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Recent evidence indicates that both the phosphatidylinositol 3-kinase (PI3K)/AKT and the MEK/ERK pathways are strictly regulated by epidermal growth factor receptor in non-small cell lung cancer (NSCLC) that responds to Gefitinib. Gefitinib resistance is partly owing to the activation of two major downstream signaling pathways PI3K/AKT or MEK/ERK. In this study, we found that in Gefitinib-sensitive cell lines, Gefitinib could induce tumor cell apoptosis via upregulation of a proapoptotic protein BIM. Small interfering RNA results showed that silencing of BIM could alleviate apoptosis induced by Gefitinib. We adopted a combination of PI3K inhibitor (LY294002) and MEK inhibitor (U0126) against Gefitinib resistance in cell lines. As expected, the combination substantially induced apoptosis and restored the sensitivity to Gefitinib by increasing the expression of BIM. Our studies provided a theoretical basis for overcoming drug resistance in NSCLC via combination therapy.

Bevacizumab is a monoclonal antibody that specifically inhibits vascular endothelial growth factor, and is the first antiangiogenic agent to be approved for first-line treatment of advanced non-small cell lung cancer (NSCLC). Evidence from two large phase III trials demonstrates that bevacizumab combined with chemotherapy improves outcomes for patients with non-squamous NSCLC. In patients with adenocarcinoma without epidermal growth factor receptor (EGFR) mutation, a median overall survival of 18.0 months is achieved. Several post-registration phase IV studies have confirmed bevacizumab's efficacy and tolerability profile and have clarified the eligibility criteria. Clinical research is still ongoing to define the role of bevacizumab in different settings, such as single-agent bevacizumab for continuation maintenance therapy in advanced disease, treatment beyond disease progression, adjuvant therapy in early-stage NSCLC, or bevacizumab in combination with other targeted agents. A number of antiangiogenic tyrosine kinase inhibitors (TKI) have also been investigated in phase II and III trials. None of these drugs has proven significant clinical benefit in unselected patient populations. This article reviews the extensive information from randomized trials and large observational studies for bevacizumab in advanced NSCLC, and shortly describes the current clinical development of antiangiogenic monoclonal antibodies, TKIs and related compounds.

Background: Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement may predict the outcome of targeted drug therapy and also are associated with the efficacy of chemotherapy in patients with nonsmall cell lung cancer (NSCLC). The authors of this report investigated the relation of EGFR mutation or ALK rearrangement status and the expression of DNA repair or synthesis genes, including excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthetase (TS), and breast cancer-early onset (BRCA1), as a potential explanation for these observations., Methods: In total, 104 resected lung adenocarcinomas from women who were nonsmokers were analyzed concurrently for EGFR mutations, ALK rearrangements, and mRNA expression of the ERCC1, RRM1, TS, and BRCA1 genes. EGFR mutations were detected with a proprietary detection kit, ALK rearrangements were detected by polymerase chain reaction analysis, and genetic mRNA expression was detected by real-time polymerase chain reaction analysis., Results: Of 104 patients, 73 (70.2%) had EGFR mutations, and 10 (9.6%) had ALK rearrangements. ERCC1 mRNA levels in patients who had EGFR mutations were 3.44 ± 1.94 × 10(-3) , which were significantly lower than the levels in patients who were positive for ALK rearrangements and in patients who were negative for both biomarkers (4.60 ± 1.95 × 10(-3) and 4.95 ± 2.33 × 10(-3) , respectively; P = .010). However, TS mRNA levels were significantly lower in patients who had EGFR mutations (1.15 ± 1.38 × 10(-3) vs 2.69 ± 3.97 × 10(-3) ; P = .006) or ALK rearrangements (1.21 ± 0.78 × 10(-3) vs 2.69 ± 3.97 × 10(-3) ; P = .020) than in patients who were negative for both biomarkers., Conclusions: NSCLC specimens that harbored activating EGFR mutations were more likely to express low ERCC1 and TS mRNA levels, whereas patients with NSCLC who had ALK rearrangement were more likely to express low TS mRNA levels., (Copyright © 2012 American Cancer Society.)

