Lung Cancer - Articles in Press

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

2010-02-08

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

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

2010-02-08

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

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

2010-02-08

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

Meeting report: 2nd meeting of the European Thoracic Oncology Platform (ETOP) - Corrected Proof

2010-02-08

In Europe, a renewed interest in promoting and improving collaboration in clinical and translational research in lung cancer has emerged. Many investigators, representing collaborative study groups and institutions, are trying to find new ways to improve dissemination of knowledge and expertise in the field of rapidly evolving customized therapy. To accomplish this goal, discussions with European investigators during one of the thoracic oncology meetings in Dublin (BTOG) were initiated in early 2008. During the second meeting in April 2008 in Geneva, the decision was made that a formal structure was required to achieve this goal. Rolf Stahel from Switzerland and Paul Baas from the Netherlands took the initiative to prepare a draft for a foundation based on the model of the International Breast Cancer Study Group. The idea of the European Thoracic Oncology Platform (ETOP) was constructed and presented to representatives of European collaborative groups and trial institutions in September 2008 at the ESMO meeting in Stockholm. During this 1st ETOP meeting the ideas were accepted, suggestions for members of foundation council were made, and the collection of funds by interested groups and institutions agreed on. A first meeting of the ETOP foundation council including Rolf Sahel, Paul Baas, Cesare Gridelli, Ken O’Byrne and Rafael Rosell took place in January 2009 in Dublin during the BTOG meeting. In March 2009 the foundation, seated in Bern, Switzerland, was approved by the authorities.

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

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

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

Large cell/neuroendocrine carcinoma - Corrected Proof

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

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

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

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

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

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

2010-02-01

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

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

2010-02-01

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

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

2010-01-29

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

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

2010-01-25

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

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

2010-01-22

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

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

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

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

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

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

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

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

2010-01-20

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

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

2010-01-18

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

Radiotherapy for lung cancer in the elderly - Corrected Proof

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

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

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

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

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

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

2010-01-13

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

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

2010-01-11

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

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

2010-01-11

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

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

2010-01-11

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

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

2010-01-11

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

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

2010-01-08

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

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

2010-01-08

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

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

2010-01-06

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

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

2009-12-28

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

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

2009-12-25

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

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

2009-12-23

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

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

2009-12-18

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

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

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

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

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

2009-12-17

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

Oral Chinese herbal medicine (CHM) as an adjuvant treatment during chemotherapy for non-small cell lung cancer: A systematic review - Corrected Proof

2009-12-16

Abstract: Background: Non-small cell lung cancer (NSCLC) remains a major global health problem because of its prevalence and poor prognosis. Treatment options are limited and there is a need to explore alternatives. This systematic review evaluates the role of Chinese herbal medicine (CHM) in association with chemotherapy for NSCLC.Methods: English and Chinese databases were searched for RCTs comparing CHM with conventional biomedical treatment or placebo. Papers were reviewed systematically and data were analysed using standard Cochrane software Revman 5.Results: Fifteen Chinese trials involving 862 participants met the inclusion criteria. All trials were of poor quality with a considerable risk of bias. There was a significant improvement in quality of life (QoL) (increased Karnofsky Performance Status) (RR 1.83, 95% CI 1.41–2.38, p<0.00001 for both stages III, IV only NSCLC and all stages NSCLC) and less anaemia (RR 0.37, 95% CI 0.15–0.91, p=0.03 for stages III, IV only NSCLC; p=0.005 for all stages NSCLC) and neutropenia (RR 0.42, 95% CI 0.22–0.82, p=0.01 for stages III, IV only NSCLC; p<0.00001 for all stages NSCLC) when CHM is combined with chemotherapy compared to chemotherapy alone. There was no significant difference in short term effectiveness and limited inconclusive data concerning long term survival. Five promising herbs have been identified.Conclusion: It is possible that oral CHM used in conjunction with chemotherapy may improve QoL in NSCLC. This needs to be examined further with more rigorous methodology.

