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Background: Mediastinal lymphadenopathy in combination with lung cancer is suggestive for lymph node metastases but can also have other origins. Case report: We describe a patient diagnosed with stage IV lung cancer presenting with parenchymal lesions and enlarged mediastinal lymph nodes. A second opinion including FDG-PET scan review and a mediastinoscopy followed by surgery revealed tumor specimens originating from a single primary tumor with a sarcoid-like reaction in the mediastinal lymph nodes, changing the diagnosis from metastasized to resectable lung cancer. Discussion: PET positive lesions are not always synonymous with metastatic disease in the presence of a malignant tumor. Conscientious review of FDG-PET scans and tissue sampling are therefore mandatory to determine definitive staging and subsequent interventions. © 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Ziel: Die aktuellen nationalen Leitlinien enthalten Empfehlungen der Kategorie 1 für perioperative Chemotherapie (CT) oder adjuvante Radiochemotherapie (RCT) bei chirurgischer Resektion eines Magenkarzinoms im Stadium IB-IIIB. Wir führten eine Meta-Analyse randomisierter Studien durch, in denen CT und RCT bei chirurgischer Resektion prospektiv gegenübergestellt wurden.Methoden: Wir durchsuchten PubMed und EMBASE nach randomisierten, kontrollierten klinischen Studien zur Entwicklung des gastrischen Adenokarzinoms bei Patienten nach R0-Resektion. Die adjuvante CT und RCT wurden als Interventionen verglichen, unabhängig von den CT-Schemata. Die primären Zielgrößen waren das krankheitsfreie Überleben (DFS) und das Gesamtüberleben. Mit dem «Random-Effects»-Modell von Mantel-Haenszel wurden die Effektstärken berechnet.Ergebnisse: Sechs Studien mit insgesamt 1171 Teilnehmern wurden ausgewertet; 599 Patienten waren einer adjuvanten RCT und 572 einer alleinigen CT randomisiert zugeordnet worden. Die RCT war im Vergleich zur alleinigen CT mit einem signifikant längeren DFS assoziiert (Odds-Ratio: 1,48; 95%-KI: 1,08-2,03). Beim Gesamtüberleben bestand jedoch kein signifikanter Unterschied (Odds-Ratio: 1,27; 95%-KI: 0,95-1,71). In Bezug auf die Toxizität wurden in 5 Studien keine statistisch signifikanten Unterschiede zwischen beiden Gruppen festgestellt.Schlussfolgerung: Bei Patienten mit Magenkarzinom war die adjuvante RCT nach einer R0-Resektion mit einem längeren DFS assoziiert als die CT allein. Es bleibt angezeigt, weitere Studien zur Prüfung neuer systemischer Wirkstoffe in Verbindung mit einer Strahlentherapie zu konzipieren.Übersetzung aus Oncology 2014;86:79-85 (DOI: 10.1159/000354641)

Background: Fibrosis is associated with various cardiac pathologies and dysfunction. Current quantification methods are time-consuming and laborious. We describe a semi-automated quantification technique for myocardial fibrosis and validated this using traditional methods.Methods: Pulmonary Hypertension (PH) was induced in adult Wistar rats by subcutaneous monocrotaline (MCT) injection (40 mg/kg). Cryosections of myocardial tissue (5 μm) of PH rats (n=9) and controls (n=9) were stained using Picrosirius red and scanned with a digital microscopic Mirax slide scanner. From these sections 21 images were taken randomly of each heart. Using ImageJ software a macro for automated image analysis of the amount of fibrosis was developed. For comparison, fibrosis was quantified using traditional polarisation microscopy. Both methods were correlated and validated against stereology as the gold standard. Furthermore, the method was tested in paraffin-embedded human tissues.Results: Automated analysis showed a significant increase of fibrosis in PH hearts vs. control. Automated analysis correlated with traditional polarisation and stereology analysis (r2=0.92 and r2=0.95, respectively). In human heart, lungs, kidney and liver, a similar correlation with stereology (r2=0.91) was observed. Time required for automated analysis was 22 and 33% of the time needed for stereology and polarisation analysis, respectively.Conclusion: Automated quantification of fibrosis is feasible, objective and time-efficient.

