Non-malignant Lung Diseases Research Articles

Abstract 4568: Multivariate analysis of a panel of protein biomarkers for early detection of non-small cell lung cancer

Abstract Introduction: Lung cancer is the leading cause of cancer mortality in the US; it has been estimated that 219,440 individuals will be diagnosed with lung cancer and 159,390 will die from the disease in 2009 alone. Low dose CT, while very sensitive at visualizing early stage tumors, also identifies non malignant solitary pulmonary nodules (false positives) in a significant fraction of smokers. Biomarker panels may have considerable value when combined with imaging protocols in helping to discriminate benign from malignant nodules. We have employed a novel mass spectrometry-based approach to identify serum biomarkers which we have previously shown to detect non-small cell lung cancer (NSCLC) representing all 4 stages of disease. In this study we extend these findings to a cohort highly representative of early stage lung cancer. Methodology: Validation of non small cell lung cancer markers was performed by ELISA analysis on a cohort of sera collected at the NYU Langone Medical Center. In this study lung cancer cases represent predominantly early stage disease (65 stage I/ 91 all cancer). Controls comprise current and former healthy smokers (n=90) as well as subjects with non-malignant lung disease (COPD, n=46). Samples were randomly divided into a training set (cancer n=39; smokers n= 38; COPD n=20) and a test set (cancer n=52; smokers n=52; COPD n=26). Logistic regression analysis revealed several multi-marker panels capable of distinguishing malignant samples from matched controls in the training set. A classifier developed for each panel was then applied to the test set. Multivariate approaches were employed to analyze this data together with other key clinical parameters including: tumor stage, size, histology and lung-function data. Results: Markers for the panel were selected based on both individual marker performance and complementation of the performance of the relevant biomarker panel. Logistic regression analysis on the training set revealed a 9-marker panel which resolved malignant samples with 90% sensitivity at 96% specificity (AUC=0.977). The panel resolved malignant lesions under 1 cm and demonstrated good discrimination of COPD patients. A 6-marker panel was identified with similar performance characteristics (AUC=0.974). Applying the classifier generated from the training set to the test set also showed strong performance in this study, with an AUC of 0.92 for the 9 marker set in preliminary analyses. Conclusion: Panels of lung biomarkers identified initially through proteomic analysis have shown robust performance in a study cohort strongly biased toward early-stage disease. The findings from these studies suggest that these biomarker panels provide the performance and flexibility to design tests suitable for a variety of diagnostic applications such as screening high risk subjects prior to CT scanning and improving the discrimination of nodules identified by radiologic imaging. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4568.