Pain in patients with lung cancer: Pathophysiology and treatment - Corrected Proof

Sebastiano Mercadante, Valentina Vitrano — 2009-12-15

Abstract: This review analyses the characteristics of the principal pain syndromes associated with lung cancer, their physiopathology and causes, and provides updated information on available treatments. Pain associated with lung cancer is characterized by multiple expressions, due to either the progression of disease and/or induced by oncological treatment. The analgesic treatment is principally based on the use of opioids. Other than the oral route, which is the preferred one, alternative modalities to administer opioids may be helpful in different clinical circumstances. According to the opioid response, other routes and other opioids, may improve the balance between analgesia and adverse effects providing the best individual response to a specific opioid drug. More complex strategies, such as interventional procedures, are seldom necessary and require an appropriate selection of patients.

Unsuspected pulmonary emboli in lung cancer patients: The impact on survival and the significance of anticoagulation therapy - Corrected Proof

2009-12-15

Abstract: Background: Many pulmonary emboli (PE) are detected unsuspectedly in lung cancer patients. The purpose of our study was to retrospectively evaluate the role of anticoagulation therapy for unsuspected PE in lung cancer patients. We also aimed to evaluate risk factors associated with the development of PE as well as the prognostic power of PE in lung cancer patients.Patients and methods: The Samsung Medical Information System was used to evaluate predictors and prognosis of PE in lung cancer patients. We found patients with PE using the Radiation Interpretation Registry and reviewed their medical records.Results: Among 8014 lung cancer patients, PE developed in 180 patients (cumulative incidence rates=2.2%). Metastasis and prior history of chemotherapy were significant predictors of the development of PE. Pulmonary embolism detected within 3 months after diagnosis of lung cancer was a significant poor prognostic factor (hazard ratio [HR], 1.5; 95% CI, 1.1–2.0) in the complete lung cancer cohort. One hundred thirteen (63%) out of total 180 PE patients were incidentally found to have PE. Among the 113 patients with unsuspected PE, 62 patients (55%) did not receive anticoagulation therapy, and died sooner than those who received anticoagulation therapy for unsuspected PE (HR, 4.1; 95% CI, 2.3–7.6).Conclusion: Anticoagulation therapy for unsuspected PE is associated with increased overall survival in lung cancer patients.

ATM polymorphisms and risk of lung cancer among never smokers - Corrected Proof

2009-12-11

Abstract: The ataxia-telangiectasia mutated (ATM) gene, an important caretaker of overall genome stability, is thought to play a role in the development of human malignancy. Therefore, we hypothesized that sequence variants in ATM may influence the disposition to lung cancer. In this hospital-based matched case-control study, nine ATM single nucleotide polymorphisms (rs189037, rs228597, rs228592, rs664677, rs609261, rs599558, rs609429, rs227062, and rs664982) were genotyped in 730 lung cancer patients and 730 healthy controls. Pairwise linkage disequilibrium among nine polymorphisms in the ATM gene was very high. None of the main effects of any of the ATM polymorphisms were related to the risk of lung cancer. Interestingly, ATM polymorphisms were significantly associated with lung cancer among never smokers, and the association was modulated by low-level exposure to carcinogens such as environmental tobacco smoke. When the haplotypes of nine ATM polymorphism sites were studied, no overall association between ATM haplotypes and risk of lung cancer was found. However, the frequency distribution of haplotypes between lung cancer cases and controls was significant in the never smokers (P=0.009), demonstrating that haplotypes have a significant effect on the risk of lung cancer. In conclusion, we found that never smokers with sequence variants of the ATM gene may be at increased risk for lung cancer. Our data also suggest this association may be further modified by exposure to environmental tobacco smoke. This study suggests support to the literature that ATM polymorphisms and environmental tobacco smoke exposure have a role in lung carcinogenesis among never smokers.

Value of quantitative analysis of circulating cell free DNA as a screening tool for lung cancer: A meta-analysis - Corrected Proof

