Lung Cancer - Articles in Press

Haplotypes of estrogen receptor-beta and risk of non-small cell lung cancer in women - Corrected Proof

2010-07-26

Abstract: Epidemiologic and biologic evidence suggests that lung cancer has different clinical and biological characteristics in women, and that estrogen may contribute to the pathogenesis of non-small cell lung cancer (NSCLC). We investigated whether germline variation in the estrogen receptor-beta gene (ESR2) is associated with lung cancer risk among 1021 female cases and 826 female controls enrolled in the Lung Cancer Susceptibility Study at the Massachusetts General Hospital from 1992 to 2004. Four haplotype-tagging polymorphisms (htSNPs) (rs3020450, rs1256031, rs1256049, rs4986938) captured the common genetic variation across the ESR2 locus from a set of markers culled from healthy controls from a public database and sequencing the coding regions of 95 breast cancer cases. Using the expectation-maximization algorithm, five common haplotypes were resolved (CCGC (43%), TCAT (287%), TCAC (11%), CCAC (9%) and CCAT (6%)). Multivariate logistic regression was used to estimate adjusted odds ratios (OR) and their 95% confidence intervals (95% CI) for individual htSNPs and haplotype scores. Neither the four individual htSNPs nor their resolved haplotypes were associated with lung cancer risk in the entire population, nor in strata defined by parity (yes versus no), age (<50 years versus ≥50 years) or smoking history (current-, former-, never-smokers). Our findings indicate that ESR2 is not associated with risk of lung cancer in women.

A different TRAP220 expression in distinct histologic subtypes of lung adenocarcinoma and the prognostic significance - Corrected Proof

2010-07-23

Abstract: Adenocarcinomas are a very heterogeneous subgroup of lung cancers, in which oncogenesis is linked to different molecular events. Recent evidence suggests that the hormonal status may contribute to the pathogenesis of lung adenocarcinoma. TRAP220 is the main subunit of the TRAP/Mediator complex and it binds to nuclear hormone receptors in the presence of their cognate ligand, as a cofactor of the transcription machinery. Since TRAP220 is an essential coactivator that interacts directly with estrogen receptor β (ERβ), we examined the expression of TRAP220 protein to investigate its role in lung adenocarcinoma, with particular attention being paid to its different histologic subtypes and the ERβ expression. We performed immunohistochemical detection of TRAP220 and ERβ protein in eighty-seven tissue samples from lung adenocarcinoma patients by using a tissue microarray, and Western blotting was then done to confirm the immunohistochemical observations. TRAP220 immunoreactivity was observed in 27 (31.0%) of the 87 adenocarcinoma cases. Analysis of the TRAP220 expression by Western blotting confirmed the immunohistochemical results. The TRAP220 expression was more frequently positive in the non-solid subtypes (bronchioloalveolar, acinar, and papillary patterns) than that in the solid subtype (P=0.027) and the TRAP220 expression was more frequently positive in the well-differentiated adenocarcinomas than that in the moderately or poorly differentiated adenocarcinomas (P=0.005). The tumors with a negative TRAP220 expression were larger in size (P=0.048) and they more frequently showed lymph node metastasis (P=0.002), pleural invasion (P=0.026) and an advanced TNM stage (P=0.012). The frequency of the TRAP220 expression in the cases with an ERβ expression was significantly higher than that in those cases without an ERβ expression (P=0.003). The Kaplan–Meier survival curves demonstrated that the patients with a positive TRAP220 expression had a significantly longer survival time than those patients with a negative TRAP220 expression (P=0.014). The multivariate analysis revealed that a TRAP220 expression was an independent good prognostic factor (P=0.049). Our data may be useful to understand the different biologic basis for the development and progression of the subtypes of lung adenocarcinoma.

Geminin expression in small lung adenocarcinomas: Implication of prognostic significance - Corrected Proof

2010-07-22

Abstract: Geminin is an important molecule which plays a role in cell cycle regulation, and this has been considered to be a useful biomarker of cell proliferation. The purpose of this study was to evaluate the pathological and prognostic significance of geminin expression in small lung adenocarcinoma (AC). We performed Western blot analysis of five human lung AC cell lines and immunohistochemistry on 100 surgically resected specimens of lung AC with a diameter less than 3cm. We counted the number of positively stained tumor cells, and calculated the labeling indices (LIs). Geminin proteins were variably detected in all five cell lines examined on Western blotting. The mean LIs for geminin, Ki-67, and MCM7 were 7.5%, 12.3%, and 18.5%, respectively. The geminin LIs were associated with some clinicopathological profiles including gender, histological grade, subtypes, N-status, p-factor, and tumor stage. A significantly worse prognosis was noted in the higher geminin LIs group than in the lower group (p<0.01). Multivariate Cox regression analysis also confirmed that geminin LIs was an independent prognostic marker in stage IA lung AC patients. These results suggest that geminin is overexpressed in small lung ACs, and geminin LIs might be a useful prognostic indicator in patients with lung AC.

Up-regulation of cytochrome P450 and phase II enzyme systems in rat precision-cut rat lung slices by the intact glucosinolates, glucoraphanin and glucoerucin - Corrected Proof

2010-07-20

Abstract: It is believed that the chemopreventive activity of cruciferous vegetables in the lung and other tissues is exclusively the result of exposure to degradation products of glucosinolates, such as the isothiocyanates, and that the parent glucosinolates make no contribution. In the present study, evidence is presented for the first time that, in rat lung, the intact glucosinolates, glucoraphanin and glucoerucin, can modulate carcinogen-metabolising enzyme systems. The glucosinolates were isolated from cruciferous vegetables and incubated (1–25μM) with precision-cut rat lung slices for 24h. Both glucosinolates, at concentrations as low as 1μM, up-regulated the O-deethylation of ethoxyresorufin and the apoprotein levels of CYP1A1 and CYP1B1; supplementation of the incubation medium with myrosinase, the enzyme that converts glucosinolates to their corresponding isothiocyanates, abolished the rise in ethoxyresorufin O-deethylase activity. In contrast, neither glucosinolate, at the concentrations studied, influenced quinone reductase activity in the lung slices, but addition of myrosinase to the glucosinolate incubations led to a marked rise in activity. Glutathione S-transferase activity, monitored using 1-chloro-2,4-dinitrobenzene as the accepting substrate, was elevated in lung slices exposed to glucoraphanin. GSTα protein levels were increased by glucoraphanin and, to a much lesser extent, glucoerucin. It may be concluded that intact glucosinolates can modulate the activity of pulmonary carcinogen-metabolising enzyme systems, and can thus contribute to the documented chemopreventive activity of cruciferous vegetables in the lung.

Tumor histology affects the accuracy of clinical evaluative staging in primary lung cancer - Corrected Proof

2010-07-12

Abstract: Objective: Pathological examination of lung cancer often reveals a more advanced stage than clinical stage. The objective of this study was to evaluate whether the association between clinical and pathologic stages depends on tumor histology.Methods: This retrospective study enrolled patients who had undergone major lung resections and systemic lymph node dissections (1990–2004). In total, 483 patients had adenocarcinoma and 225 had squamous cell carcinoma.Results: Clinical and pathologic N-status were significantly different in patients with adenocarcinoma (p<0.0001) but not in those with squamous cell carcinoma. Patients with adenocarcinoma were more likely to be upstaged from clinical N0 disease to pathologic N2 disease than those with squamous cell carcinoma (p=0.04). Of those patients with adenocarcinoma, surgical procedure, clinical N-status, metastatic pathologic N2 stations and curability were significant prognostic factors. It is of interest, however, that a similar statistically significant difference could not be shown in patients with squamous cell carcinoma. Furthermore, multivariate analysis demonstrated that clinically detectable N2 disease and multiple pathologic N2 stations significantly affected the poorer prognosis in adenocarcinoma. Adenocarcinoma patients with clinically undetectable N2 disease had significantly better 5-year survival than those with clinically detectable N2 disease (p<0.0001), although this was not the case for patients with squamous cell carcinoma (p=0.81).Conclusion: In adenocarcinoma patients with pathologic N2 disease, clinical N-status and metastatic pathologic N2 stations were significant prognostic factors. A similar difference was not found in patients with squamous cell carcinoma. Adenocarcinoma and squamous cell carcinoma appear to have different tendencies for lymph node metastasis.

Prognostic significance of expression of eukaryotic initiation factor 4E and 4E binding protein 1 in patients with pathological stage I invasive lung adenocarcinoma - Corrected Proof

2010-07-12

Summary: Background: Both eukaryotic initiation factor 4E (eIF4E) and eIF4E binding protein 1 (4E-BP1) are involved in the malignant progression of human cancers. However, the role of eIF4E and 4E-BP1 expression as prognostic markers has not been evaluated concurrently in any human cancers.Methods: The expression of eIF4E and 4E-BP1 was semiquantitatively examined with immunohistochemical staining in 80 patients with pathological stage I invasive lung adenocarcinoma.Results: The 10-year survival rate was significantly lower for patients with high eIF4E expression (64.0% [n=36]) than for patients with low eIF4E expression (89.9% [n=44], P=0.024), and in patients with high eIF4E expression the 10-year survival rate was lower for patients with low 4E-BP1 expression (39.0% [n=12]) than for patients with high 4E-BP1 expression (85.2% [n=24], P=0.036). In patients with low eIF4E expression, the 10-year survival rate was lower for patients with low 4E-BP1 expression (87.6% [n=36]) than for patients with high 4E-BP1 expression (100% [n=8]), but statistical analysis was impossible because all patients with high 4E-BP1 expression were censored. Unfavorable prognostic factors for survival were age greater than 65 years (P=0.015), pathological stage IB disease (P=0.045), high eIF4E expression (P=0.008), and low 4E-BP1 expression (P=0.007).Conclusions: Both eIF4E and 4E-BP1 are potential new prognostic factors for survival and stratification in patients with pathological stage I lung adenocarcinoma. The eIF4E and 4E-BP1 status may provide a basis for individualized therapy.

