Lung Cancer - Articles in Press

Chemotherapy for pulmonary large cell neuroendocrine carcinoma: Similar to that for small cell lung cancer or non-small cell lung cancer? - Corrected Proof

2012-05-14

Abstract: Background: There is controversy regarding palliative chemotherapy for large cell neuroendocrine carcinoma (LCNEC). We evaluated whether advanced LCNEC should be treated similarly to small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).Patients and methods: The clinical reports and tumor specimens of 45 consecutive patients who were diagnosed with advanced LCNEC were reviewed. They were divided into SCLC (n=11) and NSCLC regimen groups (n=34) according to first-line chemotherapeutic regimens.Results: Most patients were male (96%) and smokers (93%) with a median age of 64 years. Neuroendocrine differentiation was established in 42 (93%) tumors by immunohistochemical analyses. Regarding the efficacy of first-line chemotherapy in the SCLC and NSCLC regimen groups, the response rates were 73% and 50% (P=0.19), and the median progression-free survival times were 6.1 and 4.9 months (P=0.41), respectively. The difference in overall survival between the two treatment groups was 7.3 months (16.5 vs. 9.2 months, P=0.10). There was also a considerable difference in the type and efficacy of salvage chemotherapeutic regimens between the two groups: salvage regimens with irinotecan, platinum, or taxanes were commonly used with relatively high objective responses in the SCLC regimen group, whereas frequently used agents in the NSCLC regimen group such as pemetrexed, gefitinib, or erlotinib were associated with no objective response.Conclusion: Regarding palliative chemotherapy for advanced LCNEC, treatment similar to SCLC is more appropriate than NSCLC.

Successful erlotinib rechallenge for leptomeningeal metastases of lung adenocarcinoma after erlotinib-induced interstitial lung disease: A case report and review of the literature - Corrected Proof

2012-05-14

Abstract: The most serious adverse reaction associated with treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is drug-induced interstitial lung disease (ILD). Because EGFR-TKIs are key drugs for patients with non-small cell lung cancer who have somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations), several cases of retreatment with EGFR-TKIs after ILD induced by these drugs have been reported. Here, we present a 68-year-old man with lung adenocarcinoma and leptomeningeal metastases having an EGFR mutation who was retreated with erlotinib after erlotinib-induced ILD. He suffered no ILD recurrence and his leptomeningeal metastases dramatically improved. In addition to the present case, reports of nine patients who were retreated with EGFR-TKIs after ILD were found in the literature. Only one patient had recurrence of ILD (although seven were retreated at a reduced dose of EGFR-TKIs, including the patient with recurrence). In contrast, three patients had no recurrence of ILD even without dose-reduction. These reports suggest that dose-reduction plays a limited role in preventing recurrence. Many patients received corticosteroids during retreatment, but not the one with recurrence of ILD. This may suggest that corticosteroids can prevent recurrence due to their antiinflammatory properties.

National survey of the medical treatment status for non-small cell lung cancer (NSCLC) in China - Corrected Proof

2012-05-14

Abstract: Introduction: Treatment choice for NSCLC in China has not previously been reported. This paper explores the clinical practice and adherence to treatment guidelines for NSCLC.Methods: A specifically designed questionnaire was used. It consisted of personal information of the responders and treatment details (patient identification data was excluded). Questionnaires were delivered to doctors in 12 major cities in China. Doctors were asked to answer the questionnaires based on real cases in their daily practice.Results: 987 cases of NSCLC were included. In first-line chemotherapy, regimens were mostly platinum-based among which gemcitabine plus platinum was predominately used (27.4%), followed by docetaxel plus platinum (16.2%) and paclitaxel plus platinum (13.5%). In second-line therapy some were treated with single agents, such as docetaxel (12.9%), gefitinib (11.1%), pemetrexed (9.3%), and erlotinib (3.5%). 44.5% were with doublet therapy. Detection rate of epidermal growth factor receptor (EGFR) mutation was only 9.6% because of the limited prevalence of testing technology. EGFR mutation rate was 46.8%. EGFR-tyrosine kinase inhibitors (TKIs) were used more frequently as salvage (14.8%) rather than upfront therapy (5.3%).Conclusions: This survey reveals the daily clinical treatment for NSCLC in China. Overall data showed modest adherence to the national guideline (NCCN guideline Chinese version) for first-line chemotherapy. We believe this survey is valuable to provide a reference for further clinical trial design and policy making.

Prognostic impact of nestin expression in resected large cell neuroendocrine carcinoma of the lung - Corrected Proof

2012-05-09

Abstract: Background: Large cell neuroendocrine carcinoma (LCNEC) of the lung is categorized as a high-grade neuroendocrine carcinoma with an aggressive clinical behavior. Nestin is a class VI intermediate filament protein expressed in stem/progenitor cells during central nervous system development. Recently, we reported that nestin expression is a prognostic indicator of a poorer survival probability in patients with resected NSCLC. In the present study, we aimed to determine its prognostic significance concerning survival in patients with resected LCNEC.Materials and methods: Nestin expression in tumor cells was immunohistochemically studied in 30 patients with resected LCNEC, and its associations with clinicopathologic parameters including the Ki-67 labeling index (LI) and TTF-1 expression were evaluated. Kaplan–Meier survival analysis and Cox proportional hazards models were used to estimate the effect of nestin expression on survival.Results: Nestin expression was observed in 8 of the 30 (26.7%) LCNECs. Clinicopathologically, although no significant association between nestin expression and age, gender, smoking habits, p-TNM stage, tumor size, nodal status, or TTF-1 expression was observed, nestin expression was significantly associated with a high Ki-67 LI (P=0.012). On survival analysis, nestin expression was significantly associated with a poorer prognosis in patients with LCNEC (P=0.016). The Cox proportional regression model confirmed that the crude hazard ratio (95%CI) of nestin expression was 3.40 (1.18–9.77).Conclusions: The present study suggests that nestin expression seems to be a prognostic indicator of a poorer survival probability in patients with resected LCNEC, although its prognostic significance still requires confirmation with larger patient populations.

Phase II study of maintenance sunitinib following irinotecan and carboplatin as first-line treatment for patients with extensive-stage small-cell lung cancer - Corrected Proof

2012-05-07

Abstract: Background: Inhibition of angiogenesis may be effective in the treatment of small-cell lung cancer (SCLC). Sunitinib, an oral agent that inhibits the VEGF signaling pathway, may delay progression in sequence with chemotherapy. This phase II trial was designed to evaluate the role of sunitinib monotherapy following 6 cycles of irinotecan and carboplatin in patients with newly diagnosed extensive-stage (ES) SCLC.Method: Patients aged ≥18years with previously untreated ES-SCLC were eligible. Additional criteria included: ECOG PS 0–1, no active brain metastases, and adequate organ function. Patients received 28-day cycles of irinotecan (60mg/m2, days 1, 8, 15) and carboplatin (AUC=4, day 1), and were assessed for response every 8weeks. After 6 cycles of chemotherapy, patients with stable disease or responding disease proceeded to sunitinib monotherapy (25mg orally daily) until disease progression or unacceptable toxicity. The primary endpoint was 1-year overall survival (OS).Results: Between 2/09 and 10/09, 34 patients (median age 65years [range, 41–80]) were enrolled. 53% of patients were male, 47% had ECOG PS 0.21 patients (62%) completed 6 cycles of chemotherapy, and 17 (50%) initiated sunitinib monotherapy (median duration: 9weeks; range, 2–28+weeks). After a median follow-up of 50weeks (range: 37–68weeks), 22 (62%) of the patients remain alive. The objective response rate with chemotherapy was 59%, and an additional 20% had stable disease. 1-year OS was 54% and median time to progression was 7.6months. Grade 3/4 toxicity was rare during sunitinib monotherapy.Conclusions: This phase II trial provides support for further study of sunitinib maintenance therapy following platinum-doublet chemotherapy in patients with ES-SCLC. The 1year OS of 54% is encouraging, and a randomized trial would be appropriate to assess sunitinib's impact following chemotherapy.

Clinical and molecular analysis of synchronous double lung cancers - Corrected Proof

2012-05-07

Abstract: Background: Since multiple lung cancer treatment strategies differ, it is essential for clinicians to be able to distinguish between separate primary lesions and metastasis. In the present study, we used array comparative genomic hybridization (aCGH) and somatic mutation (epidermal growth factor receptor: EGFR) to analyze genomic alteration profiles in lung cancer patients. To validate the consistency among the pathological assessments and clarify the clinical differences between double primary lesions and metastasis, we also examined synchronous double lung cancer clinical data.Methods: Between January 1970 and March 2010, 2215 patients with lung cancer underwent surgical resection at Nagasaki University Hospital. We performed molecular analysis of 12 synchronous double lung cancer patients without lymph node metastasis (intrapulmonary metastasis in the same lobe (pm1): n=6, primary: n=6). We then evaluated the clinical outcomes of patients with pathologically diagnosed synchronous double lung cancers (intrapulmonary metastasis (pm): n=80, primary: n=39) and other T3 tumors (n=230).Results: Examination of the concordance rate (CR) of the copy number changes (CNCs) for paired tumors showed that the metastasis group was larger than the primary group (55.5% vs. 19.6%, p=0.04). Pathological diagnosis and molecular classification were the same in 10 out of 12 cases (83%). As compared to the primary group, there tended to be an inferior 5-year survival curve for the pm group. However, in N0 patients, the survival curve for the pm group overlapped the primary group, while the survival rate of the pm1 group was much higher than that of other T3 group (p<0.01).Conclusions: Both pathological and molecular assessment using aCGH adapted in the current study appeared to have a consistency. Pathological pm1(T3)N0 patients may have a better prognosis than other T3N0 patients.