Objective. Systemic sclerosis-associated pulmonary arterial hypertension (SScPAH) has a disturbed function of the right ventricle (RV) when compared to idiopathic PAH (IPAH). Systemic sclerosis may also affect the heart. We hypothesize that RV differences may occur at the level of interstitial inflammation and—fibrosis and compared inflammatory cell infiltrate and fibrosis between the RV of SScPAH, IPAH, and healthy controls.Methods. Paraffin-embedded tissue samples of RV and left ventricle (LV) from SScPAH (n=5) and IPAH (n=9) patients and controls (n=4) were picrosirius red stained for detection of interstitial fibrosis, which was quantified semiautomatically. Neutrophilic granulocytes (MPO), macrophages (CD68), and lymphocytes (CD45) were immunohistochemically stained and only interstitial leukocytes were counted. Presence of epi- or endocardial inflammation, and of perivascular or intimal fibrosis of coronary arteries was assessed semiquantitatively (0–3: absent to extensive).Results. RV's of SScPAH showed significantly more inflammatory cells than of IPAH (cells/mm2, mean±sd MPO11±3versus6±1; CD68 11±3versus6±1; CD45 11±1versus5±1,P<.05) and than of controls. RV interstitial fibrosis was similar in SScPAH and IPAH (4±1versus5±1%,P=.9), and did not differ from controls (5±1%,P=.8). In 4 SScPAH and 5 IPAH RV's foci of replacement fibrosis were found. No differences were found on epi- or endocardial inflammation or on perivascular or intimal fibrosis of coronary arteries.Conclusion. SScPAH RVs display denser inflammatory infiltrates than IPAH, while they do not differ with respect to interstitial fibrosis. Whether increased inflammatory status is a contributor to altered RV function in SScPAH warrants further research.

Background: Autofluorescence bronchoscopy is more sensitive than conventional bronchoscopy for detecting early airway mucosal lesions. Decreased specificity can lead to excessive biopsy and increased procedural time. Onco-LIFE, a device that combines fluorescence and reflectance imaging, allows numeric representation by expressing red-to-green ratio (R/G ratio) within the region of interest. The aim of the study was to determine if color fluorescence ratio (R/G ratio) added to autofluorescence bronchoscopy could provide an objective means to guide biopsy. Methods: Subjects at risk for lung cancer were recruited at two centers: VU University Medical Centre (Amsterdam) and BC Cancer Agency (Canada). R/G ratio for each site appearing normal or abnormal was measured before biopsy. R/G ratios were correlated with pathology, and a receiver operating characteristic curve of R/G ratio for high-grade and moderate dysplasia was done. Following analysis of the training data set obtained from two centers, a prospective validation study was done. Results: Three thousand three hundred sixty-two adequate biopsies from 738 subjects with their corresponding R/G ratios were analyzed. R/G ratio 0.54 conferred 85% sensitivity and 80% specificity for the detection of high-grade and moderate dysplasia, area under the curve was 0.90, and 95% confidence interval was 0.88 to 0.92. In another 70 different sites that were assessed, κ measurements of agreement of R/G ratios with visual scores and pathology were 0.66 (P < 0.0001) and 0.61 (P < 0.0001), respectively. R/G ratio combined with visual score improved specificity to 88% (95% confidence interval, 0.73-0.96) for high-grade and moderate dysplasia. Conclusion: Color fluorescence ratio can objectively guide the bronchoscopist in selecting sites for biopsy with good pathologic correlation.

The purpose of this study is to evaluate the prognostic value of the combined assessment of multiple molecular markers related to the epidermal growth factor receptor (EGFR) pathway in resected non-small cell lung cancer (NSCLC) patients. Tumour specimens of 178 NSCLC patients were collected and analysed for EGFR and KRAS mutation status by DNA sequencing, and for EGFR copy number by fluorescent in situ hybridisation. Tissue microarrays were generated and used to determine the expression of multiple EGFR pathway-related proteins by immunohistochemistry. We analysed the association between each marker and patient prognosis. Univariate analyses for each clinical variable and each molecular marker were performed using Kaplan–Meier curves and log-rank tests. From these results, we selected the variables KRAS mutations and expression of cytoplasmic EGFR, granular pERK, nuclear pSTAT3, cytoplasmic E-cadherin and cytoplasmic pCMET to enter into a Cox proportional hazards model, along with stage as the strongest clinical variable related with prognosis. Of the EGFR-related markers evaluated here, the markers EGFR, pERK, pSTAT3, E-cadherin, pCMET and mutations in KRAS were associated with survival when analysed in combination in our patient cohort, with P=0.00015 as the P-value for a test of the additional impact of markers on prognosis, after taking stage into consideration. Confirmation of the impact of these markers in independent studies will be necessary.