Characteristics, treatment patterns and outcomes of patients with small cell lung cancer—A retrospective single institution analysis - Corrected Proof

Andreas Hermes, Benjamin Waschki, Ulrich Gatzemeier, Martin Reck — 2010-07-12

Abstract: Purpose: The aim of this retrospective study is to present data on patient characteristics, treatment patterns, and treatment results in an unselected contemporary patient population with small cell lung cancer (SCLC) in limited disease (LD) and extensive disease stage (ED).Patients and methods: From June 2004 to December 2008, our electronic database including all in-patient and out-patient contacts was searched for patients with newly diagnosed lung cancer. 397 patients were found having SCLC. We collected data on patient characteristics, chemotherapy, side effects, response on treatment and survival.Results: 39% of all patients had LD SCLC. Median age was 63 years. The response rate (RR) reached 76%. Stable disease was the result of first line therapy in 16%. Consecutive thoracic radiotherapy was given in 72%. Additional prophylactic cranial irradiation (PCI) was administered to 33%. 43% received second line therapy. Median survival was 18.8 months.In 61% of cases, ED SCLC was diagnosed. Median age was 61 years. Main metastatic sites were liver, bone, brain and adrenal glands. RR was 69%. Stable disease and progressive disease were the result of first line chemotherapy both in 12%. 15% received palliative cranial irradiation, 3% PCI. 51% were treated with second line therapy. Median survival reached 10.6 months.Conclusion: We provide a comprehensive analysis of a contemporary patient population. Treatment patterns and survival data fit well in the context of current international trials on more selected patients. Multivariate analyses confirmed extend of disease, performance status and LDH serum levels as independent prognostic factors for survival. Age and gender reached no statistical significance.

Antitumor activity of bortezomib in human cancer cells with acquired resistance to anti-epidermal growth factor receptor tyrosine kinase inhibitors - Corrected Proof

2010-07-12

Abstract: The understanding of the molecular mechanisms which regulate cancer cell sensitivity to epidermal growth factor receptor (EGFR) inhibitors is necessary for the optimal use of these drugs in cancer treatment. We developed an in vitro model of acquired resistance to two EGFR tyrosine kinase inhibitors (TKI), erlotinib and gefitinib, by continuously treating the human non-small cell lung cancer (NSCLC) cell line CALU-3 with escalating doses of each drug. In these two EGFR inhibitor-resistant cancer cell lines a significant increase in the expression of activated, phosphorylated AKT and of survivin compared to parental cells was observed. Treatment with several agents known to target directly or indirectly the AKT signalling pathway did not affect significantly EGFR inhibitor-resistant cancer cell proliferation. In contrast, bortezomib, a proteasome inhibitor, induced a significant inhibition of cancer cell growth and an increase in apoptosis in EGFR inhibitor-resistant cancer cells as compared to treatment with LY294002, a PI3K inhibitor, suggesting that, in addition to interference with AKT signalling, other mechanisms are involved in the pro-apoptotic effects of bortezomib. Bortezomib treatment activated endoplasmic reticulum (ER) stress-mediated apoptosis, as demonstrated by the induction of GADD153, an ER stress-inducible transcription factor, and of the death receptor DR5, in EGFR inhibitor-resistant cells, but not in parental cells. This effect resulted in the activation of the extrinsic apoptotic pathway, as shown by caspase 8 dependent-PARP and bid cleavage. Bortezomib significantly inhibited the growth of EGFR inhibitor-resistant CALU-3 cells which were established as subcutaneous tumor xenografts in athymic nude mice. These results suggest that bortezomib treatment could be a useful approach to overcome resistance to anti-EGFR therapies.

Contamination during 4 years of annual CT screening in the Danish Lung Cancer Screening Trial (DLCST) - Corrected Proof

2010-07-12

Abstract: Introduction: Contamination, defined as screening in the control arm, may dilute the statistical power of randomised screening trials. We investigated the rate of contamination in DLCST during 4 years of annual CT screening.Methods: DLCST is a randomised trial involving 4104 healthy current and ex smokers. 2052 subjects were randomised to annual low dose chest CT scans (CT group) and 2052 were given no intervention (control group). The study is performed in collaboration with the NELSON trial (Nederlands Leuvens Screening Onderzoek) and mortality data will be pooled at the end. We defined contamination as off study CT scan received for lung cancer screening purposes. Annually during the screening period, the participants were asked whether they had received a CT scan and if so the purpose. The causes were divided into the following categories: ‘Off study screening for lung cancer’, ‘Investigation of lung symptoms’, ‘Investigation of incidental finding on chest radiograph’, ‘Participation in other scientific trial involving chest CT’, and finally ‘Chest CT for other reasons’.Results: Response rates were high in both groups: 86.1% (control group), 93.6% (CT group) p<0.001.Control group: 199 out of 7065 answers (2.8%) indicating acquisition of a chest CT during 4 years of the trial. Three answers fulfilled the definition of contamination, while 8 received chest CT due to involvement in other scientific trials. 126 reported CT scans as part of investigation for other diseases, while 10 and 52 went through investigations for abnormal chest radiograph and lung symptoms, respectively.CT group: Significantly lower number of answers (n=134) indicated acquisition of an off study chest CT. None had received off study lung cancer screening. Three were involved in other scientific trials, while 17 and 115 went through investigation of lung symptoms and chest CT for other reasons, respectively.Conclusion: Although the frequency of off study chest CT was significantly higher in the control group, it was relatively small in both randomisation groups, and thus contamination seems to be modest and acceptable in the DLCST.Clinical Trial no.: Clinical Trials.gov Protocol Registration System (identification no. NCT00496977).

Definitive radiotherapy plus regional hyperthermia with or without chemotherapy for superior sulcus tumors: A 20-year, single center experience - Corrected Proof

2010-07-09

Abstract: Purpose: To assess the efficacy and toxicity of definitive radiotherapy (RT) plus regional hyperthermia (HT) in treating superior sulcus tumors (SSTs), and to identify predictors of positive outcomes.Methods and materials: Twenty-four patients with SSTs treated with definitive RT plus regional HT were retrospectively analyzed. The median total dose of RT was 70Gy. All patients were treated with an 8-MHz RF-capacitive heating device. Twelve of 24 (50%) patients also underwent chemotherapy. Those with either subcutaneous fat measuring 2.5cm or greater, or any other serious complications did not undergo this therapy.Results: Overall survival, local control, and distant metastasis-free survival rates at 3 years were 47%, 55%, and 71%, respectively. Chemotherapy and younger age (<65 years) were significant predictors of the overall survival rate. Clinical stage (IIB) was a statistically significant prognostic indicator for local control survival rate. Toxicities were mild, with Grade 3 dermatitis seen in one patient.Conclusions: Definitive RT plus regional HT with chemotherapy may be a promising treatment for SSTs. The results justify further evaluation with detailed treatment protocols in a large number of patients.

Occult mediastinal lymph node metastasis in NSCLC patients diagnosed as clinical N0-1 by preoperative integrated FDG-PET/CT and CT: Risk factors, pattern, and histopathological study - Corrected Proof

2010-07-09

Abstract: Background: Integrated F18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is widely used for mediastinal lymph node (MLN) staging in patients with non-small cell lung cancer (NSCLC). However, FDG-PET/CT has certain limitations. Prediction of occult MLN metastasis could allow selection of candidates for preoperative cervical mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration. This study defined risk factors for occult MLN metastasis in patients with NSCLC patients who were diagnosed as clinical N0-1 by preoperative integrated FDG-PET/CT and CT.Methods: Consecutive patients with NSCLC who underwent staging using integrated FDG-PET/CT as an adjunct to CT prior to lung resection from October 2006 to September 2009 were evaluated retrospectively. The prevalence of MLN metastasis in patients diagnosed as clinical N0-1 was analyzed according to clinicopathological factors such as tumor location, tumor size, histology, and FDG uptake by the primary tumor. Risk factors for occult MLN metastasis were defined by multivariate analysis. Patterns of occult MLN metastasis were also analyzed and the involved MLNs were further examined histopathologically.Results: The incidence of MLN metastasis was 11% (24 patients of 224). Multivariate analysis identified adenocarcinoma (P=0.04), tumors located in upper or middle lobe (P=0.02), tumor size >3cm (P=0.01), and SUVmax of primary tumor >4.0g/ml (P=0.04) as significant risk factors for MLN metastasis. The pattern of occult MLN metastasis was typical for NSCLC cases. The size of metastatic foci were small, with 68% of foci smaller than 4.0mm.Conclusions: The present study demonstrated that adenocarcinoma, tumors located in the upper or middle lobe, tumor size >3cm, and SUVmax of primary tumor >4.0g/ml are risk factors for occult MLN metastasis in patients with NSCLC who were diagnosed as clinical N0-1 by preoperative integrated FDG-PET/CT and CT. Patients with tumors located in the right upper or middle lobe are considered candidates for cervical mediastinoscopy because the involved metastatic mediastinal lymph nodes are easily accessible by these modalities.

Expression of estrogen receptor beta predicts a clinical response and longer progression-free survival after treatment with EGFR–TKI for adenocarcinoma of the lung - Corrected Proof

Naohiro Nose, Hidetaka Uramoto, Teruo Iwata, Takeshi Hanagiri, Kosei Yasumoto — 2010-07-09

Abstract: Purpose: Epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (EGFR–TKI) demonstrates a dramatic clinical response for the lung adenocarcinoma patients harboring a somatic mutation of EGFR. Such EGFR mutations are frequently found in adenocarcinoma with a strong expression of estrogen receptor (ER) beta, which has been shown to correlate with a favorable prognosis for the patients with EGFR mutations. The aim of this study is to elucidate the correlation between expression of ER beta and the therapeutic effect of EGFR–TKI in adenocarcinoma of the lung.Patients and methods: Forty-three patients who were treated with EGFR–TKI for adenocarcinoma of the lung were evaluated. The expression of ER beta and the EGFR mutation were evaluated by immunohistochemistry and the polymerase chain reaction, respectively. Patients divided into two groups by the nuclear expression of ER beta. The clinical response and survival data were compared between the two groups.Result: Strong (S) and weak (W) expression of ER beta was observed in 21 and 22 patients, respectively. EGFR mutations were detected in 30 (69.8%) cases. The S group had more frequent EGFR mutations than the W group (85.7%, 54.5%, p=0.045). The S group had better response rate (p=0.006) and longer progression-free survival (PFS; p=0.001) than the W group. Even in a limited analysis in the patients with EGFR mutations, the S group had tended to have a better response rate (77.8%, 41.7%, p=0.063), and significant longer PFS (p=0.012) than the W group.Conclusion: A strong expression of ER beta predicts a good clinical outcome for patients with adenocarcinoma of the lung after treatment with EGFR–TKI. This suggests that the expression status of ER beta can be a candidate surrogate marker for EGFR–TKI treatment of patients with adenocarcinoma of the lung. Further investigation will be necessary to identify biomarkers using a larger cohort of patients in a prospective study.

