Lung Cancer - Articles in Press

Dose-escalation study of pemetrexed in combination with carboplatin followed by pemetrexed maintenance therapy for advanced non-small cell lung cancer - Corrected Proof

2010-03-17

Abstract: Introduction: The primary objectives of this study were to determine the recommended dose of pemetrexed and carboplatin in patients with chemo-naive advanced non-small cell lung cancer (NSCLC).Methods: Patients received escalated doses of carboplatin area under the concentration–time curve (AUC) of 5 (cohort 1) or 6 (cohort 2) and pemetrexed 500mg/m2 every 3 weeks for six cycles. For patients with objective response and stable disease, pemetrexed were continued until disease progression or unacceptable toxicity.Results: In cohort 1, a dose-limiting toxicity (DLT) was observed in one of the six patients: grade 4 thrombocytopenia. No DLTs were seen in the first 6 patients of cohort 2, and thus the combination of pemetrexed 500mg/m2 plus carboplatin at AUC 6 was determined as the recommended dose. Among a total of 20 patients, 8 patients received a median of four cycles of pemetrexed monotherapy in a maintenance setting without unexpected or cumulative toxicities. No complete responses and 12 partial responses were observed, giving an overall response rate of 60.0% [95% confidence interval (CI), 36.1–80.9%]. Median progression-free survival time for all patients was 7.6 months (95% CI: 4.8–8.0 months).Conclusions: Pemetrexed 500mg/m2 plus carboplatin AUC 6 combination therapy followed by pemetrexed maintenance therapy, is generally tolerable, and shows encouraging antitumor activity in chemotherapy-naive patients with advanced NSCLC.

Subcarinal lymph node in upper lobe non-small cell lung cancer patients: Is selective lymph node dissection valid? - Corrected Proof

2010-03-17

Abstract: Little is known about selective lymph node dissection in non-small cell lung cancer (NSCLC) patients. We sought to gain insight into subcarinal node involvement for its frequency and impact on outcome to evaluate whether it is valid to omit subcarinal lymph node dissection in upper lobe NSCLC patients. We reviewed node metastases distribution according to node region, tumor location, and histology among 1099 patients with upper lobe NSCLC. We paid special attention to subcarinal metastases patients without superior mediastinal node metastases, because their pathological stages would have been underdiagnosed if subcarinal node dissection had been omitted. We also assessed the outcome and the pattern of failure among subcarinal metastases patients. To identify subcarinal node involvement predictors, we analyzed 7 clinical factors. Subcarinal node metastases were found in 20 patients and were least frequent among squamous cell carcinoma patients (0.5%). Two of them were free from superior mediastinal metastases but died of the disease at 1 month and due to an unknown cause at 18 months, respectively. Seventeen of the 20 patients developed multi-site recurrence within 37 months. The 5-year survival rate of the 20 patients with subcarinal metastases was 9.0%, which was significantly lower than 32.0% of patients with only superior mediastinal metastases. Clinical diagnosis of node metastases was significantly predictive of subcarinal metastases. Subcarinal node metastases from upper lobe NSCLC were rare and predicted an extremely poor outcome. It appears valid to omit subcarinal node dissection in upper lobe NSCLC patients, especially in clinical N0 squamous cell carcinoma patients.

Smells like cancer - Corrected Proof

Ildiko Horvath — 2010-03-15

According to the World Health Organization lung cancer is the leading cancer-related cause of death killing about 1.3 million people every year. Conventional diagnostic tests for lung cancer are costly and unsuitable for widespread screening. Approaches that can increase the rate of early detection have been the subject of considerable enthusiasm.

Histology classification is not a predictor of clinical outcomes in advanced non-small cell lung cancer (NSCLC) treated with vinorelbine or gemcitabine combinations - Corrected Proof

2010-03-15

Abstract: Background: Until recently, histology has not been clearly or consistently described in the literature as a prognostic or predictive variable in advanced NSCLC studies. We have categorised patients treated with vinorelbine and gemcitabine based first line chemotherapy regimes for advanced NSCLC as either squamous or non-squamous, and also as either adenocarcinoma and non-adenocarcinoma, and compared outcome.Material and methods: 420 patients treated with platinum/gemcitabine, platinum/vinorelbine or single agent gemcitabine or vinorelbine as first line chemotherapy for advanced NSCLC were identified. The influence of pathology on progression free survival (PFS) and overall survival (OS) has been investigated by means of a Cox regression analysis. Hazard ratios with 95% CIs have been given for each pathological type after adjusting for the effects of age, gender, stage (III vs. IV), PS (0/1 vs. 2/3) and treatment type (platinum doublet vs. single agent).Results: Neither univariate nor multivariate analysis suggested that there was a significant difference in the response rates for adenocarcinoma vs. non-adenocarcinoma or between squamous and non-squamous pathology. There was no difference in PFS between adenocarcinoma and non-adenocarcinoma pathologies until 8 months (p=0.98), and there was a statistically significant advantage in PFS for squamous vs. non-squamous pathologies (p=0.04). Using multivariate Cox regression analysis to adjust for the effects of age, gender, stage, PS, and treatment type, the pathology subtype was not significant. There was no difference in OS in any group.Conclusions: These results suggest that histology may not be considered as a predictor of clinical outcome using these drugs.

Surgical treatment of bronchial carcinoid tumors: A single-center experience - Corrected Proof

2010-03-11

Abstract: Background: Bronchial carcinoid is an infrequent neoplasm with a neuroendocrine differentiation. Surgical treatment is the gold standard therapy, with procedures varying from sublobar resections to complex lung sparing broncoplastic procedures. This study evaluates the results of surgical treatment of bronchial carcinoids and its prognostic factors.Patients and methods: Retrospective review of 126 consecutive patients who underwent surgical treatment for bronchial carcinoid tumors between December 1974 and July 2007.Results: There were 70 females (55%) and the mean age was 46 years, ranging from 17 to 81 years. Upon clinical presentation, 38 patients (30%) have had recurrent respiratory tract infection, 31 (24%) cough, 16 (12%) chest pain and 25 (20%) were asymptomatic. Preoperative bronchoscopic diagnosis was obtained in 74 cases (58.7%). The procedures performed were: 19 sublobar resections (14,9%), 58 lobectomies (46%), 8 bilobectomies (6.3%), 6 pneumonectomies (4.7%), 2 sleeve segmentectomies (1.5%), 26 sleeve lobectomies (20.6%) and 9 bronchoplastic procedures without lung resection (7.1%). Operative mortality was 1.5% (n=2) and morbidity was 25.8% (n=32), including 12 respiratory tract infections and 4 reinterventions due to bleeding (3) and pleural empyema (1). Among the 112 patients available for follow-up, the overall survival at 3, 5 and 10 years was 89.2%, 85.5% and 79.8%, respectively. Five and 10-year survival for typical and atypical carcinoids were 91, 89% and 56, 47%, respectively. Overall disease-free survival at 5 years was 91.9% Statistical analysis showed that overall disease-free survival correlated with histology – typical vs. atypical – (p=0.04) and stage (p=0.02).Conclusion: Surgery provides safe and adequate treatment to bronchial carcinoid tumors. Histology and stage were the main prognostic factors.

The immunohistochemical overexpression of ribonucleotide reductase regulatory subunit M1 (RRM1) protein is a predictor of shorter survival to gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC) - Corrected Proof

2010-03-11

Abstract: We evaluated whether ribonucleotide reductase regulatory subunit M1 (RRM1) protein expression by immunohistochemistry (IHC) is a predictor of survival and response in gemcitabine-treated, advanced non-small cell lung cancer (NSCLC). We retrospectively collected 40 formalin-fixed, paraffin-embedded NSCLC tissues to investigate the protein expression of RRM1 by IHC with a purified rabbit anti-human RRM1 polyclonal antibody (ProteinTech Group, Chicago, IL, USA). RRM1 expression was positive in 14 (35%) and negative in 26 (65%) cases. Ten (25%) patients were treated as first-line and 30 (75%) patients as second-line. The median age was 61 years and M/F was 31/9. Stage IIIB/IV was 7/33 and adenocarcinoma/squamous cell carcinoma/other cell type was 20/16/4. Other characteristics, including age, gender, stage, cell type and first/second-line were not statistically different in the RRM-positive and RRM-negative groups. The overall survival of RRM1-positive groups was significantly shorter than RRM-negative groups (5.1 months vs. 12.9 months, p=0.022). The response rates of 38 out of 40 patients were assessable. Disease control rate (PR+SD) of the RRM1-positive groups was significantly lower than that of RRM1-negative groups (23% vs. 56%, p=0.053). In patients with gemcitabine-treated advanced NSCLC, patients with RRM1-positive tumors had worse overall survival and disease control than patients with RRM1-negative tumors.

Phase I study of autologous dendritic cell tumor vaccine in patients with non-small cell lung cancer - Corrected Proof

2010-03-11

Abstract: Background: A dendritic cell vaccine has been developed as a novel strategy for generating antitumor immunity in the treatment of cancer. The purpose of this study was to assess the maximal tolerated dose, safety, and immunologic response of a new dendritic cell vaccine (DC-Vac) into which tumor lysate was loaded by electroporation and pulse in patients with advanced non-small cell lung cancer (NSCLC).Patients and methods: Fifteen patients with inoperable stage III or IV NSCLC were assigned to cohorts that received 3, 6, or 12×106 DC-Vac intradermally 3 times at 2 week intervals. We also evaluated immunologic and tumor responses.Results: The maximum dose of DC-Vac (12×106) was shown to be safe. In 5 of 9 patients, the vaccine resulted in increased interferon (IFN)-γ production by CD8+ cells after exposure to tumor lysate. Additionally, there were mixed responses which do fulfill progressive disease definition but demonstrate some clinical benefit in two patients.Conclusion: The administration of tumor lysate-loaded autologous dendritic cells by electroporation and pulse was non-toxic and induced immunologic responses to tumor antigens. The two mixed tumor responses which were achieved may represent a potential benefit of this new DC-Vac.