The use of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is considered safe in the treatment of non-small cell lung cancer. Recently, cases of erlotinib-associated interstitial lung disease have been reported. This disease entity remains poorly understood and the histopathology is rarely documented. We describe two cases of histologically confirmed fatal interstitial lung disease after erlotinib treatment for non-small cell lung cancer. After starting erlotinib treatment both patients developed clinical and radiologic signs of interstitial lung disease resulting in respiratory failure and death. Autopsy confirmed diffuse alveolar damage. As the use of erlotinib is increasing, physicians should be aware of this potentially fatal complication. The sparse data on the clinical presentation, radiographic patterns, and histologic findings of epidermal growth factor receptor tyrosine kinase inhibitor-associated interstitial lung disease are discussed.

It is important to determine the relation among the various lesions in patients presenting with multiple malignant lung tumors to define the best treatment approach. A better understanding of the molecular alterations present in the different lesions may help in defining this relation.We performed a detailed molecular analysis of several tumor specimens obtained from three patients presenting with multiple lung lesions. Tumor specimens were analyzed for epidermal growth factor receptor (EGFR) and k-ras mutations by direct DNA sequencing. In addition, a genome-wide chromosomal copy number analysis was performed on DNA extracted from the various lesions using array-based comparative genomic hybridization.In one case, a deletion of 15 base pairs in exon 19 of EGFR was present in all tumor sites analyzed. Furthermore, a similar pattern of chromosomal aberrations was observed among the various lesions, suggesting that they share the same clonal origin. In the other two cases, in contrast, we identified distinct k-ras genotypes among the various lesions from the same patient. These lesions, moreover, showed different chromosomal aberration patterns, indicating that they may have different underlying pathways of tumorigenesis.Our results show that EGFR and k-ras mutation analysis, combined with chromosomal copy number profiling, can help in defining the relationship among different tumors in one patient.

Bronchial epithelium exposed to cigarette smoke undergoes a series of histologic changes that may ultimately lead to invasive cancer. Inhaled corticosteroids reduce the number of lung tumors developing in rats exposed to cigarette smoke.We studied the effect of inhaled fluticasone on premalignant lesions in smokers and patients curatively treated for head and neck cancer or lung cancer.Participants were screened for premalignant lesions by bronchoscopy. Biopsies were taken from three to five locations and classified using WHO criteria. In case of a metaplasia index of15%, participants were randomized to receive a powder inhalation device containing either fluticasone 500 microg or a placebo, to be used twice a day. After 6 months, biopsies were obtained from the same locations as previously sampled. Efficacy of treatment was assessed by reversal of metaplasia/dysplasia; secondary endpoints were reversal of increased p53 and KI-67 immunoreactivity and expression of human telomerase reverse transcriptase.Of the 201 subjects that were screened, 108 were included. Mean age was 53 yr (35-71), mean number of pack-years 48 (18-99), mean metaplasia index 48%, and 32% had some degree of dysplasia at baseline. The two treatment arms did not differ with respect to response or change in either metaplasia index or the expression of the markers p53, KI-67, or human telomerase reverse transcriptase.Inhaled fluticasone in a dose of 500 mug twice a day does not affect the natural course of premalignant lesions in the central airways.

Rationale: In severe idiopathic pulmonary arterial hypertension, iPAH, pulmonary vascular resistance is increased due to remodeling of the small (resistance) arteries. Most information on arterial remodeling is limited to assessments of averaged increases in wall thickness. Quantitative information on the number of arteries affected and their internal diameter decrease in relation to vessel size is limited. Our objective was therefore to quantify numbers of affected small arteries and their internal diameter decrease for the differently sized vessels. Methods: Internal and external arterial diameters were measured in 5 controls and 6 iPAH subjects. Resistance arteries (13 to 500 μm) were classified in Strahler orders (1–8), and the number fraction of affected vessels and their internal diameter decrease calculated. Results: In iPAH not all resistance arteries are affected, on average about 70% of arteries have diameters not different from the control subjects, with the number of affected arteries varying between 20 and 50%. Within each order the diameters of affected vessels vary greatly and are decreased to 70-20% of control with on average to about 60% of control. We conclude that narrowing of resistance arteries a feature of iPAH and is heterogeneous: not all arteries are narrowed, and internal diameters of narrowed arteries, even within single orders vary largely. Determination of total vessel numbers of arteries and of veins is necessary to gain insight into the possible role of rarefaction and of changes in the venous system.