Local failure after complete resection of N0–1 non-small cell lung cancer - Corrected Proof

2010-07-08

Abstract: Purpose: To estimate the risk of local–regional failure (LRF) after surgery for operable NSCLC, and the effect of clinical/pathologic factors on this risk.Methods: Records of 335 patients undergoing complete resection (lobectomy, pneumonectomy) for pathological T1–4 N0–1 NSCLC (without post-operative radiation) from 1996 to 2006 were reviewed. Crude and actuarial estimated failure rates were computed; local–regional sites included ipsilateral lung, surgical stump, hilar, mediastinal, or supraclavicular nodes. Failure times in sub-groups were calculated with the Kaplan-Meier method and compared via log-rank test. Independent factors adversely affecting LRF were determined with Cox regression.Results: The median follow-up duration for event-free surviving patients was 40 months (range: 1–150). The crude and actuarial 5-year probability of any failure (LR or distant) were 33% and 43%, respectively. Of all failures; 37% were LR only, 35% LR and distant and 28% distant only. The 5-year crude and actuarial probability of LRF were 24% and 35% (95% CI: 29–42%). Five-year crude LRF rates for T1–2N0, T1–2N1, T3–4N0 and T3–4N1 disease were 19% (41/216), 27% (16/59), 37.5% (15/40) and 40% (8/20), respectively. The corresponding actuarial estimates were T1–2N0 28%, T1–2N1 39%, T3–4N0 50% and T3–4N1 67%. In Cox multiple regression analysis, lymphovascular space invasion (p=0.03, HR: 1.7) and tumor size (p=0.01, HR: 1.67 for 5cm increment) were associated with an increased risk of LRF.Conclusion: Five-year LRF rates are ≥19% in essentially all patient subsets.

Predictors of skeletal-related events in non-small cell lung cancer patients with bone metastases - Corrected Proof

2010-07-05

Abstract: Background: Skeletal-related events (SREs) cause significant pain and morbidity to many non-small cell lung cancer (NSCLC) patients. We try to evaluate the predictive factor of SREs in NSCLC patients with bone metastases.Patients and methods: We retrospectively examined the medical charts of 273 patients diagnosed with bone metastases secondary to NSCLC. The predictive factor of SREs was analyzed using the first-event analyses and a survival-adjusted multiple-event analysis.Results: Out of 273 patients with bone metastases, 171 (62.6%) had at least one SRE and 46 of these experienced multiple SREs. In the first-event analyses, a larger proportion of ever-smokers have experienced the SRE compared with never-smokers (odds ratio, 2.80; 95% CI, 1.32–6.00). In addition, ever-smokers (hazard ratio [HR], 1.75; 95% CI, 1.05–2.92), patients without history of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) therapy (HR, 2.12; 95% CI, 1.49–3.00) and patients with histology of nonadenocarcinoma (HR, 1.59; 95% CI, 1.14–2.22) had a shorter median time from bone metastasis to first SRE. In a survival-adjusted multiple-event analysis, clinical characteristics such as ever-smoking, nonadenocarcinoma, poor performance status (ECOG≥2), and no history of EGFR TKI therapy were independent risk factor of development of SRE throughout the course of disease.Conclusion: Our data indicate that patients with characteristics such as ever-smoking, nonadenocarcinoma, poor performance status, and no history of treatment with EGFR TKI are more likely to have SRE, so more vigilant surveillance and prevention should be considered to these patients.

Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells - Corrected Proof

Yidan Lin, Ziqiang Wang, Lunxu Liu, Longqi Chen — 2010-07-05

Abstract: Cisplatin [cis-diaminodichloroplatinum (II) (CDDP)] is the cornerstone of lung cancer chemotherapy. However, its efficacy is limited due to the development of drug resistance in cancer cells. This study was designed to uncover the mechanisms under CDDP resistance in lung cancer cells involving endoplasmic reticulum (ER) stress tolerance-induced and GRP78-dependant Akt activation. In this study we established ER stress-tolerant (ERST) human lung cancer lines H460et and A549et. We found that the ERST Lung cancer cells are resistant to CDDP treatment. We further showed that, compared to the parental cell lines, H460et and A549et show significantly increased GRP78 and phospho(p)-Akt levels. And phosphorylation of Akt, which can be regulated by GRP78, is essential to the ERST-associated CDDP resistance. Our findings identify a new mechanism of regulating Akt activity and a new mechanism through which CDDP resistance is formed in lung cancer cells.

A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients - Corrected Proof

2010-06-28

Abstract: Introduction: Sorafenib has demonstrated single agent activity in non-small cell (NSCLC) and small cell lung cancer (SCLC). Carboplatin/pemetrexed (CbP) and cisplatin/etoposide (PE) are commonly used in the treatment of these diseases.Methods: A phase I trial escalating doses of sorafenib in combination with fixed doses of PE (Arm A) or CbP (Arm B) was performed using a 3-patient cohort design to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT); DLT were assessed in the first cycle. The trial was subsequently amended with closure of Arm B and to include Arm C with a reduced dose of carboplatin.Results: Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 42–73), male/female ratio 12/8, PS 0/1 ratio 6/14, and median number of prior therapies 2 (range 1–4). The most common tumor types were NSCLC and SCLC. On Arm A at dose level 0 (sorafenib 200mg BID), 2 of 4 patients experienced DLT; 2 patients were enrolled at dose level −1 (sorafenib 200mg QD) without DLT, but this arm was closed due to slow accrual. On Arm B, 2 of 3 patients experienced DLT at dose level 0 (sorafenib 200mg BID). On Arm C at dose level 0 (sorafenib 200mg BID), 1 of 6 patients experienced DLT, and at dose level +1 (sorafenib 400mg BID) 2 of 5 patients experienced a DLT.Conclusions: The MTD of sorafenib was 200mg BID continuously in combination with carboplatin (AUC of 5) and pemetrexed 500mg/m2 every 3 weeks. However, only 6 patients were treated at this dose level, and the results should be interpreted cautiously.

Therapy of small cell lung cancer with emphasis on oral topotecan - Corrected Proof

2010-06-24

Abstract: Systemic chemotherapy plays the major role in the management of patients with small cell lung cancer. Cisplatin plus etoposide is the most widely used regimen and is considered as standard in patients with limited disease. Cisplatin plus irinotecan improved survival compared to cisplatin plus etoposide in a Japanese trial but failed to do so in two trials in Caucasians. Cisplatin plus topotecan had similar efficacy compared to cisplatin plus etoposide in patients with extensive disease. In the second-line setting, topotecan showed similar efficacy but better tolerability compared to cyclophosphamide, doxorubin plus vincristine. Oral topotecan was as efficacious as its intravenous formulation and was shown to improve survival compared to best supportive care alone in patients previously treated with chemotherapy. Thus topotecan is considered as the standard second-line chemotherapy in patients with small cell lung cancer.

Biologic correlates of 18F-FDG uptake on PET in pulmonary pleomorphic carcinoma - Corrected Proof

2010-06-21

Abstract: Background: Pulmonary pleomorphic carcinoma is a rare epithelial tumor, and little is also known about the information on the usefulness of 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET). Therefore, we conducted the study including the underlying biologic analysis of 18F-FDG uptake.Methods: Fifteen patients with pulmonary pleomorphic carcinoma who underwent 18F-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1α); cell proliferation (Ki-67 labeling index); vascular endothelial growth factor (VEGF); microvessels (CD34); cell cycle control marker (p53); and apoptosis marker (bcl-2). These parameters were correlated with a control group of patients with other non-small cell lung cancer (NSCLC) (n=33).Results: The maximal standardized uptake value (SUVmax) of the primary tumors in 15 patients ranged from 6.1 to 26.8 (median 19.3). There were positive correlation between 18F-FDG uptake and Glut1 (p=0.0016), Glut3 (p=0.0080), VEGF (p=0.0048), and microvessel density (MVD) (p=0.0005). HIF-1α, p53 and bcl-2 showed no positive correlation with 18F-FDG uptake. 18F-FDG uptake, Glut1, Glut3, HIF-1α, VEGF and Ki-67 were significantly higher in patients with pulmonary pleomorphic carcinoma than those with other NSCLC.Conclusion: 18F-FDG uptake in pulmonary pleomorphic carcinoma is closely associated with the presence of glucose metabolism (Glut1 and Glut3) and angiogenesis (VEGF and MVD). The relationship between 18F-FDG uptake and these biomarkers may lead to a more rational use of PET scan in pulmonary pleomorphic carcinoma.

Repressive coping style: Relationships with depression, pain, and pain coping strategies in lung cancer out patients - Corrected Proof

Nusara Prasertsri, Janean Holden, Francis J. Keefe, Diana J. Wilkie — 2010-06-17

Abstract: Researchers have shown that coping style is related to pain and adjustment in people with chronic illness. This study was the first to examine how coping style related to pain, pain coping strategies, and depression in lung cancer outpatients. We conducted a comparative, secondary data analysis of 107 lung cancer patients (73% male, mean age 61.4±10.43 years, 88% Caucasian). As in prior studies, we classified patients into four coping style groups based on Marlowe–Crowne Social Desirability Scale and trait anxiety scores. The coping style groups were low-anxious (n=25); high-anxious (n=31); defensive high-anxious (n=21); and repressive (n=30). Compared to other coping style groups, the repressive group reported statistically significant lower mean scores for pain quality, pain catastrophizing, and depression. Assessing coping style by measuring personal characteristics such as social desirability and trait anxiety may help clinicians to identify vulnerable individuals with lung cancer who may be candidates for early and timely intervention efforts to enhance adjustment to pain.

Role of emphysema and airway obstruction in prognosis of lung cancer - Corrected Proof

J.A. Gullón, I. Suárez, A. Medina, G. Rubinos, R. Fernández, I. González — 2010-06-16

Abstract: Background and objective: It has been reported that the presence of COPD and emphysema is associated with an increased risk of lung cancer, but the prognosis significance of these two conditions is not well known. The aim of our study was to analyze the influence of COPD and emphysema in the prognosis of non-small cell lung cancer (NSCLC).Methods: Three hundred and fifty-three patients with cytohistologic diagnosis of NSCLC were prospectively collected. The relationship between survival at two years and the following variables: age, sex, smoking habit, comorbid diseases (cardiovascular diseases, previous tumour and COPD), weight loss, presence of emphysema on CT scan, performance status (PS) and treatment, was analyzed. The Kaplan–Meier method and log-rank test were used for survival analysis. A multivariate Cox proportional hazard model, stratified by TNM stage, was used to evaluate prognostic factors.Results: Emphysema was present in 110 patients, associated with COPD in 78 (70.9%). In univariate analysis, survival decreased with age>70 years (p=0.01), presence of emphysema (p=0.02), weight loss (p=0.00001), PS≥2 (p=0.00001) and symptomatic treatment (p=0.0001). Multivariate analyses identified emphysema (HR=1.49 (95% CI 1.11–2.01)), PS≥2 (HR=2.12 (95% CI 1.31–3.38)) and treatment: surgery (HR=0.3 (95% CI 0.15–0.56)) and chemotherapy (HR=0.34 (95% CI 0.31–0.57)) as independent prognostic factors.Conclusion: The presence of emphysema affects the prognostic outcome of patients with non-small cell lung cancer. Emphysema should therefore be considered for prognostic studies on comorbidity.