Honorary memberships in the European Histamine Research Society

There are three types of membership in the EHRS: ordinary, corporate and affiliated, and honorary (life). The highest award is that of honorary membership which is only given to very special people. To obtain honorary membership, the person has to be elected by over twothirds of the ordinary members at the General Assembly. There are only nine current Honorary Members of the Society: James Black, Robin Ganellin, Wilfred Lorenz, Piero Mannaioni, Walter Schunack, Henk Timmerman, Ingrid Olhagen-Uvnas, Takehiko Watanabe and Jean West. At this meeting, the society awarded honorary membership to three special people who have all contributed significantly to the EHRS; they are Professor Madeleine Ennis, Professor Bruno Mondovi and Professor Fred Pearce. The oration for Professor Madeleine Ennis was given by Professor Fred Pearce. Madeleine was awarded a BSc in Chemistry from UCL in 1974 and a PhD in Biological Chemistry (supervisor Charles Vernon) in 1978. Her thesis was entitled ‘‘Some Studies on Nerve Growth Factor and its Antiserum’’ and provided important information about the mechanism of immunosympathectomy. She then spent 3 years carrying out postdoctoral work with Fred Pearce, and together they established the mast cell group in the Chemistry Department at UCL. Her main interests were calcium and histamine release and mast cell heterogeneity. This was a most productive period and resulted in 25 publications, one of which became a mini-citation classic and another EHRS Milestone Paper. Madeleine then spent 2 years in the Department of Clinical Pharmacology at the Royal Postgraduate Medical School in Hammersmith before joining Wilfried Lorenz in the Institute for Theoretical Surgery in Marburg. Her main interest in Marburg was adverse allergic and pseudoallergic drug reactions. This period in Germany consolidated Madeleine’s scientific reputation and she moved in 1989 to a lectureship in Clinical Biochemistry at Queen’s University, Belfast. Thereafter, she was rapidly promoted to Senior Lecturer in 1996 and to Professor of Immunopharmacology in 1999. Madeleine’s current research interests span the role of infection, inflammation and inflammatory markers in all of the major, non-malignant lung diseases. Madeleine consolidated these interests by founding the Respiratory Research Group at Queen’s, and she is now Director of the Respiratory Medicine Research Cluster and widely recognised as one of the United Kingdom’s leading experts in the pathogenesis of respiratory disease. She has supervised a huge number of research students all of whom hold her in universal affection. She also carried out some rigorous research into the basis of homeopathy which attracted enormous publicity and led to an appearance on the BBC television programme ‘‘Horizon’’. Madeleine has also found time to serve on the Women’s Forum Committee at Queen’s and to chair the Mentoring Sub-Group of that Committee. She is the Mentoring Champion at the M. Ennis Respiratory Medicine Research Group, The Queen’s University of Belfast, Belfast BT12 6BN, Northern Ireland, UK

Gene Expression Profiles in Peripheral Blood Mononuclear Cells Can Distinguish Patients with Non–Small Cell Lung Cancer from Patients with Nonmalignant Lung Disease

Early diagnosis of lung cancer followed by surgery presently is the most effective treatment for non-small cell lung cancer (NSCLC). An accurate, minimally invasive test that could detect early disease would permit timely intervention and potentially reduce mortality. Recent studies have shown that the peripheral blood can carry information related to the presence of disease, including prognostic information and information on therapeutic response. We have analyzed gene expression in peripheral blood mononuclear cell samples including 137 patients with NSCLC tumors and 91 patient controls with nonmalignant lung conditions, including histologically diagnosed benign nodules. Subjects were primarily smokers and former smokers. We have identified a 29-gene signature that separates these two patient classes with 86% accuracy (91% sensitivity, 80% specificity). Accuracy in an independent validation set, including samples from a new location, was 78% (sensitivity of 76% and specificity of 82%). An analysis of this NSCLC gene signature in 18 NSCLCs taken presurgery, with matched samples from 2 to 5 months postsurgery, showed that in 78% of cases, the signature was reduced postsurgery and disappeared entirely in 33%. Our results show the feasibility of using peripheral blood gene expression signatures to identify early-stage NSCLC in at-risk populations.

Review Series: What goes around, comes around: childhood influences on later lung health?: Relationship between environmental exposures in children and adult lung disease: The case for outdoor exposures

There is a growing understanding that chronic respiratory diseases in adults have their origins in early life. Adverse environmental exposures occurring in vulnerable periods during lung growth and development in the fetal period and in early childhood that alter lung structure and limit the growth in lung function may have lifelong consequences. Evidence is increasing that exposure to the ambient environment, including air pollutants, persistent toxic substances, water pollutants and respiratory viral infections, can inhibit lung function growth and predispose to chronic non-malignant lung diseases. These exposures generally interact with a genetic predisposition, and gene-environment interactions and epigenetic phenomena are attracting considerable study. An understanding of how ambient exposures impact on normal lung growth and development will aid in understanding of how chronic respiratory diseases of adults develop and may lead to new preventative strategies.