Characterization of vitamin D receptor (VDR) in lung adenocarcinoma - Corrected Proof

2012-05-07

Abstract: Purpose: The anti-proliferative effects of 1α,25-dihydroxyvitamin D3 (1,25-D3, calcitriol, the active form of vitamin D) are mediated by the nuclear vitamin D receptor (VDR). In the present study, we characterized VDR expression in lung adenocarcinoma (AC).Experimental design: We examined VDR mRNA expression using a quantitative real-time PCR (qRT-PCR) in 100 patients who underwent surgery for lung AC. In a subset of these patients (n=89), we examined VDR protein expression using immunohistochemistry. We also examined the association of VDR protein expression with circulating serum levels of 25-hydroxyvitamin D3 (25-D3) and 1,25-D3. The antiproliferative effects and cell cycle arrest of 1,25-D3 were examined using lung cancer cell lines with high (SKLU-1) as well as low (A549) expression of VDR mRNA.Results: Higher VDR expression correlates with longer survival after adjusting for age, sex, disease stage and tumor grade (HR 0.73, 95% CI 0.58–0.91). In addition, there was a positive correlation (r=0.38) between serum 1,25-D3 and tumor VDR protein expression. A greater anti-proliferative effect of 1,25-D3 was observed in high compared to low VDR-expressing cell lines; these effects corresponded to G1 cell cycle arrest; this was associated with a decline in cyclin D1, S-phase kinase protein 2 (Skp2), retinoblastoma (Rb) and minichromosome maintenance 2 (MCM2) proteins involved in S-phase entry.Conclusions: Increased VDR expression in lung AC is associated with improved survival. This may relate to a lower proliferative status and G1 arrest in high VDR-expressing tumors.

ERCC1 expression in circulating tumor cells (CTCs) using a novel detection platform correlates with progression-free survival (PFS) in patients with metastatic non-small-cell lung cancer (NSCLC) receiving platinum chemotherapy - Corrected Proof

2012-05-03

Abstract: Purpose: To utilize a novel circulating tumor cell (CTC) technology to quantify ERCC1 expression on CTCs and determine whether ERCC1 expression levels predict efficacy of platinum-based chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC).Experimental design: ERCC1 expression was measured in 17 metastatic NSCLC patients who received platinum-based therapy and had ≥2 intact CTCs with acceptable ERCC1 expression assay results. ERCC1 levels were determined from average expression on individual CTCs in each sample. Progression-free survival (PFS) was calculated from the date of therapy initiation.Results: PFS decreased with increasing ERCC1 expression (p<0.04, F-test, linear regression). Lack of ERCC1 expression was associated with longer PFS (266 days versus 172 days, log-rank, p<0.02) in a Kaplan–Meier analysis using ERCC expression level of 1 as a cutoff (range 0–30). The difference in survival was statistically significant with a hazard ratio of 4.20 (95% CI 1.25–14.1, p<0.02, log-rank). PFS was also observed to decrease with increased cytokeratin (CK) expression (p<0.01 long-rank (Cox regression) and F-test (linear regression)). The hazard ratio is 4.38 (95% CI 1.76–10.9) for each log-change in CK value until progression was noted on imaging.Conclusion: Low expression of ERCC1 on CTCs correlates with PFS in patients with metastatic NSCLC receiving platinum-based therapy.

The Glasgow Prognostic Score (GPS) predicts toxicity and efficacy in platinum-based treated patients with metastatic lung cancer - Corrected Proof

2012-05-01

Abstract: Purpose: Lung cancer is the most common cause of cancer death. A cumulative prognostic score based on C-reactive protein and albumin, termed the Glasgow Prognostic Score (GPS), indicates the presence of systemic inflammatory response. GPS has been proposed as a powerful prognostic tool for patients with various types of malignant tumors, including lung cancer. The aim of this study was to assess the predictive value of baseline GPS in terms of toxicity and response in lung cancer patients treated with platinum-based chemotherapy.Patients and methods: Patients referred to our institution for consideration of first-line platinum-based treatment were eligible. Demographics and disease-related characteristics were recorded. Toxicity was graded according to NCI CTCAE version 3.0 throughout first-line therapy. GPS was calculated before the onset of treatment and was related to the development of toxicity. Response to first-line therapy and survival data were also collected.Results: Totally, 96 lung cancer patients were accrued. GPS was associated with increased mucositis p=0.004), neurotoxicity (p=0.038), neutropenia (p=0.02), dose reductions or/ and need for granulocyte colony-stimulating factor (G-CSF) support (p=0.005), toxicity-related termination of treatment (p=0.001) and chemotherapy-related toxic deaths (p=0.013). GPS was associated with overall survival (p=0.016) and progression-free survival (p=0.016) as well as response to treatment (p=0.05).Conclusions: Our data demonstrate that GPS assessment is predictive of the most important aspects of platinum-related toxicity and this may partly explain its associations with poor clinical outcome in patients with metastatic lung cancer.

Single agent maintenance therapy for advanced stage non-small cell lung cancer: A meta-analysis - Corrected Proof

2012-04-30

Abstract: Background: Maintenance therapy is a new treatment paradigm for advanced non-small cell lung cancer (NSCLC). We conducted a meta-analysis of randomized studies with single agent maintenance therapy.Methods: An electronic literature search of public databases (MEDLINE, EMBASE, Cochrane library) and manual search of relevant conference proceedings was performed. A formal meta-analysis was conducted using Comprehensive Meta Analysis software (Version 2.0). Outcome data were pooled and reported as hazard ratio (HR). The primary outcome of interest was overall survival (OS) and secondary outcome was progression free survival (PFS).Results: Twelve studies were included (5 meeting abstracts, 7 full manuscripts) with a total of 4286 patients (maintenance arm/control arm – 2449/1837, median age 61years, males – 69%). The OS (HR 0.86, 95% confidence intervals [CI] 0.80–0.92; P=0.0003) and PFS (HR 0.80, 95% CI 0.77–0.84; P<0.0001) were superior with maintenance therapy. ‘Switch’ maintenance was associated with significant OS and PFS improvement (OS HR 0.84, 95% CI 0.77–0.91; P=0.00026; PFS HR 0.62, 95% CI 0.57–0.67; P<0.0001). Despite a modest improvement in PFS (HR 0.90, 95%CI 0.85–0.95; P=0.007), “continuation” maintenance was not associated with survival benefit (HR 0.927, 95%CI 0.78–1.09; P=0.33). Improvements in OS and PFS were observed with both EGFR-targeted agents (HR 0.83, 95% CI 0.74–0.92; P=0.004; HR 0.64, 95% CI 0.58–0.71 P<0.0001) and cytotoxic agents (HR 0.89, 95% CI 0.80–0.98; P=0.018; HR 0.85, 95% CI 0.80–0.89; P<0.0001).Conclusions: Single agent maintenance therapy improves overall survival, though statistical significance was only noted with ‘switch’ maintenance.

Loss of heterozygosity of the Mutated in Colorectal Cancer gene is not associated with promoter methylation in non-small cell lung cancer - Corrected Proof

2012-04-30

Abstract: ‘Mutated in Colorectal Cancer’ (MCC) is emerging as a multifunctional protein that affects several cellular processes and pathways. Although the MCC gene is rarely mutated in colorectal cancer, it is frequently silenced through promoter methylation. Previous studies have reported loss of heterozygosity (LOH) of the closely linked MCC and APC loci in both colorectal and lung cancers. APC promoter methylation is a marker of poor survival in non-small cell lung cancer (NSCLC). However, MCC methylation has not been previously studied in lung cancer. Therefore, we wanted to determine if MCC is silenced through promoter methylation in lung cancer and whether this methylation is associated with LOH of the MCC locus or methylation of the APC gene. Three polymorphic markers for the APC/MCC locus were analysed for LOH in 64 NSCLC specimens and matching normal tissues. Promoter methylation of both genes was determined using methylation specific PCR in primary tumours. LOH of the three markers was found in 41–49% of the specimens. LOH within the MCC locus was less common in adenocarcinoma (ADC) (29%) than in squamous cell carcinoma (SCC) (72%; P=0.006) or large cell carcinoma (LCC) (75%; P=0.014). However, this LOH was not accompanied by MCC promoter methylation, which was found in only two cancers (3%). In contrast, 39% of the specimens showed APC methylation, which was more common in ADC (58%) than in SCC (13%). Western blotting revealed that MCC was expressed in a subset of lung tissue specimens but there was marked variation between patients rather than between cancer and matching non-cancer tissue specimens. In conclusion, we have shown that promoter methylation of the APC gene does not extend to the neighbouring MCC gene in lung cancer, but LOH is found at both loci. The variable levels of MCC expression were not associated with promoter methylation and may be regulated through other cellular mechanisms.

Angiolymphatic invasion exerts a strong impact on surgical outcomes for stage I lung adenocarcinoma, but not non-adenocarcinoma - Corrected Proof

2012-04-30

Abstract: Angiolymphatic invasion (ALI), representing lymphatic invasion (Ly) and intratumoral vascular invasion (V), is considered to be a useful prognostic factor for pathological stage I non-small cell lung carcinoma (NSCLC). However, the types of tumor for which prognoses are most influenced by ALI positivity have not previously been discussed, nor has the question of whether these findings should influence postoperative therapeutic decision-making after complete resection. The present study investigated 195 cases of stage I NSCLC treated by potentially curative surgical resection of the primary tumor and systematic lymphadenectomy. ALI-positive (ALI(+)) results were found in 31.8% of tumors, and 5.1% exhibited both Ly(+) and V(+). Five-year recurrence-free survival was significantly lower in ALI(+) cases (50.6%) than in ALI(−) cases (85.9%; p<0.0001, log-rank test). In particular, 5-year recurrence-free survival rate was only 10.0% for Ly(+)V(+) cases. ALI(+) correlated with high age, male sex, tumor size (>2.0cm), elevated preoperative serum carcinoembryonic antigen level (≥5.0ng/mL), high maximum standard uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) (≥5.0), pleural invasion, and histological classification of non-adenocarcinoma (ADC). According to histopathological subset analyses, ALI(+) was associated with shorter recurrence-free survival than ALI(−) only among ADC patients (p<0.0001, log-rank test), and not among non-ADC patients (p=0.7710). High preoperative serum CEA level, high SUVmax on FDG-PET, pleural invasion, Ly(+), and V(+) were significant risk factors for recurrence in univariate Cox survival analysis among stage I ADC patients. Importantly, Ly(+) and V(+) were identified as independent risk factors for recurrence by multivariate analysis. Histopathological detection of ALI as a risk factor for recurrence should be considered for inclusion in the staging criteria and as additional information for determining postoperative adjuvant treatment of stage I NSCLC, particularly among ADC patients, but not among non-ADC patients.