Evaluation of an early exercise intervention after thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength and exercise tolerance: Randomised controlled trial - Corrected Proof

Gill Arbane, David Tropman, David Jackson, Rachel Garrod — 2010-06-14

Abstract: Deterioration in exercise tolerance and impairment in quality of life (QoL) are common consequences of lobectomy. This study evaluates additional exercise and strength training after lung resection on QoL, exercise tolerance and muscle strength. Fifty-three (28 male) patients attending thoracotomy for lung cancer, mean age, range 64 (32–82) years; mean pack years (SD) 31.9 (26.8); BMI 25.6 (4.2); FEV1 2.0 (0.7) l were randomised to control (usual care) or intervention (twice daily training plus usual care). After discharge the intervention group received monthly home visits and weekly telephone calls, the control group received monthly telephone calls up to 12 weeks. Assessment pre-operatively, 5 day and 12 weeks post-operatively consisted of quadriceps strength using magnetic stimulation, 6 Minute Walking Distance (6MWD) and QoL-EORTC-QLQ-LC13. QoL was unchanged over 12 weeks; 6MWD showed significant deterioration at 5 days post-operatively compared with pre-operatively, mean difference (SD)−131.6 (101.8) m and −128.0 (90.7) m in active and control groups respectively (p=0.89 between groups) which returned to pre-operative levels by 12 weeks in both groups. Quadriceps strength over the 5 day in-patient period showed a decrease of −8.3 (11.3) kg in the control group compared to increase of 4.0 (21.2) kg in the intervention group (p=0.04 between groups). Strength training after thoracotomy successfully prevented the fall in quadriceps strength seen in controls, however, there was no effect on 6MWD or QoL. 6MWD returned to pre-operative levels by 12 weeks regardless of additional support offered.

Concurrent cetuximab and radiotherapy after docetaxel–cisplatin induction chemotherapy in stage III NSCLC: Satellite—A phase II study from the Swedish Lung Cancer Study Group - Corrected Proof

2010-06-14

Abstract: Background: Several attempts to increase the locoregional control in locally advanced lung cancer including concurrent chemotherapy, accelerated fractionation and dose escalation have been made during the last years. As the EGFR directed antibody cetuximab has shown activity concurrent with radiotherapy in squamous cell carcinoma of the head and neck, as well as in stage IV NSCLC combined with chemotherapy, we wanted to investigate radiotherapy with concurrent cetuximab in locally advanced NSCLC, a tumour type often over expressing the EGF-receptor.Methods: Between February 2006 and August 2007 75 patients in stage III NSCLC with good performance status (PS 0 or 1) and adequate lung function (FEV1>1.0) were enrolled in this phase II study at eight institutions. Treatment consisted of 2 cycles of induction chemotherapy, docetaxel 75mg/m2 and cisplatin 75mg/m2 with 3 weeks interval. An initial dose of cetuximab 400mg/m2 was given before start of 3D-CRT to 68Gy with 2Gy per fraction in 7 weeks concurrent with weekly cetuximab 250mg/m2. Toxicity was scored weekly during radiotherapy (CTC 3.0), and after treatment the patients were followed every third month with CT-scans, toxicity scoring and QLQ.Results: Seventy-one patients were eligible for analysis as four were incorrectly enrolled. Histology: adenocarcinoma 49%, squamous cell carcinoma 39% and other NSCLC 12%. The majority had PS 0 (62.5%), median age 62.2 (42–81), 50% were women and 37% had a pre-treatment weight loss>5%. Toxicity: esophagitis grade 1–2: 72%; grade 3: 1.4%. Hypersensitivity reactions grade 3–4: 5.6%. Febrile neutropenia grade 3–4: 15.4%. Skin reactions grade 1–2: 74%; grade 3: 4.2%. Diarrhoea grade 1–2: 38%; grade 3: 11.3%. Pneumonitis grade 1–2: 26.8%; grade 3: 4.2%; grade 5: 1.4%. The median follow-up was 39 months for patients alive and the median survival was 17 months with a 1-, 2- and 3-year OS of 66%, 37% and 29% respectively. Until now local or regional failure has occurred in 20 patients and 22 patients have developed distant metastases. Weight loss, PS and stage were predictive for survival in univariate as well as in multivariate analysis.Conclusion: Induction chemotherapy followed by concurrent cetuximab and RT to 68Gy is clearly feasible with promising survival. Toxicity, e.g. pneumonitis and esophagitis is low compared to most schedules with concurrent chemotherapy. This treatment strategy should be evaluated in a randomised manner vs. concurrent chemoradiotherapy to find out if it is a valid treatment option.

Imaging in pleural mesothelioma: A review of Imaging Research Presented at the 9th International Meeting of the International Mesothelioma Interest Group - Corrected Proof

2010-06-14

Abstract: Imaging of malignant pleural mesothelioma (MPM) poses many challenges for imaging specialists and clinicians due to the anatomic location and unique growth pattern of this tumor. Nevertheless, imaging in MPM plays a critical role in diagnosis, prognostication, prediction or measurement of response to therapy, and monitoring of disease recurrence after aggressive surgical management. Imaging-based studies presented at the 9th International Conference of the International Mesothelioma Interest Group (IMIG) in October 2008 sought to further define the current practice and future potential of imaging for the mesothelioma patient. The Imaging Session was dominated by presentations that addressed the use of fluorodeoxyglucose positron emission tomography (FDG-PET), a clear indication of the expanding role of this modality. These uses included FDG-PET imaging at the point of diagnosis, in prognostication, and in the assessment of response to chemotherapy. Often FDG-PET studies were combined with computed tomography (CT) scans in an attempt to overcome limitations associated with either imaging modality alone. At diagnosis, FDG-PET parameters had a high sensitivity and specificity for differentiation of benign from malignant pleural disease. The use of FDG-PET to extract quantitative features from metabolically active tumor volume was shown to be a significant factor in the prediction of patient survival. The prognostic value of FDG-PET was not confounded by prior talc pleurodesis, despite the inflammatory response associated with the procedure. Metabolic response based on FDG-PET was found to be significantly correlated with progression-free survival. CT-based assessment of mesothelioma was determined to be inconsistent with spherical-model-based criteria so that changes in tumor area, a presumably more complete assessment of tumor burden, exhibited a 46% concordance rate with changes in linear measurements.

The platinum-based treatments for advanced non-small cell lung cancer, is low/negative ERCC1 expression better than high/positive ERCC1 expression? A meta-analysis - Corrected Proof

Sufeng Chen, Jie Zhang, Rui Wang, Xiaoyang Luo, Haiquan Chen — 2010-06-11

Abstract: Background: The predictive value of ERCC1 for prognosis and sensitivity to platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC) remains controversial. This meta-analysis was performed to provide an assessment of whether expression variations of ERCC1 are associated with objective response and median survival in patients with advanced NSCLC treated with platinum-based chemotherapy.Methods: We searched MEDLINE, EMBASE and CNKI for all eligible studies and conducted a meta-analysis of 12 studies (n=836 patients) that evaluated the correlation between ERCC1 levels (detected by immunohistochemistry or real-time reverse transcriptase PCR) and objective response or median survival in patients receiving platinum-based chemotherapy for advanced NSCLC. Pooled odds ratios (OR) for the objective response were calculated using the Mantel–Haenszel method. Pooled median ratios for median survival were calculated using the weighted sum of the log-ratio of median ratios from each individual study.Results: Among 836 tumors, ERCC1 expression was high/positive in 416 (49.8%) and low/negative in 420 (50.2%). Response to platinum-based chemotherapy was significantly higher in patients with ERCC1 low/negative expression (OR=0.48; 95% CI, 0.35–0.64; P<0.00001). Median survival time was significantly prolonged when ERCC1 low/negative expression was compared with ERCC1 high/positive expression (MR: 0.77; 95% CI, 0.47–1.07; P<0.00001).Conclusions: Low/negative expression of ERCC1 was associated with higher objective response and median survival in advanced NSCLC patients treated with platinum-based chemotherapy. ERCC1 may be a suitable marker of prognosis and sensitivity to platinum-based chemotherapy in patients with advanced NSCLC.

Correlations between thin-section CT findings, histopathological and clinical findings of small pulmonary adenocarcinomas - Corrected Proof

2010-06-07

Abstract: Study objectives: Previously, we reported that small pulmonary adenocarcinomas (tumor diameter 20mm or less) could be classified according to attenuation on thin-section CT (TS-CT) images as either ‘air-containing type’ or ‘solid-density type’ (Lung Cancer 2002;36:49–57). Air-containing type was defined as having areas where TOM (tumor opacity on mediastinal window images) was half or less than half the size of those noted on lung window images. Solid-density type was defined as having areas where TOM was greater than half the size of those noted on lung window images. Our findings indicated that there was no microscopic evidence of metastasis with air-type nor any relapses nor deaths, after resection. By contrast, patients with solid-density types demonstrated a poor prognosis. At this time, the histopathological characteristics of areas of TOM have not been fully investigated. The purpose of this study is to define the correlations between TOM and histopathological findings of small lung adenocarcinomas.Method: We retrospectively reviewed the records and CT scans of 134 patients, who had undergone surgical resection of peripheral adenocarcninomas. All tumor diameters were 20mm or less in size. All 134 patients had undergone TS-CT prior to surgery. TS-CT Images were acquired by a model X-Vigor/Real or an Aquillion CT scanner (Toshiba Medical Systems). Thin-section images of tumors were obtained at 135kVp at 250mAs with 1–2mm section thicknesses. All images were photographed using mediastinal (level, 40HU; width, 400HU) and lung (level, −600HU; width, 1600HU) window settings. We researched the histopathological components corresponding to the areas of TOM.Results: Areas of TOM demonstrated five possible histopathological findings; (1) collapse (C), (2) collapse with bronchioloalveolarcell carcinoma (CwB), (3) adenocarcinoma cells (Cells), (4) fibroblasts (F), and (5) mucus (M). Areas of TOM in air-containing type adenocarcinomas (52 cases) demonstrated predominantly C and/or CwB (C/CwB type, 44 cases). Areas of TOM in solid-density type adenocarcinomas (82 cases), in comparison, demonstrated predominantly Cells and/or Cells/F (Cell/F type, 67 cases). We noted a statistically significant difference between the histopathological findings of the areas of TOM of air-containing type and solid-density type tumors. The 39 cases of Cell/F type adenocarcinomas revealed microscopic evidence of metastasis (pleural involvement, vascular invasion, lymphatic permeation, or lymphnode metastasis). Whereas, no C/CwB type adenocarcinomas cases revealed any microscopic metastasis. The prognosis of C/CwB type after resection is better than for Cell/F type.Conclusion: We found that air-containing type adenocarcinomas demonstrated C/CwB type, and that solid-density type adenocarcinomas demonstrated Cell/F type. The histopathological findings of small pulmonary adenocarcinomas could be classified into three groups: C/CwB type, Cell/F type and M type. The prognosis of C/CwB type is better than for Cell/F type. Our results indicate that there are clear correlations between the areas of TOM and the histopathological components of small pulmonary adenocarcinomas. Therefore TS-CT findings are a useful aid in determining the best surgical methods.