Clinical outcomes in extracranial tumor sites and unusual toxicities with concurrent whole brain radiation (WBRT) and Erlotinib treatment in patients with non-small cell lung cancer (NSCLC) with brain metastasis - Corrected Proof

2010-03-08

Abstract: Background: Thirty percent of newly diagnosed NSCLC patients present with synchronous brain metastases, most of whom are treated with whole brain radiation. Systemic chemotherapy is usually avoided during WBRT due to concerns regarding toxicity. However, concurrent administration of targeted agents, such as Erlotinib, during WBRT may address systemic disease without causing toxicity. We report our institutional data on outcomes and toxicities with this treatment approach.Materials and methods: Medical records of patients with newly diagnosed NSCLC and brain metastases receiving concurrent WBRT and Erlotinib treatment were reviewed. Radiographic response to therapy and toxicities were analyzed.Result: Eight patients were identified and 7 were evaluable for response. All patients had intracranial disease control. In the extracranial sites, 3 (37.5%, intent-to-treat) showed partial response (PR), 2 (25%) had stable disease (SD), 1 (12.5%) had progression (PD) and 1 (12.5%) had new air space disease obscuring tumor response assessment. Among the three responders, two were female never smokers, while one was a female current smoker. Unanticipated grade 3 hepatotoxitity, hyponatremia, mental status changes, grade 3 and 4 thrombocytopenia, and grade 4 neutropenia with sepsis were observed. Three deaths occurred without clear signs of disease progression: one from neutropenic sepsis, one from wide spread air space disease, and one from neurologic deterioration.Conclusion: Our data demonstrates a high percentage of extracranial tumor response rates with first line Erlotinib in selected NSCLC patients. We observed unexpected serious complications and postulate possible mechanisms. We recommend caution to be exercised when considering Erlotinib treatment during WBRT, particularly in regard to drug–drug interactions and infection control. Data from prospective trials are needed to determine the benefits and toxicities of Erlotinib during WBRT.

Involvement of LKB1 in epithelial–mesenchymal transition (EMT) of human lung cancer cells - Corrected Proof

2010-03-08

Abstract: Epithelial–mesenchymal transition (EMT) is a critical phenotypic alteration of cancer cells that triggers invasion and metastasis. Lung cancer cells often show mesenchymal phenotypes; however, a causative genetic alteration for the induction of EMT in lung cancer cells remains unknown. Recent studies have shown that the LKB1 gene is mutated in up to one-third of lung adenocarcinomas. Therefore, to pursue the possible involvement of LKB1 inactivation in the induction of EMT in lung carcinogenesis, we generated immortalized lung epithelial cells and lung adenocarcinoma cells with stable or transient LKB1 knockdown. LKB1 knockdown increased cell motility and invasiveness, and induced the expression of several mesenchymal marker proteins accompanied by the expression of ZEB1, a transcriptional repressor for E-cadherin and an EMT inducer. In agreement with the recent findings, expression of miR-200a/c was inversely correlated with that of ZEB1 in LKB1 knockdown clones with mesenchymal phenotype. Furthermore, transient knockdown of LKB1 induced ZEB1 mRNA and increased cell motility, and this motility was suppressed by ZEB1 repression. These results strongly indicate that LKB1 inactivation triggers EMT in lung cancer cells through the induction of ZEB1.

Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: A phase I dose-escalation study - Corrected Proof

2010-03-02

Abstract: Purpose: To determine the maximum tolerated dose (MTD) of sunitinib plus gemcitabine/cisplatin for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Safety, pharmacokinetics, and antitumor activities were evaluated.Methods: Patients ≥18 years with Eastern Cooperative Oncology Group performance status 0/1 and stage IIIB/IV NSCLC were included in this open-label, multicenter, dose-escalation phase I study. Treatment was administered in 3-week cycles: oral sunitinib 37.5 or 50mg/day intermittently (Schedule 2/1: 2 weeks on treatment, 1 week off treatment) or 25mg continuous daily dosing (CDD) schedule with intravenous infusions of gemcitabine (1000 or 1250mg/m2 days 1, 8) and cisplatin (80mg/m2 day 1).Results: A total of 28 evaluable patients were assigned to four dose levels. Most adverse events (AEs) on the Schedule 2/1 MTD were mild to moderate. Dose delays due to myelosuppression occurred on both schedules, limiting treatment to a median of four cycles. Four of 18 evaluable patients (22%) on Schedule 2/1 and 1 of 6 patients (17%) on the CDD schedule had confirmed partial responses.Conclusions: The MTD was identified as sunitinib 37.5mg (Schedule 2/1), gemcitabine 1250mg/m2, and cisplatin 80mg/m2, with most AEs being mild to moderate. However, frequent dose delays due to myelosuppression occurred. There was evidence of antitumor activity with this combination.

Exhaled ERCC-1 and ERCC-2 microsatellite alterations in NSCLC patients - Corrected Proof

2010-02-26

Abstract: Background: The excision repair cross-complementation (ERCC) enzyme plays a rate-limiting role in nucleotide excision repair pathway. Microsatellite alterations (MAs) at the long arm of chromosome 19, where are located the ERCC genes, have recently been associated with non-small cell lung cancer (NSCLC) pathogenesis and reduced survival.The aim of the present study was to explore MAs at 19q in DNA from exhaled breath condensate (EBC) of NSCLC patients investigating their possible correlation with the smoking habit, with the biological behaviour of the tumour and their predictive survival power.Methods: 34 NSCLC patients and 33 healthy controls (19 non-smokers and 14 smokers) were enrolled. All the subjects underwent 19q microsatellite analysis of their EBC. A total of 25 patients were either given a follow-up of at least 102 weeks, or were followed up until death.Results: No MAs were found in EBC or WB in the healthy non-smokers, while 16% of exhaled MAs were found in healthy smokers and 25% of exhaled MAs in NSCLC patients. The number of MAs resulted related with tobacco consumption and with NSCLC patients’ survival.Conclusions: In conclusion, the study of MAs at 19q resulted feasible in EBC-DNA. These genetic alterations are specific for lung cancer and predictive of survival in NSCLC patients. Our results suggest interesting clinical perspectives for the analysis of exhaled MAs at 19q in NSCLC patients.

Maintenance or consolidation therapy in small-cell lung cancer: A systematic review and meta-analysis - Corrected Proof

2010-02-26

Abstract: Objective: To assess the role of maintenance or consolidation therapy in the treatment of small-cell lung cancer (SCLC), a meta-analysis of all published randomized clinical trials (RCTs) was performed in order to provide an overall meta-analysis and indirectly compare the effect of chemotherapy, interferons, and other biologic agents.Methods: Electronic databases were searched for publication reporting of RCTs comparing maintenance or consolidation therapy versus placebo or follow-up alone until December 2008. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS), with their relative 95% confidence intervals (CI), were derived. In the calculation of HRs, the “no maintenance” arm served as a reference. The a priori value of p<0.05 was chosen as significant level for statistical tests.Results: Twenty-one RCTs, encompassing 3,688 patients, were eligible for the present analysis: 11 RCTs employing chemotherapy, 6 interferons (4 alpha and 2 gamma), and 4 other biological agents. Overall, no statistical advantage in OS (HR 0.93, 95% CI 0.87–1.00; p=0.05) or in PFS (HR 0.98, 95% CI 0.91–1.06; p=0.63) was reported for maintenance or consolidation therapy. Statistical evidence of different effects among the four types of therapy was detected for OS (χ2 test for heterogeneity: 8.07 [3 df]; p=0.04), but not for PFS. A statistically significant reduction of mortality was detected in those studies assessing the efficacy of chemotherapy (HR 0.89, 95% CI 0.81–0.98; p=0.02) and of interferon-alpha (HR 0.78, 95% CI 0.64–0.96; p=0.02).Conclusions: The maintenance or the consolidation approach failed to improve the outcomes of SCLC. A survival advantage is suggested for maintenance chemotherapy and interferon-alpha, but its clinical impact needs to be confirmed by further studies.

Copy number alterations and expression profiles of candidate genes in a pulmonary inflammatory myofibroblastic tumor - Corrected Proof

2010-02-25

Summary: Inflammatory myofibroblastic tumor (IMT) is a soft tissue neoplasm composed of myofibroblastic spindle cells accompanied by the inflammatory infiltrate. In addition to its phenotypic ambiguity, pathogenic mechanisms of the IMT also remain elusive. Although several chromosomal aberrations have been identified by karyotyping, detailed characteristics and extent of copy number alterations in IMT are unknown. Copy number alterations of an IMT case were examined using 30K whole-genome oligoarray-comparative genomic hybridization. RNA expression of putative cancer-related genes located in the chromosomal altered regions was assessed by qRT-PCR. We identified seven copy number gained regions, seven lost regions, nine amplifications and six homozygous deletions, which covers 2.5% of total genome. In homozygously deleted regions, RNA levels of putative tumor suppressors, SEMA3B, SEMA3F and SULT2A1, were significantly repressed being consistent with copy number status. In high-level amplification regions, RNA expression of four potential cancer-related genes was examined; GSTT1, ESR1, EVI1 and MITF. Among them, GSTT1 and ESR1 were significantly up-regulated, but EVI1 and MITF showed insignificant elevation of RNA expression. To our knowledge, this is the first genome-wide analysis of copy number alterations in IMT. Most of the putative cancer-related genes identified in this study are supposedly novel in IMT. Taken together, our results will help to elucidate the pathogenic mechanisms of IMT.