Use of mutation specific antibodies to detect EGFR status in small biopsy and cytology specimens of lung adenocarcinoma - Corrected Proof

Adnan Hasanovic, Daphne Ang, Andre L. Moreira, Maureen F. Zakowski — 2012-04-30

Abstract: Background: EGFR mutation status is the best predictor of response to tyrosine kinase inhibitors (TKIS) in primary lung adenocarcinoma. Approximately 70% of lung cancers are diagnosed in advanced stages where small biopsies and cytological specimens are the only source of material for both diagnosis and mutation testing. Specific antibodies that can detect mutant EGFR protein were evaluated for the detection of EGFR mutation by immunohistochemistry (IHC) in cytology and small biopsy specimens.Methods: Assessment of EGFR mutation status was performed by using antibodies specific to the two major forms of mutant EGFR, exon 21 L858R and exon 19 deletion (15bp). The study was performed in 145 lung adenocarcinomas, including cytology material, core biopsy, and decalcified bone biopsy. Stains were scored as negative (0), 1+ (weak and focal), 2+ (moderate intensity and focal), and 3+ (strong and diffuse). The result of the IHC stains was correlated with mutations status determined by standard molecular methods.Results: Validation using clinical material showed deletions in exon 19 were detected in 35% and L858R mutation in 17.6% of all cases by standard molecular methods. A cutoff value of 2+ was used as positive by IHC. No wild type cases were immunoreactive. The positive predictive value (PPV) and specificity for both antibodies was 100%. The antibodies performed well in cytology, core biopsies and decalcified bone biopsies.Conclusion: Immunostaining to detect specific mutant EGFR shows a good correlation with mutation analysis and can be used as a screening method to identify patients for TKI therapy. IHC methodology is potentially useful when molecular analysis is not available and for use in small biopsies when material is too scant for molecular tests. Importantly mutation specific antibodies are useful in determining EGFR status in tissues obtained from bone biopsy as decalcification processes used in molecular based studies often result in DNA degradation hindering mutation detection.

Impact of non-small cell lung cancer histology on survival predicted from the graded prognostic assessment for patients with brain metastases - Corrected Proof

2012-04-30

Abstract: Introduction: The Graded Prognostic Assessment (GPA) provides prognostic classification for patients with brain metastases (BM), based on Radiation Therapy Oncology Group (RTOG) data. Recent evidence suggests differential response and outcomes to chemotherapy for different non-small cell lung cancer (NSCLC) histologies. Using a large BM patient database, we assessed the impact of histologic subtypes on survival stratified by the GPA.Methods: From an IRB-approved database, we analyzed 780 patients with NSCLC BM treated from 1982 to 2004. GPA classification variables included age, KPS, number of BM, and presence of extracranial disease. Histology was identified for each patient. Median survival time (MST) based on GPA class and histology were calculated using Kaplan–Meier analysis. The log rank test was used to determine statistical differences.Results: MST, in months, by histology were: adenocarcinoma (AC) 6.2 (n=464), large cell (LC) 4.1 (n=98), squamous (SQ) 4.2 (n=108) (p=0.0549). For GPA 3.5–4.0, MSTs did not differ significantly by histology. Differences in MST by histology were noted for GPA 3.0 (p=0.04), GPA 1.5–2.5 (p=0.01), and GPA 0–1.0 (p=0.02). For all patients with brain metastases BM from NSCLC, MSTs by GPA score were: GPA 3.5–4.0, 12.6; GPA 3.0, 10.2; GPA 1.5–2.5, 5.8; and GPA 0–1.0, 2.7.Conclusions: Adenocarcinoma showed a statistically significant higher MST than other histologies of NSCLC for patients with GPA 0–3.0. Using histology as a prognostic factor for BM from NSCLC warrants further investigation. Our cohort of NSCLC BM patients validates the GPA, with MST comparable to that of published data.

Expression and prognostic significance of centromere protein A in human lung adenocarcinoma - Corrected Proof

2012-04-30

Abstract: Background: Centromere protein A (CENP-A), one of the fundamental components of the human active kinetochore, is frequently upregulated in many cancers and plays important roles in cell cycle regulation, cell survival, and genetic stability. The aim of the present study was to explore the expression and prognostic significance of CENP-A in lung adenocarcinoma.Experimental design: The expression of CENP-A was detected in 20 fresh human lung adenocarcinoma specimens and corresponding non-tumorous lung tissues by real-time polymerase chain reaction (RT-PCR) and Western blotting analysis. Using immunohistochemistry, we analyzed CENP-A protein expression in additional 309 lung adenocarcinomas. The clinicopathological and prognostic significance of CENP-A expression was analyzed.Results: RT-PCR and Western blotting analysis revealed an enhanced expression of CENP-A in lung adenocarcinomas relative to adjacent non-tumorous lung tissues at both transcriptional and translational levels. Immunohistochemistry showed that 146 of 309 lung adenocarcinomas (47.3%) had high expression of CENP-A. CENP-A overexpression was significantly correlated with pathological grade (P=0.009), pT status (P=0.017), pN status (P=0.002), pleural invasion (P=0.013), high Ki-67 expression (P=0.003), and P53 positivity (P=0.001). Patients with high CENP-A expression had shorter overall survival time compared with those with low CENP-A expression. Multivariate analysis identified CENP-A as an independent prognostic factor for lung adenocarcinoma.Conclusion: Our results demonstrate that elevated CENP-A expression is closely associated with lung adenocarcinoma progression and has an independent prognostic value in predicting overall survival for patients with lung adenocarcinoma.

Peroxiredoxins and tropomyosins as plasma biomarkers for lung cancer and asbestos exposure - Corrected Proof

2012-04-26

Abstract: The prognosis of lung cancer is poor due to late diagnosis, the lack of established screening programs, and the paucity of early biomarkers for high-risk populations. Plasma proteome analysis was used to identify novel biomarkers for diagnosing lung cancer, and to unravel the mechanisms of underlying pathogenesis. Plasma proteins obtained from asbestos-exposed lung cancer cases detected by CT screening, asbestos-exposed subjects, clinical lung cancer patients, and healthy tobacco smokers, 5–6 cases in each group, were separated by two-dimensional gel electrophoresis, and identified with tandem mass spectrometry (LC–MS/MS). Nine proteins were selected for immunological confirmation in a test or validation set of plasma samples from an additional 49 clinical lung cancer cases, 66 asbestos-exposed patients, and 107 healthy tobacco smokers. Twenty-eight unique proteins were differentially expressed between the four study groups (p<0.05). Peroxiredoxin 1 (PRX1) was detected as a novel plasma marker for lung cancer (p=0.001). We also confirmed the previously found association of serum amyloid A with lung cancer (p<0.001). High plasma levels of tropomyosin 4 (TPM4: p<0.001) and peroxiredoxins 1 and 2 (PRX2: p<0.001) correlated with asbestos exposure or a diagnosis of asbestosis. PRX1 and PRX2 exhibited an inverse correlation with tobacco smoking (p<0.001). Plasma peroxiredoxins 1 and 2, and tropomyosin 4 were shown to associate with asbestos-exposure, and peroxiredoxin 1 with lung cancer. High plasma levels of peroxiredoxin 1 may result from genetic damage caused by reactive oxygen species. This study has identified several biomarkers worthy of further investigation in lung cancer and asbestos-related diseases.

Prospective study of transarterial infusion of docetaxel and cisplatin to treat non-small-cell lung cancer in patients contraindicated for standard chemotherapy - Corrected Proof

Masanori Nakanishi, Yoshimasa Yoshida, Toshiki Natazuka — 2012-04-26

Abstract: Our previous retrospective study indicated a good response rate of non-small-cell lung carcinoma (NSCLC) to transarterial infusion chemotherapy, but the precise effect remains unresolved. This prospective study enrolled 25 patients with stage III or IV or recurrent NSCLC without distant metastasis (M1b) who were not candidates for either standard chemotherapy or chemoradiotherapy. The feeding arteries of each tumor detected by angiography were recorded and tumor staining was visually graded on a scale of I–IV. Docetaxel and cisplatin (25 and 25mg/m2, respectively) were administered by arterial infusion. The total dose of each was divided among feeding arteries according to the degree of tumor staining. The end points included response rate, progression-free survival (PFS), overall survival (OS) and toxicity. Correlations between effects and some clinical aspects were investigated. Of 25 patients enrolled between May 2007 and April 2011, 24 of them were evaluable. One complete response and 12 partial responses were achieved for an overall response rate of 52% (95% confidence interval [CI]: 35–69%). The median progression-free survival and overall survival periods were 6.5 (95% CI: 5.4–7.6) and 17.4 (95% CI: 14.2–20.6) months, respectively. The 1- and 2-year survival rates were 81% and 32%, respectively. Grade 3–4 hematological toxicity was not evident. Grade 3 general fatigue or appetite loss developed in patients with performance status (PS) ≥3. Neither grade 4 non-hematological toxicity nor treatment-related death occurred. Among various clinical aspects, ECOG PS significantly correlated with PFS and OS, whereas tumor staining significantly correlated with response. Survival was significantly better for patients with good PS (0 or 1) than poor PS (≥2) and those with, than without grade IV tumor staining. If a sufficient number of feeding arteries are detected and the tumor is appropriately stained, then arterial infusion chemotherapy has favorable response rates with less toxicity for patients with stage III or IV or recurrent NSCLC without distant metastasis (M1b) who cannot tolerate standard chemotherapy.