Single nucleotide polymorphisms in MDR1 gen correlates with outcome in advanced non-small-cell lung cancer patients treated with cisplatin plus vinorelbine - Corrected Proof

2010-06-07

Abstract: New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying NSCLC could influence chemosensitivity. In this study, we assessed whether the presence of polymorphisms in ERCC1, XPD, RRM1 and MDR1 genes can affect the efficacy and the tolerability of cisplatin and vinorelbine in NSCLC patients.Material and methods: Eligible patients had histological confirmed stage IV or IIIB (with malignant pleural effusion) non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy; World Health Organization performance status (PS) 0–1. Patients received intravenous doses of vinorelbine 25mg/m2 on day 1 and 8 and cisplatin 75mg/m2 on day 1, every 21 days, for a maximum of eight cycles.Results: 94 patients were included. Median age was 61 years; 84% were male; WHO performance status (PS) was 0 in 24%; and 88% of patients had stage IV disease. The median number of cycles was 6. Overall median survival was 10.92 months (95% CI 9.0–12.9). Overall median time to progression was 5.89 months (95% CI 5.2–6.6).Results of the multivariate analysis for time to progression showed that ECOG 0 (hazard ratio [HR] ECOG 1 vs. ECOG 0, 1.74; p=0.036), MDR13435CC (HR CT vs. CC, 2.01; p=0.017; HR TT vs. CC, 1.54; p=0.22), and decreasing age (HR of age, 0.97; p=0.016) were the most powerful prognostic factors significantly related to lower risk of progression. Whereas ECOG 0 was the only prognostic factor for survival (HR ECOG 1 vs. ECOG 0, 3.02; p=0.001).There was no significant association between any of the SNPs analysed and the occurrence of vinorelbine and cisplatin-related toxicity.Conclusion: In our results, the most important prognostic factors associated with lower risk of progression were MDR1 3435 CC genotype, PS 0 and younger age.

Prognostic value of xanthine oxidoreductase expression in patients with non-small cell lung cancer - Corrected Proof

2010-06-07

Abstract: Background: Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in the purine metabolism pathway. Lack of XOR expression is associated with unfavorable clinical outcomes. The objective of this study was to correlate XOR expression with prognosis in surgically resected non-small cell lung cancer (NSCLC).Methods: Immunohistochemical staining was performed on deparaffinized specimens from 82 patients with stage I–IV NSCLC using a polyclonal anti-XOR rabbit antibody. Cytoplasmic XOR staining was scored on frequency and intensity scales from 0 to 4 with low expression defined as 0–1 and high expression defined as ≥2–4. XOR immunostaining was correlated with clinical characteristics and outcomes and analyzed using Kaplan–Meier and Cox proportional hazard methods.Results: Positive XOR expression was observed in 53/82 cases (65%). Patients with high XOR frequency had a longer median survival of 3053 days (95% CI: 2190–3916) vs. 592 days (95% CI: 492–692 days) for patients with low XOR frequency, p=0.0089, HR 0.47. Neither XOR intensity nor the overall score of XOR frequency multiplied by XOR intensity demonstrated any significant association with survival. Surgical resection was performed on 61 patients of which 34 (56%) received adjuvant chemotherapy. Patients who received adjuvant chemotherapy with low XOR expression, 15/34 (44%) had a shortened median survival compared with patients who received adjuvant chemotherapy with high XOR expression (543 days vs. 2023 days, respectively, p=0.007 and HR=0.33).Conclusion: Low XOR expression was associated with shortened survival and also conferred a worse prognosis for patients with NSCLC who received adjuvant chemotherapy. Further studies of the XOR pathway are warranted to validate and mechanistically explain these outcomes.

Exponential decay nonlinear regression analysis of patient survival curves: Preliminary assessment in non-small cell lung cancer - Corrected Proof

David J. Stewart, Carmen Behrens, Jack Roth, Ignacio I. Wistuba — 2010-06-07

Abstract: Background: For processes that follow first order kinetics, exponential decay nonlinear regression analysis (EDNRA) may delineate curve characteristics and suggest processes affecting curve shape. We conducted a preliminary feasibility assessment of EDNRA of patient survival curves.Methods: EDNRA was performed on Kaplan–Meier overall survival (OS) and time to relapse (TTR) curves for 323 patients with resected NSCLC and on OS and progression-free survival (PFS) curves from selected publications.Results and conclusions: In our resected patients, TTR curves were triphasic with a “cured” fraction of 60.7% (half-life [t1/2] >100,000 months), a rapidly relapsing group (7.4%, t1/2=5.9 months) and a slowly relapsing group (31.9%, t1/2=23.6 months). OS was uniphasic (t1/2=74.3 months), suggesting an impact of co-morbidities; hence, tumor molecular characteristics would more likely predict TTR than OS. Of 172 published curves analyzed, 72 (42%) were uniphasic, 92 (53%) were biphasic, 8 (5%) were triphasic. With first-line chemotherapy in advanced NSCLC, 87.5% of curves from 2 to 3 drug regimens were uniphasic vs. only 20% of those with best supportive care or 1 drug (p<0.001). 54% of curves from 2 to 3 drug regimens had convex rapid-decay phases vs. 0% with fewer agents (p<0.001). Curve convexities suggest that discontinuing chemotherapy after 3–6 cycles “synchronizes” patient progression and death. With postoperative adjuvant chemotherapy, the PFS rapid-decay phase accounted for a smaller proportion of the population than in controls (p=0.02) with no significant difference in rapid-decay t1/2, suggesting adjuvant chemotherapy may move a subpopulation of patients with sensitive tumors from the relapsing group to the cured group, with minimal impact on time to relapse for a larger group of patients with resistant tumors. In untreated patients, the proportion of patients in the rapid-decay phase increased (p=0.04) while rapid-decay t1/2 decreased (p=0.0004) with increasing stage, suggesting that higher stage may be associated with tumor cells that both grow more rapidly and have a higher probability of surviving metastatic processes than in early stage tumors.This preliminary assessment of EDNRA suggests that it may be worth exploring this approach further using more sophisticated, statistically rigorous nonlinear modelling approaches. Using such approaches to supplement standard survival analyses could suggest or support specific testable hypotheses.

Growth rate of newly developed metastatic brain tumors after thoracotomy in patients with non-small cell lung cancer - Corrected Proof

2010-06-07

Abstract: Among 1372 lung cancer patients without brain metastasis that underwent resection of lung cancer at our center from 2001 to 2007, brain metastases developed in 72 patients (5.2%) during their hospital course. We hypothesized that there were micro-metastases in the brain at the time of lung surgery in these patients, even though there were no detectable brain metastases on the MRI. The purpose of this study was to evaluate the growth rates of metastatic brain tumors in this unique subset of patients, and to compare the findings with our previous study that calculated the growth rate of brain metastases during chemotherapy. Among 72 patients, 23 with cystic or hemorrhagic metastases were excluded. Seventy-six metastatic brain tumors in 49 patients were reviewed. Twenty-five patients underwent adjuvant or neoadjuvant chemotherapy; however, for the rest of the patients, chemotherapy was not added after lung cancer surgery. The tumor volume was determined using V-works software (v. 4.0) (Cybermed, Seoul, Korea) and T1 gadolinium enhanced MR images. The overall median tumor growth rate was 11.7mm3/day (interquartile range, 4.9–26.8). There were no statistically significant differences in the tumor growth among the lung cancer stages and the growth rate was similar regardless of the use of chemotherapy. The growth rate reported in this study shows consistency with that of our previous report (12.1mm3/day). These findings may help optimize patient management during follow up.

Evaluation of the efficacy and safety of chemotherapy for patients with wet stage IIIB/IV non-small-cell lung cancer aged 80 years old or more - Corrected Proof

2010-06-07

Abstract: Background: Because of the number of elderly patients with NSCLC is increasing, it is becoming a public health problem world wide. In elderly patients with advanced NSCLC, mono-chemotherapy is the standard treatments. But little information is available for patients aged ≥80 regarding the management of advanced NSCLC.Purpose: The purpose of the present study is to evaluate the efficacy and safety of chemotherapy for patients aged ≥80.Methods: 110 patients aged ≥75 with advanced NSCLC were retrospectively reviewed. Data was collected from the electronic medical records of our hospital from January 2005 to August 2008. The patient population was divided into three age groups: patients aged ≥80 who received chemotherapy (group A), patients aged 75–79 who received chemotherapy (group B), and patients aged ≥75 who received only best supportive care (group C). Date cut-off of this study was on 20th June, 2009. We evaluated and compared the survival and the toxicity between three groups.Results: Among 110 patients, there were 21 patients in group A, 55 patients in group B, 34 patients in group C.Among group C, there were 8 patients aged 75–79 and the main reasons for BSC were poor PS in 7 patients, and there were 26 patients aged ≥80 and the main reason for BSC were age itself in 17 patients.Response rate and disease control rate were similar in group A and group B (16.4% vs. 23.8%, and 57.1% vs. 49.1%). MST was 237 days in group A with PS 0–2 and was 232 days in group C with PS 0–2. Median PFS and MST were 86 and 237 days in group A with PS 0–2 and was 107 and 263 days in group B.Toxicity profile of group A seems to be acceptable: over grade 3 leucopenia was observed 33%; over grade 3 neutropenia was 52%; but no febrile neutropenia; over grade 3 non-hemotological toxicity was observed 14%.Conclusion: There was no obvious difference between patients aged ≥80 and 75–79 in terms of safety and efficacy of chemotherapy. Patients aged ≥80 with advanced NSCLC who have good PS might be good candidates for the chemotherapy.