SummaryPulmonary hypertension is a rare disease with a poor prognosis. It was first described in the late 19th century as a clinical-pathological syndrome characterised by obstruction of the small pulmonary arteries and right ventricular hypertrophy in patients presenting with severe dyspnoea and cyanosis. After the development of right heart catheterisation in the second half of the 20th century, it was found that many diseases could cause pulmonary hypertension, which is now recognised to be high blood pressure in the arteries that supply the lungs. In the 1960s, an epidemic of pulmonary hypertension caused by appetite suppressants initiated a systematic collection of information on pulmonary hypertension, leading to the first international classification of pulmonary hypertension. Increased understanding of the pathogenesis of the various forms of pulmonary hypertension has led to novel treatments and holds promise for the future.

Contains fulltext : 185764.pdf (Publisher’s version ) (Closed access) Asthma exacerbations are frequently linked to rhinovirus infections. However, the associated inflammatory pathways are poorly understood, and treatment of exacerbations is often unsatisfactory. In the present study we investigated whether antiinflammatory treatment with inhaled corticosteroids prevents any rhinovirus-induced worsening of lower airway inflammation. To that end, we selected 25 atopic patients with mild asthma who underwent experimental rhinovirus 16 (RV16) infection, while receiving double-blind, placebo-controlled treatment with the inhaled corticosteroid budesonide (800 microg twice a day) throughout the study period, starting 2 wk before infection. We assessed inflammatory cell numbers in the bronchial mucosa as obtained by bronchial biopsies 2 d before and 6 d after RV16 infection, and analyzed those in relation to cold symptoms, changes in blood leukocyte counts, airway obstruction, and airway hyperresponsiveness. RV16 colds induced an increase in CD3(+) cells in the lamina propria (p = 0.03) and tended to decrease the numbers of epithelial eosinophils (p = 0.06) in both groups analyzed as a whole. The T cell accumulation was positively associated with cold symptoms. Budesonide pretreatment improved airway hyperresponsiveness (p = 0.02) and eosinophilic airways inflammation (p = 0.04). Yet it did not significantly affect the RV16-associated changes in the numbers of any of the inflammatory cell types. We conclude that RV16 infection by itself induces only subtle worsening of airway inflammation in asthma, which is not improved (or worsened) by inhaled corticosteroids. The latter finding is in keeping with the limited protection of inhaled corticosteroids against acute asthma exacerbations.

Exhaled nitric oxide (NO) is elevated in asthmatics, and varies with disease severity. We postulated that a respiratory virus infection increases exhaled NO levels in asthma, and examined the relationship between the virus-induced changes in exhaled NO and in airway hyperresponsiveness to histamine. In a parallel study, seven patients underwent experimental rhinovirus 16 (RV16) inoculation at days 0 and 1, whilst seven patients received placebo. Exhaled NO was measured at baseline (day 0) and at days 1, 2 and 3 after inoculation. Histamine challenges were performed prior to (day -7) and after inoculation (day 3), and were expressed as provocative concentration causing a 20% fall in forced expiratory volume in one second (FEV1) (PC20). Following RV16 infection there was a significant increase in NO at days 2 and 3 as compared to baseline (median change (range): 4.2 (7.5) parts per billion (ppb), p=0.03, and 3.0 (10.1) ppb, p=0.02, respectively). Furthermore, PC20 decreased significantly following RV16 infection (mean+/-SD change in doubling dose: -0.65+/-0.54, p=0.02), whereas PC20 did not change in the placebo group (p=0.1). There was a significant correlation between the RV16-induced changes in exhaled NO levels at day 2 and the accompanying changes in PC20 at day 3 (rank correlation coefficient (rs): 0.86, p=0.01). Hence, the greater the increase in exhaled NO, the smaller the decrease in PC20. We conclude that rhinovirus infection increases exhaled nitric oxide levels in asthmatics, and that this increase is inversely associated with worsening of airway hyperresponsiveness to histamine. These results suggest that viral induction of nitric oxide synthase within the airways may play a protective role in exacerbations of asthma.