Modeling of contrast agent kinetics in the lung using T1‐weighted dynamic contrast‐enhanced MRI

Assessment of perfusion and capillary permeability is important in both malignant and nonmalignant lung disease. Kinetic modeling of T(1)-weighted dynamic contrast-enhanced MRI (DCE-MRI) data may provide such an assessment. This study establishes the feasibility and interrelationship of kinetic modeling approaches designed to estimate microvascular properties in malignant and nonmalignant tissues of the lung. DCE-MRI data were acquired using a low molecular weight contrast agent with 4-sec temporal resolution in lung cancer patients. A model-free parameterization and three kinetic models of increasing complexity, each related to the classical Kety model, were applied. Comparison of an extended Kety model and the adiabatic approximation to the tissue homogeneity (AATH) model using Akaike's Information Criterion suggested that in most cases the best description of the lung tumor data is obtained using the AATH model. In the normal lung parenchyma the temporal resolution was insufficient to separate effects of flow and contrast agent leakage and in this case the extended Kety model yielded the best fit to the data.

Indoor air pollution from solid fuel use, chronic lung diseases and lung cancer in Harbin, Northeast China

In some areas of China, indoor air pollution (IAP) originating principally from the combustion of solid fuels has a relevant role in lung cancer. Most previous studies focused on the female population and only a few on both the sexes. We analyzed the relationship between IAP from solid fuel use and selected chronic lung diseases and lung cancer risk in Harbin, Northeast China, an area with a very high base line risk of lung cancer for both the sexes. We used data from a case-control study conducted between 1987 and 1990, including 218 patients with incident, histologically confirmed lung cancer and 436 controls admitted to the same hospitals as cases. We calculated an index of IAP from solid fuel use exposure using data on heating type, cooking fuel used, and house measurements. Cases reported more frequently than controls an exposure to coal fuel for house heating and/or cooking, and the odds ratio (OR) for ever versus never exposed was 2.19 [95% confidence interval (CI): 1.08-4.46]. The ORs of lung cancer according to subsequent tertiles of IAP exposure index were 1.82 (95% CI: 1.14-2.89) and 1.99 (95% CI: 1.26-3.15) as compared with the lowest tertile. The ORs of lung cancer for participants with a history of chronic bronchitis and tuberculosis were 3.79 (95% CI: 2.38-6.02) and 3.82 (95% CI: 1.97-7.41), respectively. This study gives further support and quantification of the positive association between IAP, history of selected nonmalignant lung diseases, and lung cancer risk for both the sexes.

Integrity of Cell‐Free Plasma DNA in Patients with Lung Cancer and Nonmalignant Lung Disease

In several papers an increased quantity of cell-free plasma DNA as well as the presence of long DNA fragments in cell-free plasma and serum has been described. We isolated cell-free DNA from plasma, serum, and bronchial lavage supernatants from 33 lung cancer patients and 27 patients with a benign lung disease. The DNA was amplified by real-time PCR, and the quantity as well as the DNA integrity was determined. We did not find significant differences between the patient populations. Our results led us to conclude that this method is not useful in a diagnostic setting and is not able to differentiate between lung cancer patients and patients with a benign lung disease.

Health Effects of Early Life Exposure to Arsenic

Inorganic arsenic is a potent human carcinogen and general toxicant. More than one hundred million people are exposed to elevated concentrations, mainly via drinking water, but also via industrial emissions. Arsenic is metabolized via methylation and reduction reactions, methylarsonic acid and dimethylarsinic acid being the main metabolites excreted in urine. Both inorganic arsenic and its methylated metabolites easily pass the placenta and both experimental and human studies have shown increased risk of impaired foetal growth and increased foetal loss. Recent studies indicate that prenatal arsenic exposure also increases the risk of adverse effects during early childhood. There is a growing body of evidence that the intrauterine or early childhood exposure to arsenic also induces changes that will become apparent much later in life. One epidemiological study indicated that exposure to arsenic in drinking water during early childhood or in utero was associated with an increased mortality in young adults from both malignant and non-malignant lung disease. Furthermore, a series of experimental animal studies provide strong support for late effects of arsenic, including various forms of cancer, following intrauterine arsenic exposure. The involved modes of action include epigenetic effects, mainly via DNA hypomethylation, endocrine effects (most classes of steroid hormones), immune suppression, neurotoxicity, and interaction with enzymes critical for foetal development and programming.