Efficacy of circulating plasma DNA as a diagnostic tool for advanced non-small cell lung cancer and its predictive utility for survival and response to chemotherapy - Corrected Proof

2010-02-24

Abstract: Background: Increased presence of circulating DNA has been reported in lung cancer. However, the utility of circulating DNA as a diagnostic and prognostic marker and in assessing therapeutic efficacy is yet to be realized.Methods: Circulating plasma DNA levels were quantified in 100 patients with non-small cell lung cancer and 100 age-matched controls. Forty-two patients received platinum-based chemotherapy for a minimum of three cycles after which response was assessed by computed tomography. Association of circulating plasma DNA levels with lactate dehydrogenase (LDH) levels, leukocyte counts, response to therapy and survival was determined.Results: The mean (±SD) plasma level of circulating DNA in lung cancer patients was 122.7 (±47.4)ng/mL, which was significantly higher than the controls (74.0 (±19.8)ng/mL; p<0.001). At 95% specificity, circulating plasma DNA levels detected lung cancer with a sensitivity of 52% at a cut-off of 104.5ng/mL. Circulating plasma DNA levels significantly correlated with higher LDH levels, but not with leukocyte counts or any of the prognostic factors. There was no significant difference in pre-treatment circulating plasma DNA levels between responders and non-responders to chemotherapy. However, circulating plasma DNA levels were significantly higher in patients with progressive disease as compared to patients with partial remission or stable disease.Conclusions: In our opinion, circulating DNA can serve as a diagnostic tool, especially if combined with other more sensitive tumor markers or imaging modalities. Further, circulating DNA may predict therapeutic efficacy which may help in better management of cancer patients.

A bibliometric analysis of scientific production in mesothelioma research - Corrected Proof

2010-02-19

Abstract: This study aims at comparing scientific production in malignant mesothelioma (MM) among countries and evaluating publication trends and impact factor (IF).The PubMed database was searched with a strategy combining keywords listed in the Medical Subject Headings and free-text search. Publications numbers and IF were evaluated both as absolute values and after standardization by population and gross domestic product (GDP).5240 citations were retrieved from the biennium 1951–1952 (n=22) to 2005–2006 (n=535). The 177% increase of MM publications from 1987 to 2006 exceeded by large the corresponding value of total cancer literature (123.5%). In these two decades, 2559 articles with IF were published: 46.4% came from the European Union (EU) (the UK, Italy and France ranking at the top), and 36.2% from the US. The highest mean IF was reported for the US (3.346), followed by Australia (3.318), and EU (2.415, with the UK, Belgium and the Netherlands first). Finland, Sweden and Australia had the best ratio between IF (sum) and resident population or GDP. The number of publications correlated with GDP (p=0.001) and national MM mortality rates (p=0.002). An association was found between a country commitment to MM research and the burden of disease (p=0.04). Asbestos, survival, prognosis, occupational exposure, differential diagnosis, and immunohistochemistry were the most commonly used keywords.This report represents the first effort to explore the geographical and temporal distribution of MM research and its determinants. This is an essential step in understanding science priorities and developing disease control policies.

Rationale of a relaunch of gefitinib in Caucasian non-small cell lung cancer patients - Corrected Proof

Andreas Pircher, Ferdinand Ploner, Helmut Popper, Wolfgang Hilbe — 2010-02-19

Abstract: In 2002 results of two-phase II studies with the new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib showed not only promising efficacy in second and third line non-small cell lung cancer (NSCLC) therapies but also an excellent tolerability. Since then, thousands of patients have been treated in one of the largest expanded access programs ever performed and the successful application in daily routine led to a preliminary approval of the drug by the U.S. Food and Drug Administration in 2003. In the light of the negative results of a subsequent phase III trial comparing gefitinib with best supportive care, the approval was withdrawn. In 2009 gefitinib was relaunched for Caucasian patients in the US and Europe based on new data and on the re-interpretation of previous studies. The approval is now recommended exclusively for patients with an activating EGFR mutation. For the first time in lung cancer, molecular work-up is of clinical relevance and will change the diagnostic and therapeutic algorithms. The present review summarizes these data, presents the rationale for this development and proposes a diagnostic work-up.

Phase I/II trial of gemcitabine plus oral TS-1 in elderly patients with advanced non-small cell lung cancer: Thoracic oncology research group study 0502 - Corrected Proof

2010-02-15

Abstract: A phase I/II trial of TS-1 combined with gemcitabine was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients older than 70 years of age received TS-1 orally b.i.d. on days 1–14 and gemcitabine intravenously on days 8 and 15 every 4 weeks. In phase I (n=22), each cohort received escalating doses of TS-1 (30–40mg/m2 b.i.d.) and gemcitabine (800–1000mg/m2); MTD was 40mg/m2 b.i.d. TS-1 and 1000mg/m2 gemcitabine; RD was 30mg/m2 b.i.d. TS-1 and 1000mg/m2 gemcitabine. Dose-limiting toxicities included a grade 3 infection, skin toxicity, and stomatitis. In phase II (n=37), the overall response rate was 27% (90% confidence interval (CI): 15–42%) and the median time to progression and overall survival were 4.2 months (90% CI: 3.2–5.7) and 12.9 months (90% CI: 10.4–14.7), respectively. The most common grade 3 or higher toxicity was neutropenia (45.9%), and thrombocytopenia was observed in 13.5% of patients. Two cases each of grade 3 pneumonitis and skin toxicity were observed, but nonhematological toxicities occurred at generally low frequencies. TS-1 with gemcitabine is a promising doublet regimen in elderly patients with advanced NSCLC with acceptable toxicities.

Population-based patterns and cost of management of metastatic non-small cell lung cancer after completion of chemotherapy until death - Corrected Proof

2010-02-15

Abstract: Background: The aim of this study was to examine the patterns and costs of management of non-small cell lung cancer (NSCLC) after completion of chemotherapy until death in a population of patients in Manitoba, Canada.Patients and methods: Stage IIIB and IV NSCLC patients diagnosed between January 1997 and June 2000 who received chemotherapy as the primary treatment, completed their chemotherapy and survived for at least 28 days since their last treatment, and were on best supportive care (BSC) were selected. Treatment, services received, costs, and survival were determined by chart review and examining various databases including the Manitoba Cancer Registry, medical claims, hospitalizations, and prescription drugs. Costs of treatment, average cost per patient, and lifetime treatment costs were calculated.Results: Of the 2463 patients diagnosed with NSCLC over the study period, 150 patients matched our study criteria. From the beginning of the first chemotherapy treatment, the median survival time was 31.8 weeks, while from the date of BSC the median survival time was 13.8 weeks. The average cost per case was $10,805 from last date of chemotherapy and $8654 during the BSC period. The average cost per patient-month ranged from $1645 to $1792 in current prices. Lifetime treatment costs ranged from $8702 to $11,057. Hospitalizations accounted for 80% of the total treatment costs.Conclusion: The largest overall component of cost after the end of chemotherapy was hospitalizations. Effective new therapies that reduce the episodes of hospitalizations would have a significant impact on decreasing aggregate costs.

Chemotherapy with cetuximab or chemotherapy alone for untreated advanced non-small-cell lung cancer: A systematic review and meta-analysis - Corrected Proof

Hao Lin, Jingwei Jiang, Xiaohua Liang, XinLi Zhou, Ruofan Huang — 2010-02-11

Abstract: Purpose: To compare the efficacy and toxicities of chemotherapy plus cetuximab (Erbitux, E; E-chemo) with chemotherapy alone (chemo alone) in patients with previously untreated advanced non-small-cell lung cancer (NSCLC). The primary endpoint was overall survival; the secondary endpoints were progression-free survival, overall response rate, one-year survival and safety.Methods: The PubMed database, the Cochrane Library, conference proceedings, database of ongoing trials and references of published trials and reviews were screened. Two reviewers independently assessed the quality of the trials and extracted data. The hazard ratios (HRs) for overall survival and progression-free survival, relative risks (RRs) for overall response rate and one-year survival, and odds ratios (ORs) for the different types of toxicity were pooled using STATA SE10.1 package.Results: Four trials involving 2018 patients with previously untreated NSCLC were ultimately analyzed. The pooled HR for overall survival (HR, 0.87; 95%CI, 0.79–0.96; p=0.004) was in favor of E-chemo, which also gave rise to a higher overall response rate (RR, 1.19; 95%CI, 1.04–1.37; p=0.013). The analysis failed to show benefit of E-chemo in progression-free survival (HR, 0.91; 95%CI, 0.83–1.00; p=0.06) and one-year survival (RR, 1.10; 95%CI, 0.98–1.26; p=0.172). E-chemo indeed caused more grade 3/4 rash and infusion reaction (OR, 43.86; 95%CI, 12.46–154.44; p=0.000; OR, 3.69; 95%CI, 1.89–7.25; p=0.000; respectively).Conclusion: Our data showed that the addition of cetuximab to chemotherapy would improve overall survival and overall response rate. It may provide new option for clinical treatment for untreated advanced non-small-cell lung cancer. The side effects of E-chemo are predictable and manageable.