Randomized phase II trial of first-line treatment with pemetrexed-cisplatin, followed sequentially by gefitinib or pemetrexed, in East Asian, never-smoker patients with advanced non-small cell lung cancer - Corrected Proof

2012-04-25

Abstract: Introduction: Treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors or chemotherapy have shown improved survival outcomes in East Asian, never-smoker patients with non-small cell lung cancer (NSCLC). However, treatment sequence has not been optimized in patients with unknown EGFR mutation status. This trial compared first-line chemotherapy with pemetrexed (P)-cisplatin (C), followed by either gefitinib (G) or P maintenance.Methods: East Asian, never-smoker, chemo-naïve patients with stage IIIB/IV NSCLC, performance status ≤1 and unknown EGFR mutation status were randomized 1:1 to receive 4 cycles of pemetrexed [500mg/m2]+cisplatin [75mg/m2] q3 weeks, followed by maintenance with either gefitinib [250mg/d] (PC/G) or pemetrexed [500mg/m2] q3 weeks and ≤2 optional cycles of cisplatin (PC/P). The primary endpoint, progression-free survival (PFS), was calculated from randomization date.Results: Between Feb and Nov 2007, 70 patients from China, Korea, and Taiwan were randomized and treated, among whom 59 patients (84.3%) had non-squamous NSCLC. Forty-nine patients (70.0%) completed the full sequential treatment (n=25 G; n=24 P). Median PFS was numerically longer for patients on PC/G (9.95 months) than those on PC/P (6.83months; hazard ratio [HR]=0.53, 95% confidence interval [CI]=0.27, 1.04). In contrast, median overall survival was numerically higher for patients on PC/P (HR=2.15, 95% CI=0.83, 5.60), though there was a high censoring rate. Response rate was similar in both arms. Treatment arms were similar for grade 3/4/5 toxicities.Conclusions: East Asian never-smoker patients with advanced NSCLC and unknown EGFR mutation status had improved PFS following treatment with first-line PC and sequential G. Irrespective of subsequent maintenance treatment, induction PC was safe and efficacious, leading to prolonged OS in the Asian patient population.

Proteomics-based identification of secreted protein dihydrodiol dehydrogenase 2 as a potential biomarker for predicting cisplatin efficacy in advanced NSCLC patients - Corrected Proof

2012-04-25

Abstract: Background and purpose: Cisplatin is the major agent in the standard first-line chemotherapy for NSCLC. However, only a small portion of patients achieve a tumor response to cisplatin-based chemotherapy and eventually develop acquired resistance. The aim of this study was to identify potential biomarkers that could predict the efficacy of cisplatin. Methods: Human lung adenocarcinoma cell line A549 was exposed to cisplatin for development of a resistant cell line, A549/DDP, and cisplatin-sensitivity was tested through the MTT assay. The global protein profiles from A549 and A549/DDP were compared using a proteomic approach. Western blot, real-time PCR and immunohistochemistry validated the expression of DDH2 in cell lines and tumor xenografts. Serum levels of DDH2 were measured by ELISA in 105 NSCLC patients treated with cisplatin-based chemotherapy. Result: The resistance of A549/DDP to cisplatin was 8.07-fold higher than that of A549 cells. Proteomic approach identified eight differentially (>5-fold) expressed proteins. Among them, secreted protein DDH2 was further investigated and it was found overexpressed through the method of Western blot, real-time PCR in cell lines, consistent with immunohistochemistry validation in xenograft. Clinical research showed that baseline serum DDH2 level in the patients with a progression disease was significantly higher than the patients of response or stable disease (9.036 vs. 3.529 and 3.982ng/mL, P<0.001) and serum DDH2 levels were significantly increased after cisplatin-based doublet chemotherapy (5.515 vs. 12.935 vs. 18.406ng/mL P<0.001, respectively). Conclusion: DDH2 expression might be a potential predictor and monitor of cisplatin efficacy in advanced NSCLC patients.

Use of erlotinib throughout pregnancy: A case-report of a patient with metastatic lung adenocarcinoma - Corrected Proof

2012-04-25

Abstract: The use of erlotinib throughout pregnancy has not been previously reported. We present the case of a 40year-old female patient with stage IV lung adenocarcinoma, mediastinal, bone and cerebral metastasis, a EGFR mutation and no smoking history, who had begun first line treatment with erlotinib 150mg once daily. After two and a half months of treatment a fourteen-week pregnancy was documented, and after informing on fetal risks secondary to erlotinib use and maternal risks secondary to treatment withholding, she decided to continue with treatment under clinical surveillance by both the oncology and obstetrics clinics. At thirty-three weeks gestation a live born 1600g female was born by caesarean section without evidence of congenital malformations. Imaging assessment after eight months of treatment showed complete bone and central nervous system response and partial lung and mediastinal response. The patient is currently undergoing the 11th month of treatment and is asymptomatic, the baby is 4months old and is in good health.

Reduced expression of cyclin D2 is associated with poor recurrence-free survival independent of cyclin D1 in stage III non-small cell lung cancer - Corrected Proof

2012-04-25

Abstract: Background: Compared to well-known function of cyclin D1 in lung cancer, the role of cyclin D2 is not clear. This study was aimed at understanding the clinicopathological significance of cyclin D2 in primary non-small cell lung cancer (NSCLC).Methods: We retrospectively analyzed expression statuses of cyclin D1, cyclin D2, p16, p21, p27, Ki-67, and phospho-pRb (Ser-807/811) using immunohistochemistry in 626 NSCLCs.Results: Cyclin D2 was expressed in normal lung tissue, and its expression was reduced in 170 (27%) of 626 NSCLCs with a median duration of follow-up of 64 months. Mean phospho-pRb (Ser-807/811) levels were not associated with expression levels of cyclin D2 (P=0.15). The relationship between recurrence and the reduced expression of cyclin D2 was not homogenous by stage (Breslow–Day test for homogeneity, P=0.04). Reduced expression of cyclin D2 was not associated with patient's prognosis in 370 stage I, 112 stage II, and 18 stage IV NSCLCs. However, for 126 stage III NSCLCs, reduced expression of cyclin D2 was adversely associated with recurrence-free survival (RFS) (hazard ratio [HR]=3.71, 95% CI=1.54–13.17; P=0.01), independent of histology and expression of cyclin D1. The reduced expression of cyclin D2 was not associated with the overexpression of cyclin D1 (P=0.65).Conclusion: The present study suggests that reduced expression of cyclin D2 in stage III NSCLC may be associated with poor RFS. And, cyclin D2 may have a distinct role from cyclin D1 in NSCLC.

EBUS-TBNA in patients presented with superior vena cava syndrome - Corrected Proof

Matthew K. Wong, Terence C. Tam, David C. Lam, Mary S. Ip, James C. Ho — 2012-04-23

Abstract: Introduction: Expedient pathological diagnosis is crucial in selection of appropriate treatment in patients presented with superior vena cava syndrome (SVCS). The performance and safety of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in this setting is unknown.Methods: Over a 4-year period, patients presented with SVCS in the presence of mediastinal mass and referred for EBUS-TBNA were enrolled for the study. The procedure was performed under local anaesthesia with conscious sedation. TBNA was performed under real-time with the curvilinear probe of EBUS. Rapid on site cytological examination (ROSE) was not available.Results: Eighteen procedures of EBUS-TBNA were performed in 17 patients. Malignancy was confirmed in 16 patients (diagnostic yield 94.1%). There was no major complication including significant bleeding or pneumothorax related to the procedures.Conclusions: EBUS-TBNA has high diagnostic yield and is safe in patients presented with SVCS and mediastinal mass.

EGFR mutations as a predictive marker of cytotoxic chemotherapy - Corrected Proof

2012-04-23

Abstract: Background: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) are important predictive markers for the response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Whether EGFR mutations can also predict the clinical outcomes in NSCLC patients receiving chemotherapy has not yet been established.Methods: We included 217 locally advanced/metastatic NSCLC cases in our study cohort. Each patient had received platinum doublet chemotherapy as a first line treatment, and had been screened for an EGFR mutation.Results: The subject cohort comprised 80 EGFR wild type and 137 EGFR-mutated lung cancer patients. Gemcitabine-based and taxane-based regimens were administered in 131 (60.4%) and 86 (39.6%) cases, respectively. Among the patients with a wild type EGFR, there was no significant difference in the response rate (RR), disease control rate (DCR), or progression-free survival (PFS) between gemcitabine-based and taxane-based therapies. Among the patients with EGFR mutations, no difference in RR was observed between gemcitabine-based and taxane-based treatments. On the other hand, the DCR and PFS associated with taxane-based therapy were superior when compared with the gemcitabine-based treatments. When we analyzed patients with an EGFR exon 19 deletion, the PFS of the taxane treated cases was better than that of the gemcitabine treated cases (5.3months vs 3.7months, P=0.012).Conclusions: Our current data indicate that lung cancer patients with EGFR-mutations had longer PFS with taxane than gemcitabine when receiving a platinum-based doublet regimen. The predictive meaning of EGFR mutations for cytotoxic chemotherapy should be further investigated.

Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients - Corrected Proof

2012-04-19

Abstract: Background: Cisplatin toxicity severely obstacles successful chemotherapy in lung cancer patients. Cisplatin uptake is considered as one of the major factors contributing to the side effects of cisplatin. Genetic variances of core genes also affect cisplatin toxicity. It has been identified that CTR1, copper transporter protein 1, plays an essential role in cisplatin uptake. The purpose of this study is to investigate whether CTR1 polymorphism is associated with platinum toxicity in non-small cell lung cancer (NSCLC) patients.Method: 204 incident NSCLC patients from three different institutions were enrolled and followed up. These patients were histologically confirmed with non-small cell lung cancer. All patients have accepted cisplatin-based chemotherapy for at least two cycles. Twenty SNPs of CTR1 were detected in these patients.Result: CTR1 rs10981694 A>C polymorphism is associated with cisplatin induced severe toxicity in NSCLC patients. C-carrier subjects presented poorer tolerance to ototoxicity (p<0.05). The survival times of patients with different rs10981694 genetic polymorphism were not significantly different.Conclusion: NSCLC patients carrying C allele of CTR1 rs10981694 presented more sensitivity to ototoxicity after cisplatin treatment. CTR1 plays an essential role in cisplatin toxicity and could be considered as a predictor for pretreatment evaluation in lung cancer patients.