Ruifeng Zhang, Fangchun Shao, Xiaohong Wu, Kejing Ying — 2009-12-11

Abstract: Objective: Quantitative analysis of circulating cell free DNA is considered as a possible aid for lung cancer screening. We aimed to comprehensively review the evidence for use of circulating cell free DNA to screen for lung cancer.Methods: After a systematic review of English language studies, sensitivity, specificity, and other measures of accuracy of circulating DNA assay in the diagnosis of lung cancer were pooled using random-effects models. Summary receiver operating characteristic curves were used to summarize overall test performance.Results: Ten studies met our inclusion criteria. The summary estimates for quantitative analysis of circulating cell free DNA in lung cancer screening in the studies included were as follows: sensitivity, 0.80 (95% confidence interval (CI), 0.77–0.83); specificity, 0.77 (95% CI, 0.74–0.80); positive likelihood ratio, 4.54 (95% CI, 2.66–7.76); negative likelihood ratio, 0.28 (95% CI, 0.19–0.40); and diagnostic odds ratio, 20.33 (95% CI, 10.12–40.86).Conclusions: The current evidence suggests that the diagnostic accuracy of quantitative analysis of circulating DNA is not lower than conventional serum biomarkers for lung cancer screening, at least. However, it is not recommend for lung cancer screening alone, because its discrimination power is not very perfect. The value of circulating DNA assay in combination with conventional markers for lung cancer detection deserved further investigation.

Are adenosquamous lung carcinomas a simple mix of adenocarcinomas and squamous cell carcinomas, or more complex at the molecular level? - Corrected Proof

2009-12-09

Abstract: Adenocarcinomas (AC), squamous cell carcinomas (SCC) and adenosquamous carcinomas (ASC) are three histological subtypes of non-small-cell lung carcinomas (NSCLC). ASC are morphologically mixed tumours that contain the two cell components AC and SCC. To understand if they are a “simple” mix of AC and SCC or if they present molecular specificities, as compared with the molecular characterization of both components, we performed a comparative transcriptome analysis on a series of nine ASC, five AC and five SCC induced in rats by radon exposure. We found that 72, 40 and 39 genes were differentially expressed when comparing AC_SCC, ASC_SCC and AC_ASC, respectively. Moreover, when classifying the three histological subtypes, using genes that discriminated AC and SCC, we observed that all ASC were classified as intermediate between the AC and SCC, some being closer to AC, others to SCC. These results indicated that, regarding gene expression, ASC could be considered as a mix of AC and SCC, both in various proportions. However, they also exhibit molecular specificities since we found specific genes discriminating ASC_SCC and AC_ASC. In conclusion, the ASC mixed lung tumours are more complex than simple mixes of AC and SCC components. Neuroendocrine differentiation and ERK proliferation pathways seemed preferentially deregulated in ASC compared to AC and SCC respectively, pathways that are worthy of being explored because they could partially explain the high clinical aggressiveness of ASC.

Emodin enhances cisplatin-induced cytotoxicity via down-regulation of ERCC1 and inactivation of ERK1/2 - Corrected Proof

2009-12-07

Abstract: Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants; it exhibits an anticancer effect on many malignancies. The most important chemotherapeutic agent for patients with advanced non-small cell lung cancer (NSCLC) is a platinum-containing compound such as cisplatin or carboplatin. The molecular mechanism underlying decreased NSCLC cell viability after treatment with emodin and cisplatin is unclear. Therefore, the aim of this study was to assess the cytotoxic effect of combined emodin and cisplatin on NSCLC cell lines and to clarify underlying molecular mechanisms. Exposure of human NSCLC cells to emodin decreased cisplatin-elicited ERK1/2 activation and ERCC1 protein induction by increasing instability of ERCC1 protein. Cisplatin alone did not affect expression of ERCC1 mRNA. However, emodin alone or combined with cisplatin significantly decreased expression of ERCC1 mRNA levels. Enhancement of ERK1/2 activation by transfection with constitutively active MKK1/2 (MKK1/2-CA) vector increased ERCC1 protein levels and protein stability, as well as increasing viability of NSCLC cells treated with emodin and cisplatin. In contrast, blocking ERK1/2 activation by U0126 (an MKK1/2 inhibitor) decreased cisplatin-elicited ERCC1 expression and enhanced cisplatin-induced cytotoxicity. Depletion of endogenous ERCC1 expression by si-ERCC1 RNA transfection significantly enhanced cisplatin's cytotoxic effect. In conclusion, ERCC1 protein protects NSCLC cells from synergistic cytotoxicity induced by emodin and platinum agents. Further investigation of combined emodin and cisplatin may lead to novel therapy in the future for NSCLC through down-regulating expression of ERCC1.

