In the last decade, important advances have been made in understanding of cancer biology, particularly non-small-cell lung cancer (NSCLC) with the discovery of oncogenic drivers of the disease. The epidermal growth factor receptor (EGFR) gene and its pathways was the first oncogenic driver discovered to be mutated and treatable in lung cancer. Treatment with EGFR tyrosine kinase inhibitors (TKIs) is the standard of care for molecularly selected EGFR-mutant patients, while its role in unselected lung cancer patients is nowadays controversial. This review will provide an overview of the EGFR pathway and options for its treatment of lung cancer.
It is unknown whether serial pulmonary function tests are necessary for the correct diagnosis of chronic obstructive pulmonary disease (COPD) in patients with stable non-congested chronic heart failure (CHF). The aim of this study was to determine the prevalence of COPD in outpatients with stable CHF without pulmonary congestion using initial as well as confirmatory spirometry three months after treatment for COPD.
BACKGROUND:SALL4 and OCT4 are transcription factors and play essential roles in stem cell development and oncogenesis. However, the expression of these transcription factors has not been well studied in lung cancers. In this study, we evaluated the expression of SALL4 and OCT4 in non-small cell lung carcinomas (NSCLC) by immunochemistry. NSCLC tissue microarrays (TMAs) were constructed with a total of 77 primary lung adenocarcinomas (ADCs) and 90 primary lung squamous cell carcinomas (SqCCs). A mouse monoclonal anti-human SALL4 (1:400 dilution) and a polyclonal anti-human OCT4 (1:200 dilution) antibodies were used. Nuclear staining of SALL4 and OCT4 was scored semi-quantitatively using a three tiered scale. The expressions of SALL4 and OCT4 were correlated with the tumor differentiation, pathological stage, and patients' clinical information.RESULTS:In primary ADCs, the stronger expression of SALL4 and OCT4 was 7.8% and 9.1%, respectively. The stronger expression of SALL4 was inversely correlated with tumor differentiations. In primary SqCCs, the stronger expressions of SALL4 and OCT4 were 16.7% and 0%, respectively. The expression of SALL4 is correlated with the expression of OCT4, but inversely correlated with the tumor stage in SqCCs.CONCLUSIONS:We found that both SALL4 and OCT4 were differentially expressed in a subset of primary ADC and SqCC. Our finding suggest that different stem cell markers may be expressed and/or play differential role in different subtypes of NSCLC. The potential role of SALL4 and OCT4 needs to be further investigated in NSCLC.
Background ESMO consensus recommends EGFR mutation testing in never/former light smokers (<15 pack-years) or patients with non-squamous NSCLC. The aim of this work was to determine the frequency and clinical predictors of EGFR mutations, and the role of specimen sampling tests, in Caucasian standard practice setting. Methods We screened 297 patients according to this consensus. Mutational analysis of EGFR was performed using the Therascreen EGFR RGQ PCR mutation kit. Clinical and pathological correlative data were collected. Results An EGFR activating mutation was found in 32 patients (11%), twelve exon 19 deletions, two exon 18 and eighteen exon 21 point mutations. Most were in females, but half were in smokers. Negative TTF-1 staining had a very strong negative predictive value (all except one patient had TTF-1 positive adenocarcinoma). Both biopsies as well as cytology specimens (mainly EBUS-TBNA) did well: 24 mutations in 213 biopsy samples (11.2%) and 8 in 84 cytology samples (9.5%), respectively. The Therascreen acted as a sensitive test in all types of samples: 7 activating mutations were found in samples rated to have <5% of tumour cells, and there were only 4 test failures in the whole series. Conclusion In this Caucasian standard practice NSCLC cohort, tested according to the ESMO consensus, activating EGFR mutation occurred in 11% of the patients. Half of these were in former/current smokers. With our sampling technique and use of the Therascreen kit, EBUS-TBNA cell blocks performed as good as biopsies.
Wnt/β-catenin signaling has been suggested to regulate proximal-distal determination of embryonic lung epithelium based upon genetically modified mouse models. The previously identified and characterized small molecule inhibitor IQ1 can pharmacologically decrease the interaction between β-catenin and its transcriptional coactivator p300, thereby enhancing the β-catenin/CBP interaction. Inhibition of the β-catenin/p300 interaction by IQ1 blocks the differentiation of embryonic stem cells and epicardial progenitor cells; however, whether differential coactivator usage by β-catenin plays a role in proximal-distal determination of lung epithelium is unknown.