Risk factors for radiation-induced lung toxicity in patients with non-small cell lung cancer who received postoperative radiation therapy - Corrected Proof

2012-04-18

Abstract: Background and purpose: To evaluate the risk factors for radiation-induced lung toxicity (RILT) from post-operative radiation therapy (PORT) in patients with non-small cell lung cancer (NSCLC).Material and methods: Ninety NSCLC patients who received PORT with or without chemotherapy from November 2002 to March 2006 were retrospectively analyzed. Each individual's radiotherapy plans were reviewed to determine the percentage of the whole lung volume that received more than a specific dose of irradiation (Vdose). The endpoint was RILT of grade 2 or higher. Data of potential risk factors for RILT were extracted from the medical records and evaluated by logistic regression modeling, the t-test, and the Chi-square test.Results: A total of 20 patients received pneumonectomy, while the remaining 70 received lobectomy. In the lobectomy group, 9 patients (10%) developed ≥grade 2 RILT. Among the clinical factors, only adjuvant chemotherapy was significantly correlated with RILT (p=0.039). For lung dosimetric factors, V20 through V40 were all significantly higher in the RILT group than in the non-RILT group. In the lobectomy group, the incidence of RILT was 27.3% in patients who received adjuvant chemotherapy and whose V20 was greater than 20%. It was 9.7% in lobectomy patients with one of the risk factors, and 0.0% in those with no risk factors (p=0.032).Conclusions: The lung toxicity of PORT was found to be acceptably low. Adjuvant chemotherapy and lung dosimetric factors of V20–V40 were significantly correlated with RILT risk in NSCLC patients.

Perineal and colonic metastases in two cases of malignant mesothelioma - Corrected Proof

Bhajneek Grewal, Gordon Reid, Hannah Lord — 2012-04-16

Abstract: Two patients with rare sites of metastatic pleural mesothelioma are presented and the literature on similar cases is examined. One patient developed colonic metastases from a sarcomatoid mesothelioma. Another patient with epithelioid mesothelioma developed perineal metastases.

Prognostic factors in patients with advanced non-small cell lung cancer: Data from the phase III FLEX study - Corrected Proof

2012-04-13

Abstract: The FLEX study demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). In the FLEX intention to treat (ITT) population, we investigated the prognostic significance of particular baseline characteristics. Individual patient data from the treatment arms of the ITT population of the FLEX study were combined. Univariable and multivariable Cox regression models were used to investigate variables with potential prognostic value. The ITT population comprised 1125 patients. In the univariable analysis, longer median survival times were apparent for females compared with males (12.7 vs 9.3 months); patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 compared with 1 compared with 2 (13.5 vs 10.6 vs 5.9 months); never smokers compared with former smokers compared with current smokers (14.6 vs 11.1 vs 9.0); Asians compared with Caucasians (19.5 vs 9.6 months); patients with adenocarcinoma compared with squamous cell carcinoma (12.4 vs 9.3 months) and those with metastases to one site compared with two sites compared with three or more sites (12.4 months vs 9.8 months vs 6.4 months). Age (<65 vs ≥65 years), tumor stage (IIIB with pleural effusion vs IV) and percentage of tumor cells expressing EGFR (<40% vs ≥40%) were not identified as possible prognostic factors in relation to survival time. In multivariable analysis, a stepwise selection procedure identified age (<65 vs ≥65 years), gender, ECOG PS, smoking status, region, tumor histology, and number of organs involved as independent factors of prognostic value. In summary, in patients with advanced NSCLC enrolled in the FLEX study, and consistent with previous analyses, particular patient and disease characteristics at baseline were shown to be independent factors of prognostic value. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798.

Inhibition of RalA signaling pathway in treatment of non-small cell lung cancer - Corrected Proof

2012-04-12

Abstract: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and relatively resistant to chemotherapy. The most prevalent molecular abnormality in NSCLC is the overactivation of K-Ras proto-oncogene; therefore, elucidating down-stream Ras signaling in NSCLC is significantly important in developing novel therapies against this malignancy. Our work indicates that RalA, an important effector of Ras, is activated in NSCLC cell lines. While RalA was also overactivated in fetal human broncho-epithelial cells, RalBP1 (Ral binding protein-1), an important down-stream effector of RalA, was expressed at higher levels in cancer cell lines. Aurora kinase-A (AKA), an upstream activator of RalA, was also found to be active only in malignant cells. The outcome of inhibition of RalA (by gene specific silencing using a lentivirus) on the malignant phenotype of A549 cells was also studied. While proliferation and invasiveness of A549 cells were reduced upon silencing RalA, apoptosis and necrosis were elevated in such conditions. Additionally, the in vivo tumorigenesis of A549 cells was reduced upon partial inhibition of RalA and AKA using pharmacological inhibitors. Finally, we were interested in evaluating the level of active RalA in the fraction of NSCLC cells expressing cancer stem cell markers. For this purpose cells with increased expression of CD44 were separated from A549 cells and compared with cells with low level of expression of this marker and an unsorted population. A significant enhancement of RalA activation in high CD44+ cells was found as potential evidence for involvement of RalA signaling in initiation of the neoplastic procedure and an important contributor for tumor maintenance in NSCLC. Further studies can reveal therapeutic, preventive and diagnostic value of RalA pathway in this deadly disease.

Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma - Corrected Proof

2012-04-12

Abstract: Malignant pleural mesothelioma (MPM) is resistant to conventional treatments. Novel, targeted treatments are hampered by the relative lack of MPM-associated tumour antigens. The aim of this study was to evaluate the level of expression and the relevance of 5T4 as a tumour-associated antigen in MPM. 5T4 expression was assessed by Western blotting, flow cytometry, immuno-cytochemistry and -histochemistry in 11 mesothelioma cell lines, 21 tumour biopsies, and ex vivo tumour cells obtained from the pleural fluid (PF) of 10 patients. 5T4 antibody levels were also determined in the plasma of patients and healthy donors. The susceptibility of MPM cells to 5T4-specific T-cell-mediated killing was determined using an HLA-A2+, CD8+ T-cell line, developed against the 5T417–25 peptide. We report here that cell surface 5T4 expression was detected in all mesothelioma cell lines and PF cell samples. Mesothelin and CD200, a suggested mesothelioma marker, were co-expressed with 5T4 on tumour cells in PF. Immunohistochemistry confirmed overexpression of 5T4, similar to mesothelin, on tumour cells but not on reactive stroma in all tissue sections tested. Median 5T4 antibody levels were 46% higher in patient than in healthy donor plasma, indicating immune recognition. Importantly, 5T4-specific CD8+ T-cells were able to kill four out of six HLA-A2+ MPM cell lines but not an HLA-A2− cell line, demonstrating immune recognition of MPM-associated 5T4 antigen at the effector T-cell level. We conclude that 5T4 is a potential new antigen for targeted therapies such as immunotherapy in MPM, as it is overexpressed on mesothelioma cells and recognised by 5T4-specific cytotoxic T-cells. Our findings have been translated into a Phase II clinical trial applying 5T4-targeted therapies in MPM patients.

Efficacy and safety of maintenance erlotinib in Asian patients with advanced non-small-cell lung cancer: A subanalysis of the phase III, randomized SATURN study - Corrected Proof

2012-04-11

Abstract: Maintenance therapy, commenced immediately after the completion of first-line chemotherapy, is a promising strategy for improving treatment outcomes in patients with non-small-cell lung cancer (NSCLC). The global phase III SequentiAl Tarceva in UnResectable NSCLC (SATURN) study evaluated the efficacy and safety of the epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib as maintenance treatment in NSCLC patients without progression after first-line chemotherapy. We report a retrospective subanalysis of Asian patients enrolled in SATURN.Patients with advanced NSCLC with no evidence of progression after four cycles of chemotherapy were randomized to receive erlotinib 150mg/day or placebo, until progressive disease or limiting toxicity. The co-primary endpoints of SATURN were progression-free survival (PFS) in all patients and in those with positive EGFR immunohistochemistry (IHC) status. Secondary endpoints included overall survival (OS), disease control rate, safety, quality of life (QoL) and biomarker analyses.In total, 126 patients from East and South-East Asian centers were randomized (14% of the intent-to-treat population): 88 from Korea, 28 from China and 10 from Malaysia; one patient was excluded from this analysis due to Indian ethnicity. PFS was significantly prolonged in the erlotinib treatment arm, both overall (hazard ratio [HR]: 0.57; p=0.0067) and in patients with EGFR IHC-positive disease (HR=0.50; p=0.0057). There was a trend towards an increase in OS, which reached statistical significance in the EGFR IHC-positive subgroup (p=0.0233). The overall response rate was significantly higher with erlotinib compared with placebo (24% versus 5%; p=0.0025). Erlotinib was generally well tolerated and had no negative impact on QoL in this subpopulation. The most common treatment-related adverse events were rash, diarrhea and pruritus.Erlotinib was effective and well tolerated in Asian patients, producing benefits consistent with those observed in the overall SATURN population. Maintenance treatment with erlotinib appears to be a useful option for the management of Asian patients with advanced NSCLC without progression after first-line chemotherapy.

Detection of EML4-ALK fusion genes in a few cancer cells from transbronchial cytological specimens utilizing immediate cytology during bronchoscopy - Corrected Proof

2012-04-11

Abstract: The presence of fusion genes between the anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) genes is useful for determining appropriate molecular-targeted therapies in patients with non-small cell lung cancer (NSCLC). The diagnosis of NSCLC is often judged from transbronchial cytological specimens. The efficacy of RT-PCR for detection of EML4-ALK fusion genes in transbronchial cytological specimens has not been studied. Here, we evaluated the detection rate of EML4-ALK fusion genes in transbronchial cytological specimens positive for NSCLC by immediate cytology during bronchoscopic examination. Various numbers of H2228 cells carrying EML4-ALK variant 3 were combined with 1×106 wild-type WBCs. The RNA was extracted and the sensitivity of detection of the EML4-ALK fusion gene was determined using a nested RT-PCR. A total of 161 cell samples, from cases without available tissue samples, obtained by bronchoscopic examinations utilized for immediate cytology in patients with NSCLC were subsequently analyzed for EML4-ALK fusion genes using a nested multiplex RT-PCR. EML4-ALK variant 3 was detected in a small number of H2228 cells (10 cells), even in the presence of 1×106 WBCs (sensitivity: 0.001%). In the patient cytological samples, EML4-ALK fusion genes were detected in five of 161 NSCLCs (3.1%) and four of 88 adenocarcinomas (4.5%). Sequencing confirmed that these samples included three variant 1 genes, one variant 2 gene and one variant 3 gene. Using the same cytological samples, EGFR mutations were detected in 39 of 161 NSCLCs (24.2%) and 36 of 88 adenocarcinomas (40.9%). There was no case in which both EML4-ALK fusion and EGFR mutation were simultaneously detected. Rapid diagnosis during bronchoscopy utilizing immediate cytology contributed to the selection of the best samples for genetic analysis. EML4-ALK fusion genes as well as EGFR mutations were successfully detected in a small number of cancer cells from transbronchial cytological specimens using a nested multiplex RT-PCR. Our present strategy can be integrated into the clinical process without additional invasive examination of patients. In the era of molecular-targeted treatments for NSCLC, the combination of rapid diagnosis during bronchoscopic examination and stocking samples as cDNA could further correspond to genetic analyses of accumulating driver genes in NSCLC.

Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group - Corrected Proof

2012-04-10

Abstract: Objective: We examined the prognosis of patients with leptomeningeal metastasis (LM) from non-small cell lung cancer (NSCLC) and that stratified by epidermal growth factor receptor (EGFR) mutation status in LM patients receiving EGFR-tyrosine kinase inhibitors (TKIs).Methods: We retrospectively analyzed a series of 91 consecutive NSCLC patients with LM between 2001 and 2010.Results: Most of the LM patients had adenocarcinoma histology and a poor performance status (PS). The median survival time (MST) for all patients was 3.6 months. Adenocarcinoma and TKI treatment were associated with a better prognosis. Among the patients, 51 received EGFR-TKIs. Of these, the EGFR mutation status was assessed in 30 patients; 7 (23%) showed no mutation (group 1), 10 (33%) had a mutation in exon 21 (group 2), and 13 (43%) had deletions in exon 19 (group 3). Interestingly, PS was significantly improved in groups 2 and 3 but not in group 1. The MST in these subgroups was 1.4, 7.1, and 11.0 months in groups 1, 2, and 3, respectively (p<0.001). The median time to progression or symptom deterioration was 0.9, 2.0, and 7.8 months for groups 1, 2, and 3, respectively (p<0.001). A multivariate analysis showed that EGFR-mutant tumors were associated with a better prognosis in patients receiving EGFR-TKIs.Conclusions: The prognosis for patients with LM from NSCLC was still poor. Survival after the initiation of EGFR-TKI treatment differed according to the type of EGFR mutation, suggesting the potential benefit of TKIs for patients with EGFR mutations, even though they suffered from LM.

The gefitinib long-term responder (LTR)—A cancer stem-like cell story? Insights from molecular analyses of German long-term responders treated in the IRESSA expanded access program (EAP) - Corrected Proof

2012-04-09

Abstract: Background: In selected patients with advanced non-small cell lung cancer (NSCLC) the EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor (TKI) gefitinib (IRESSA) shows response rates of ≥70% and a significant prolongation of progression free survival (PFS). However, cogent biomarkers predicting long-term response to EGFR-TKIs are yet lacking. Cancer stem-like cells (CSC) are thought to play a pivotal role in tumor regeneration and appear to be influenced by the EGFR-pathway. This makes them a promising candidate for predicting long-term response to EGFR-TKIs.Materials and methods: We analyzed pre-therapeutic tissue specimens of a rare and specific subset of previously treated German patients with advanced NSCLC who experienced ≥3 year response to gefitinib within the International IRESSA EAP. 11/20 identified long-term responders (LTRs) had appropriate tissue specimens available. Those were analyzed for EGFR and k-ras (Kirsten rat sarcoma) mutations, EGFR and c-met (met proto-oncogene) amplifications and protein expression of EGFR, E-cadherin/vimentin and the CSC antigens CD133 and BCRP1 (breast cancer resistance protein 1). The results were compared to primary resistant patients (RPs) and intermediate responders (IRs) showing a median response of 8.6 months.Results: Each group consisted of 6 women and 5 men, with 1 squamous cell carcinoma (SCC) and 10 adenocarcinoma (AC). Along the LTRs, all but the SCC had EGFR mutations, whereas the RPs had no EGFR, but k-ras mutations in 5/11 cases. 8/11 IRs had EGFR and 3/11 k-ras mutations, of which 2 occurred concomitantly. One patient of each group had an EGFR and/or c-met amplification. EGFR and E-cadherin/vimentin expression was not different between the groups, whereas CD133 was expressed only in 4/10 LTRs and BCRP1 predominantly in responders. The LTRs showed a substantially longer mean PFS to previous therapies, a substantially lower number of metastatic sites and almost exclusively pulmonary or pleural metastasis.Conclusion: LTRs display established properties of EGFR-TKI responders. Antigens characterizing CSC might identify a fraction of LTRs and matter of interest for further evaluation.

VEGF and sVEGFR-1 in malignant pleural effusions: Association with survival and pleurodesis outcomes - Corrected Proof

C.E. Hooper, K.T. Elvers, G.I. Welsh, A.B. Millar, N.A. Maskell — 2012-04-09

Abstract: VEGF is a key mediator of tumour growth and metastasis and is considered central to the formation of exudative pleural effusions. This study examined the relationship between levels of VEGF and its soluble receptor, sVEGFR-1 in the pleural fluid and plasma of patients with malignant pleural effusions and their association with pleurodesis outcomes and survival.103 patients with malignant pleural effusions were recruited at their first presentation. Follow-up was to 6months or death. Survival and pleurodesis outcomes were robustly ascertained. VEGF and sVEGFR-1 were measured in pleural fluid and plasma by ELISA.VEGF and sVEGFR-1 were present in significantly higher concentrations in pleural fluid than plasma. There was no significant correlation between mediators within or between sample types. There was no association between baseline pleural fluid VEGF or sVEGFR-1 levels and pleurodesis failure.In both sample types, survival was inversely associated with sVEGFR-1 and within the non-small cell lung cancer sub-group (n=26), a highly significant association between increased pleural fluid VEGF and sVEGFR-1 and reduced survival was demonstrated (p=0.02 and 0.004 respectively).In conclusion, we have shown for the first time that sVEGFR-1 can be reproducibly measured in pleural fluid from malignant effusions. High levels at presentation in those with non-small cell carcinoma are strongly associated with poor outcomes.

Clinicoradiologic characteristics of patients with lung adenocarcinoma harboring EML4-ALK fusion oncogene - Corrected Proof

2012-04-09

Abstract: Introduction: The fusion oncogene of echinoderm microtubule-associated protein like 4 (EML4) and anaplastic lymphoma kinase (ALK) defines a new molecular subset of non-small-cell lung cancer. We explored the EML4-ALK gene in a relatively large cohort and reviewed the clinicoradiologic background of the patients.Methods: We studied 720 patients with lung adenocarcinoma. The clinicopathological characteristics of each patient were compared among the subgroups stratified by the EML4-ALK gene status. For radiographic evaluation, we scored the proportion of the ground-glass opacity (GGO) component and calculated the tumor disappearance rate (TDR) in each tumor in the cohort of 168 patients that were extracted by using a case-matching procedure.Results: Twenty-eight (3.9%) patients harbored the EML4-ALK gene. Younger age (p=0.001), no or light history of smoking (p=0.05) and normal serum carcinoembryonic antigen (CEA) level (p=0.04) were characteristics of the patients with EML4-ALK. No significant difference was observed for overall and disease free survival between the two groups. All but one tumor in the EML4-ALK-positive group exhibited no GGO, whereas half of the tumors (69/140 patients) in the EML4-ALK-negative group exhibited some GGO (p=0.0004). The mean TDRs were 0.33 and 0.54, respectively, which was significantly lower in the positive group (p=0.0006).Conclusions: We identified younger age, no or light history of smoking, and normal serum CEA as clinical features of patients with EML4-ALK-positive lung adenocarcinoma. In addition, EML4-ALK-positive tumors exhibited a solid pattern on CT. These features may be of value in predicting for patient selection for ALK inhibition therapy in the absence of genetic screening.

Thymoma and solid-organ transplantation - Corrected Proof

2012-04-09

Abstract: Solid-organ-transplant recipients are at high risk of developing cancer, including thoracic malignancies. Herein, we report on two cases of thymoma in solid-organ recipients. One case was a female kidney-transplant recipient who had a type B2, Masaoka stage IVA thymoma that was treated by extended surgical resection followed by postoperative radiation therapy. The second case was type A Masaoka II thymoma that occurred after a liver transplant. The role of EBV in the oncogenesis of thymoma is controversial. We suggest that viruses may induce neoplasms in this specific population, as observed in post-transplant lymphoproliferative disorders. However, Epstein–Barr-encoded RNA (EBER) was negative in both patients.

SNPs in PTGS2 and LTA predict pain and quality of life in long term lung cancer survivors - Corrected Proof

2012-04-05

Abstract: Purpose: Lung cancer survivors report the lowest quality of life relative to other cancer survivors. Pain is one of the most devastating, persistent, and incapacitating symptoms for lung cancer survivors. Prevalence rates vary with 80–100% of survivors experiencing cancer pain and healthcare costs are five times higher in cancer survivors with uncontrolled pain. Cancer pain often has a considerable impact on quality of life among cancer patients and cancer survivors. Therefore, early identification, and treatment is important. Although recent studies have suggested a relationship between single nucleotide polymorphisms (SNPs) in several cytokine and inflammation genes with cancer prognosis, associations with cancer pain are not clear. Therefore, the primary aim of this study was to identify SNPs related to pain in lung cancer survivors.Patients and methods: Participants were enrolled in the Mayo Clinic Lung Cancer Cohort upon diagnosis of their lung cancer. 1149 Caucasian lung cancer survivors (440 surviving <3 years; 354 surviving 3–5 years; and 355 surviving >5 years) completed study questionnaires and had blood DNA samples available. Ten SNPS from PTGS2 and LTA genes were selected based on the serum-based studies in the literature. Outcomes included pain, and quality of life as measured by the SF-8.Results: Of the 10 SNPs evaluated in LTA and PTGS2 genes, 3 were associated with pain severity (rs5277; rs1799964), social function (rs5277) and mental health (rs5275). These results suggested both specificity and consistency of these inflammatory gene SNPs in predicting pain severity in lung cancer survivors.Conclusion: These results provide support for genetic predisposition to pain severity and may aid in identification of lung cancer survivors at high risk for morbidity and poor QOL.