Expression of candidate tumor suppressor gene ING2 is lost in non-small cell lung carcinoma - Corrected Proof

2009-12-07

Abstract: ING2 is a candidate tumor suppressor gene involved in cell cycle control, apoptosis and senescence. Furthermore, we have recently shown that loss of ING2 expression is associated with increased genome instability. We investigated its status in a series of 120 non-small cell lung cancer (NSCLC) by using immunohistochemistry (IHC). The results showed that ING2 protein expression is downregulated in more than 50% of NSCLC, with a higher frequency in adenocarcinoma (ADK) as compared to squamous cell carcinoma (SCC) (68% versus 45%, P=0.021). Loss of ING2 expression occurs in a high proportion of tumors from stage I and was not associated with patient's gender, age and 5-year survival. When investigating the possible mechanisms responsible for the decrease of ING2 expression, we did not observe any loss of heterozygosity or mutation in the ING2 gene. However, in 95% of the cases examined, we identified a silent single nucleotide polymorphism (SNP). By using quantitative RT-PCR, we found that ING2 loss of expression may be due to the decrease of its mRNA level. Analysis of CpG islands present in the promoter region of the ING2 gene did not allow for the detection of methylation. Mechanistically, although p53 can regulate ING2 transcription and ING2 enhances p53 activity, no correlation between ING2 and p53 IHC status was observed. Overall, these results indicate that loss of ING2 expression could contribute to lung tumorigenesis independently of p53.

Accuracy of RECIST 1.1 for non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors - Corrected Proof

2009-12-03

Abstract: Background: The Response Evaluation Criteria in Solid Tumors (RECIST) has been revised (RECIST 1.1) since initial publication of RECIST 1.0 in 2000. Major changes in RECIST 1.1 involve lymph node measurement, the maximum number of target lesions, and the definition of disease progression (PD). The purpose of this study was to evaluate the accuracy of RECIST 1.1 for non-small cell lung cancer (NSCLC) patients being treated with epidermal growth factor receptor tyrosine kinase inhibitors (TKIs).Patients and methods: We compared responses of 104 NSCLC patients treated with TKIs from eight prospective studies using RECIST 1.0 and 1.1.Results: The short axis measurement for lymph nodes was the most influential change in RECIST 1.1 for the evaluation of response. Overall response rates (ORRs) using RECIST 1.0 and 1.1 were 35.6% and 38.5%, respectively. Under RECIST 1.1, six best responses were reclassified: two partial responses (PR) were re-categorized as complete responses, three cases of stable disease (SD) were reclassified as PR, and one case of SD was reclassified as PD. The progression-free survivals of three patients were extended. RECIST 1.1 showed a slightly increased ORR compared with RECIST 1.0.Conclusion: RECIST 1.1 may reflect tumor burden more accurately than RECIST 1.0 in NSCLC patients treated with TKIs.

An investigation on electronic nose diagnosis of lung cancer - Corrected Proof

2009-12-03

Abstract: The use of gas sensor arrays as medical diagnosis instruments has been proposed several years ago. Since then, the idea has been proven for a limited number of diseases.The case of lung cancer is particularly interesting because it is supported by studies that have shown the correlation between the composition of breath and the disease. However, it is known that many other diseases can alter the breath composition, so for lung cancer diagnosis it is necessary not only to detect generic alterations but those specifically consequent to cancer.In this paper an experiment, performed in the bronchoscopy unit of a large hospital, aimed at discriminating between lung cancer, diverse lung diseases and reference controls is illustrated. Results show not only a satisfactory identification rate of lung cancer subjects but also a non-negligible sensitivity to breath modification induced by other affections.Furthermore, the effects of some compounds frequently found in the breath of lung cancer subjects have also been studied. Results indicate that breath samples of control individuals drift towards the lung cancer group when added with either single or mixtures of these alleged cancer-related compounds.