SUMMARYGlucocorticoids (GC) play an important role in the treatment of inflammatory diseases like asthma. However, in selected patients a relative resistance to GC has been reported. Recently, it has been suggested that GC sensitivity of peripheral blood leucocytes may be regulated in a dynamic fashion during exercise, in association with activation of the hypothalamic–pituitary–adrenal (HPA) axis. The aim of the present study was to explore changes in the GC sensitivity of cytokine production by leucocytes following strenuous exercise by well trained oarsmen. These changes were studied using lipopolysaccharide (LPS)-induced and anti-CD2/anti-CD28 MoAb-stimulated cytokine release in whole blood and its modulation by dexamethasone. Following exercise, significant decreases in LPS-induced release of IL-6, tumour necrosis factor-alpha (TNF-α) and IL-10 and anti-CD2/anti-CD28 MoAb-stimulated secretion of interferon-gamma (IFN-γ) were observed. In addition, the inhibitory effect of dexamethasone on both IL-6 and TNF-α secretion was significantly reduced following exercise, whereas that on IL-10 and IFN-γ release was not affected. These exercise-induced changes were accompanied by activation of the HPA axis, as indicated by an increase in circulating adrenocorticotropic hormone (ACTH) levels immediately following exercise. The results from the present study suggest that GC sensitivity of whole blood cytokine release can be regulated in a dynamic fashion and that this can be assessed using an ex vivo stimulation assay. Moreover, since dexamethasone responsiveness of anti-CD2/anti-CD28 MoAb-induced IFN-γ secretion in whole blood is not affected by exercise, it may suggest that exercise differentially affects monocytes and lymphocytes. The dynamic regulation of steroid responsiveness of leucocytes, as observed in the present study, could have important consequences for the effectiveness of GC treatment in inflammatory diseases.

Disturbance of the balance between excitatory and inhibitory activity of the airway sensory nerves has been implicated in asthma pathogenesis, particularly during exacerbations of the disease. The objective of this study was to examine the effect of experimental rhinovirus 16 (RV16) infection on airway responsiveness to bradykinin, a potent sensory nerve stimulus, in asthma. Thirteen atopic, mildly asthmatic subjects participated in a parallel, placebo-controlled study. A total dose of 2.6 to 5.6 x 10(4) TCID50 RV16 (n = 7) or its diluent (n = 6) was inoculated on 2 consecutive days (Days 0 and 1). Histamine and bradykinin challenges were performed before (Days-7 and-6) and after (Days 3 and 4) inoculation. The response was measured by FEV1 and partial flow-volume curves, and it was expressed as PC20FEV1 and PC40V40p, respectively (changes expressed in doubling dose: DD). Before inoculation, PC20FEV1 and PC40V40p to histamine were not significantly different between the groups (p > or = 0.22), whereas PC20FEV1 and PC40V40p to bradykinin tended to be higher in the RV16 group (p = 0.11 and p = 0.06, respectively). PC20FEV1 and PC40V40p to histamine decreased significantly in the RV16 group (mean change +/- SEM: -0.65 +/- 0.20 DD, p = 0.02 and -0.98 +/- 0.28 DD, p = 0.01, respectively), but not in the placebo group (p > or = 0.26). PC40V40p to bradykinin increased significantly in the placebo group (+2.46 +/- 0.92 DD, p = 0.04), with a similar trend for PC20FEV1 (+1.50 +/- 0.62 DD, p = 0.06), whereas there were no significant changes in the RV16 group (p > or = 0.77). These changes in PC40V40p to histamine and bradykinin were significantly different between the groups (p = 0.02). We conclude that repeated bradykinin challenge over a 10-d interval induces tachyphylaxis in asthmatic subjects in vivo and that experimental RV16 infection abolishes such tachyphylaxis to bradykinin while it enhances airway responsiveness to histamine. These results do not favor a predominant role of airway sensory nerves in rhinovirus-induced exacerbations of asthma