Methylation of MGMT in malignant pleural mesothelioma occurs in a subset of patients and is associated with the T allele of the rs16906252 MGMT promoter SNP - Corrected Proof

Lasse Sommer Kristensen, Helene Myrtue Nielsen, Henrik Hager, Lise Lotte Hansen — 2010-06-03

Abstract: Silencing of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) by promoter methylation is an early event in several human cancers. MGMT removes alkyl adducts from the O6 position of guanine thereby preventing G>A mutations in the genome. For this reason, MGMT promoter methylation predicts a favorable outcome for glioblastoma patients treated with alkylating agents. In this study, we investigated whether MGMT becomes silenced by promoter methylation in malignant pleural mesothelioma (MPM), an aggressive cancer of the pleura associated with a poor prognosis. Ninety-five samples from patients diagnosed with MPM were studied. These samples were genotyped for the MGMT rs16906252 promoter SNP using high-resolution melting, and methylation status was analyzed using SMART-MSP and confirmed by Sanger sequencing. The SMART-MSP assay was designed to provide information on the allelic methylation status in samples heterozygous for rs16906252. MGMT immunohistochemistry was performed on samples showing no methylation, monoallelic methylation, and biallelic methylation. Thirteen of the 95 MPM samples (13.7%) were methylation positive and a strong association with the T allele of the rs16906252 SNP (P<0.001) was observed. Detection of the protein was found to be dependent not only on the allelic methylation status but also on the methylation level, and complete silencing was observed in only one sample, showing biallelic methylation and a methylation level close to 100%. In conclusion, methylation of the MGMT promoter occurs in a subset of MPM patients and is associated with the T allele of the MGMT rs16906252 SNP. However, complete silencing of MGMT in MPM is a rare event.

Are levels of pro-gastrin-releasing peptide or neuron-specific enolase at relapse prognostic factors after relapse in patients with small-cell lung cancer? - Corrected Proof

2010-05-31

Abstract: The purposes of this study were to assess the relationship of serum levels of pro-gastrin-releasing protein (ProGRP) and neuron-specific enolase (NSE) at relapse with survival after relapse and the response to salvage therapy and to assess whether serum levels of ProGRP and NSE at relapse are useful markers for detecting relapse earlier than are symptoms or radiographic findings in patients with small-cell lung cancer (SCLC). The subjects of this study were 103 patients with SCLC who had achieved a complete response (CR) or partial response (PR) to first-line chemotherapy. We retrospectively evaluated whether ProGRP or NSE increased earlier than symptoms or radiographic findings appeared, and the association between response to salvage therapy and levels of ProGRP or NSE at relapse. In addition, we evaluated the association between survival after relapse and clinical and demographic factors at relapse, including age, sex, response to first-line treatment, sensitivity to first-line treatment, stage, performance status (PS), and serum levels of ProGRP, NSE, and lactate dehydrogenase. At relapse, 69.3% of patients had elevated serum levels of ProGRP, 60.2% had elevated serum levels of NSE, and 81.3% had elevated serum levels of either ProGRP or NSE. However, almost all asymptomatic relapses were detected with radiographic studies. The rate of CR to salvage chemotherapy was significantly lower in patients with elevated levels of NSE (2.2%) than in patients without (26.7%; p=0.001). Univariate analysis showed that sensitivity to first-line treatment, serum levels of NSE, stage, and PS at relapse were prognostic factors for survival after relapse. Multivariate analysis showed that sensitivity to first-line treatment, serum levels of NSE, and PS at relapse were independent prognostic factors after relapse. In conclusion, serum levels of ProGRP and NSE at relapse are not useful markers for detecting relapse earlier than are symptoms or radiographic findings. On the other hand, the serum level of NSE at relapse is a useful predictive marker for CR to salvage chemotherapy and a useful prognostic factor after relapse in patients with SCLC who have achieved a CR or PR to first-line chemotherapy.

Randomized phase II study of gemcitabine and carboplatin +/− sequential docetaxel in non-small cell lung cancer - Corrected Proof

Gunnar Hillerdal, Christer Sederholm, Kerstin Andersson — 2010-05-26

Abstract: Sequential administration of chemotherapeutic drugs might have advantages: additive toxicity is avoided and the individual drugs can be given in full dosages. The Swedish group earlier found the combination of gemcitabine and carboplatin to be effective and with acceptable toxicity. The group therefore decided to add docetaxel in a sequential way in a randomized phase II study. Patients were randomized to either gemcitabine or carboplatin for six cycles or the same regimen for three cycles followed by weekly single agent docetaxel. The primary objective was time to progression (TTP). One hundred and twenty-three patients with performance status WHO 0–2 and with earlier un-treated non-small cell lung cancer with measurable stage IIIB disease, not amenable to curative treatment, or stage IV disease without known metastatic spread to the CNS, were enrolled. Hematological toxicity was more common in the GC group but clinically significant bleeding or leucopenic fever occurred only in a minority of patients. No complete responses were noted. Partial response (PR) was observed in 19.3% and 20.8% in the GC and GCD group, respectively. Progression-free survival was 5.6 and 4.8 months and overall survival time 10.6 and 10.1 months in the GC and GCD groups, respectively. Thus, sequential treatment with docetaxel after treatment with gemcitabine and carboplatin did not improve time to progression, response rates, or overall survival.

A pilot study of mRNA expressions of 5-fluorouracil pathway genes in peripheral blood mononuclear cells and tumor tissues in patients with lung adenocarcinoma - Corrected Proof

2010-05-24

Abstract: To assess whether early lung cancer prediction might be informed by an mRNA assay for 5-fluorouracil pathway genes in peripheral blood mononuclear cells (PBMNCs), we examined specimens taken from 51 adenocarcinoma patients and 38 controls (including six patients with benign tumors). PBMNCs and tumor-tissue specimens were taken for measurement of the mRNAs of various 5-fluorouracil pathway genes [thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyl transferase (OPRT)]. By quantitative RT-PCR, all four mRNAs were detected in both PBMNCs and tumor tissues. In PBMNCs, TS mRNA/GAPDH mRNA levels were significantly higher in adenocarcinoma patients than in the controls, and significantly higher for pathological stages 2–4 and lymph-node involvement pN1–pN3 than for pathological stage 1 and pN0, respectively. No correlation between PBMNCs and tumor-tissue specimens was found for the level of any mRNA. Thus, the measurement of TS mRNA in PBMNCs might aid the diagnosis of lung adenocarcinoma.

The safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small cell lung cancer with idiopathic interstitial pneumonias - Corrected Proof

2010-05-21

Abstract: Background: Idiopathic interstitial pneumonias (IIPs) are one of the most common complications in patients with lung cancer. In lung cancer patients with IIP, the most serious toxicity is acute exacerbation of IIP caused by anticancer treatment in Japan. However, there has been no consensus and no evidence presented, regarding optimal treatment for advanced lung cancer with IIP.Patients and methods: Chemotherapy-naïve patients of inoperable stage, or post-operative recurrent non-small cell lung cancer (NSCLC) with IIPs were enrolled. Patients received paclitaxel at a dose of 100mg/m2 on Days 1, 8, 15, and carboplatin every 28 days at a target dose of area under the curve (AUC) 5.0 on Day 1.Results: Between May 2004 and October 2008, 18 patients, including 6 with idiopathic pulmonary fibrosis (IPF), were enrolled and treated for a median of four cycles (range, 1–6). One patient (5.6%; 95% confidence interval (CI), 0–17%) with histologically confirmed IPF had acute exacerbation of IIPs associated with the treatment. The overall response rate was 61% (95% CI, 36–86%). The median progression-free survival, median survival time, and 1-year survival rate were 5.3 months, 10.6 months, and 22%, respectively.Conclusion: This is the first report indicating that advanced NSCLC patients with IIP may benefit from chemotherapy. Weekly paclitaxel and carboplatin combination chemotherapy was as effective as conventional regimens in advanced NSCLC patients without IIP and was safer than previously reported for NSCLC patients with IIP. The results from this study would support, on ethical grounds, the conduct of a large-scale study to confirm the feasibility of this regimen.

Characterization of side population cells in human malignant mesothelioma cell lines - Corrected Proof

2010-05-21

Abstract: Side population (SP) assay composed of Hoechst 33342 staining and subsequent flow cytometric analysis has been widely utilized for characterizing putative cancer stem cells (CSCs) in various human malignancies. The present study was designed to evaluate the SP assay as a research tool for mesothelial CSCs. A distinct fraction of SP cells was identified in various human malignant mesothelioma (HMM) cell lines, ranging from 0.05 to 1.32%. The sorted mesothelial SP cells exhibited enhanced proliferation potentials and higher expression of stem-cell genes, compared to non-SP (NSP) cells. Cisplatin treatment increased percentage of SP cells in the HMM cell lines. However, tumorigenic potential of SP cells in immunodeficient mice was similar to that of the NSP cells. These data indicated that SP assay may not be appropriate for enriching putative CSCs in HMM cell lines, and thus warrants the development of a novel tool for mesothelial CSC study.

TTF-1 mRNA-positive circulating tumor cells in the peripheral blood predict poor prognosis in surgically resected non-small cell lung cancer patients - Corrected Proof

2010-05-17

Abstract: Circulating tumor cells (CTCs) have been identified in peripheral blood of cancer patients, and reproducible detection of CTCs has demonstrated the potential as useful diagnostic and prognostic tools in several cancers. Present study aimed to determine the clinical relevance of CTCs in surgically resected non-small cell lung cancer (NSCLC) patients. CTC status in presurgery and postsurgery peripheral blood samples from 79 surgically resected NSCLC patients was investigated using thyroid transcription factor-1 (TTF-1) and cytokeratin19 (CK19) mRNA markers by nested real-time RT (reverse transcription)-PCR assay. Detection of TTF-1(+)CTCs was found to be specific to NSCLC patients. TTF-1(+)CTCs were detected in 36.1% (22/61) of patients before surgery and in 37.5% (18/48) after surgery. For CK19 mRNA-expressing CTCs (CK19(+)CTCs), the detection rate was 42.6% (26/61) before surgery, and 25.0% (12/48) after surgery. Cases with postsurgery TTF-1(+) and/or CK19(+)TCs was more associated with disease progression (P=0.004) and shorter disease progression-free survival (P=0.006) as compared to those without postsurgery CTCs. As an individual marker, postsurgery TTF-1(+)CTCs-positive status was more associated with disease progression (P=0.004) and shorter disease progression-free survival (P=0.004) as compared to postsurgery TTF-1(+)CTCs-negative status. Particularly, patients with postsurgery TTF-1(+)CTCs, but not presurgery (Pre(−)Post(+) cases) showed marked shorter disease progression-free survival than other patients (P<0.001). On the other hand, a CK19(+)CTC status individually did not show significant clinical relevance, and presurgery CK19(+)CTC status did not either. Present study suggests that TTF-1 mRNA-expressing CTCs might be a useful surrogate predictor of disease progression before clinical manifestations are apparent, and that monitoring of TTF-1(+)CTCs status after surgery may be useful for identifying high-risk patients among surgically resected NSCLC cases.