Arsenic and non-malignant lung disease

Many aquifers in various parts of the world have been found to be contaminated with arsenic at concentration above 0.05 mg/L. However reports of large number of affected people in India and Bangladesh are unprecedented. Characteristic skin lesions (pigmentation, depigmentation and keratosis) are the hallmark signs of chronic arsenic toxicity. Emerging evidences show that ingestion of arsenic through drinking water may also lead to non-malignant respiratory effects. Early report of non-malignant pulmonary effect of chronic ingestion of arsenic was available from studies in children in Chile as early as 1970. However on the basis of case studies, respiratory effect of chronic arsenic toxicity in adults following dinking of arsenic contaminated water in West Bengal was first reported in 1997. Epidemiological studies carried out in West Bengal on a population of 7683 showed that the prevalence odds ratio (POR) estimates were markedly increased for participants with arsenic induced skin lesions who also had high levels of arsenic in their current drinking water source (≥0.5 mg/L) compared with individuals who had normal skin and were exposed to low levels of arsenic (< 0.05 mg/L). In participants with skin lesions, age-adjusted POR estimates for chronic cough were 7.8 for females (95% CI:3.1–19.5) and 5.0 for males (95% CI:2.6–9.9). In Bangladesh, similar study carried out on a population of 218 showed that the crude prevalence ratio for chronic bronchitis was found to be 10.3 (95% CI:2.4–43.1) for females and 1.6 (95% CI:0.8–3.1) for males. Reports of lung function tests were available from both hospital and population based studies. Results show evidences of restrictive, obstructive and combined obstructive and restrictive lung disease in different people having chronic lung disease associated with chronic arsenic toxicity. On the basis of clinical study, chest X-ray and HRCT done in Arsenicosis patients with features of chronic lung disease, the abnormalities observed were varied. Evidences of obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and bronchiectasis were found in some of the cases. Results of studies carried out on people showing features of Arsenicosis due to drinking arsenic contaminated water provide evidence that arsenic is a potent respiratory toxicant, even following ingestion.

Serum Levels of CA19‐9 in patients with nonmalignant respiratory diseases

CA19-9 is a specific tumor marker in patients with gastrointestinal cancer; however, some patients with respiratory disease can have elevated serum levels of CA19-9 as well. In this study we evaluated serum CA19-9 levels of patients with nonmalignant respiratory diseases. We also estimated the prognostic significance of elevated serum levels of CA19-9 in patients with interstitial lung diseases. The study included 554 patients who had been diagnosed at our hospital during the period of 1984-2005. Serum CA19-9 levels in these patients were measured with a commercially available kit. Elevated levels (>37 U/mL) of CA19-9 were observed in 30.7% of patients with lung cancer. Furthermore, 38.9% of patients with idiopathic interstitial pneumonia (IIP), collagen disease-associated pulmonary fibrosis (CDPF), diffuse panbronchiolitis (DPB), and bronchiectasis had elevated serum CA19-9 levels. Survival rates were significantly lower in patients with interstitial lung diseases (IIP and CDPF) and elevated serum CA19-9 levels than in those with levels in the normal range (P=0.0065). Serum CA19-9 was elevated in some patients with nonmalignant diffuse lung diseases. Therefore, clinicians should pay attention to the evidence that increased serum CA19-9 levels can be found in nonmalignant respiratory disease patients. In patients with IIP and CDPF, elevated serum CA19-9 levels may be related to poor prognosis.