Lipid raft modulation inhibits NSCLC cell migration through delocalization of the focal adhesion complex - Corrected Proof

2009-11-30

Abstract: Lipid raft, a specialized membrane structure enriched with cholesterol and glycosphingolipid, contains molecules that convey environmental stimuli to the intracellular systems. Authors investigated the effects of raft cholesterol depletion on non-small cell lung cancer (NSCLC) cell migration. Incubation of NSCLC cells in media containing lovastatin resulted in inhibition of cell migration by 63.1–83.3%, whereas raft cholesterol depletion with successive treatment using methyl-β cyclodextrin (MβCD) followed by lovastatin further suppressed their migration by 35.0–57.8%. Raft cholesterol depletion partially inhibited EGF-induced phosphorylation of EGFR and FAK, however, no change was observed in other molecules comprising focal adhesion complex. It resulted in disappearance of filopodia, inhibition of EGF-induced pY397 FAK aggregation, and its destabilization. Cholesterol depletion inhibited phosphorylation of Src on Y416 in the detergent-insoluble fraction followed by decreased localization of total and pY397 FAK in the detergent-insoluble fraction. Minimal changes in these molecules were observed in the detergent-soluble fraction and interactions between FAK and other molecules of the focal adhesion complex were not influenced. Immunocytochemical analysis confirmed translocation of Src from the raft into cytoplasm and disappearance of EGF-induced membrane ruffling by raft cholesterol depletion. In cholesterol-depleted cells, EGF-induced phosphorylation of Src, Akt, and p44/42 in the detergent-insoluble fraction were inhibited whereas phosphorylation of GSK-3β was unaffected. We conclude that raft cholesterol depletion inhibited NSCLC migration through inhibition of phosphorylation of raft associated Src and dislocation of molecules comprising focal adhesion complexes from raft rather than by inhibiting their recruitment to Src and interaction.

The variation of prognostic significance of Maximum Standardized Uptake Value of [18F]-fluoro-2-deoxy-glucose positron emission tomography in different histological subtypes and pathological stages of surgically resected Non-Small Cell Lung Carcinoma - Corrected Proof

2009-11-30

Abstract: Even if the prognostic role of SUVmax of 18-FDG-PET has been largely investigated, many issues regarding its relationship with pathologic staging and histological subtypes still remain controversial. This retrospective study investigated the prognostic significance of SUVmax in 119 completely resected, pathologically proven NSCLC. The SUVmax values resulted significantly related to histological subtypes (p<0.001), histological grading (p<0.001), and pathologic stage (p<0.001). The optimal cut-off value of SUVmax to predict prognosis in the whole series was 6.7 (p=0.029). 2-Year disease-specific survival (DSS) was 91% for SUVmax ≤6.7 and 55% for SUVmax >6.7 (p<0.001). SUVmax still remain a significant predictor of survival in Stage IB (2-year DSS of 100% for SUVmax ≤6.7; 51% for SUVmax >6.7, p=0.016). The optimal cut-off values of SUVmax to predict prognosis were 5 for adenocarcinoma (p=0.027) and 10.7 for other non-adenocarcinoma NSCLC subtypes (p=0.010). These histologic-specific cut-offs resulted significantly related to survival when stratified for stage: 2-year DSS for Stage IB adenocarcinoma were 100% for SUV≤5 and 40% for SUVmax >5 (p=0.051); 2-year DSS for Stage IB non-adenocarcinoma were 83% for SUVmax ≤10.7 and 26% for SUVmax >10.7 (p=0.018). Adenocarcinomas showed significantly lower survival results respect to other NSCLC for intermediate SUVmax level (range 5.5–11.3) (p=0.021). High SUVmax resulted an independent negative prognostic factor at multivariate analysis (HR of 15.7, 95% CI of 2.50–98.44, p=0.003). In conclusion, SUVmax represents a significant prognostic factor in surgically resected NSCLC but a great variability between different histological subtypes, even when adjusted for stage, is present and could be considered when planning future trials on prognostic role of FDG uptake.

Cine MRI enables better therapeutic planning than CT in cases of possible lung cancer chest wall invasion - Corrected Proof

2009-11-30

Abstract: The objective: To evaluate the hypothesis that lung cancer treatment planning (whether or not to use induction therapy) can be improved if respiratory dynamic cine magnetic resonance imaging (RD MR) is used.Method: We studied 100 lung cancer patients, 76 men and 21 women, scheduled for thoracotomies between May 1997 and December 2006 wherein it was unclear preoperatively whether chest wall invasion would be found. We evaluated the accuracy of RD MR as compared with the findings at operation and postoperative pathology. The accuracy of RD MRI for evaluating chest wall invasion was compared with the efficacy of CT and MRI within our own group of patients and with data from the studies of other investigators.Results: Concerning the evaluation of chest wall invasion, conventional computed tomography (CT) had 43.9% specificity, 60.0% sensitivity and 47.1% accuracy, while RD MR had 68.5% specificity, 100.0% sensitivity and 77.0% accuracy. RD MRI was particularly useful in the evaluation of cancers around 5cm in diameter that were located adjacent to the diaphragm. Postoperative evaluation of superior sulcus tumor cases that had received induction therapy also showed that the RD MR procedure enabled an accurate decision in 87.5% of cases, and there were no false negative cases.Conclusions: RD MR is more useful than CT or standard MRI for evaluating thoracic wall invasion. This noninvasive method enhances the reliability of deciding whether induction therapy should be employed.