Human umbilical cord matrix-derived stem cells expressing interferon-β gene significantly attenuate bronchioloalveolar carcinoma xenografts in SCID mice - Corrected Proof

2010-02-08

Abstract: Mesenchymal stem cells derived from the human umbilical cord matrix (hUCMSCs) have great potential for therapeutic use for multiple diseases. The strategy that uses therapeutic gene-transfected hUCMSCs as cellular vehicles for targeted biologic agent delivery has solved the problem of short half-life or excessive toxicity of biological agent(s) in vivo. Interferon-β (IFN-β) has demonstrated a potent antitumor effect on many types of cancer cell lines in vivo. The aim of this study was to determine the anti-cancer effect of IFN-β gene-transfected hUCMSCs (IFN-β-hUCMSCs) on cells derived from bronchioloalveolar carcinoma, a subset of lung adenocarcinoma that is difficult to treat. The co-culture of a small number of IFN-β-hUCMSCs with the human bronchioloalveolar carcinoma cell lines H358 or SW1573 significantly inhibited growth of both types of carcinoma cell lines. The culture medium conditioned by these cells also significantly attenuated the growth of both carcinoma cells, but this attenuation was abolished by adding anti-IFN-β antibody. Finally, systemic administration of IFN-β-hUCMSCs through the tail vein markedly attenuated growth of orthotopic H358 bronchioloalveolar carcinoma xenografts in SCID mice by increasing apoptosis. These results clearly indicate that IFN-β-hUCMSCs caused cell death of bronchioloalveolar carcinoma cells through IFN-β production, thereby attenuating tumor growth in vivo. These results indicate that IFN-β-hUCMSCs are a powerful anti-cancer cytotherapeutic tool for bronchioloalveolar carcinoma.

Belotecan for relapsing small-cell lung cancer patients initially treated with an irinotecan-containing chemotherapy: A phase II trial - Corrected Proof

2010-02-08

Abstract: Background: Belotecan is a topoisomerase I inhibitor. This phase II trial was conducted to evaluate the efficacy and toxicity of belotecan in relapsing small-cell lung cancer (SCLC) patients after irinotecan failure.Patients and methods: SCLC patients, who had relapsed at least 3 months after achieving objective response to irinotecan plus platinum chemotherapy, were eligible. Belotecan was administered at a dose of 0.5mg/m2/day for 5 consecutive days every 3 weeks.Results: Twenty-seven patients were enrolled in this study. Twenty-five patients were evaluated for response, and 27 patients were evaluated for toxicity and survival. The overall response rate was 22%. The median time to progression was 4.7 months (95% CI, 3.6–5.8 months), and the median overall survival was 13.1 months (95% CI, 10.4–15.8 months). The most frequent grade 3/4 toxicities were neutropenia (93%) and thrombocytopenia (48%). There was one treatment-related death due to pneumonia.Conclusion: Belotecan showed modest activity and manageable toxicities in relapsing SCLC patients in this study which was conducted in Asia. But further study in Caucasian patients is needed.

Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of lung cancer - Corrected Proof

2010-02-08

Abstract: Purpose: We performed this study to evaluate the role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the pathologic diagnosis of lung cancer including lung masses as well as lymph nodes as targets.Methods: We retrospectively reviewed 126 patients who underwent EBUS-TBNA to diagnose radiologically suspected lung cancer. The patients had masses or lymph nodes that were highly suspicious for malignancy and accessible by EBUS-TBNA.Results: EBUS-TBNA was performed on 195 lesions (lymph nodes, n=151; lung masses, n=44). In 61 cases, other diagnostic methods had failed previous to EBUS-TBNA. In 118 patients, no definite endobronchial mucosal tumor invasion was observed. In eight patients with endobronchial tumor invasion, EBUS-TBNA was chosen due to tumor bleeding, necrosis, or difficult location for endobronchial biopsy. EBUS-TBNA confirmed 105 lung cancers, five other malignancies and six specific benign cases, demonstrating a diagnostic yield of 92.1% (116/126). Nine cases were diagnosed by other methods (lung cancer, n=2; other malignancies, n=2; benign cases, n=5). One case that was not confirmed by any diagnostic method was considered false negative. The sensitivity and diagnostic accuracy of EBUS-TBNA in the diagnosis of lung cancer were 97.2% (105/108) and 97.6% (123/126), respectively.Conclusions: EBUS-TBNA targeting lymph nodes or masses highly suspicious for malignancy demonstrated high diagnostic value in the diagnosis of lung cancer. EBUS-TBNA is recommended for these cases, especially when other diagnostic methods have failed or are difficult.

Diminished lipocalin-type prostaglandin D2 synthase expression in human lung tumors - Corrected Proof

Louis Ragolia, Thomas Palaia, Christopher E. Hall, Jonathan Klein, Arzu Büyük — 2010-02-08

Abstract: Previously, we demonstrated that lipocalin-type prostaglandin D2 synthase (L-PGDS) induces apoptosis and prevents cell cycle progression in several cell types. In this study we determined the expression of L-PGDS in a variety of human lung tumor types. While L-PGDS expression was evident in the surrounding margins, we observed significantly decreased protein and gene expression in the tumor tissue. Using RT-PCR we demonstrated that L-PGDS gene expression decreased proportionately with tumor progression. In addition, we demonstrated that exogenously added L-PGDS could suppress the hyperproliferation and PDGF-stimulated migration of A549 cells, a cultured carcinomic human alveolar basal epithelial cell line. We conclude that L-PGDS may play a key role in modulating lung cancer growth and may offer a novel diagnostic and therapeutic approach for treatment.

Large cell/neuroendocrine carcinoma - Corrected Proof

Russell Gollard, Sejal Jhatakia, Max Elliott, Michael Kosty — 2010-02-05

Abstract: Large cell neuroendocrine tumors of the lung represent a recently reclassified subtype of lung cancer with features of both small cell and non-small cell lung cancer. We review diagnostic difficulties, typical presentations, and the natural history of this tumor. We review treatment data, and suggest that as in more common types of lung cancer, multi-modality therapy may be the most promising course of treatment.

The trajectory of lung cancer patients in Western Australia—A data linkage study: Still a grim tale - Corrected Proof

Moyez Jiwa, Eric Maujean, Katrina Spilsbury, Tim Threlfal — 2010-02-03

Abstract: Objective: To plot the trajectory of lung cancer patients by linking multiple data sources in Western Australia.Design: Database survey, data linkage and postal survey.Setting: Western Australia.Participants: Lung cancer patients registered on the cancer registry database of Western Australia, April 2006 to March 2007.Main outcome measures: Morbidity, mortality, and medical procedures.Results: 950 lung cancer patients were registered on the cancer registry database from April 2006 to March 2007. Sixty five percent were male with a mean age at diagnosis of 70 years (SD 11 years). Approximately 30% were from regional and remote areas of Western Australia. 76% reported a history of smoking, with a mean of 41 pack-years per smoker. One in four cases had metastases at diagnosis. 18% of cases from a tertiary hospital received no active treatment. The median time from the first visit to GP with recognized cancer symptoms until consultation with a specialist was 2 weeks. One in five cases presented directly to the hospital Emergency Department. For 16% of all cases, no symptoms were recorded in the hospital administrative records at the time of presentation. Fifty-two percent of patients had chemotherapy, 49% received radiotherapy and 21% had surgery. 13% of treated patients were readmitted to hospital with complications of therapy. Median survival was 33 weeks (95% CI 30–40).Conclusion: Data linkage offers limited prospects for exploring the trajectory of patients with lung cancer in Western Australia. The available data indicate that the prognosis of lung cancer remains very poor and that a high proportion of patients are still diagnosed with advanced disease. There is no evidence to suggest that a greater proportion of patients are being offered surgical treatment compared to more than a decade ago. However a greater proportion of cases now receive adjuvant therapies and overall median survival has improved by a matter of weeks.

Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations - Corrected Proof

2010-02-01

Abstract: The activation status of signal transduction pathways involving receptor tyrosine kinases and its association with EGFR or KRAS mutations have been widely studied using cancer cell lines, although it is still uncertain in primary tumors.To study the activation status of main components of growth factor-induced pathways, phosphorylated Akt (pAkt), extracellular signal-regulated kinases 1 and 2 (pERK) and other downstream proteins were immunohistochemically examined using surgical samples of 193 primary lung adenocarcinomas. Also, thyroid transcription factor-1 (TTF-1) expression and mutation status of EGFR and KRAS were examined.Advanced tumor stages (p<0.001), negative TTF-1 expression (p<0.001) and Akt activation (p=0.015) were independent and significant poor prognostic markers. Akt activation related to advanced stage (p=0.021), invasiveness (p=0.004), and not to mutations. TTF-1 expression associated with never-smoker (p=0.013), pre- or minimally invasiveness (p<0.001) and EGFR mutations (p=0.017) as well as with pERK (p=0.039) expression. EGFR mutations did not correlated with pAkt and pERK expression, which was different from the results based on cultured cells, while KRAS mutations were solely and significantly linked to ERK activation (p=0.009).In lung adenocarcinoma, tumors with TTF-1 expression have distinct characteristics regarding mutations, signal protein activation and clinical issues. Moreover, this property was revealed to be important in outcome estimation at any tumor stage, whereas Akt activation is abnormally affected according to the tumor stage regardless of their cell origin. The signal proteins were differently related to mutation status from cultured cells.