A Liquid Path to Lung Disease: EarlyArsenicExposureand EffectsinYoung Adults

Vol. 114, No. 8 EnvironewsOpen AccessA Liquid Path to Lung Disease: EarlyArsenicExposureand EffectsinYoung Adultsis accompanied byIncreased Mortality from Lung Cancer and Bronchiectasis in Young Adults after Exposure to Arsenic in Utero and in Early Childhood Tanya Tillett Tanya Tillett Search for more papers by this author Published:1 August 2006https://doi.org/10.1289/ehp.114-a486aAboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Increased rates of cancer and mortality have been documented in areas of the world where drinking water contains high concentrations of naturally occurring arsenic. A new study by a group of Californian and Chilean researchers now provides strong evidence of a link in humans between prenatal and early childhood arsenic exposure and significantly higher rates of lung disease in young adulthood [EHP 114:1293–1296; Smith et al.].Both malignant and nonmalignant lung disease are known to develop with exposure to arsenic in drinking water. Recent evidence from a project in India by the same research group showed decreased lung function similar to that of smokers in adults exposed to the semimetallic carcinogen.The current study took advantage of a unique opportunity to study the long-term health effects of a discrete prenatal and early childhood exposure. From 1958 to 1970, the water supply for the neighboring Chilean cities of Antofagasta and Mejillones was supplemented with water from rivers with arsenic concentrations near 1,000 μg/L, 100 times the current acceptable standard for arsenic concentration in the United States. With the 1971 activation of an arsenic removal plant, however, levels plummeted to about 90 μg/L and have continued to drop ever since.The research team studied mortality data obtained from Chile’s Ministry of Health for the years 1989 through 2000 for all 13 regions of the country. They divided the population into two groups: individuals born between 1958 and 1970 (who likely would have had prenatal arsenic exposure if their mothers lived in Antofagasta or Mejillones) and those born between 1950 and 1957 (who likely would have had childhood but not prenatal exposure if they lived in either of the two cities). The researchers also divided overall deaths for Chile into two groups: residents of Antofagasta and Mejillones, and residents of all other regions. They used the International Classification of Diseases, Ninth Revision, to code causes of death, including lung cancer and bronchiectasis, a form of chronic respiratory disease.The investigators’ findings show a distinct connection between prenatal and early childhood exposure to arsenic and lung disease–related mortality before age 50. Lung cancer death rates for those exposed to arsenic in early childhood were 7 times higher than those for the rest of the Chilean population, and bronchiectasis death rates were 12 times higher. In cases where exposure occurred both prenatally and in early childhood, lung cancer death rates were 6 times higher and bronchiectasis death rates were 46 times higher than those for the rest of the population.The authors believe these results describe the highest increase in death rates for arsenic-related lung cancer and bronchiectasis ever documented among young adults, and add that this study is one of the first to provide evidence of human adult disease resulting from prenatal and early childhood exposure to any environmental toxicant. They conclude that an increase in young adult mortality should be of concern to public health officials, and should influence future decisions regarding sources of drinking water.A big gulp of newsThe link between early arsenic exposure and later lung disease is the first such association to be confirmed in humans.FiguresReferencesRelatedDetailsRelated articlesIncreased Mortality from Lung Cancer and Bronchiectasis in Young Adults after Exposure to Arsenic in Utero and in Early Childhood27 March 2006Environmental Health Perspectives Vol. 114, No. 8 August 2006Metrics About Article Metrics Publication History Originally published1 August 2006Published in print1 August 2006 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Increased Mortality from Lung Cancer and Bronchiectasis in Young Adultsafter Exposure to Arsenic in Utero and in Early Childhood