Aspirin and non-aspirin non-steroidal anti-inflammatory drug use and risk of lung cancer - Corrected Proof

2012-04-05

Abstract: There is evidence that aspirin and non-aspirin non-steroidal anti-inflammatory drug (NSAID) have anti-carcinogenic properties, but their effect on lung cancer, in particular in never-smokers, is unclear. Information on past or current use of anti-inflammatory medication was obtained in 398 Chinese female primary lung cancer cases and 814 controls in a hospital-based study in Singapore. 65% of cases and 88% of controls were never-smokers. Controls were excluded if they had been admitted for conditions associated with aspirin or NSAID use (n=174). Regular aspirin use (twice a week or more, for a month or more) was associated with a reduced risk of lung cancer (adjusted odds ratio [OR] 0.50, 95% confidence intervals [95%CI] 0.31–0.81 in non-smokers; OR 0.38, 95%CI 0.16–0.93 in smokers). Regular use of non-aspirin NSAID, paracetamol, steroid creams and steroid pills was uncommon and no association with lung cancer was detected. Our results suggest that aspirin consumption may reduce lung cancer risk in Asian women and are consistent with current understanding of the role of cyclooxygenase in lung carcinogenesis.

Immunohistochemical screening for anaplastic lymphoma kinase (ALK) rearrangement in advanced non-small cell lung cancer patients - Corrected Proof

2012-04-02

Abstract: Fluorescence in situ hybridization (FISH) is currently used to detect non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK) gene rearrangement, who are candidates for ALK inhibitor therapy. However, FISH may not be a practical method for screening for ALK-positive patients in a large population due to its cost and difficulty in interpretation. We investigated the role of immunohistochemistry (IHC) to screen for ALK rearrangement in advanced NSCLC. We identified 1,166 stage IIIB or IV NSCLC patients with non-squamous histology from the Seoul National University Hospital NSCLC database. To enrich ALK-positive cases, we selected 262 patients who were either EGFR wild-type or non-responders to previous EGFR tyrosine kinase inhibitors (TKI). ALK IHC and ALK FISH were performed on formalin-fixed, paraffin-embedded tissue. ALK protein was expressed in 28 (10.7%) tumors in 262 patients. ALK FISH was positive in 25 (9.5%) cases. All patients with IHC score of 3 (n=9) were FISH-positive and all patients with score of 0 (n=234) were FISH-negative. Among patients with IHC scores of 1 and 2, five (83.3%, 5/6) and eleven (84.6%, 11/13) were FISH-positive, respectively. The sensitivity and specificity of ALK IHC with intensity score of 1 or more were 100% and 98.7%, respectively. IHC can be a useful test for screening ALK FISH-positive cases in advanced NSCLC. FISH testing should be considered for advanced NSCLC patients with tumors showing mild to moderate staining for ALK by IHC to confirm ALK translocation.

Generalisability of the results of the Dutch–Belgian randomised controlled lung cancer CT screening trial (NELSON): Does self-selection play a role? - Corrected Proof

2012-03-29

Abstract: The degree of self-selection in the Dutch–Belgian randomised controlled lung cancer screening trial (NELSON) was determined to assess the generalisability of the study results. 335,441 (mainly) men born in 1928–1953 received a questionnaire. Of the respondents (32%), eligible subjects were invited to participate (19%). Fifty-five percent gave informed consent and was randomised. Background characteristics were compared between male respondents on the first questionnaire (n=92,802), eligible subjects among them (n=18,570) and those randomised (n=10,627) and Statistics Netherlands 2002–2005 (SN) (n=5289) or GLOBE study-data (Dutch cohort) (n=696).Initial respondents were less likely to be highly educated (ORadj=0.84; 95% CI: 0.74–0.96) and comprised of significantly less current smokers (ORadj=0.65; 95% CI: 0.61–0.69) compared to the general population. These current smokers smoked more heavily (ORadj=1.23; 95% CI: 1.10–1.37), but for a shorter time-period (respondents: 31, SN: 42 years, p<0.001). Age, general health, BMI, alcohol use and cancer prevalence were comparable. The randomised population was younger (Age 50–65) (randomised subjects: 85.3%, SN: 72% (p<0.01)) comprised of more heavy current smokers (OR=2.08; 95% CI: 1.75–2.44), that smoked for a shorter period of time (randomised subjects: 37, SN_selection: 42 years (p<0.001)).Both the respondents (32%) of the first questionnaire as well as the randomised population of the NELSON trial appeared to differ slightly on smoking characteristics, but the differences were limited and probably balance each other. Results of the NELSON trial will be roughly applicable to the Dutch and probably other populations that fulfil our selection criteria.

Exploratory analysis of activation of PTEN–PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM) - Corrected Proof

2012-03-29

Abstract: Background: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with elevated AKT/mTOR activity. We aimed to identify the expression and phosphorylation status of PTEN, PI3K and downstream signaling in MPM.Patients and methods: Thirty consecutive MPM patients were identified. Clinical data analyzed: sex, age, histology, performance status (PS), white blood count, and neutrophil–lymphocyte ratio (NLR). Paraffin-embedded biopsies were used for immunohistochemical analysis.Results: Overexpression of PTEN, pMAPK, mTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 80%, 100%, 43.3%, 96.7%, 100%, 63.3% and 100% of tumors respectively. There was a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.9 vs 5.6 months; p=0.04) and overall survival (OS: 23.4 vs 5.6 months; p=0.05). Patients with concomitant low expression of pS6 and p4E-BP1 and overexpression of FOXO3a had significantly better prognosis (34.6 vs 1.9 months; p=0.004). In multivariate analysis, histology and NLR were independent prognostic factors (p=0.02 and p=0.04 respectively), but pS6 only showed a trend (p=0.8).Conclusions: This study shows PI3K pathway and downstream proteins in MPM are frequently activated and provides prognostic information. The role of PI3K pathway is worth of prospective validation in future studies on MPM.

Prognostic significance of MCM7 expression in the bronchial brushings of patients with non-small cell lung cancer (NSCLC) - Corrected Proof

2012-03-28

Abstract: Purpose: To identify potential biomarkers for the prognosis of non-small cell lung cancer (NSCLC) patients by using bronchial brushing specimens.Methods: The expression of MCM7, Ki67 and EGFR was evaluated in 494 NSCLC tissues and 174 bronchial brushings using immunohistochemical and immunocytochemical techniques. Associations between protein expression and clinico-pathologic parameters were assessed, and the impact on overall survival (OS) was analyzed.Results: High expression of MCM7, Ki67 and EGFR was detected in 33.3%, 23.5% and 12.7% of tissues and in 52.4%, 52.7% and 20.6% of bronchial brushings, respectively. Expression of MCM7 and Ki67 was associated with squamous cell carcinoma (SCC) in both tissues and bronchial brushings (MCM7: P=0.0007, 0.00003; Ki67: P<0.00001, 0.00001). Overexpression of MCM7 in tumor tissues was detected more frequently in poorly differentiated tumors (P=0.0120) and non-bronchioloalveolar carcinomas (non-BACs) (P=0.0238). EGFR overexpression was observed in tissues of larger tumors (P=0.00004) and in bronchial brushings at later stage (P=0.0262). Kaplan–Meier curves indicated that patients with overexpression of MCM7 or Ki67 had a poorer OS compared to those with low expression for all stages (P<0.00001, 0.0233) and early-stages (P<0.00001, 0.0032). In particular, the patients with MCM7 overexpression in bronchial brushings had a poorer prognosis (P=0.0045). Multivariate Cox regression analysis showed that MCM7 was an independent prognostic indicator both in tissue samples and bronchial brushings.Conclusions: Our data suggest that MCM7 and Ki67 in tumor tissues may be potential markers of a poor prognosis for NSCLC patients. MCM7 in bronchial brushings also showed an independent prognostic value, which may be useful when biopsies are unavailable.

Re-irradiation plus regional hyperthermia for recurrent non-small cell lung cancer: A potential modality for inducing long-term survival in selected patients - Corrected Proof

2012-03-26

Abstract: Purpose: The purpose of this study was to assess the toxicity and efficacy of re-irradiation plus regional hyperthermia for recurrent NSCLC and to identify the predictors of long-term survival.Methods and materials: A total of 33 patients with recurrent NSCLC treated with re-irradiation plus regional hyperthermia were retrospectively analyzed. The median total dose of initial radiotherapy and re-irradiation were 70Gy and 50Gy, respectively. A median of 5 hyperthermia treatments using an 8-MHz radiofrequency-capacitive device were applied during re-irradiation in all patients.Results: Toxicity of Grade 3 was seen in 3 (9%) patients, and no Grade 4 or 5 toxicity was observed. The median overall survival, local control, and disease progression-free survival times after re-irradiation were 18.1, 12.1, and 6.7months, respectively. Eight patients achieved a long-term survival (more than 3years after re-irradiation), and 4 of them underwent a third round of irradiation for re-recurrent tumors. Univariate analyses showed that a smaller tumor size (<4cm) and the absence of distant metastases were significant predictors for a better overall survival. The absence of distant metastases was also found to be a significant predictor for better disease progression-free survival in the univariate analyses. In the subset analyses of 23 patients treated with hyperthermia using electrodes of 30cm in diameter, the use of a higher radiofrequency-output power tended to be associated with a better prognosis in terms of the local control rate.Conclusions: Re-irradiation plus regional hyperthermia for recurrent NSCLC appears feasible, with acceptable toxicity, and may be a promising treatment that can result in the long-term survival of patients without distant metastasis and larger recurrent tumors.