BACKGROUND: Asthma exacerbations are closely associated with respiratory virus infections. However, the pathophysiological consequences of such infections in asthma are largely unclear. OBJECTIVE: To examine the effect of rhinovirus 16 (RV16) infection on airway hypersensitivity to histamine, and on interleukin-8 (IL-8) in nasal lavage. METHODS: Twenty-seven non-smoking atopic, mildly asthmatic subjects participated in a placebo-controlled, parallel study. A dose of 0.5-2.9 x 10(4) TCID50 RV16 or placebo was nasally administered. Cold symptoms were recorded by questionnaire throughout the study. Histamine challenges were performed at entry, and on days 4 and 11 after inoculation. Nasal lavages were obtained at entry, and on days 2 and 9. The response to histamine was measured by PC20 (changes expressed as doubling doses: DD) IL-8 levels were obtained by ELISA, and were expressed in ng/ml. RESULTS: RV infection was confirmed by culture of nasal lavage and/or by antibody titre rise in each of the RV16-treated subjects. Among the 19 RV 16-treated subjects, eight developed severe cold symptoms. Baseline FEV1, did not change significantly during the study in either treatment group (P = 0.99). However, in the RV16-treated subjects there was a decrease in PC20 at day 4, which was most pronounced in those with a severe cold (mean change +/- SEM: -1.14 +/- 0.28 DD, P = 0.01). In addition, IL-8 levels increased in the RV16 group at days 2 and 9 (P < 0.001). The increase in nasal IL-8 at day 2 correlated significantly with the change in PC20 at day 4 (r = -0.48, P = 0.04). CONCLUSION: We conclude that the severity of cold, as induced by experimental RV16 infection, is a determinant of the increase in airway hypersensitivity to histamine in patients with asthma. Our results suggest that this may be mediated by an inflammatory mechanism, involving the release of chemokines such as IL-8.

7200 Background: Bronchial epithelium exposed to cigarette smoke undergoes a series of histological changes that may ultimately lead to invasive cancer. In rats exposed to cigarette smoke inhaled corticosteroids reduce the number of lung tumors. We studied the effect of fluticasone on premalignant lesions in volunteers with a smoking history of ≥10 pack-years and patients cured of head and neck cancer or lung cancer. Methods: Participants were screened for premalignant lesions by bronchoscopy. At least 3 standard locations and suspicious lesions (if present) were biopsied. Use of systemic corticosteroids in the past 12 months or serious comorbidity precluded participation. Biopsies were classifed using WHO criteria. In case of a metaplasia index > 15%, participants were randomised to receive a powder inhalation device containing either fluticasone 500 μg or a placebo. Compliance and side effects were monitored monthly. After 6 months, biopsies were taken from the same locations as previously sampled. Efficacy of treatment was assessed by reversal of metaplasia/dysplasia; secondary end-points were reversal of increased p53 immunoreactivity and hTERT expression. CT-scans were obtained at baseline and after intervention. Results: From February 2002 until October 2004, 201 subjects were screened. Two were excluded because of lung cancer detected during screening. Of the 108 volunteers included, 74 were male, mean age was 53 years (35–71), mean number of pack-years 48 (18–99), mean metaplasia index 48%, 32% had some degree of dysplasia at baseline. There were no significant differences between these characteristics in the intervention and placebo groups. Outcome: there was no significant difference with respect to reversal of metaplasia/dysplasia. Additional molecular studies will be performed to assess possible changes at a molecular level. Results will be presented at the ASCO annual meeting 2006. Conclusions: Fluticasone does not alter the natural course of premalignant lesions in the central airways when standard histological criteria are applied. No significant financial relationships to disclose.

Introduction In the past decade, major progress has been made toward personalized medical treatment of non–small-cell lung cancer (NSCLC) through the discovery of epithelial growth factor receptor ( EGFR ) mutations. However, mutation analysis takes extra time and additional costs in the diagnostic evaluation of lung cancer patients. It has been hypothesized that EGFR mutations are restricted to terminal respiratory unit -type adenocarcinoma expressing thyroid transcription factor-1 (official symbol NKX2-1) as determined by immunohistochemistry. The aim of the current study is to evaluate the potential of NKX2-1 immunohistochemistry as a prescreening test for EGFR mutation analysis. Methods From 2004 to December 2010, 810 consecutive NSCLC tumor specimens were tested for EGFR mutations in a routine diagnostic procedure. Immunohistochemistry for NKX2-1 was performed (clone 8G7G3/1 [Dako]) and the results were compared with tumor EGFR -mutation status and clinicopathological characteristics. Results EGFR mutations were detected in 114 specimens (14%). NKX2-1 expression was present in 68%. In the cases with EGFR mutation, NKX2-1 staining was positive in 92%. NKX2-1 immunohistochemical (IHC) staining was significantly associated with the presence of EGFR mutations ( p = 5.3×10 −10 ). NKX2-1 increased the negative predictive value in NSCLC to more than 95%. Conclusions In case of a negative NKX2-1 IHC staining, and only if clinically urgent, the high negative predictive value of more than 95% for EGFR mutations is a suitable temporary surrogate marker for the choice of starting with chemotherapy. In case of positive NKX2-1 IHC, the best strategy is to wait for the outcome of EGFR -mutation analysis and then choose the appropriate treatment.