (n=11) exhibited recurrence, documented by tissue diagnosis. Group A was 73% stage I, 20% stage II and 7% stage III. Group B was 36% stage I, 9% stage II and 55% stage III. All evaluable patients were included in the analysis. RNA was isolated from whole tumor tissue and individual tumors were compared using U133 Affymetrix chips. Results A set of 35 T and B cell, dend...

The function of the level of serum carcinoembryonic antigen on early recurrence of non-small cell lung cancer

To explore clinical and pathological factors correlating with early recurrence of resected non small cell lung cancer (NSCLC), and to further understand the function of serum carcinoembryonic antigen (CEA) on NSCLC. 93 patients of NSCLC were selected. All of them received resection and were followed up for more than one year. The first time of recurrence was recorded. Logistic univariate and multivariable analysis were used to find the factors that affect the early recurrence of NSLSC, including age, sex, serum CEA level, tumor size, tumor location, tumor differentiation, histological type and clinical staging, and the ability of factors predicting the recurrence were compared by receiver operating characteristic (ROC) curve. Of all the clinical and pathological factors that are correlated with early recurrence of NSCLC, the serum carcinoembryonic antigen (CEA) value, clinical staging, and tumor difference are of statistical significance. The preoperative serum CEA value is the most valuable factor to predict early recurrence of NSCLC (ROC area: 0.843, 95% CI: 0.723 approximately 0.963, P = 0.000). When preoperative serum CEA value > 10 micro g/L, patients of NSCLC will have an early recurrence rate of 88%; and when preoperative serum CEA value </= 10 micro g/L, the probability of no early recurrence is 92%. For the patients with respectable NSCLC, it is very important to know the precise clinical stage and pathological difference, and so is the preoperative serum CEA value. When preoperative serum CEA value > 10 micro g/L, even if the lesion is of early stage and well differenced, the general situation of patients should be carefully examined for the prompt and accurate treatment to them and close follow up is needed to treat these patients.

Visceral Pleural Invasion And Bronchovascular Bundle Thickening To The Same Lobe In NSCLC: Diagnostic Usefulness And Clinical Significance Using HRCT

BACKGROUND: To assess the utility of HRCT in the evaluation of visceral pleural invasion and to determine whether visceral pleural invasion and bronchovascular bundle thickening on the same lobe could be related to the recurrence and survival in non-small cell lung cancer (NSCLC). METHOD: Eighty one patients, which were fulfilled long-term follow-up at least 18 months (maximum 103 months) among which 434 patients had underwent curative surgical resection for NSCLC from 1986 to 1995, were studied. They were analyzed to evaluate whether the prognostic factors such as the recurrence and survival depend on visceral pleural invasion and bronchovascular bundle thickening to the same lobe. Thirty two patients adjacent to a chest wall or a fissure were evaluated for visceral pleural invasion by HRCT. CT criteria included abutting pleura along the chest wall, abutting and/or compressing fissure, crossing fissure, and pleural tail. RESULTS: The positive predictive value and the negative predictive value of crossing fissure were 100% and 100%, respectively. Two patients showing spiculated interface between a mass and abutting fissure were confirmed to have visceral pleural invasion at surgery. Visceral pleural invasion confirmed at surgery was significant to local recurrence and survival (p<.05, p<.05, respectively). Brochovascular bundle thickening to the same lobe on CT scan was significant to survival (p<.05) but was not significant to local and distant recurrence (p>.05). CONCLUSION: Visceral pleural invasion and bronchovascular bundle thickening to the same lobe have a role in predicting prognosis such as recurrence and survival in NSCLC. Therefore, the analysis of visceral pleural invasion on CT scan and the pathological analysis of bronchovascular bundle thickening to the same lobe may be necessary to predict the prognosis in NSCLC.

Tissue polypeptide specific antigen for early prediction of non-small cell lung cancer recurrence

TPS is a new tumor marker immunoassay that indicates tumor proliferative rate rather than tumor burden. Thirty-nine patients with non-small cell lung cancer (NSCLC), including 18 cases with recurrence and 21 cases without recurrence 1 year postoperation, were enrolled in this study. The serial serum levels of tissue polypeptide specific antigen (TPS) were measured before operation and 1 week, 4 weeks, 3 months, 6 months, 9 months, and 12 months after operation, using an immunoradiometric assay (IRMA), for early detection of recurrence. The results revealed that mean serum values of TPS were higher in 18 patients with recurrent cancer (103.5, 69.2, 88.1, 137.0, 108.6, 170.5, and 106.3 U/l) when compared with 21 patients without recurrent cancer (86.7, 53.0, 54.5, 57.4, 52.3, 52.0, and 58.6 U/l), preoperation and at all times after operation. If the TPS serum level 1 week after operation was considered as the baseline level (1x), elevated TPS ratios were higher in 18 patients with recurrence (1.2x, 2.5x, 2.1x, 4.3x, and 3.0x) when compared with 21 patients without recurrence (1.1x, 1.1x, 1.0x, 1.0x, and 1.1x), 4 weeks to 12 months after operation. We conclude that TPS is a suitable marker for early prediction of NSCLC recurrence. Patients with recurrent NSCLC within 1 year postoperation showed higher serum TPS levels and elevated TPS ratios than patients without recurrent NSCLC.

Bcl-2 oncoprotein in surgically resected non-small cell lung cancer: possibly favorable prognostic factor in association with low incidence of distant metastasis.

The bcl-2 oncoprotein serves a regulatory function in permitting several cell types to die in an apoptotic process. Its overexpression probably plays a role in tumorigenesis and tumor development. The aim of this study was to determine the clinicopathological and prognostic significance of the bcl-2 oncoprotein in patients with nonsmall cell lung cancer (NSCLC). Immunostaining for bcl-2 oncoprotein was performed on 182 operable NSCLCs. Thirty-six patients (19.8%) showed a positive immunostaining for bcl-2 oncoprotein. Histologically, its incidence was higher in squamous cell carcinomas (29.6%). Its expression status was inversely correlated with tumor development-associated parameters such as tumor stage in NSCLCs, especially in squamous cell carcinomas, bcl-2 positive patients with NSCLCs, especially squamous cell carcinomas, showed better overall survival and disease-free survival (DFS). In a multivariate analysis, this oncoprotein status had prognostic value in DFS for NSCLCs and in overall survival for squamous cell carcinomas. The recurrence of bcl-2 positive NSCLCs was significantly uncommon in distant extrathoracic organs. The expression of bcl-2 oncoprotein in NSCLCs may be an early event of tumor development, especially in squamous cell carcinomas, and may be of importance in determining tumor progression and prognosis.