A combination of functional polymorphisms in the CASP8, MMP1, IL10 and SEPS1 genes affects risk of non-small cell lung cancer - Corrected Proof

2010-05-14

Abstract: Exposure to tobacco smoke as well as environmental and occupational factors is the major cause of lung cancer. Non-small cell lung cancer (NSCLC) is the major histological type. Genes in pathways affecting inflammation, cellular stress and apoptosis are important, and the extent of inflammation in the lung could be affected by polymorphisms modifying these responses. In the present study we have investigated whether a combination of potential functional polymorphisms in genes related to inflammation may modulate risk of NSCLC. Eleven functional polymorphisms in nine genes were analyzed for association with risk of NSCLC in 882 subjects from the Norwegian population. The results showed that individuals carrying combination of three functional polymorphisms in the caspase-8, matrix metalloproteinase-1, seleno-protein S1, and interleukin-10 genes had two-fold increased risk of NSCLC (OR 2.06 (95% CI, 1.19–3.47) whereas individuals with four risk genotypes had 4.62-fold increased risk (OR 4.62, 95% CI, 1.69–12.63). These results highlight the need to investigate the combinatory effects of multiple SNPs in the carcinogenesis of the lung.

Secretoglobin 3A2/uteroglobin-related protein 1 is a novel marker for pulmonary carcinoma in mice and humans - Corrected Proof

2010-05-13

Abstract: Secretoglobin (SCGB) 3A2, also called uteroglobin-related protein (UGRP) 1, is a downstream target for a homeodomain transcription factor NKX2-1, which is critical for the development of lung, thyroid and ventral forebrain. Both SCGB3A2 and NKX2-1 are expressed in airway epithelial cells and the latter also in alveolar Type II cells. NKX2-1 has been used clinically for diagnosis of human pulmonary tumors. Recently, the expression of SCGB3A2 was reported in human carcinomas, suggesting the use of this protein as a tumor marker. In this study, 28 lung tumors from aging B6;129 mice and nine lung adenocarcinomas from CC10TAg transgenic mice that express SV40 large T antigen under the mouse Scgb1a1 (CC10) gene promoter, were subjected to histopathological and immunohistochemical analyses for the expression of NKX2-1 and SCGB3A2. NKX2-1 was expressed in all types of tumors albeit more focally in carcinomas. In contrast, SCGB3A2 normally expressed in Clara cells, was negative in Type II cell hyperplasias and adenomas. However, it was expressed in alveolar Type II cell carcinomas and Clara cell adenocarcinomas. In these carcinomas, SCGB3A2 expression was observed in the portion of the tumor where NKX2-1 expression was reduced or almost abolished. As a comparison, the expression of SCGB3A2 and NKX2-1 from 23 human non-small cell lung carcinoma specimens was also examined. The results demonstrate that SCGB3A2 is a useful marker for diagnosis of pulmonary tumors both in mice and humans.

Histologic features of low- and intermediate-grade neuroendocrine carcinoma (typical and atypical carcinoid tumors) of the lung - Corrected Proof

2010-05-13

Abstract: Background: Determining the differential diagnosis between typical (TCs) and atypical carcinoid tumors (ACs) is imperative, as the distinction between TCs and ACs is currently based on histologic criteria that are not always correlated with the unfavorable clinical outcomes.Patients and methods: We conducted a retrospective study of patients who were diagnosed with carcinoid tumors between 1990 and 2005 at M. D. Anderson Cancer Center. We reviewed the slides for the following pathologic features: infiltrative growth; pleural, blood, or lymphatic vessel invasion; tumor stroma; presence of active fibroblastic proliferation; chromatin pattern; presence of nucleolus; and nuclear pleomorphism. We also evaluated the necrotic patterns. Finally, we evaluated three methods for calculating the number of mitoses: randomly selected, the most mitotically active in 10 high-power fields (HPFs), or overall mean mitotic count.Results: Our cohort consisted of 80 patients (68 with TCs and 12 with ACs). Older age (P=0.002), pathologic stage III or IV disease (P=0.04), active fibroblastic proliferation (P=0.041), and comedo-like necrosis (P=0.001) were significantly associated with tumor recurrence or patient's death. Among the three mitotic counting methods, the overall mean number of mitoses was significantly correlated with recurrence-free survival (P<0.0001). Our criteria for distinguishing AC from TC included the presence of comedo-like necrosis and/or an overall mean number of mitoses ≥0.2/HPF.Conclusions: Using an overall mean number in counting mitoses and detecting comedo-like necrosis is important for classifying lung carcinoid tumors.

Health-related quality of life among early-stage, non-small cell, lung cancer survivors - Corrected Proof

2010-05-12

Abstract: Background: Limited data are available about the physical and mental functioning of individuals diagnosed and treated for early-stage lung cancer. To develop post-treatment guidelines and targeted resources for the growing number of lung cancer survivors, clinically relevant information about longer term health-related quality of life (HQOL) is needed. The current study examines lung cancer survivors’ HQOL and identifies associations between HQOL and demographic, disease and medical risk factors.Methods: A total of 359 individuals diagnosed and surgically treated for stage IA or IB non-small cell lung cancer completed a post-treatment survey via mail or telephone that included the SF-36v2 as well as questions regarding demographic and medical factors. To better understand the impact of lung cancer treatment, we examined age- and gender-adjusted differences in HQOL as compared to a demographically matched sample of older adults, most with a significant smoking history, who participated in a lung cancer screening trial. Risk factors for impairments in HQOL were also identified.Results: Compared to the screening sample, lung cancer survivors reported lower physical health scores, but did not differ in terms of mental health status. Dyspnea and distressed mood were most associated with HQOL impairments.Conclusions: Early-stage lung cancer survivors are likely to experience mild impairment in physical functioning. They may benefit from management of distressed mood and referral to physical activity and pulmonary rehabilitation programs to promote HQOL outcomes.

A phase I study of nimotuzumab in combination with radiotherapy in stages IIB–IV non-small cell lung cancer unsuitable for radical therapy: Korean results - Corrected Proof

2010-05-10

Abstract: Purpose: This study was undertaken to determine safety and tolerability of nimotuzumab, a humanized anti-epidermal growth factor receptor monoclonal antibody, in combination with radiotherapy in stages IIB–IV non-small cell lung cancer (NSCLC) patients who are unsuitable for radical therapy or chemotherapy.Methods: Nimotuzumab (100mg, 200mg and 400mg) was administered weekly from week 1 to week 8 with palliative radiotherapy (30–36Gy, 3Gy/day). If tumor control was achieved, nimotuzumab was continued every 2 weeks until unacceptable toxicity or disease progression. Serial skin biopsies were collected for pharmacodynamic assessment.Results: Fifteen patients were enrolled in the study, with cohorts of five patients assigned in each dose level of nimotuzumab. Patients and disease characteristics included median age 73 years; Eastern Cooperative Oncology Group performance status (PS) 0–1/2 (n=3/12); female sex (n=2); adenocarcinoma (n=5); never-smoker status (n=2); and stages IIB/IIIB/IV (n=1/8/6). All patients were unable to tolerate radical therapy because of old age or multiple comorbidities. The most commonly reported adverse events were lymphopenia and asthenia (grades 1–2 in most patients). No skin rash or allergic toxicities appeared. Dose-limiting toxicity occurred with pneumonia with grade 4 neutropenia at the 200mg dose of nimotuzumab. Objective response rate and disease control rate inside the radiation field were 46.7% and 100.0%, respectively.Conclusions: Nimotuzumab in combination with radiotherapy is well-tolerated and feasible. Further clinical investigation of nimotuzumab in NSCLC patients is warranted.

A phase I study of S-1 with concurrent thoracic radiotherapy in elderly patients with localized advanced non-small cell lung cancer - Corrected Proof

2010-05-07

Abstract: S-1, an oral 5-fluorouracil derivative, is effective against advanced non-small cell lung cancer (NSCLC) with mild toxicity and synergistic effects with radiation in preclinical trials. In this phase I study, we evaluated the dose-limiting toxicity and recommended dose of S-1 for a future phase II study when administered concurrently with thoracic radiation (total dose of 60Gy at 2Gy per daily fraction) in elderly patients (>75 years old) with localized advanced NSCLC. S-1 was administered on days 1–14 and 29–42 at the following dosages: 60, 70, and 80mg/m2/day. Twenty-two previously untreated patients were enrolled in this study. Dose-limiting toxicity included febrile neutropenia, thrombocytopenia, stomatitis, and pneumonitis. One patient had grade 5 radiation pneumonitis. No other patient experienced radiation pneumonitis or esophagitis exceeding grade 2. The recommended dose for S-1 was determined to be 80mg/m2/day, which produced an overall response rate of 75% (n=12). The median progression-free survival time was 11.5 months (95% confidence interval: 7.1–15.8 months) with a median follow-up time of 27.9 months. These results indicate that concurrent treatment with S-1 and thoracic radiation is a feasible option for NSCLC in the elderly. A phase II study is currently under way.

PI3K/PTEN/AKT/mTOR pathway genetic variation predicts toxicity and distant progression in lung cancer patients receiving platinum-based chemotherapy - Corrected Proof

2010-05-06

Abstract: Non-small cell lung cancer (NSCLC) is still the leading cause of cancer-related deaths. The effect of the PI3K/PTEN/AKT/mTOR signaling pathway on cancer treatment, including NSCLC, has been well documented. In this study, we analyzed associations between genetic variations within this pathway and clinical outcomes following platinum-based chemotherapy in 168 patients with stage IIIB (wet) or stage IV NSCLC. Sixteen tagging SNPs in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) of this pathway and identified SNPs associated with development of toxicity and disease progression. We observed significantly increased toxicity for patients with PIK3CA:rs2699887 (OR: 3.86, 95% CI: 1.08–13.82). In contrast, a SNP in PTEN was associated with significantly reduced risk for chemotherapeutic toxicity (OR: 0.44, 95% CI: 0.20–0.95). We identified three SNPs in AKT1 resulting in significantly decreased risks of distant progression in patients carrying at least one variant allele with HRs of 0.66 (95% CI: 0.45–0.97), 0.52 (95% CI: 0.35–0.77), and 0.62 (95% CI: 0.42–0.91) for rs3803304, rs2498804, and rs1130214, respectively. Furthermore, these same variants conferred nearly 2-fold increased progression-free survival times. The current study provides evidence that genetic variations within the PI3K/PTEN/AKT/mTOR signaling pathway are associated with variation in clinical outcomes of NSCLC patients. With further validation, our findings may provide additional biomarkers for customized treatment of platinum-based chemotherapy for NSCLC.