Background: Doppler echocardiography is the method of choice for diagnosis and evaluation of aortic stenosis. However, there are well-known limitations to this method in difficult-to-image patients. Flow acceleration in the left ventricular outflow tract (LVOT) can lead to overestimation of stroke volume (SV) and poor acoustic windows may impede the exact measurement of the LVOT. The present study aimed to evaluate the use of inert gas rebreathing (IGR)-derived SV in this situation., Patients and Methods: We replaced Doppler-derived SV measurements in the continuity equation (method A) by SV determined by IGR (method B) and by thermodilution during right heart catheterization (method C) to calculate the aortic valve area (AVA) in 21 consecutive patients with moderate or severe aortic stenosis., Results: Mean SV and AVA did not differ between methods at 72±21 ml and 0.71±0.2 cm(2) (method A) vs. 66±18 ml and 0.67±0.21 cm(2) (method B) vs. 64±15 ml and 0.67±0.21 cm(2) (method C), respectively (all p-values >0.05). The mean difference and limits of agreement for AVA were 0.04±0.23 cm(2) and -0.40 to 0.47 cm(2) between methods A and B, 0.05±0.14 cm(2) and -0.26 to 0.27 cm(2) between A and C, and -0.05±0.23 cm(2) and -0.45 to 0.35 cm(2) between B and C, respectively (all p-values >0.05)., Conclusion: The presented approach is a reliable method for the calculation of AVA and can add a diagnostic option for the use in difficult-to-image patients. Whereas the use of thermodilution is limited due to its invasive nature, IGR allows the fast and non-invasive determination of cardiac function at low cost.

Background and Objective: Endobronchial ultrasound (EBUS) is now widely used in patients with resectable non-small-cell lung cancer to sample mediastinal lymph nodes (LN) for preoperative staging. The aim of this study was to investigate prospectively the utility of six ultrasound criteria to predict malignancy in mediastinal LN., Methods: EBUS was performed in patients with mediastinal lymphadenopathy irrespective of the underlying disease. The following criteria were expected to predict malignancy: short axis >1 cm, heterogeneous pattern, round shape, distinct margin, absence of a central hilar structure and high blood flow in a LN. A sum score prediction model for malignancy was built. If more than two criteria were present, LN was classified as high risk for malignancy. Moreover, interrater variability of two blinded investigators was evaluated., Results: Two hundred eighty-one LN in 145 patients were analysed. Forty-four percent of LN were found malignant, 10% revealed sarcoidosis, and 10% revealed tuberculosis. Interobserver agreement was very good. Positive predictive value was best for heterogeneity (73%), with a negative predictive value of more than 80%. The sum score resulted in an odds ratio of 15.5 if more than two criteria were positive (P < 0.00001)., Conclusions: The assessment of ultrasound criteria during routine EBUS examinations is feasible and reproducible with very good interrater agreement. If less than three of the described criteria are present, a LN has a very low chance of being malignant. The best single criterion to predict malignancy is heterogeneity. The introduction of the sum score of ultrasound criteria could potentially increase diagnostic accuracy., (© 2012 The Authors. Respirology © 2012 Asian Pacific Society of Respirology.)

With standard doublet chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC), we have reached an outcome plateau of about 10 months median overall survival over the last decades. Several studies have now demonstrated some survival benefits for patients treated beyond induction chemotherapy. In the current discussion about treatment duration, the terms "switch" and "continuation" maintenance therapy are now most commonly used by the scientific community. Switch maintenance is the treatment with an agent with a different mode of action after completion of induction chemotherapy in patients who's tumors have not progressed, whereas continuation maintenance is the continuation of one compound of the induction regimen. Chemotherapeutic compounds successfully investigated in the maintenance setting are Gemcitabine, Docetaxel and Pemetrexed. Targeted agents, recently investigated as maintenance therapy are Bevacizumab, Cetuximab and Erlotinib. New peer-reviewed publications of phase III randomized clinical trials on maintenance chemotherapy have led to a change in current practice guidelines and the use of maintenance therapy represents a new treatment option in advanced NSCLC. The pivotal trials are described and summarized in this review article.