Respiratory viral infections are the most common trigger of acute exacerbations in patients with allergic asthma. The anti-viral response of airway epithelial cells (AEC) may be impaired in asthmatics, while cytokines produced by AEC may drive the inflammatory response. We investigated whether AEC cultured in the presence of Th2 cytokines associated with an allergic environment exhibited altered responses to double-stranded RNA, a virus-like stimulus.
Background Prevalence of bronchial asthma, asthma treatment assessment, and estimation of the control level among asthma patients in Henan Province, China are reported in this paper. Methods We selected 10 among the 109 cities and districts in Henan province using a multistage stratified cluster random sampling method. A total of 500 households from each city and district were chosen. Approximately 20,000 residents from a total of 5,000 households were randomly selected to answer a questionnaire recommended by the China Asthma Alliance. Asthma patients were asked to answer a detailed questionnaire using the symptom-based guidelines to assess the levels of disease control. Results The overall prevalence of asthma was 0.73% ± 0.12%. Urban and rural residents had asthma prevalence rates of 1.1% ± 0.23% (88/7,924) and 0.48% ± 0.12% (57/11,792), respectively. Among the asthma patients, only 33.8% (52) received regular medication, 25% (13) used oral glucocorticoids, and 71.1% (37) used oral theophylline. The classified control levels of patients were as follows: 33.1% controlled, 49.7% partially controlled, and 17.2% uncontrolled. A total of 38.5% and 27.5% of regularly and irregularly treated asthma patients reached controlled level, respectively. The two groups significantly differed in asthma control level. Conclusion Asthma prevalence is low in Henan Province, China. Urban residents have higher prevalence of asthma than rural residents do. Patients with asthma receive insufficient medication, resulting in suboptimal asthma control. Improvement in diagnosis and treatment of asthma patients is urgently needed.
Until the late 1990s, aerosol therapy consisted of beta2-adrenergic agonists, anti-cholinergics, steroidal and non-steroidal agents, mucolytics and antibiotics that were used to treat patients with asthma, COPD and cystic fibrosis. Since then, inhalation therapy has matured to include drugs that: (1) are designed to treat diseases outside the lung and whose target is the systemic circulation (systemic drug delivery); (2) deliver nucleic acids that lead to permanent expression of a gene construct, or protein coding sequence, in a population of cells (gene therapy); and (3) provide needle-free immunization against disease (aerosolized vaccination). During the evolution of these advanced applications, it was also necessary to develop new devices that provided increased dosing efficiency and less loss during delivery. This review will present an update on the success of each of these new applications and their devices. The early promise of aerosolized systemic drug delivery and its outlook for future success will be highlighted. In addition, the challenges to aerosolized gene therapy and the need for appropriate gene vectors will be discussed. Finally, progress in the development of aerosolized vaccination will be presented. The continued expansion of the role of aerosol therapy in the future will depend on: (1) improving the bioavailability of systemically delivered drugs; (2) developing gene therapy vectors that can efficiently penetrate the mucus barrier and cell membrane, navigate the cell cytoplasm and efficiently transfer DNA material to the cell nucleus; (3) improving delivery of gene vectors and vaccines to infants; and (4) developing formulations that are safe for acute and chronic administrations.
Acute respiratory distress syndrome (ARDS) in humans involves ≥ 200,000 individuals in the United States, and has a mortality rate (40%) for which no specific drug has been approved for use in humans. We have studied experimental acute lung injury (ALI) in mice following airway deposition of bacterial lipopolysaccharide (LPS) or the recombinant mouse complement anaphylatoxin, C5a. As ALI developed over 6 hr, extracellular histones appeared in bronchoalveolar lavage fluids (BALF). Extracellular histone appearance required both C5a receptors (C5aR, C5L2) as well as neutrophils (PMNs) and lung macrophages, as genetic loss of either C5a receptor or depletion of PMNs or macrophages reduced histone levels found in BALF during ALI. It is possible that extracellular histones were derived from formation of neutrophil extracellular traps (NETs) in lung after PMN contact with C5a. When purified histones were delivered to lung via the airways, intense inflammatory injury ensued and type II cells developed large blebs indicating cellular damage and apoptosis. Detailed physiological measurements revealed severe disruption of blood/alveolar gas exchange. These data suggest a key role for histones in development of experimental ALI.