Cystic fibrosis transmembrane conductance regulator gene mutation and lung cancer risk - Corrected Proof

2010-02-01

Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) holds an important role in retaining lung function, but its association with lung cancer is unclear. A case-control study was conducted to determine the possible associations of the genetic variants in the CFTR gene with lung cancer risk. Genotypes of the most common deletion ΔF508, one functional SNP, and eight tag SNPs in the CFTR gene were determined in 574 lung cancer patients and 679 controls. A logistic regression model, adjusting for known risk factors, was used to evaluate the association of each variant with lung cancer risk, as confirmation haplotype and sub-haplotype analyses were performed. ΔF508 deletion and genotypes with minor alleles in one tag SNP, rs10487372, and one functional SNP, rs213950, were inversely associated with lung cancer risk. The results of haplotype and sub-haplotype analyses were consistent with single variant analysis, all pointing to deletion ΔF508 being the key variant for significant haplotypes and sub-haplotypes. Individuals with ‘deletion-T’ (ΔF508/rs10487372) haplotype had a 68% reduced risk for lung cancer compared to common haplotype ‘no-deletion-C’ (OR=0.32; 95% CI=0.15–0.68; p=0.01). Genetic variations in the CFTR gene might modulate the risk of lung cancer. This study, for the first time, provides evidence of a protective role of the CFTR deletion carrier in the etiology of lung cancer.

Chemoprevention of murine lung cancer by gefitinib in combination with prostacyclin synthase overexpression - Corrected Proof

2010-01-29

Abstract: Introduction: We hypothesized that the combination of the EGFR tyrosine kinase inhibitor (TKI) gefitinib with the powerful chemopreventive manipulation of lung-specific transgenic prostacyclin synthase (PGIS) overexpression on tumorigenesis in FVB/N mice would result in augmented chemoprevention.Materials and methods: Wildtype and littermate PGIS overexpressors (OE) were given urethane, 1mg/kg i.p. followed by thrice weekly i.p. injections of gefitinib, 50mg/kg or 100mg/kg, or vehicle. Pulmonary adenomas were enumerated and measured.Results: Gefitinib at either 50mg/kg or 100mg/kg administered i.p. three times weekly was effective in inhibiting EGF induced EGFR tyrosine phosphorylation and downstream signaling. The PGIS overexpressors showed significant decreases in tumor multiplicity consistent with prior studies. Gefitinib had no effect on tumor multiplicity or volume in wildtype mice. Among the PGIS overexpressors, a significant reduction in tumor multiplicity was shown in the 50mg/kg, but not the 100mg/kg, gefitinib treatment group vs. vehicle control animals (1.13±0.29 vs. 2.29±0.32 tumors/mouse, p=0.015). We examined the phosphorylation status in selected downstream effectors of EGFR (Erk, Akt, Src, PTEN). The major difference in the 50mg/kg vs. 100mg/kg group was an increase in p-Src in the PGIS OE mice receiving the higher dose.Conclusion: We conclude that gefitinib alone has no chemopreventive efficacy in this model; it augmented the effect of PGIS overexpression at 50mg/kg but not 100mg/kg. Increased p-Src is correlated with loss of efficacy at the higher dose, suggesting the potential for combined EGFR and Src inhibition strategies in chemoprevention.

Pemetrexed and cisplatin with concurrent radiotherapy for locally advanced non-small cell and limited disease small cell lung cancer: Results from 2 phase I studies - Corrected Proof

2010-01-25

Abstract: Background: The objectives were to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent radiotherapy. Secondary objectives include incidence and nature of acute and late toxicities, tumor response and overall survival.Patients and methods: Treatment naïve patients received 1 cycle of cisplatin 80mg/m2 in study I (stage III NSCLC), 75mg/m2 in study II (LD-SCLC) and pemetrexed 500mg/m2 before the phase I part. In study I, patients were treated in cohorts with escalating cisplatin doses (60–80mg/m2), pemetrexed doses (400–500mg/m2) and concurrent escalating radiotherapy doses (66Gy in 33–27 fractions). In study II, patients were treated with cisplatin 75mg/m2 and escalating pemetrexed doses (400–500mg/m2) with concurrent escalating radiotherapy doses (50–62Gy).Results: The trials closed prematurely: study I because of poor accrual, study II because of sponsor decision. Thirteen patients were treated: 4 with NSCLC, 9 with LD-SCLC. No dose-limiting toxicity was observed. There was no grade 4 toxicity, grade 3 hematological toxicity was mild. One patient developed grade 3 acute esophagitis, but was able to complete radiotherapy without delay. Two patients experienced grade 2 late pulmonary toxicity, 1 complete response, 6 partial responses and 1 progressive disease were observed.Conclusions: Although the studies stopped too early to assess MTD, we have demonstrated that the combination of cisplatin and pemetrexed with concurrent radiotherapy up to 66Gy (33×2Gy) is well tolerated and this new combination shows activity in NSCLC. Pemetrexed is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent radiotherapy.

A phase II study of pemetrexed and carboplatin as a salvage therapy for platinum-pretreated patients with non-small cell lung cancer - Corrected Proof

2010-01-22

Abstract: Background: Although platinum-based doublet chemotherapy is considered as standard of care for patients with advanced non-small cell lung cancer (NSCLC), most of them are eventually supposed to experience disease progression. Pemetrexed, docetaxel, erlotinib, and gefitinib have been shown to be active as monotherapy for pretreated patients. In this study, the efficacy of pemetrexed and carboplatin as a salvage therapy for patients with advanced NSCLC is evaluated.Patients and methods: From March 2007 to February 2009, 32 patients who were diagnosed with inoperable NSCLC and treated with one or more prior cisplatin-based chemotherapies were enrolled. Treatment consisted of pemetrexed 500mg/m2 over a 10-min intravenous infusion and carboplatin at an AUC 5mg/mL/min over a 30-min intravenous infusion on Day 1 of a 21-day cycle. All patients were supplemented with folic acid and vitamin B12 to reduce the hematological toxicity of pemetrexed.Results: There were one (3.1%) complete response and five partial (15.6%) responses. The overall response rate was 18.8% and the median response duration was 4.4 months. Among the responders, four patients had adenocarcinoma and two had squamous cell carcinoma. Nine patients had stable disease, and the disease control rate was 46.9%. With a median follow up duration of 9.4 months, the median time to progression was 2.3 months and the median OS was 9.4 months. Seven patients (21.9%) experienced grade 3 and 4 hematologic toxicities; one anemia (3.1%), six neutropenia (18.8%), and six thrombocytopenia (18.8%). Two patients experienced grade 4 febrile neutropenia with infection. Four patients (12.5%) experienced grade 3 non-hematologic toxicities; four asthenia (12.5%), two anorexia (6.3%), and one stomatitis (3.1%). Grade 1–2 peripheral neuropathy developed in 13 patients (40.6%).Conclusion: The combination of pemetrexed and carboplatin showed favorable toxicity profiles and activity in the pretreated patients with advanced NSCLC. It is suggested that this regimen can be a good chemotherapeutic option as a salvage therapy for patients with NSCLC.

New strategies to overcome limitations of reversible EGFR tyrosine kinase inhibitor therapy in non-small cell lung cancer - Corrected Proof

Robert C. Doebele, Ana B. Oton, Nir Peled, D. Ross Camidge, Paul A. Bunn — 2010-01-21

Abstract: The epidermal growth factor receptor (EGFR), a member of the HER family of receptors, has become a well-established target for the treatment of patients with non-small cell lung cancer (NSCLC). Several EGFR-targeted agents produce objective responses in a minority of unselected patients, but a majority of those with EGFR-activating mutations; however, all responders eventually develop resistance. The modest activity of agents that target only EGFR may be due, in part, to the complexity and interdependency of HER family signaling. The interdependent signaling that occurs between EGFR and HER2 provides a rationale for the simultaneous inhibition of these receptors with reversible and irreversible inhibitors. Several agents with activity against both EGFR and HER2 are currently under development. Irreversible EGFR/HER2 tyrosine kinase inhibitors (TKIs) (e.g., BIBW 2992, HKI-272) and pan-HER TKIs (e.g., PF00299804) comprise a novel class of agents in clinical development that may prevent and overcome inherent and acquired resistance to first-generation reversible EGFR TKIs. Other agents in development include the monoclonal antibody pertuzumab, and XL-647, which inhibits EGFR and HER2, as well as multiple vascular endothelial growth factor receptor family members. Here we briefly review the currently available EGFR-targeted agents, discuss the rationale for extending inhibition to other HER family members, weigh the merits of irreversible HER family inhibition, and summarize preclinical and clinical data with EGFR/HER2 and pan-HER inhibitors under clinical development.

