Elevated levels of survivin and livin mRNA in bronchial aspirates as markers to support the diagnosis of lung cancer.

Survivin and livin are two members of the inhibitor of apoptosis gene family, which have been found to be expressed in many human cancer tissues. But their expression could not be detected in normal adult tissue. The aim of our study was to evaluate the diagnostic role of survivin and livin mRNA expression in the bronchial aspirates of patients with lung cancer. Seventy lung cancer patients and 26 benign lung disease patients participated in our study. The bronchial aspirates (bronchial wash or bronchoalveolar lavage fluids) obtained during bronchoscopy. Survivin and livin mRNA were determined by reverse transcriptase-polymerase chain reaction. Receiver operating characteristic (ROC) curve was used to analyze diagnostic performance of the two markers. Survivin and livin mRNA levels in patients with lung cancer were significantly higher than in those with benign lung disease (p < 0.001 and p = 0.001, respectively). In lung cancer patients, specimens taken from cancerous bronchi had significantly higher levels of survivin and livin mRNA than specimens from the mirror side bronchi in the same patients (p < 0.001 and p = 0.001, respectively). The best cutoff values of survivin and livin were selected according to ROC curves. The survivin mRNA expression in bronchial aspirates had sensitivity and specificity of 83 and 96% for diagnosis of lung cancer. Livin mRNA detection in bronchial aspirates showed 63% sensitivity and 92% specificity. Our findings suggest that survivin and livin mRNA detection in bronchial aspirates may be valuable diagnostic marker for the early diagnosis of lung cancer.

Evaluation of pleural fluid survivin and XIAP for the diagnosis of malignant pleural effusion.

Survivin and X-linked inhibitor of apoptosis (XIAP) are two inhibitors of apoptosis that are expressed highly in most malignancies and may be diagnostic markers of cancer. The aim of this study was to assess the diagnostic value of survivin and XIAP as tumor markers in malignant pleural effusion. Ninety-eight consecutive patients (including 56 malignant effusions and 42 benign effusions) with pleural effusion were enrolled in the study. Levels of survivin and XIAP mRNA in pleural fluid were measured by reverse transcription polymerase chain reaction. Carcinoembryonic antigen (CEA) was also detected simultaneously. Results showed that levels of survivin and XIAP mRNA were significantly higher in malignant than in benign effusion (P < 0.001 and P = 0.002, respectively). In the diagnosis of malignant pleural effusion, survivin achieved the highest sensitivity (89.3 %) and specificity (95.2 %), as compared with XIAP (66.1 % sensitivity and 85.7 % specificity), or CEA (71.4 % sensitivity and 80.9 % specificity). The combination of survivin and CEA reached 94.6 % sensitivity, with 90.5 % specificity, whereas the combined analysis of survivin and XIAP yielded the highest specificity (95.2 %) and a very good sensitivity (91.1 %). In conclusion, survivin mRNA assay is a useful tumor marker for discriminating malignant from benign pleural effusion. XIAP may be a good candidate for molecular detection of malignant effusion. The combination of survivin and CEA, or XIAP, can increase diagnostic performance.

Expression of MRP1, BCRP, LRP and ERCC1 as prognostic factors in non-small cell lung cancer patients receiving postoperative cisplatin-based chemotherapy.

The development of resistance to chemotherapy is one of the major obstacles in the treatment of non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the prognostic value of multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance-related protein (LRP), and excision repair cross-complementing 1 (ERCC1) in NSCLC patients receiving cisplatin-based adjuvant chemotherapy (cisplatin plus vinorelbine or gemcitabine) after tumor resection. We used semiquantitative reverse-transcription polymerase chain reaction to detect the expression of MRP1, BCRP, LRP and ERCC1 mRNA in surgical resection specimens of 60 patients with stage IB through IIIA NSCLC. The expression level of each gene was analyzed in relation to clinicopathological factors, tumor-free survival (TFS), and overall survival. The results showed that stage IIIA (p=0.011), N1 and N2 status (p=0.008), high expression of MRP1 (p=0.034) and LRP (p=0.018) were associated with shorter TFS. Stage IIIA (p=0.0105), N1 and N2 status (p=0.009), high expression of MRP1 (p=0.021) and ERCC1 (p=0.012) were related to a shorter overall survival. Cox multivariate analyses revealed that early stage (p=0.013 and p=0.024), negative lymph node status (p=0.006 and p=0.011), and low MRP1 expression (p=0.022 and p=0.035) were independent predictors of favorable TFS and overall survival, respectively. Additionally, ERCC1 (p=0.019) was an independent predictor of favorable overall survival.