This discourse contains three perspectives on various aspects of Stem Cell Biology and tools available to study and translate into Regenerative Medicine. The lung incessantly faces onslaught of the environment, constantly undergoes oxidative stress, and is an important organ of detoxification. In degenerative diseases and inflammation, the lung undergoes irreversible remodeling that is difficult to therapeutically address and/or transplant a dying tissue. The other difficulty is to study its development and regenerative aspects to best address the aforementioned problems. This perspective therefore addresses- firstly, review of types of stem cells, their pathway of action and models in invertebrate organisms vis-a-vis microenvironment and its dynamics; secondly, stem cells in higher organisms and niche; and lastly data and inference on a novel approach to study stem cell destruction patterns in an injury model and information on putative lung stem cell niche. Stem cells are cryptic cells known to retain certain primitive characteristics making them akin to ancient cells of invertebrates, developmental stages in invertebrates and vertebrates and pliant cells of complex creatures like mammals that demonstrate stimulus-specific behavious, whether to clonally propagate or to remain well protected and hidden within specialized niches, or mobilize and differentiate into mature functionally operative cells to house-keep, repair injury or make new tissues. In lung fibrosis, alveolar epithelium degenerates progressively. In keeping with the goal of regenerative medicine, various models and assays to evaluate long and short term identity of stem cells and their niches is the subject of this perspective. We also report identification and characterization of functional lung stem cells to clarify how stem cell niches counteract this degenerative process. Inferences drawn from this injury model of lung degeneration using a short term assay by tracking side population cells and a long term assay tracking label retaining cells have been presented.
BACKGRUOND:Since their first description, activating epidermal growth factor receptor (EGFR) mutations identify a distinct clinical entity of patients with non-small-cell lung cancer (NSCLC).FINDINGS:New targeted therapies for molecularly selected NSCLC are changing the natural history of the disease, with results superior to standard chemotherapy as demonstrated in large phase III studies with first generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR). In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs.CONCLUSIONS:Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib.
Chronic airway diseases like cystic fibrosis, chronic bronchitis, asthma, diffuse panbronchiolitis, and bronchiectasis are all associated with chronic inflammation. The airway mucosa responds to infection and inflammation in part by surface mucous (goblet) cell and submucosal gland hyperplasia and hypertrophy with mucus hypersecretion. Products of inflammation including neutrophil derived DNA and filamentous actin, effete cells, bacteria, and cell debris all contribute to mucus purulence and, when this is expectorated it is called sputum. Mucus is usually cleared by ciliary movement, and sputum is cleared by cough. These airway diseases each are associated with the production of mucus and sputum with characteristic composition, polymer structure, and biophysical properties. These properties change with the progress of the disease making it possible to use sputum analysis to identify the potential cause and severity of airway diseases. This information has also been important for the development of effective mucoactive therapy to promote airway hygiene.
The complex tasks of making a confident diagnosis of a specific form of interstitial lung disease (ILD) and formulating a patient-centered, personalized management plan in an attempt to achieve remission or stabilization of the disease process can pose formidable challenges to clinicians. When patients are evaluated for suspected ILD, an accurate diagnosis of the specific form of ILD that a patient has developed must be made to provide the patient with useful prognostic information and to formulate an appropriate management plan that can relieve symptoms and restore or significantly improve quality of life. A well-performed patient history and physical examination provides invaluable information that can be combined with appropriate laboratory testing, imaging, and, if needed, tissue biopsy to reach a confident ILD diagnosis, and high-resolution computed tomography (HRCT) of the thorax is usually a key component of the diagnostic evaluation. If treatment is indicated, many forms of ILD can respond significantly to immunosuppressive anti-inflammatory therapies. However, ILD accompanied by extensive fibrosis may be difficult to treat, and the identification of an effective pharmacologic therapy for idiopathic pulmonary fibrosis (IPF) has remained elusive despite the completion of many phase 3 clinical trials over the past decade. Nonetheless, patients with IPF or advanced forms of non-IPF ILD can benefit significantly from detection and treatment of various co-morbid conditions that are often found in patients (especially the elderly patient), and supportive care (oxygen therapy, pulmonary rehabilitation) can have a beneficial impact on quality of life and symptom palliation. Finally, lung transplantation is an option for patients with progressive, advanced disease that does not respond to other therapies, but only a relatively small subset of patients with end-stage ILD are able to meet wait listing requirements and eventually undergo successful lung transplantation.