Arsenic in drinking water is an established cause of lung cancer, and preliminary evidence suggests that ingested arsenic may also cause nonmalignant lung disease. Antofagasta is the second largest city in Chile and had a distinct period of very high arsenic exposure that began in 1958 and lasted until 1971, when an arsenic removal plant was installed. This unique exposure scenario provides a rare opportunity to investigate the long-term mortality impact of early-life arsenic exposure. In this study, we compared mortality rates in Antofagasta in the period 1989–2000 with those of the rest of Chile, focusing on subjects who were born during or just before the peak exposure period and who were 30–49 years of age at the time of death. For the birth cohort born just before the high-exposure period (1950–1957) and exposed in early childhood, the standardized mortality ratio (SMR) for lung cancer was 7.0 [95% confidence interval (CI), 5.4–8.9; p < 0.001] and the SMR for bronchiectasis was 12.4 (95% CI, 3.3–31.7; p < 0.001). For those born during the high-exposure period (1958–1970) with probable exposure in utero and early childhood, the corresponding SMRs were 6.1 (95% CI, 3.5–9.9; p < 0.001) for lung cancer and 46.2 (95% CI, 21.1–87.7; p < 0.001) for bronchiectasis. These findings suggest that exposure to arsenic in drinking water during early childhood or in utero has pronounced pulmonary effects, greatly increasing subsequent mortality in young adults from both malignant and nonmalignant lung disease.

Matrix Metalloproteinase-9 (MMP-9) Elevated in Serum but not in Bronchial Lavage Fluid in Patients with Lung Cancer

Matrix metalloproteinase (MMP) family member MMP-9 degrades type IV collagen, which is one of the main constituents of the basement membrane. MMP-9 is closely associated with the invasive and metastatic potential of most types of lung cancer. In this study we investigated the levels of MMP-9 in serum and bronchial lavage fluid from lung cancer patients and compared them with the levels in patients with nonmalignant lung disease. We also attempted to clarify the possible relationship between serum and bronchial lavage fluid MMP-9 levels and histopathology, staging and metastasis of lung cancer. The study group consisted of 34 patients with lung cancer. The control group comprised 21 patients with nonmalignant lung disease. MMP-9 levels in serum and bronchial lavage fluid were evaluated by ELISA. MMP-9 levels in serum samples from the group with malignant disease were significantly higher than those from the control group (P <0.05). Bronchial lavage MMP-9 levels did not differ significantly between the two groups (P > 0.05). Serum MMP-9 levels were two-fold higher than those in bronchial lavage, but there was no correlation between bronchial lavage and serum levels in both groups (r = 0.18, P > 0.05). In the group with malignant disease, MMP-9 levels in serum and bronchial lavage fluid did not show any relationship with histopathological type and tumor stage. There was a statistically significant correlation between serum MMP-9 levels and local tumor stage in smoking non-small cell lung cancer (NSCLC) patients (r = 0.33, P < 0.05). Karnofsky scores of lung cancer patients were inversely correlated with MMP-9 levels of serum (r = -0.39, P < 0.05) but not of bronchial lavage fluid. From our data it can be concluded that MMP-9 levels of serum but not of bronchial lavage fluid can be helpful in differentiating between malignant and benign lung diseases, and are related to the local stage in NSCLC patients and general clinical status of lung cancer patients.

An Approach to Studying Lung Cancer-related Proteins in Human Blood

Early stage lung cancer detection is the first step toward successful clinical therapy and increased patient survival. Clinicians monitor cancer progression by profiling tumor cell proteins in the blood plasma of afflicted patients. Blood plasma, however, is a difficult cancer protein assessment medium because it is rich in albumins and heterogeneous protein species. We report herein a method to detect the proteins released into the circulatory system by tumor cells. Initially we analyzed the protein components in the conditioned medium (CM) of lung cancer primary cell or organ cultures and in the adjacent normal bronchus using one-dimensional PAGE and nano-ESI-MS/MS. We identified 299 proteins involved in key cellular process such as cell growth, organogenesis, and signal transduction. We selected 13 interesting proteins from this list and analyzed them in 628 blood plasma samples using ELISA. We detected 11 of these 13 proteins in the plasma of lung cancer patients and non-patient controls. Our results showed that plasma matrix metalloproteinase 1 levels were elevated significantly in late stage lung cancer patients and that the plasma levels of 14-3-3 sigma, beta, and eta in the lung cancer patients were significantly lower than those in the control subjects. To our knowledge, this is the first time that fascin, ezrin, CD98, annexin A4, 14-3-3 sigma, 14-3-3 beta, and 14-3-3 eta proteins have been detected in human plasma by ELISA. The preliminary results showed that a combination of CD98, fascin, polymeric immunoglobulin receptor/secretory component and 14-3-3 eta had a higher sensitivity and specificity than any single marker. In conclusion, we report a method to detect proteins released into blood by lung cancer. This pilot approach may lead to the identification of novel protein markers in blood and provide a new method of identifying tumor biomarker profiles for guiding both early detection and therapy of human cancer.