Purpose: 23Na-MRI has been proposed as a potential imaging biomarker for the assessment of tumor viability and the evaluation of therapy response but has not yet been evaluated in patients with lung cancer. We aimed to assess the feasibility of 23Na-MRI in patients with lung cancer., Materials and Methods: Three patients with stage IV adenocarcinoma of the lung were examined on a clinical 3 Tesla MRI system (Magnetom TimTrio, Siemens Healthcare, Erlangen, Germany). Feasibility of 23Na-MRI images was proven by comparison and fusion of 23Na-MRI with 1H-MR, CT and FDG-PET-CT images. 23Na signal intensities (SI) of tumor and cerebrospinal fluid (CSF) of the spinal canal were measured and the SI ratio in tumor and CSF was calculated. One chemonaive patient was examined before and after the initiation of combination therapy (Carboplatin, Gemcitabin, Cetuximab)., Results: All 23Na-MRI examinations were successfully completed and were of diagnostic quality. Fusion of 23Na-MRI images with 1H-MRI, CT and FDG-PET-CT was feasible in all patients and showed differences in solid and necrotic tumor areas. The mean tumor SI and the tumor/CSF SI ratio were 13.3 ± 1.8 × 103 and 0.83 ± 0.14, respectively. In necrotic tumors, as suggested by central non-FDG-avid areas, the mean tumor SI and the tumor/CSF ratio were 19.4 × 103 and 1.10, respectively., Conclusion: 23Na-MRI is feasible in patients with lung cancer and could provide valuable functional molecular information regarding tumor viability, and potentially treatment response., (© Georg Thieme Verlag KG Stuttgart · New York.)

In the last decades significant progress has been achieved in the biological understanding of non-small-cell lung cancer (NSCLC) and its tumor heterogeneity has become more evident. The identification of novel tumor targets with different pathways has stimulated the search for anti-tumor agents with a specific target directed mode of action, stipulating the need of testing these agents in clinical trials with an appropriate choice of the study endpoint. Gold standard as an endpoint has been so far overall survival (OS). By definition there are 3 categories of classical endpoints applied generally in clinical lung cancer studies: survival time endpoints, symptom endpoints, and endpoints relying on patients' reporting. Beside classical endpoints like OS which are tending to show the direct clinical effect of treatment, efforts have been taken to substitute these classical endpoints by surrogates. As a surrogate candidate for OS progression-free survival (PFS) should have the inherent considerable advantage, that it can detect subpopulations with longer PFS intervals early. Based on the (sub-) population treated and having in mind the risk-benefit profile of the drug under consideration, PFS can be considered for regulatory decision making. If accompanied by some independent measures like quality of life or treatment toxicity, PFS should be able to cover the clinical benefit achieved by treatment. Selecting PFS as primary endpoint in Phase III trials of advanced NSCLC may be based on a number of questions such as: Does the definition of PFS fit into the setting used by other trials? Are there accepted consensus standards? Are there consistent surveillance intervals? Is validation for each agent group planned? Is the incremental improvement of PFS big enough (≥30%)? And are there some additional measures to confine clinical benefit? OS is still accepted as the gold standard in trials investigating advanced NSCLC. OS is easy to measure and precise but it may be difficult to interpret if treatment action takes place only in a small subinterval of overall survival. PFS with some additional measures has become attractive when it seems advisable to make study results available earlier. Candidates for supporting PFS as "additional measures" may be treatment toxicity and quality of life measures. PFS allows a more precise detection and attribution to effects of the investigational treatment without being compromised by subsequent treatments. Therefore "enriched PFS" can be considered as an alternative primary endpoint replacing OS in studies investigating advanced NSCLC. The endpoint selection process should always be performed carefully considering all true and surrogate endpoint options in respect to the hypotheses to be proven.

Inhibition of epidermal growth factor receptor (EGFR) has become an important target in the treatment of advanced non-small cell lung cancer (NSCLC). Erlotinib and gefitinib, two small molecular agents that target the tyrosine kinase domain of the EGFR, were approved in many countries for the treatment of locally advanced or metastatic NSCLC as a second- or third-line regimen. Since then, randomized trials have evaluated the role of these two targeted agents alone or combined with chemotherapy in maintenance and first-line settings. This review summarizes the results of recent clinical trials with these tyrosine kinase inhibitors, with a focus on erlotinib, as first-line treatment towards a form of personalized medicine aimed at improving clinical outcome in advanced NSCLC.

Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors ((EGFR-TKIs)- namely gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. Despite the fact that this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as T790M or amplification of the MET proto-oncogene, there are other mechanisms which need to be explored. MicroRNAs (miRs) are a class of small non-coding RNAs that play pivotal roles in tumorigenesis, tumor progression and chemo-resistance. In this study, we firstly successfully established a gefitinib resistant cell line-HCC827/GR, by exposing normal HCC827 cells (an NSCLC cell line with a 746E-750A in-frame deletion of EGFR gene) to increasing concentrations of gefitinib. Then, we found that miR-214 was significantly up-regulated in HCC827/ GR. We also showed that miR-214 and PTEN were inversely expressed in HCC827/GR. Knockdown of miR-214 altered the expression of PTEN and p-AKT and re-sensitized HCC827/GR to gefitinib. Taken together, miR-214 may regulate the acquired resistance to gefitinib in HCC827 via PTEN/AKT signaling pathway. Suppression of miR-214 may thus reverse the acquired resistance to EGFR-TKIs therapy.

With ongoing technical improvements such as multichannel MRI, systems with powerful gradients as well as the development of innovative pulse sequence techniques implementing parallel imaging, MRI has now entered the stage of a radiation-free alternative to computed tomography (CT) for chest imaging in clinical practice. Whereas in the past MRI of the lung was focused on morphological aspects, current MRI techniques also enable functional imaging of the lung allowing for a comprehensive assessment of lung disease in a single MRI exam. Perfusion imaging can be used for the visualization of regional pulmonary perfusion in patients with different lung diseases such as lung cancer, chronic obstructive lung disease, pulmonary embolism or for the prediction of postoperative lung function in lung cancer patients. Over the past years diffusion-weighted MR imaging (DW-MRI) of the thorax has become feasible with a significant reduction of the acquisition time, thus minimizing artifacts from respiratory and cardiac motion. In chest imaging, DW-MRI has been mainly suggested for the characterization of lung cancer, lymph nodes and pulmonary metastases. In this review article recent MR perfusion and diffusion techniques of the lung and mediastinum as well as their clinical applications are reviewed., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Rationale and Objectives: The aim of this study was to assess the findings of chest radiography and high-resolution computed tomography in patients requiring intensive care unit treatment for severe H1N1 virus pneumonia., Materials and Methods: In 2009, 10 patients required treatment in an intensive care unit for confirmed H1N1 pneumonia. All patients underwent chest radiography and high-resolution computed tomography. All 10 patients required mechanical ventilation because of respiratory failure. Nine patients presented with severe acute respiratory distress syndrome, and one patient died. Four patients underwent extracorporeal membrane oxygenation (ECMO) therapy. The results of chest radiography and high-resolution computed tomographic scans of these patients were systematically analyzed., Results: The mean age of all patients was 44.1 +/- 12.3 years. All 10 patients showed abnormal results on chest radiography. The radiographic abnormalities were bilateral and multifocal in 10 patients. The predominant radiographic findings were consolidations (n = 9), ground-glass opacities (n = 8), and reticular opacities (n = 2). The most frequent computed tomographic findings at presentation consisted of bilateral ground-glass opacities (n = 9), pleural effusion (n = 9), areas of consolidation (n = 8), interstitial marking (n = 8), and crazy paving (n = 4). All patients undergoing ECMO therapy showed extensive bilateral ground-glass opacities, multifocal areas of consolidation, and crazy paving. Pleural effusion was present in three of four patients undergoing ECMO therapy., Conclusion: Patients requiring treatment in an intensive care unit for severe H1N1 pneumonia are at high risk for developing acute respiratory distress syndrome and frequently require ECMO therapy., (Copyright (c) 2010 AUR. Published by Elsevier Inc. All rights reserved.)

Pemetrexed is a novel multi-targeted antifolate that is used in the treatment of both malignant pleural mesothelioma and non-small-cell lung cancer (NSCLC). Lung cancer is the most common cancer in the world and NSCLC represents approximately 80% of all lung cancers. Pemetrexed is the first NSCLC drug for which 'treatment-by-histology' has been determined. This refers to the greater efficacy of pemetrexed in patients with advanced NSCLC other than of predominantly squamous-cell histology. The advent of treatment-by-histology represents a significant step forward in the treatment of lung cancer, allowing physicians to tailor therapies to the individual patient. Ongoing trials aim to establish the place of pemetrexed in maintenance, in combination with other 'targeted agents', in adjuvant therapy in early NSCLC and in concurrent radio/chemotherapy.