Diagnostic value of the FHIT and p16 mRNA loss and the K-ras gene mutation in pleural fluids for malignant pleural effusion.

Inactivation of the tumor suppressor genes and activation of oncogenes are involved in the development of cancer. The aim of this study was to evaluate the diagnostic value of the fragile histidine triad (FHIT) and p16 mRNA loss and the K-ras gene mutation in distinguishing malignant from benign pleural effusion. A total of 50 patients with malignant pleural effusion and 30 patients with benign pleural effusion were enrolled in this study. All pleural fluid specimens were evaluated in parallel by cytology, reverse transcriptase-PCR for the loss of FHIT and p16 mRNA, and PCR-SSCP (single-stranded conformation polymorphism) for the mutation of K-ras gene. The detection rates of FHIT and p16 mRNA loss were significantly higher in malignant than in benign pleural effusion (P < 0.001 and P = 0.001). The K-ras mutations were more frequent in malignant than benign pleural effusion (P = 0.006). The sensitivity and specificity were 58% and 93% for FHIT loss, 48% and 90% for p16 loss, and 44% and 87% for the K-ras mutation, respectively. In combined evaluation with both FHIT and p16 loss, the sensitivity was 68%, and specificity was 90%. The combination of the three molecular markers reached 74% sensitivity, whereas the combined use of the cytology and the three markers increased the diagnostic yield of the former by 38%. More than one third of cytology negative malignant pleural effusion could be identified by at least one of the three markers. These results suggest that the detection of FHIT and p16 mRNA loss and the k-ras gene mutation in pleural fluid could be helpful adjunct to cytology in the diagnosis of malignant pleural effusion.

Association of expression of MRP1, BCRP, LRP and ERCC1 with outcome of patients with locally advanced non-small cell lung cancer who received neoadjuvant chemotherapy.

PURPOSE: The aim of this study was to investigate prognostic value of multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance-related protein (LRP) and excision repair cross-complementing 1 (ERCC1) in patients with locally advanced non-small cell lung cancer (NSCLC) who received neoadjuvant cisplatin-based chemotherapy. METHODS: Transbronchial biopsy (TBB) specimens from 46 patients with stage IIIA (N(2)) NSCLC were collected to determine the expression level of MRP1, BCRP, LRP and ERCC1 mRNA by semiquantitative RT-PCR. The expression level of each gene was analyzed in relation to histopathologic response to chemotherapy, and tumor-free survival (TFS) and overall survival. RESULTS: Patients with MRP1 or LRP low expression had a significantly better histopathologic response (P=0.032 and 0.006), and a significantly longer TFS (P=0.043 and 0.025) and overall survival (P=0.019 and 0.013) than those with MRP1 or LRP high expression. Patients with ERCC1 low expression had a significantly longer overall survival (P=0.007), but not TFS (P=0.094) than those with ERCC1 high expression. In multivariate analysis, LRP low expression was a significantly favorable factor for TFS (P=0.027), and LRP and ERCC1 were significantly favorable factors for overall survival (P=0.012 and 0.032). CONCLUSION: Assessment of MRP1 and LRP mRNA expression in TBB specimens may predict histopathologic response and survival in locally advanced NSCLC patients who received neoadjuvant cisplatin-based chemotherapy. ERCC1 expression was predictive for overall survival.

Induction concurrent chemoradiotherapy compared with induction radiotherapy for superior sulcus non-small cell lung cancer: a retrospective study.