Extracellular Circulating Nucleic Acids in Human Plasma in Health and Disease

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Extracellular Circulating Nucleic Acids in Human Plasma in Health and Disease

The concentration of extracellular DNA and RNA in blood plasma of healthy donors, trauma patients, patients with breast and lung cancer, nonmalignant breast tumors and nonmalignant lung diseases were estimated. Significant amounts of extracellular RNA were found in plasma of trauma patients. The concentration of DNA and RNA in plasma of trauma patients correlates with the extent of posttraumatic organ failure. Extracellular RNA was not found in the plasma of breast cancer patients and patients with nonmalignant breast tumors, whereas a very high concentration of extracellular RNA was found in patients with malignant and nonmalignant diseases of lung.

Quantification of free RNA in serum and bronchial lavage: a new diagnostic tool in lung cancer detection?

Circulating cell-free nucleic acids have been detected in serum. In cancer patients levels of free DNA seem to be higher than in non-tumor controls and the detectable nucleic acids are partly of tumor origin. We asked whether free RNA can be detected as well in cell-free bronchial lavage fluid (BLF) supernatant, and whether quantification of free RNA allows to discriminate between tumor and non-tumor patients. 73 patients with lung cancer (NSCLC n=62, SCLC n=11) and 56 patients with non-malignant lung diseases were included. The RNA was isolated from 1 mL serum and lavage, respectively with the Quiamp MinElute Virus Vacuum Kit (Qiagen, Germany). A real-time quantitative RT-PCR assay was used for transcript quantification of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. Intact RNA was detectable in cell-free supernatants of BLF from 126/129 patients and was investigated in all 64 serum samples. RNA levels were higher in the cell-free supernatant of BLF than in serum. RNA concentration in the BLF from tumor patients was higher than in patients with a benign lung disease (p=0.009). In conclusion, quantification of intact RNA isolated from BLF supernatant and from serum might become a valuable tool for differentiation between tumor and non-tumor patients.

Mortality and Suicide Among Danish Women With Cosmetic Breast Implants

Epidemiologic studies indicate that women with cosmetic breast implants have a significantly increased risk of suicide. Our objectives were to examine mortality among Danish women who underwent cosmetic breast implant surgery and to evaluate the baseline prevalence of psychopathological disorders as measured by admission to a psychiatric hospital among women seeking cosmetic surgery. Cohort study of 2761 women who underwent cosmetic breast implant surgery at private clinics of plastic surgery or public hospitals, 7071 women who underwent breast reduction surgery at public hospitals, and 1736 women who attended private clinics for cosmetic surgery other than breast implantation, between 1973 and 1995. Causes of death through 1999 were identified through the Danish Mortality Files. Information on admission to psychiatric hospitals prior to cosmetic surgery was obtained from the Danish Psychiatric Central Register. Women with cosmetic breast implants had significantly elevated standardized mortality ratios (SMRs) for death overall (SMR, 1.4; 95% confidence interval [CI], 1.1-1.7), nonmalignant lung disease (3.4; 95% CI, 1.4-6.9), and suicide (SMR, 3.1; 95% CI, 1.7-5.2). Women who underwent breast reduction exhibited low SMRs for death overall (0.7; 95% CI, 0.7-0.8) and several specific causes, including breast cancer (0.4; 95% CI, 0.2-0.6), whereas death from suicide was moderately above expectation (SMR, 1.6; 95% CI, 1.0-2.5). The prevalence of psychiatric admission prior to cosmetic surgery was higher among women who underwent cosmetic breast implant surgery (8.0%; 95% CI, 7.0%-9.0%) than among women who underwent breast reduction (4.7%; 95% CI, 4.2%-5.2%) or other cosmetic procedures (5.5%; 95% CI, 4.5%-6.7%). When compared with all control groups, women with cosmetic implants had an odds ratio for prior psychiatric admission of 1.7 (95% CI, 1.4-2.0). Danish women with cosmetic breast implants experienced higher overall mortality compared with women in the general population owing in part to a 3-fold increase in suicide. Women with breast reduction had a low total and cause-specific mortality but a moderate excess risk of suicide. For the first time, to our knowledge, we found evidence of an increased prevalence of mental illness as measured by admission to a psychiatric hospital prior to implant surgery among women receiving cosmetic breast implants. Studies are needed to clarify the underlying reasons for the consistently reported 2- to 3-fold excess of suicide among women with cosmetic breast implants.