DNA hypermethylation of tumors from non-small cell lung cancer (NSCLC) patients is associated with gender and histologic type - Corrected Proof

2009-11-30

Abstract: Background: We previously identified a number of genes which were methylated significantly more frequently in the tumor compared to the non-cancerous lung tissues from non-small cell lung cancer (NSCLC) patients. Detection of methylation profiles of genes in NSCLC could provide insight into differential pathways to malignancy and lead to strategies for better treatment of individuals with NSCLC.Methods: We determined the DNA methylation status of 27 genes using quantitative MethyLight assays in lung tumor samples from 117 clinically well-characterized NSCLC patients.Results: Hypermethylation was detected in one of more of the genes in 106 (91%) of 117 cases and was detected at high levels (percentage methylation reference (PMR)≥4%) in 79% of NSCLC cases. Methylation of APC, CCND2, KCNH5 and, RUNX was significantly more frequent in adenocarcinomas compared to squamous cell carcinomas (SCC), while methylation of CDKN2A was more common in SCC. Hypermethylation of KCNH5, KCNH8, and RARB was more frequent in females compared to males. Hypermethylation of APC and CCND2 was inversely associated with proliferation score assessed by Ki-67 level.Conclusions: Our findings of differential gene hypermethylation frequencies in tumor tissues from patients with adenocarcinoma or squamous cell cancers and in females compared to males suggests that further investigation is warranted in order to more fully understand the potential disparate pathways and/or risk factors for NSCLC associated with histologic type and gender.

Expression of Mina53, a novel c-Myc target gene, is a favorable prognostic marker in early stage lung cancer - Corrected Proof

2009-11-16

Abstract: Mina53, a novel target gene product of c-Myc, is overexpressed in various malignancies. We previously demonstrated that Mina53 is overexpressed in lung cancer patients from the early clinical stages. In this paper, the association between disease prognosis and Mina53 expression in lung cancer patients is analyzed; we found that overexpression of Mina53 in lung cancer patients is associated with favorable prognosis. Statistical analysis using the Kaplan–Meier method showed that patients with negative staining for Mina53 had significantly shorter survival than patients with positive staining for Mina53, especially in stage I or with squamous cell carcinoma. Because the major cause of death in lung cancer patients after surgery is distant metastasis, the effect on cancer cell invasiveness was analyzed for the mechanisms involved in the association with favorable outcome. Overexpression of Mina53 in H226B, a lung squamous cell carcinoma cell line, inhibited cancer cell invasion. Transfection with mina53 shRNA increased the number of invading cells. These results suggest that Mina53 immunostaining is a useful prognostic marker – especially in the early stage of lung cancer – and that Mina53 negative patients should be managed particularly carefully after surgery.

The feasibility of adjuvant carboplatin and docetaxel in patients with curatively resected locally advanced non-small cell lung cancer - Corrected Proof