Emphysema detected on computed tomography and risk of lung cancer: A systematic review and meta-analysis - Corrected Proof

2012-03-22

Abstract: Background: Studies exploring the association between emphysema detected on chest computed tomography (CT) and lung cancer have yielded mixed results. Our objective was to systematically review the evidence for this association.Methods: We searched MEDLINE, EMBASE and the Cochrane Library for the terms “lung cancer”, “emphysema” and “computed tomography” without language restriction. Bibliographies were also reviewed and authors contacted for additional information. Human studies in which CTs were performed and assessed for emphysema and in which subjects were evaluated systematically for lung cancer were included. Qualitative synthesis of evidence was performed followed by pooling of effect estimates using a random-effects model.Results: Of 187 citations, 7 were included in the qualitative synthesis and 5 in the meta-analysis. Three studies assessing emphysema visually observed an association with lung cancer, independent of smoking history and airflow obstruction. Three studies using densitometry to detect emphysema found no association with lung cancer. Another study directly comparing automated and visual emphysema detection techniques found only the latter to associate with lung cancer. Among 7368 subjects included in the meta-analysis, 2809 had emphysema on CT and 870 were diagnosed with lung cancer. The pooled adjusted odds ratio for lung cancer in the presence of emphysema on CT was 2.11 (95% CI 1.10–4.04); stratification by detection method yielded OR of 3.50 (95% CI 2.71–4.51) with visually detected emphysema and 1.16 (95% CI 0.48–2.81) with densitometric emphysema.Conclusion: Systematic literature review shows emphysema detected visually on CT to be independently associated with increased odds of lung cancer. This association did not hold with automated emphysema detection.

Paclitaxel plus bevacizumab in patients with chemoresistant relapsed small cell lung cancer as salvage treatment: A phase II multicenter study of the Hellenic Oncology Research Group - Corrected Proof

2012-03-15

Abstract: Introduction: Therapeutic options for patients with relapsed, chemo-resistant small-cell lung cancer (SCLC) are limited. Since paclitaxel has demonstrated single-agent activity in the second-line setting of SCLC and angiogenesis seems to play an important role in the pathogenesis of the disease, a phase II trial was conducted in order to evaluate the efficacy and the tolerance of their combination in patients with relapsed, chemo-resistant SCLC.Patients and methods: Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 who experienced relapse within 3 months after completion of 1st line chemotherapy for SCLC were eligible. Patients were treated with paclitaxel (90mg/m2, days 1, 8 and 15) along with bevacizumab (10mg per kg of body weight, days 1 and 15) in cycles of 28 days.Results: Thirty patients (male/female: 27/3) with a median age of 64 years and ECOG performance status 0/1/2: 2/25/3 were enrolled. Nineteen patients (63.3%) had received at least two lines of prior treatment, 17 (56.7%) had undergone prior radiotherapy and nine (30%) had brain metastases at the time of study entry. The overall objective response rate was 20% (95% CI: 5.69–34.31%), including one complete remission, whereas the disease control rate was 36.7%. The median duration of response was 2.5months (range, 1.5–5.7), the median progression-free survival 2.7 months (range, 0.5–9.2) and the median overall survival 6.3 months (range, 0.5–17.9). Grades 3 and 4 toxicities were limited in neutropenia, diarrhea and fatigue. There was one case of non-fatal pulmonary embolism.Conclusions: The combination of paclitaxel with bevacizumab was feasible and active in this poor prognosis and heavily pretreated population of patients with advanced, chemoresistant SCLC, representing a valid therapeutic alternative which merits further evaluation.

Retrospective study of erlotinib in patients with advanced squamous lung cancer - Corrected Proof

2012-03-15

Abstract: Background: The effective targeted therapy for lung squamous cell carcinoma (SCC) is needed. The epidermal growth factor receptor (EGFR) mutation rate is low in lung SCC. The aim of this study was to evaluate the status of erlotinib treatment and EGFR mutation in lung SCC patients.Methods: We retrospectively enrolled lung cancer patients with SCC histology and history of erlotinib treatment. The primary objective was to assess overall response rate (ORR) and disease control rate (DCR) and the secondary objective was to assess progression-free survival (PFS) and overall survival (OS). EGFR mutations were assessed in parts of patients using both direct sequencing and protein nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp methods.Results: In total, 92 patients were analyzed (75 men and 17 women, median age 69 years, and 74 current or former smokers). Sixteen patients achieved partial response and 9 had stable disease. The ORR was 17.4% and the DCR was 27.2%. The PFS and OS were longer in patients with disease control than with progressive disease (PFS 7.8 versus 1.3 months and OS 20.7 versus 2.7 months, both p<0.0001). The 1-year survival rate was 21.7%. In 27 patients with adequate specimens for molecular analysis (including 4 PR and 4 SD), two (7.4%) had EGFR complex mutations. One patient experienced response to erlotinib and the other did not.Conclusions: A significant proportion of lung SCC patients would derive a clinical benefit from erlotinib treatment. The relatively higher response rate than the EGFR mutation rate in present study needs further evaluation.

Napsin A is an independent prognostic factor in surgically resected adenocarcinoma of the lung - Corrected Proof

Jin Gu Lee, Sewha Kim, Hyo Sup Shim — 2012-03-15

Abstract: Introduction: Napsin A is regarded as a marker of lung adenocarcinoma. However, no comprehensive analyses of napsin A-positive lung ADCs or the prognostic significance of napsin A expression have been reported to date.Methods: 110 primary lung adenocarcinoma cases were analyzed for clinicopathologic parameters, including overall survival, stage, histology, napsin A and TTF-1 expression, EGFR mutation, and ALK rearrangement.Results: Napsin A-positive adenocarcinomas were significantly more prevalent among tumors characterized as relatively small (p=0.023), non-solid predominant (p<0.001), non-mucinous/enteric (p<0.001), positive for TTF-1 expression (p<0.001), and positive for EGFR mutation (p=0.001). Multivariate analysis of overall survival demonstrated that the absence of napsin A was an independent prognostic factor for reduced survival time (p=0.002).Conclusion: Clinicopathologic characteristics associated with napsin A-positive lung ADC are similar to and overlap with those of TTF-1-positve ADCs. The absence of napsin A is an independent poor prognostic factor in surgically resected adenocarcinoma. Further studies are necessary to determine the role of napsin A in the progression of lung adenocarcinoma.

shRNA-mediated knockdown of Bmi-1 inhibit lung adenocarcinoma cell migration and metastasis - Corrected Proof

2012-03-15

Abstract: Bmi-1 has been implicated in cancer cell growth and metastasis in a variety of tumor types. In this study, we sought to evaluate the expression of Bmi-1 in lung adenocarcinoma samples, and to determine if a correlation exists between Bmi-1 expression and clinical features of lung cancer, such as metastasis. Our results showed that Bmi-1 expression is increased in lung cancer tissues compared to adjacent non-cancerous tissues, and is associated with clinical features of lung cancer, including clinical stage and distant metastasis. We were then interested in determining if shRNA-mediated knockdown of Bmi-1 would inhibit metastasis of lung adenocarcinoma cells. To this end, we chose the most efficient shRNA duplexes targeting Bmi-1, and constructed two stably transfected lung adenocarcinoma cell lines (A549 and SPCA1). The shRNA-mediated knockdown of Bmi-1 significantly reduced migration in vitro, and metastasis in vivo, of A549 and SPCA1 cells. More importantly, knockdown of Bmi-1 also upregulated PTEN expression, and downregulated p-Akt and VEGF expression. These data support the hypothesis that Bmi-1 regulates key pathways involved in the metastasis of lung adenocarcinoma cells.

Expression of heme oxygenase-1 in non-small cell lung cancer (NSCLC) and its correlation with clinical data - Corrected Proof

2012-03-15

Abstract: While changes in heme oxygenase (HO-1) in lung cancer have already been reported, conflicting results were obtained for enzyme expression in human lung cancer specimens. Therefore, the aim of this work was to study HO-1 expression in a large collection of human lung cancer samples. For this purpose, we analyzed the expression of HO-1 in an organized tissue microarray (TMA) and investigated its correlation with clinicopathological data. Ninety-six percent of tumor samples were positive for HO-1, and the expression of HO-1 was significantly higher in cancerous than in non-cancerous tissues. Importantly, HO-1 expression correlated with advanced stages and lymph node involvement. Additionally, quantitative RT-PCR in 18 pairs of human lung carcinomas and their adjacent non-malignant tissues was performed. Our results demonstrate that HO-1 protein is upregulated in epithelial malignant cells in NSCLC and its expression is associated with higher stages of the disease. Additionally, different subcellular localization is observed between tumor and adjacent non-malignant tissues.

A multicenter phase II randomized trial of gemcitabine followed by erlotinib at progression, versus the reverse sequence, in vulnerable elderly patients with advanced non small-cell lung cancer selected with a comprehensive geriatric assessment (the GFPC 0505 study) - Corrected Proof

2012-03-14

Abstract: Background: The aim of this randomized phase II trial was to evaluate the feasibility and activity of weekly gemcitabine (G) followed by erlotinib at disease progression (arm A) versus erlotinib followed by G at progression (arm B) in vulnerable elderly patients with advanced non small-cell lung cancer (NSCLC), selected on the basis of a comprehensive geriatric assessment (CGA).Methods: Vulnerable elderly chemotherapy-naive patients with stage IIIB/IV NSCLC were selected after a CGA (socioeconomic, cognitive and emotional status, depression, nutritional status, ADL and IADL assessments). The primary endpoint was the time to second progression (TTP2). Overall survival (OS), time to first progression (TTP1) and safety were secondary endpoints.Results: Between May 2006 and January 2010, 21 centers enrolled 100 patients, of whom 94 were eligible. TTP2 was 4.3 and 3.5 months in arm A and arm B, respectively; TTP1 was 2.5 and 2.2 months; and the median OS time was 4.4 and 3.9 months. The respective one-year survival rates were 27.3% and 20%. There was no major unexpected toxicity.Conclusion: In vulnerable elderly patients with NSCLC not selected for EGFR expression, both strategies were feasible but had modest efficacy. Further studies are needed to identify elderly patients who should receive palliative care only.