AIM: To evaluate the efficacy of current chemoradiotherapy on improvement of survival in patients with superior sulcus non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed the data of 39 patients with superior sulcus NSCLC treated with induction therapy followed surgery. The patients were divided into two groups according to the induction approach: the induction radiotherapy (RT) group (1993-1999), and the induction chemoradiotherapy (CT/RT) group (since 1999). RESULTS: The rate of complete resection was 65 percent in the RT group (n = 17) compared with 91 percent in the CT/RT group (n = 22, P = 0.024). Complete pathological responses from induction therapy were 12 percent in the RT group and 45 percent in the CT/RT group (P = 0.032). Overall survival (OS) was significantly longer in patients who received CT/RT than that in those who received RT, with 2- and 5-year survival rates of 77.3 percent and 36.4 percent versus 41.2 percent and 11.8 percent, respectively (P = 0.007). CT/RT also associated with a markedly longer tumor-free survival (TFS), with a median TFS of 40 and 17 months, respectively (P = 0.007). Patients achieved complete resection or complete pathological response had a significantly better survival than those with incomplete resection or pathological partial responses and no change (P < 0.0005 and P = 0.001, respectively). CONCLUSION: Our results indicate that CT/RT followed by surgery can significantly improve OS and TFS, and may be considered as an optimal option in treatment of patients with superior sulcus NSCLC.

Outcome and treatment in elderly patients with small cell lung cancer: a retrospective study.

AIM: The number of elderly patients with small cell lung cancer (SCLC) is expected to increase with the growing geriatric population. The aim of this study is to evaluate the safety and efficacy of standard chemotherapy or chemoradiotherapy in elderly patients with SCLC. METHODS: In this retrospective study, we analyzed the data of 126 patients with SCLC diagnosed between 1996 and 2005 at our hospital, and compared the outcome of younger patients less than 70 years and elderly patients 70 years or older who were treated with etoposide and cisplatin (EP regimen) and cyclophosphamide, adriamycin and vincristine (CAV regimen). Patients with limited disease SCLC received thoracic radiotherapy (RT) following chemotherapy. RESULTS: Overall response rates (complete and partial response) were not significantly different between patients less than 70 years and patients 70 years or older (69% vs 65%, P = 0.591). The median survival time was 13 months for patients less than 70 years compared with 12 months for patients 70 years or older (P = 0.263), with 2- and 5-year survival rates of 37.8% and 8.2% vs 26.2% and 3.6%, respectively. Progression-free survival of patients 70 years or older was similar to that of patients less than 70 years (P = 0.445). Grade 3 and 4 hematological toxicities were more frequent among the elderly group (leukopenia, 48% vs 31%, P = 0.049; neutropenia, 52% vs 32%, P = 0.028; thrombocytopenia, 38% vs 21%, P = 0.047). CONCLUSION: In spite of having more grade 3 and 4 hematological toxicity, elderly SCLC patients 70 years or older can benefit from the EP regimen and the CAV regimen with or without thoracic RT. Further investigations are needed to focus on ways to decrease toxicity, especially in the elderly.

Expression of MRP1, BCRP, LRP, and ERCC1 in advanced non-small-cell lung cancer: correlation with response to chemotherapy and survival.

PURPOSE: We investigated the prognostic value of the expression of multidrug resistance protein-1 (MRP1), breast cancer resistance protein (BCRP), lung resistance-related protein (LRP), and excision repair cross-complementing group-1 (ERCC1) in patients with advanced non-small-cell lung cancer (NSCLC) treated with cisplatin-based chemotherapy. PATIENTS AND METHODS: Semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR) was used for detecting the expression of MRP1, BCRP, LRP, and ERCC1 mRNA in 66 transbronchial biopsy (TBB) samples from untreated patients with advanced NSCLC. All of the patients received cisplatin-based chemotherapy. Response to chemotherapy, progression-free survival (PFS), and overall survival (OS) were compared in relation to expression of each gene and clinicopathologic factors. RESULTS: Results showed that tumor stage (P = .028) and the expression of MRP1 (P = .046) and LRP (P = .012) correlated with response to chemotherapy. Poor performance status (PS; P = .016), advanced tumor stage (P = .004), and the high expression of MRP1 (P = .012) and LRP (P = .002) predicted poorer PFS. Performance status (P = .009); tumor stage (P = .003); and the expression of MRP1 (P = .017), LRP (P = .005), and ERCC1 (P = .002) were predictive for OS. In a Cox proportional hazards multivariable analysis, PS (P = .042), tumor stage (P = .007), and the expression of LRP (P = .011) and ERCC1 (P = .026) were identified as independent prognostic factors for OS. CONCLUSION: Our data suggested that determination of MRP1, LRP, and ERCC1 mRNA expression using RT-PCR in TBB samples might be helpful in predicting outcome of patients with advanced NSCLC treated with cisplatin-based chemotherapy and in optimizing therapeutic strategy based on the expression of these genes.