A qualitative exploration of a respiratory distress symptom cluster in lung cancer: Cough, breathlessness and fatigue - Corrected Proof

A. Molassiotis, M. Lowe, F. Blackhall, P. Lorigan — 2010-05-04

Abstract: There is a growing awareness that symptoms frequently co-occur in ‘symptom clusters’ and that understanding these clusters may improve the management of unrelieved symptoms in patients. In-depth longitudinal exploration of lung cancer patients’ symptom experiences is used to examine patient symptom experiences and distress across the disease trajectory of lung cancer.Methods: Semi-structured interviews were conducted with patients and their primary caregivers at four time points: At the beginning of treatment and then subsequently at three, six, and twelve months. Interpretative Phenomenological Analysis was employed in the data analysis.Findings: Findings indicate that a cluster of interacting respiratory symptoms play a central role in patients’ symptom experiences within the lung cancer population. The interviews also suggest that symptoms such as cough which are under-represented in research within this population may play an important role in patients’ symptom experiences.Discussion: Longitudinal qualitative investigation offers a valuable method for improving our understanding of patients’ experiences of lung cancer and for identifying potential opportunities to improve patient quality of life.

Suppression of hydroxyurea-induced centrosome amplification by NORE1A and down-regulation of NORE1A mRNA expression in non-small cell lung carcinoma - Corrected Proof

2010-05-03

Abstract: The candidate tumor suppressor NORE1A is a nucleocytoplasmic shuttling protein, and although a fraction of the NORE1A in cells is localized to their centrosomes, the role of centrosomal NORE1A has not been elucidated. In this study we investigated the role of NORE1A in the numerical integrity of centrosomes and chromosome stability in lung cancer cells. Exposure of p53-deficient H1299 lung cancer cell line to hydroxyurea (HU) resulted in abnormal centrosome amplification (to 3 or more centrosomes per cell) as determined by immunofluorescence analysis with anti-γ-tubulin antibody, and forced expression of wild-type NORE1A partially suppressed the centrosome amplification. The nuclear export signal (NES) mutant (L377A/L384A) of NORE1A did not localize to centrosomes and did not suppress the centrosome amplification induced by HU. Fluorescence in situ hybridization analyses with probes specific for chromosomes 2 and 16 showed that wild-type NORE1A, but not NES-mutant NORE1A, suppressed chromosome instability in HU-exposed H1299 cells that was likely to have resulted from centrosome amplification. We next examined the status of NORE1A mRNA expression in non-small cell lung carcinoma (NSCLC) and detected down-regulation of NORE1A mRNA expression in 25 (49%) of 51 primary NSCLCs by quantitative real-time-polymerase chain reaction analysis. These results suggest that NORE1A has activity that suppresses the centrosome amplification induced by HU and that NORE1A mRNA down-regulation is one of the common gene abnormalities in NSCLCs, both of which imply a key preventive role of NORE1A against the carcinogenesis of NSCLC.

Prognostic value of SUVmax measurements obtained by FDG-PET in patients with non-small cell lung cancer receiving chemotherapy - Corrected Proof

2010-04-30

Abstract: [18F]Fluorodeoxyglucose (FDG) uptake has been shown to correlate well with tumor proliferation rates. In patients with non-small cell lung cancer (NSCLC) receiving chemotherapy, we analyzed the relationships between the maximum standardized uptake value (SUVmax) obtained by FDG positron emission tomography (FDG-PET) and other clinical factors, and examined whether or not SUVmax could predict progression-free survival (PFS) and/or overall survival (OS). This retrospective study involved 62 consecutive NSCLC patients (35 male and 27 female: median age, 65 years). All patients underwent FDG-PET examination before treatment. As the first-line treatment, the patients received chemotherapy with (n=15) or without (n=47) radiotherapy. Survival curves were obtained by the Kaplan–Meier method, and differences in survival between subgroups were analyzed by the log-rank test and the Cox proportional hazards model. Significant correlations were observed between SUVmax and gender (P=0.006), histology (P<0.001), smoking status (P=0.049), stage (P=0.015), and treatment modality (P=0.008), but not other factors, including age (P=0.402) and performance status (P=0.421). The median SUVmax was 5.1 (25–75th percentile: 3.45–7.0) in patients with adenocarcinoma and 8.3 (25–75th percentile: 6.9–9.9) in those with other types of NSCLC. Adenocarcinomas showed significantly lower SUVmax than the other tumor types (P<0.001). Cox analysis adjusting for possible confounding factors, including gender, smoking status, histology and stage, demonstrated that the hazard ratios increased as the SUVmax increased in terms of both PFS (P=0.008) and OS (P=0.045), indicating that SUVmax predicts outcome independently of other clinical factors, such as histology and stage. Our findings indicate that FDG-PET examination can provide information useful for prognostication in NSCLC.

A multicenter phase II study to evaluate the efficacy and safety of gefitinib as first-line treatment for Korean patients with advanced pulmonary adenocarcinoma harboring EGFR mutations - Corrected Proof

2010-04-30

Abstract: This study was designed to prospectively evaluate the efficacy and safety of first-line gefitinib treatment in patients with advanced pulmonary adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations and to explore the molecular factors affecting the efficacy of gefitinib. Tumor tissue, derived from either the original tumor or the metastatic or recurrent site was taken from chemo-naïve pts with advanced (stage IIIB, IV, and recurrent) pulmonary adenocarcinoma. Tumor genomic DNA underwent direct sequencing for EGFR exons 18, 19, 20, and 21. Patients with EGFR mutations received 250mg of gefitinib daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression free survival (PFS), overall survival (OS) and tolerability. Out of 147 screened patients, 45pts (31%) had EGFR mutations and received gefitinib. The most common EGFR mutations were in-frame exon 19 deletions (29pts, 64%) and L858R point mutation in exon 21 (15pts, 33%). One patient had atypical mutation of L861Q in exon 21. The ORR was 53.3% (95% CI, 38.6–67.9) and disease control rate (DCR) including stable disease was 86.7%. The median progression free survival (PFS) was 398 days and the median overall survival (OS) was 819 days. Treatment was well tolerated. Grade 3/4 adverse events (AEs) were reported by 6 patients and treatment-related Grade 3 AEs by 3 patients. There were no treatment-related Grade 4 AEs. Exploratory subgroup analysis according to the EGFR mutation subtypes was carried out. The ORR and DCR were higher in patients with exon 19 deletions than those with L858R (62.1% vs 33.3%; P=0.0705 and 96.6% vs 66.7%; P=0.0062, respectively). All 4 patients with progressive disease had a L858R mutation. No secondary resistant mutations such as T790M mutation or insertions in exon 20 were found in those patients. In addition, OS was significantly better in patients with exon 19 deletions than those with L858R (24-month OS rate was 72.1% vs 32.0%, P=0.0148). Gefitinib as the first-line treatment for Korean patients with advanced pulmonary adenocarcinoma harboring EGFR mutations was effective and well tolerated. Subgroup analysis suggests that the benefit from gefitinib treatment was more prominent in patients with the exon 19 deletion mutations (ClinicalTrials.gov number, NCT00344773).

Apolipoprotein E expression promotes lung adenocarcinoma proliferation and migration and as a potential survival marker in lung cancer - Corrected Proof

Wen-Pin Su, Yen-Ting Chen, Wu-Wei Lai, Chien-Chung Lin, Jing-Jou Yan, Wu-Chou Su — 2010-04-30

Abstract: Many human lung cancer cell lines express apolipoprotein E (ApoE), especially cells derived from malignant pleural effusions (MPE) in patients with lung adenocarcinoma. This study aimed to investigate the influence of ApoE expression on lung cancer. In lung cancer tissues, ApoE expression was more frequently found in malignant pleural effusions (MPE)-associated lung adenocarcinoma than in lung adenocarcinoma or squamous cell carcinoma without MPE (P<0.05), indicating that ApoE is associated with the pathogenesis of MPE in patients with lung adenocarcinoma. Next, we examined the roles of ApoE in an MPE-derived lung adenocarcinoma cell line that endogenously over-expresses ApoE, PC14PE6/AS2 (AS2). In that experiment we inhibited ApoE expression by transfection of a plasmid carrying ApoE siRNAs into AS2 cells to generate AS-S2 and AS-S3 cells. Compared to vector-control cells and parental AS2 cells, AS2-S2 and AS2-S3 cells grew slower (P<0.05), were more sensitive to cisplatin, and had significantly impaired cellular migration (P<0.05). Furthermore, over-expression of ApoE was independently associated with poor survival in lung adenocarcinoma patients who had MPE at the time of diagnosis (P<0.001). Conclusively, ApoE over-expression promotes cancer proliferation and migration and contributes to an aggressive clinical course in patients with lung adenocarcinoma and MPE.

Association between poor performance status and risk for toxicity during erlotinib monotherapy in Japanese patients with non-small cell lung cancer: Okayama Lung Cancer Study Group experience - Corrected Proof

2010-04-23

Abstract: Background: The relationship between poor performance status (PS) and toxicity during chemotherapy is controversial. We examined this for erlotinib monotherapy in non-small cell lung cancer (NSCLC) patients.Patients and methods: Toxicity during the first month of therapy was recorded in 209 patients receiving erlotinib for NSCLC, and its association with PS was assessed.Results: Of 209 patients, 52, 115, 30 and 12 had a PS of 0, 1, 2 and 3–4, respectively. Treatment was discontinued in 26% of patients within 1 month, with a higher rate in poorer PS patients (17%, 25%, 37% and 42%). Discontinuation was predominantly due to disease progression, rather than adverse events, in both the whole cohort (82% vs. 18%) and the poorest PS subgroup (100% vs. 0%). Three, two, and four patients with a PS of 1, 2 and 3–4, respectively, died within 1 month; all six deaths of PS 2–4 patients were attributed to disease progression. Treatment interruption and dose reduction rates were similar among the subgroups. The principal adverse event was skin rash, with identical incidence in all PS subgroups.Conclusions: Poor PS is unlikely to increase the risk for toxicity during erlotinib monotherapy, but was related to low compliance, probably because of disease progression rather than treatment-related toxicity.