Snail nuclear expression parallels higher malignancy potential in neuroendocrine lung tumors - Corrected Proof

J.A. Galván, M.V. González, G. Crespo, M.V. Folgueras, A. Astudillo — 2010-01-21

Abstract: Introduction: The aim of our study was to determine the integrity of the cell–cell adhesion E-cadherin–β-catenin complex in neuroendocrine lung tumors (NELTs) and the possible involvement of Snail in its deregulation.Methods: The studied series consisted of formalin-fixed-paraffin-embedded tissue samples from 70 patients diagnosed with NELT (2000–2006) including tumors of low malignacy potential (3 tumorlets, 33 typical carcinoids), intermediate malignancy potential (3 atypical carcinoids) and tumors of high malignancy potential (10 large cell neuroendocrine carcinomas—LCNEC and 21 small cell carcinoma—SCLC). E-cadherin, β-catenin and Snail expression were immunohistochemically evaluated and mRNA levels were assessed by Q-RT-PCR for E-cadherin and Snail.Results: Nuclear Snail signal was high in 46% tumors with the strongest level observed in high malignancy tumors. Furthermore, Snail levels correlated with tumor size, lymph node involvement and tobacco consumption. E-cadherin expression was downregulated in 24% cases and it was absent from the membrane in 31%, all of them cases of high malignancy potential. High E-cadherin levels and a membrane pattern were associated with tumor-free lymph node patients and inversely proportional to Snail protein expression. β-catenin levels were weak in 43% and absent from the membrane in 59% cases. Interestingly, among high malignancy potential tumors, β-catenin levels were significantly higher in LCNEC than in SCLC. The integrity of the E-cadherin–β-catenin complex was retained in 37% cases, most of them carcinoid tumors, and correlated with low Snail levels, low malignancy potential and free lymph nodes.Conclusion: Snail nuclear expression and loss of integrity of cell adhesion complex E-cadherin/β-catenin parallels higher malignancy potential in NELTs.

CD8+ T cells expressing IL-10 are associated with a favourable prognosis in lung cancer - Corrected Proof

2010-01-20

Abstract: The dual role of tumour-infiltrating macrophages and lymphocytes on nonsmall cell lung cancer (NSCLC) progression and prognosis may be due to the differential activity of their phenotypes. To investigate the impact of inflammatory cells on NSCLC, we first quantified the number of macrophages (CD68+) and lymphocytes (CD8+ and CD4+) and the percentage of CD8+ cells expressing IL-10 (CD8+/IL-10+) in tumour stroma and epithelium. Then, we evaluated the possible relationships between the numbers of these cells and the clinicopathological features and the overall survival of patients.Paraffin-embedded sections of surgical specimens from 64 patients who had undergone surgery for NSCLC were immunostained with antibodies directed against CD68, CD4, CD8 and IL-10.The percentage of CD8+/IL-10+ cells was higher in cancer stroma of patients with stage I NSCLC than in those with stages II, III, and IV. High percentages of stromal CD8+/IL-10+ cells were associated with longer overall patient survival. In contrast, the number of CD68+, CD8+ and CD4+ cells did not differ between stage I NSCLC and stages II, III, and IV.In conclusion, the survival advantage of patients with stage I NSCLC may be related to the anti-tumour activity of the CD8+/IL-10+ cell phenotype.

Estimation of an optimal chemotherapy utilisation rate for lung cancer: An evidence-based benchmark for cancer care - Corrected Proof

2010-01-18

Abstract: Background: Optimal chemotherapy utilisation rates can serve as benchmarks to assess the quality of cancer service delivery. This study aims to determine the optimal proportion of patients with lung cancer that should receive chemotherapy at least once during the course of their illness, based on the best available evidence.Methods: An optimal chemotherapy utilisation tree was constructed using indications for chemotherapy identified from evidence-based treatment guidelines. Data on the proportion of patient and tumour-related attributes for which chemotherapy was indicated were obtained and merged with the treatment indications to calculate an optimal chemotherapy utilisation rate. This optimal rate was compared with reported actual rates of chemotherapy utilisation.Results: Chemotherapy is recommended at least once in 73% of all patients with lung cancer (93% of small cell lung cancer (SCLC) patients and 69% of non-small cell lung cancer (NSCLC) patients). Comparison of these benchmark rates with international reported actual chemotherapy utilisation rates reveals under-utilisation of chemotherapy in all newly diagnosed lung cancer patients, regardless of histological type and stage, with the exception of stage I NSCLC.Conclusion: The optimal chemotherapy utilisation rate can serve as a feasible, evidence-based measure of the quality of cancer care. Chemotherapy may be under-utilised in the initial management of lung cancer.

Radiotherapy for lung cancer in the elderly - Corrected Proof

Neil Bayman, Nooreen Alam, Corinne Faivre-Finn — 2010-01-18

Abstract: Mortality from lung cancer is increasing in patients≥70 years. Radiotherapy has an important role in the treatment of lung cancer for this group. Despite this, there have been few elderly specific trials of radiotherapy in lung cancer and current treatment is often based on evidence extrapolated from studies treating younger patients. This review of the literature examines the impact of radiotherapy for the radical and palliative treatment of non-small-cell and small-cell lung cancer, on survival, treatment-related toxicity and quality of life in the elderly. We also comment on the need for validated, practical geriatric screening and assessment tools to help predict toxicity to treatment.

Lung cancer cell lines: Useless artifacts or invaluable tools for medical science? - Corrected Proof

Adi F. Gazdar, Boning Gao, John D. Minna — 2010-01-18

Abstract: Multiple cell lines (estimated at 300–400) have been established from human small cell (SCLC) and non-small cell lung cancers (NSCLC). These cell lines have been widely dispersed to and used by the scientific community worldwide, with over 8000 citations resulting from their study. However, there remains considerable skepticism on the part of the scientific community as to the validity of research resulting from their use. These questions center around the genomic instability of cultured cells, lack of differentiation of cultured cells and absence of stromal–vascular–inflammatory cell compartments. In this report we discuss the advantages and disadvantages of the use of cell lines, address the issues of instability and lack of differentiation. Perhaps the most important finding is that every important, recurrent genetic and epigenetic change including gene mutations, deletions, amplifications, translocations and methylation-induced gene silencing found in tumors has been identified in cell lines and vice versa. These “driver mutations” represented in cell lines offer opportunities for biological characterization and application to translational research. Another potential shortcoming of cell lines is the difficulty of studying multistage pathogenesis in vitro. To overcome this problem, we have developed cultures from central and peripheral airways that serve as models for the multistage pathogenesis of tumors arising in these two very different compartments. Finally the issue of cell line contamination must be addressed and safeguarded against. A full understanding of the advantages and shortcomings of cell lines is required for the investigator to derive the maximum benefit from their use.

Re-challenge chemotherapy for relapsed non-small-cell lung cancer - Corrected Proof

2010-01-13

Abstract: There has been no report about re-challenge chemotherapy (RC) consisting of the same regimen as first-line chemotherapy in non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the efficacy of RC as second-line chemotherapy in patients with relapsed NSCLC. We conducted a retrospective review of 28 consecutive NSCLC patients who were treated with RC and compared their clinical outcomes with those of 38 consecutive NSCLC patients who were treated with docetaxel (DOC) at our hospital between July 1992 and December 2003. The RC group consisted of 21 men and 7 women, with a median age of 62 years (range, 42–76 years). Most first-line regimens were platinum-based and the median administered course was 3 (range, 2–7). All patients had responded to the first-line chemotherapy and had performance status (PS) 1 at relapse. The median interval from the end of first-line chemotherapy to relapse was 5.0 months (range, 1.6–36.1 months). The overall response rate of RC was 29%. The median survival time from the beginning of RC was 17.0 months and the 1-year survival rate was 60%. RC led to a significantly better overall survival rate than DOC (p=0.0342). RC could be an active second-line regimen in patients with relapsed NSCLC who responded to first-line chemotherapy.

The efficacy of pemetrexed as a third- or fourth-line therapy and the significance of thymidylate synthase expression in patients with advanced non-small cell lung cancer - Corrected Proof

2010-01-11

Abstract: Background: Pemetrexed is one of the standard second-line therapies in advanced non-small cell lung cancer (NSCLC). Currently, there are no standard cytotoxic treatments beyond second-line therapy. We evaluated the efficacy and safety of pemetrexed as a salvage regimen in heavily pretreated NSCLC patients. We also analyzed thymidylate synthase (TS) expression in tumor tissues to determine whether TS expression is correlated with the clinical efficacy of pemetrexed.Methods: One hundred and ten NSCLC patients who received pemetrexed as third- or fourth-line therapy at the Samsung Medical Center between June 2006 and June 2008 were retrospectively reviewed. TS expression was analyzed by immunohistochemical staining in 55 NSCLC tissue specimens. The relationships between TS expression and clinicopathological factors were evaluated. Univariate and multivariate analyses were performed to define the predictive factors and prognostic significances.Results: The median age of patients in this study was 59 years (range: 24–84), 50.9% were men, and 27 (24.6%) were smokers or previous smokers. Sixty-five patients (59.1%) received pemetrexed as third-line treatment, and 95 (86.4%) had non-squamous cell carcinoma. Platinum-based chemotherapy (84.6%) was the most common first-line therapy, and EGFR TKIs [erlotinib (17.3%) or gefitinib (43.6%)] were a common second-line therapy. The median time from date of diagnosis to the date of the first pemetrexed treatment was 12.8 months (range: 1.8–62.2 months) and the median number of pemetrexed treatments was 4 (range 1–22). Eighteen patients achieved PR (16.3%), 41 patients SD (37.3%), and 43 patients PD (39.1%), with a disease control rate of 53.6%. The median follow-up duration was 16.1 months, the median progression-free survival (PFS) was 3.2 months (95% CI: 1.9–4.5 months), and the median overall survival (OS) was 11.6 months (95% CI: 9.0–14.1 months). Male gender was the only independent variable for poor PFS (HR=1.673, 95% CI: 1.103–2.535), with poor performance status (HR=2.454, 95% CI: 1.405–4.287) and history of smoking (HR=1.856, 95% CI: 1.087–3.168) being independent adverse factors for OS. Thirteen of 55 tumor tissues (23.6%) showed TS expression; however, there were no significant correlations between TS expression and the clinicopathological factors.Conclusion: Pemetrexed was suggested as a third- or fourth-line therapy due to its favorable efficacy and tolerable toxicity. Further studies are warranted to define the adequate sequence of salvage treatments, especially in patients with adenocarcinoma lung cancer.