The role of bacterial infection in chronic obstructive pulmonary disease (COPD) and how it should be treated has been an ongoing source of controversy. For many years bacterial infection has not been thought to have an important effect in the pathology of this condition. Recent advances in diagnostic techniques, particularly the use 16S sequencing has demonstrated that there are a large range of bacteria present in the lower respiratory tract, both in terms of exacerbations and chronic colonization. A proportion of the bacteria present in the lower respiratory have also been shown to produce inflammation and hence are likely to be relevant for the pathogenesis of COPD. The accurate diagnosis of bacterial infection in individual patients remains a major challenge. The trials that have assessed the effect of antibiotics in COPD have generally been of low quality and have not been placebo controlled. Recent studies of macrolides for long-term treatment in COPD have found significantly reduced rates of exacerbations. Major challenges remain in accurately defining the potential role of bacteria in the inflammatory process and how best to optimize the use of antibiotics without the overuse of this limited resource. Alternative strategies to treat infection in COPD remain very limited.
Lung transplantation remains the only viable treatment option for the majority of patients with advanced lung diseases. However, 5-year post-transplant survival rates remain low primarily secondary to chronic rejection. Novel insights from global gene expression profiles may provide molecular phenotypes and therapeutic targets to improve outcomes after lung transplantation.
Respiratory diseases will become one of the top 3 leading causes of estimated mortality in 2020 and become about one third of total causes of estimated mortality. The journal of Translational Respiratory Medicine is a truly international, peer-reviewed journal devoted to the publication of articles on outstanding work with translational potentials between basic research and clinical application to understanding respiratory disease. Translational respiratory medicine will more focus on biomarker identification and validation in pulmonary diseases in combination with clinical informatics, targeted proteomics, bioinformatics, systems medicine, or mathematical science; on different translational strategies of cell-based therapy to clinical application to treat lung diseases; on targeted therapies in combination with personalized medicine; and on distant electronic medicine to monitor a large population of people’s health. Translational Respiratory Medicine is an additional but unique opportunity for scientists and clinicians who work on pulmonary diseases to publish their outstanding findings, initiative results, and critical and perceptive opinions in the journal.
Acute lung injury and the acute respiratory distress syndrome are major causes of morbidity and mortality in critically ill patients. This review focuses on new developments in definitions, epidemiology, clinical and basic research, and promising new directions in treatment. There is new information about the potential contribution of environmental factors, especially exposure to cigarette smoke. Pathologic findings in ARDS have been limited to case reports of open lung biopsies and post-mortem studies but there is some new information from a recent pathology study relative to the frequency of diffuse alveolar damage and the severity of arterial hypoxemia. Further, therapy with lung-protective ventilation and fluid conservative protocol has improved outcomes, but several new trials are in progress to test several promising strategies.
Matrix-metalloproteinase (MMP)-9 has been implicated in the pathogenesis of COPD, although its link to disease severity is unclear. The purpose of the study was to examine the relationship between disease severity assessed by lung function and computed tomography (CT) and sputum MMP-9 expression, concentration and activity in patients with COPD.
Lung cancer is a heterogeneous and complex disease. Genomic and transcriptomic profiling of lung cancer not only further our knowledge about cancer initiation and progression, but could also provide guidance on treatment decisions. The fact that targeted treatment is most successful in a subset of tumors indicates the need for better classification of clinically related molecular tumor phenotypes based on better understanding of the mutations in relevant genes, especially in those oncogenic driver mutations. EGFR gene mutations, KRAS gene mutations, EML4-ALK rearrangements and altered MET signaling are widely recognized alterations that play important roles in both the biological mechanisms and the clinical sensitivity to treatment in lung cancer. In this article, we reviewed the discovery of the clinical values of these oncogenic driver mutations and the clinical studies revealing the prognostic and predictive values of these biomarkers for clinical sensitivity and resistance to anti-EGFR therapy or other targeted therapies. These form the basis of personalized treatment in lung cancer based on biomarker profiles of individual tumor, leading to therapeutic advancement and betterment.
Background The prevalence of asthma has increased over recent decades and the reasons for this are poorly understood. A sensitive tool that can evaluate potential risk factors for asthma is bronchial hyperresponsiveness (BHR), a key physiological characteristic of asthma. However, although the minimum clinically important difference in BHR for an individual is accepted to be around one doubling dose, the minimum important change in a population is not defined. As with surrogate measures of cardiovascular disease risk such as blood pressure and cholesterol, a change that is not clinically important in an individual may be extremely important in public health terms. Findings To assess the potential impact of a small absolute change in BHR across a population, we modelled the effect of different changes in BHR on the prevalence rates of moderate and severe BHR in an asthmatic population. We calculate that a one half doubling dose increase in BHR increases the prevalence of moderate and severe BHR by 30%. If this was accompanied by an equivalent increase in the population prevalence of moderate and severe asthma, this would be highly significant in public health terms. Conclusions We propose that a one half doubling dose worsening in BHR across a population may represent an important change.