Hai-bo Sun, Si-yu Wang, Wei Ou, Bin-bin Zhang, Hua Yang, Qin Fang — 2009-11-13

Abstract: Background: Adjuvant cisplatin-based chemotherapy benefits selected patients with stages II and III non-small cell lung cancer (NSCLC). However, carboplatin being tolerated better than cisplatin, carboplatin-based adjuvant therapy may have better chemotherapy compliance. This study aimed to investigate the feasibility and toxicity of adjuvant carboplatin and docetaxel in patients with completely resected locally advanced NSCLC.Methods: Eighty patients with completely resected locally advanced NSCLC were enrolled in this trial. Adjuvant chemotherapy was initiated between 1 and 4 weeks after surgery, and consisted of four cycles of carboplatin (AUC=5), and docetaxel (Taxotere, 75mg/m2) every 3 weeks, after which patients received prophylactic G-CSF supportive therapy.Results: Patient demographics were: Median age 55 years (range 34–73): gender ratio was 56.3% male/43.7% female: 72.5% of the patients were at stage IIIA and 27.5% were at stage IIIB. The two most common histologies were adenocarcinoma (62.5%) and squamous cell carcinoma (17.5%). Sixty-six patients (82.5%) received four cycles of therapy over a 12-week period. Fourteen patients (17.5%) did not complete therapy due to: patient refusal (n=12), severe adverse events (n=1) and bone metastases during chemotherapy (n=1). No treatment related deaths were observed and the primary adverse events were hematologic toxicity, alopecia, fatigue and gastointestinal reaction (nausea, vomiting and diarrhea).Conclusion: Combination therapy with carboplatin and docetaxel with the use of G-CSF supportive therapy has an acceptable toxicity profile such that the majority of patients completed four cycles of therapy in 12 weeks.

Aberrant promoter methylation of FBLN-3 gene and clinicopathological significance in non-small cell lung carcinoma - Corrected Proof

Wang Rui, Zhang You-Wei, Chen Long-Bang — 2009-11-13

Abstract: FBLN-3 has been identified as an antagonist of angiogenesis which modulates cell morphology, growth, adhesion, and motility. In the present study, we investigated the promoter methylation status of FBLN-3 gene in non-small cell lung carcinoma (NSCLC) by methylation-specific PCR and analyzed its correlation with clinicopathological factors. The methylation of FBLN-3 gene promoter was detected in 28 of 65 (43.1%) NSCLC tissue samples and 6 of 65 (9.2%) corresponding non-tumor tissue samples (P<0.05). The methylation of FBLN-3 gene promoter led to the loss of FBLN-3 gene expression in NSCLC. Additionally, FBLN-3 promoter methylation was observed to be correlated with relative poor differentiation, advanced pathological stage and lymph node metastasis of NSCLC patients (P=0.017, 0.0057 or 0.002, respectively), but not with gender, age, histological type, and smoking condition (P>0.05). These results indicated that the loss of FBLN-3 gene induced by promoter methylation might play important roles in the progression of NSCLC and FBLN-3 promoter methylation might be a promising biomarker for early detection of NSCLC.

Early and late lung radiographic injury following stereotactic body radiation therapy (SBRT) - Corrected Proof

Marco Trovo, Anna Linda, Issam El Naqa, Cylen Javidan-Nejad, Jeffrey Bradley — 2009-11-12

Abstract: Objective: To describe early and late CT patterns of radiographic lung injury after SBRT for lung cancer, and to correlate radiological findings with patient and treatment characteristics.Materials and methods: Follow-up CT scans of 68 patients with 70 tumors were divided into 4 periods: (1) 6 weeks; (2) 2–6 months; (3) 7–12 months and (4) 13–18 months after SBRT. Early (within 6 months) and late radiological injuries were evaluated according to Ikezoe and Koening, respectively. The correlation between CT findings and patient characteristics was evaluated.Results: Radiographic injury in periods 1 and 2 was: (1) diffuse consolidation 3 and 27%, (2) patchy consolidation and ground-glass opacity (GGO) 13.2 and 33%, (3) diffuse GGO 13.2 and 21%, (4) patchy GGO 16.2 and 6%, and (5) no findings 54.4 and 21%, respectively. Late injury in periods 3 and 4 were: (1) modified conventional pattern (consolidation, volume loss, bronchiectasis) 54 and 44%, (2) mass-like 20 and 28%, (3) scar-like 14 and 16% and (4) no findings 20 and 12%, respectively. The proportion of emphysema grades 2–4 was significantly higher in patients who had no radiological findings 6 weeks after treatment (p=0.021). Both patchy consolidation and GGO patterns resulted more frequently in patients who were not administered steroids (p=0.035). No relationship was found with smoking, tumor dimension and radiation dose.Conclusions: The majority of patients had no evidence of radiographic lung injury 6 weeks after SBRT; the most prevalent findings were diffuse or patchy GGO. Patchy and diffuse consolidation develops 2–6 months after SBRT. Modified conventional pattern was the most prevalent in the late periods.