Usefulness of melanoma antigen (MAGE) gene analysis in tissue samples from percutaneous needle aspiration biopsy of suspected lung cancer lesions - Corrected Proof

2010-01-11

Abstract: Background: As mortality from lung cancer is still very high, early detection prior to metastasis is important in clinical settings. We prospectively evaluated the clinical usefulness of a reverse transcription-nested polymerase chain reaction (RT-nested PCR) using melanoma antigen (MAGE) A1-6 genes with tissue samples obtained from the percutaneous needle aspiration (PCNA) biopsies used in the diagnosis of lung cancer.Methods: We enrolled 53 patients with suspected lung cancer based on CT scan (M:F, 39:14; mean age 61 years). A PCNA biopsy was performed twice and lung cancer was diagnosed by a pathological examination. The MAGE genes were analyzed using RT-nested PCR from tissue samples obtained from the PCNA biopsy of the lesion. We compared the results from the RT-nested PCR and the pathologic diagnosis. We also analyzed the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV).Results: Of the 53 patients, 39 were diagnosed with lung cancer. Six patients had tuberculosis and 8 were confirmed with chronic inflammation or benign lesion. Based on the RT-nested PCR examination, 41 of 53 patients were positive for the MAGE gene: 34 of 39 patients had lung cancer; 5 of 6 patients had tuberculosis; and 2 of 8 patients had chronic inflammation or benign lesion. The sensitivity, specificity, accuracy, PPV and NPV were 83%, 58%, 77%, 87% and 55%, respectively.Conclusion: MAGE gene analysis by RT-nested PCR may be a useful method for the diagnosis of lung cancer, but it is still limited in patients with tuberculosis.

The prognostic role of Bcl-2 mRNA expression in curatively resected non-small cell lung cancer (NSCLC) - Corrected Proof

2010-01-11

Abstract: Background: The effect of the apoptosis related gene Bcl-2 in the pathogenesis in NSCLC remains poorly investigated. Hence the aim of this study was to explore the potential role of Bcl-2 mRNA expression as a prognostic biomarker in patients with curatively resected NSCLC.Methods: 91 tumor and matching normal tissue samples from patients with NSCLC were analyzed using a quantitative real-time RT-PCR method. The relative Bcl-2 mRNA expression was measured using β-actin as a reference gene. 45 of the 91 patients had stage I tumors (49%), 19 had stage II (21%) and 27 had stage IIIa (30%). Squamous cell carcinoma was found in 43 patients (47%), adenocarcinoma in 33 (36%) and in large cell carcinoma in 15 (17%) of the patients.Results: Bcl-2 mRNA expression was detected in 83 (91%) of the investigated tumor samples and in 74 (81%) of the normal lung tissue. The median gene expression was 0.147 in tumor tissue and 0.144 in matching normal lung tissue (p=n.s., Wilcoxon Test). No associations were seen between the tumorous Bcl-2 mRNA expression levels and clinical or histopathologic parameters such as gender, tumor size, TNM stadium and grading, but with tumor histology and smoking. With a follow-up of 85.9 months, the median survival time was 59.7 months. Bcl-2 mRNA expression was significantly associated with patients prognosis (p=0.013, log-rank test). Multivariate regression analysis revealed Bcl-2 expression status and tumor stage as independent prognostic factor.Conclusions: Bcl-2 expression in NSCLC is not associated with the pathogenesis of this disease. Our data suggests that Bcl-2 mRNA expression plays a crucial role in the biological behavior of NSCLCs. Quantitation of Bcl-2 expression improves estimation of prognosis and appears to identify patients who will benefit from intensive adjuvant therapy.

The clinical significance of the tumor cell D2-40 immunoreactivity in non-small cell lung cancer - Corrected Proof

2010-01-11

Abstract: Background: A monoclonal antibody D2-40 has been widely used for tumor lymphangiogenesis and lymphatic vessel invasion (LVI) in human cancers. However, the clinical significance of the tumor cell D2-40 immunoreactivity has not been clearly understood.Patients and methods: We evaluated the tumor cell D2-40 immunoreactivity in non-small cell lung cancer (NSCLC). One hundred and forty-seven NSCLC patients were investigated. Immunohistochemistry using D2-40 was performed to evaluate the tumor cell D2-40 immunoreactivity, micro-lymphatic vessel density (Micro-LVD) and LVI. The intratumoral microvessels density (MVD) was evaluated by the CD34-immunostaining, and tumor proliferation was evaluated by the Ki-67-immunostaining.Results: The percentage of D2-40-positive tumor cells was significantly higher in squamous cell carcinomas than in adenocarcinomas (P<0.0001), and all D2-40-strong tumors were squamous cell carcinomas. The percentage of D2-40-strong tumors was significantly higher in moderately to poorly differentiated tumors than in well-differentiated tumors (P=0.0332). Furthermore, the Ki-67 proliferation index in D2-40-strong tumors was significantly the highest. However, the tumor cell D2-40 immunoreactivity was not associated with Micro-LVD, LVI, or MVD. Regarding the patient survival, the overall survival was significantly lower in patients with D2-40-strong tumors than in patients with D2-40-negative or D2-40-weak tumors (P=0.0005). Multivariate analyses also revealed the tumor cell D2-40 immunoreactivity to be a significant prognostic factor of poor prognosis for NSCLC patients (P=0.0007).Conclusion: The D2-40 immunostaining is useful to identify aggressive squamous cell carcinomas of the lung.

Prognostic significance of matrix metalloproteinase-1 levels in peripheral plasma and tumour tissues of lung cancer patients - Corrected Proof

2010-01-08

Abstract: Matrix metalloproteinase-1 (MMP-1) participates in a variety of physiological and pathological processes. We previously found that MMP-1 was one of the lung cancer-related proteins detectable in peripheral blood. To validate our preliminary observations and explore the clinical significance of MMP-1 for lung cancer further, we carried out the present study. The concentrations of MMP-1 in circulating plasma specimens of 170 lung cancer patients and 70 healthy individuals were measured by an enzyme-linked immunosorbance assay. The expression status of the MMP-1 in archival tissue samples from 122 lung cancer patients was examined by immunohistochemical analysis. The correlation between the MMP-1 levels and prognosis of the lung cancer patients was then assessed statistically. Protein levels of MMP-1 were considerably raised in the plasma from lung cancer patients relative to those in healthy controls. The high plasma MMP-1 levels were associated with advanced-stage of the disease and significantly lower overall survival rate of the patients. Coincidently, MMP-1 protein extraordinarily overexpressed in the tumour tissues of lung cancer; and the up-regulated MMP-1 was associated with the progression (including tumour size, staging and lymphatic invasion), especially with decreased survival rate of the patients. Statistic analysis revealed that MMP-1 protein levels had an independent influence on survival. MMP-1 levels were elevated in both tumour tissue and blood; the latter may serve as an independent predictor for survival of lung cancer patients. MMP-1 protein levels in plasma/serum thus represent a potential and clinically relevant biomarker for the prognosis of patients with lung cancers.

Stereotactic body radiotherapy using real-time tumor tracking in octogenarians with non-small cell lung cancer - Corrected Proof

2010-01-08

Abstract: As the incidence of stage I non-small cell lung cancer (NSCLC) increases among octogenarians and only selected patients are surgical candidates, an alternative treatment is necessary. This manuscript evaluates the overall survival, local tumor control rate, and treatment-related toxicity after stereotactic body radiotherapy (SBRT) in 38 octogenarians with stage I NSCLC. Treatment consisted of 45Gy (n=4) or 60Gy (n=25) in 3 fractions for patients with peripheral tumors. A risk adaptive schedule of 45–60Gy in 3–6 fractions was used for central (n=7) or large peripheral tumors (n=2).An overall survival rate of 65% at 1 year and 44% at 2 years was achieved in octogenarians after SBRT. The local tumor control rate was excellent (100% at 2 years) and no grade 4 or 5 treatment-related toxicity occurred. Despite the high incidence of comorbidity in these octogenarians (Charlson score ≥5 in 16% of patients), an approach that merely provides supportive care cannot always be justified. SBRT offers octogenarians with stage I NSCLC a good treatment alternative.

Second-line weekly paclitaxel in resistant or relapsed non-small cell lung cancer treated with docetaxel and carboplatin: A multi-center phase II study - Corrected Proof

2010-01-06

Abstract: We conducted a phase II trial to evaluate the safety and efficacy of weekly paclitaxel in patients with resistant or relapsed non-small cell lung cancer (NSCLC) treated with docetaxel and carboplatin. Thirty-two NSCLC patients at a median age of 58.0 years (range 33–75) were enrolled. The Eastern Cooperative Oncology Group performance status scores (0/1/2) were 18/9/5, respectively. The majority of patients had adenocarcinoma (84%) and stage IV disease (81%). The response rate for the first-line chemotherapy was 28%. Paclitaxel was administered at a dose of 80mg/m2 as an intravenous infusion 60min weekly for 6 consecutive weeks of an 8-week cycle. All patients were assessable for response and toxicity. The median number of cycles administered was two (range 1–8), and the overall response rate was 15.6%. The median survival time (MST) was 10.6 months (95% CI=8.2–12.5), while the 1-year survival rate was 37.5%, and the median progression-free survival was 4.9 months (95% CI=3.0–7.1). Hematological toxicities (grade 3 or 4) were observed in 15 patients (46.9%) with leukopenia, and in 4 (12.5%) with anemia. Non-hematological toxicity was generally mild, though grade 3 anorexia was observed in 3 patients (9.3%). No treatment-related deaths were observed. In conclusion, second-line weekly paclitaxel is effective in NSCLC patients treated with docetaxel plus carboplatin and is associated with a tolerable toxicity profile.