Increased Levels of Albumin in Bronchial Washing Fluid of Patients with Bronchial Carcinoma. Could Albumin be Considered as a Tumor Marker?

The aim of this study was to evaluate the significance of albumin in bronchial washing fluid (BWF) and its relationship to three tumor markers (CEA, CA 19-9 and NSE). Serum and BWF samples were collected in a group of 60 patients. Albumin and tumor markers in the BWF and serum of three groups: a control group (CG), a chronic bronchitis group (CBG) and a lung cancer group (CaG), were analyzed in a prospective cross-sectional study. The diagnostic yields of the tests in each environment (serum and BWF) were evaluated by using as cutoff points the values of the corresponding 90th percentile of CG and CBG taken together. A significant difference in albumin level (p < 0.001) was noted in the BWF of patients with cancer compared with the other two groups. In addition, a significant difference in CEA level (p < 0.001) was observed in the serum of cancer patients compared with the other two groups. The cutoff values for CEA in serum and albumin in BWF were 2.20 ng/mL and 2.00 g/dL, respectively. The areas under the corresponding ROC curves were 93% and 97%. Combination of CEA-serum and albumin-BWF by logistic regression analysis increased their diagnostic value. Measurement of albumin levels in BWF could be a useful additional diagnostic tool to differentiate malignant from non-malignant lung diseases. Moreover, the combined measurement of CEA in serum and albumin in BWF could be of aid in the follow-up of lung cancer patients.

Prior lung disease and risk of lung cancer in a large prospective study.

While 75-90% of people who develop lung cancer are smokers, only a small proportion of smokers develop lung cancer. Identifying factors that increase a smoker's risk of developing lung cancer may help scientists to better understand the etiology of lung cancer and more effectively target high-risk groups for screening. Information on physician-diagnosed non-malignant lung diseases [asbestosis, asthma, chronic bronchitis or emphysema (CB/E), pneumonia, and tuberculosis] was obtained at baseline from 17,698 men and women involved in CARET, a randomized lung cancer prevention trial of beta-carotene and vitamin A among heavy smokers and asbestos-exposed workers. Hazard ratios for lung cancer were estimated through Cox regression models, after controlling for potential confounding factors, included smoking. Analyses were restricted to former and current smokers. During a median follow up of 9.1 years, 1028 cases of lung cancer occurred. Those who developed lung cancer were more likely to report a history of CB/E than controls (adjusted HR = 1.29, 95% CI: 1.09-1.53). In subgroup analyses, the association between a history of CB/E and lung cancer was stronger for those who were younger at diagnosis/reference, men in the heavy smoker cohort, former smokers, and those with squamous cell carcinomas. There was little association between a history of other lung diseases and lung cancer. Smokers with a history of CB/E may be at higher risk of developing lung cancer, independent of their smoking history.