VeriStrat® classifier for survival and time to progression in non-small cell lung cancer (NSCLC) patients treated with erlotinib and bevacizumab - Corrected Proof

2009-12-28

Abstract: We applied an established and commercially available serum proteomic classifier for survival after treatment with erlotinib (VeriStrat®) in a blinded manner to pretreatment sera obtained from recurrent advanced NSCLC patients before treatment with the combination of erlotinib plus bevacizumab. We found that VeriStrat® could classify these patients into two groups with significantly better or worse outcomes and may enable rational selection of patients more likely to benefit from this costly and potentially toxic regimen.

Recent issues in first-line treatment of advanced non-small-cell lung cancer: Results of an International Expert Panel Meeting of the Italian Association of Thoracic Oncology - Corrected Proof

2009-12-25

Abstract: Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, randomized trials have recently demonstrated the efficacy of several new drugs (pemetrexed, bevacizumab, cetuximab, erlotinib, gefitinib) in this setting. Hence, the choice of optimal treatment is no longer limited to the different platinum-based doublets. In order to guide clinical management of patients with advanced NSCLC, assess the strengths and limitations of available evidence, and to suggest priorities for clinical research, the Italian Association of Thoracic Oncology organized an International Expert Panel Meeting on the first-line treatment of advanced NSCLC, which took place in Sperlonga (Italy) in May 2009. Experts recommended that every effort should be made to obtain adequate tumor tissue before initiating treatment. Tumor histology/cytology subtyping is now important for the correct choice of treatment. In particular, considering efficacy data obtained with pemetrexed and safety concerns with bevacizumab, a division between squamous and non-squamous tumors is necessary. Epidermal growth factor receptor (EGFR) mutation analysis, at present, is not recommended in all patients, but should be performed in subgroups of patients characterized by higher prevalence of sensitizing mutations (Asians, never smokers, women, adenocarcinoma). When a mutation is present, first-line treatment with single-agent EGFR tyrosine-kinase inhibitor may be considered. Finally, the potential benefit of maintenance treatment for patients without progression at the end of first-line should be carefully discussed with each patient. Although the number of treatment options for patients with advanced NSCLC has increased recently, their results remain modest and further research is mandatory.

KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: A meta-analysis of 22 studies - Corrected Proof

2009-12-23

Abstract: Epidemiologic studies have evaluated the association between KRAS mutations and resistance to the treatment of epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, results were inconclusive. To derive a more precise estimation of the relationship, we performed this meta-analysis. Systematic computerized searches of the PubMed and Medline databases (up to Jun 30, 2009) were performed. A total of 22 studies were included in the final meta-analysis, consisting of 1470 NSCLC patients, of whom 231 had KRAS mutations (16%). Current or former smokers had a higher frequency of KRAS mutations than never smokers (25% versus 6%; OR=4.36; P<0.01). Mutations were more common among adenocarcinoma than other histologies (26% versus 16%; OR=1.98; P<0.01). The objective response rate (ORR) of NSCLC patients with mutant KRAS was 3% (6/210), whereas the ORR of NSCLC patients with wild-type KRAS was 26% (287/1125). The overall pooled RR for ORR was 0.29 (95% CI: 0.18–0.47; P<0.01). Subgroup analyses were conducted on the basis of ethnicity and study treatment, all the results were not materially altered and did not draw different conclusions, indicating that our results were robust. In summary, this meta-analysis suggests that KRAS mutations may represent negative predictive biomarkers for tumor response in NSCLC patients treated with EGFR-TKIs. However, due to a mutually exclusive relationship between KRAS and EGFR mutation and no difference in survival between KRAS mutant/EGFR wild-type and KRAS wild-type/EGFR wild-type NSCLC, the clinical usefulness of KRAS mutation as a selection marker for EGFR-TKIs sensitivity in NSCLC is limited.

Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients - Corrected Proof

2009-12-18

Abstract: The presence of IL-17-positive cells is observed in a variety of inflammatory associated cancers and IL-17 has been found to be involved in angiogenesis. The aim of this study is to determine the prognostic significance of IL-17 in NSCLC patients and to examine the correlation between IL-17 expression and lymphatic vessel density in NSCLC tissues. The expression of IL-17 was measured by immunohistochemistry in 52 paraffin-embedded tissues with non-small cell lung cancer. The χ2 test was used to analyze the correlation between IL-17 expression and clinical parameters and lymphatic vessel density (LVD). The Kaplan–Meier method, univariate and multivariate regression analysis was used to analyze the correlation between IL-17 expression and overall survival and disease-free survival. High expression of IL-17 was observed in 25 of 52 lung cancer patients and was associated with smoking status, TNM stage, LVD, overall survival and disease-free survival. Univariate and multivariate analysis showed that IL-17 was an independent prognostic factor for overall survival and disease-free survival. Our results indicate that IL-17 may play a role in the metastasis of lung cancer by promoting lymphangiogenesis. IL-17 expression is an independent prognostic factor in both overall and disease-free survival in NSCLC.

Investigation and management of lung cancer in older adults - Corrected Proof

A.M. Higton, J. Monach, J. Congleton — 2009-12-17

Abstract: Background: The average age of patients with lung cancer is increasing, but there is little data of the management and outcomes of this common cancer in the elderly.Methods: Data were collected from our hospital lung cancer database, medical, radiology and pathology records, for all patients with a new diagnosis of lung cancer from Jan 2002 to Dec 2004. The investigation, treatment and outcomes of these patients were analysed, and the younger (<75 years old) and elderly (75 years+) populations were compared.Results: Data on 367 were analysed. Median age at diagnosis was 72 years and median survival was 5.2 months. Elderly patients were less likely to be fully investigated i.e. have histological confirmation (88.2% vs. 66.4%; p<0.001), stage recorded (88.6% vs. 78.1%; p=0.001) and performance status recorded (88.6% vs. 75.3%; p=0.003). They had poorer performance status. The older patients were less likely to receive active treatment (surgery 11.6% vs. 6.4%; p<0.001, chemotherapy or radiotherapy 50.9% vs. 26.2% p<0.001). Improved survival was independently associated with younger age (p<0.001), better performance status (p<0.001), early stage (p<0.001) and active treatment (p=0.005). Hazard ratios for death for poor PS vs. good PS was 1.88 (p<0.001), for late stage vs. early stage was 2.01 (p=0.011), for BSC vs. active treatment was 1.46 (p=0.005) and for 75 years+ patients vs. under 75 years was 1.36 (p=0.069). When comparing elderly with younger patients, median survival remained better in patients who were actively treated, had good PS and early stage (p<0.001).Conclusions: Elderly patients are less likely to be fully investigated and actively treated than younger patients with lung cancer. The causes of this difference are unclear but may include patient and clinicians’ more conservative approach in the elderly. Predictors of improved outcome are the same in older and younger populations, and the elderly derive a similar survival advantage if actively treated. These data show that elderly patients are managed differently to younger patients, though the clinical basis for this is not clear.Summary: Lung cancer is common in the older population and has a poor prognosis. We reviewed the investigation, treatment and survival of all patients with a new diagnosis of lung cancer over a three-year period. We compared the management of our younger (under 75 years) population with those aged 75 years or older. In our population, people over 75 years with lung cancer are less completely investigated. They were less likely to have full staging investigations, a histological or cytological diagnosis, or have their performance status recorded. Our over 75-year olds are less likely to receive active treatment (chemotherapy, radiotherapy or surgery) for lung cancer. Our older patients who received active treatment for lung cancer had similar survival advantages to younger patients.

PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers - Corrected Proof

2009-12-17

Abstract: Somatic mutations of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in non-small cell lung cancers (NSCLCs) have been investigated in but a small number of cases. In addition, the relationship between PTEN mutations and epidermal growth factor receptor (EGFR), KRAS, and TP53 mutations has not been investigated. Therefore, we investigated the frequency of PTEN mutations in 176 surgically resected NSCLCs and analyzed the relationship between PTEN mutations and EGFR, ERBB2, KRAS, and TP53 mutations. Mutations of PTEN (exons 1–9), EGFR (exons 18–21), ERBB2 (exons 19 and 20), KRAS (exon 1), and TP53 (exons 2–11) were determined by polymerase chain reaction and direct sequencing. PTEN mutations were present in 8 (4.5%) of the 176 tumors. PTEN mutations were only found in ever-smokers and were significantly more frequent in squamous cell carcinoma than in adenocarcinoma (10.2% vs 1.7%, P=0.02). Mutations of EGFR, ERBB2, KRAS, and TP53 genes were found in 36 (20.5%), 2 (1.1%), 11 (6.3%), and 66 (37.5%) cases, respectively. Of the 8 tumors with PTEN mutations, 1 case concurrently had an EGFR mutation and 4 cases had TP53 mutations. However, PTEN mutations were not found in the tumors with KRAS mutation. Our findings indicate that PTEN mutations are relatively common in NSCLC, and thus analysis of PTEN mutations may facilitate a comprehensive understanding of the genetic alterations related to the EGFR signaling pathway.