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Figure S1. Survival of females with high PAEP expression.

Purpose: The underlying molecular mechanisms of thymic epithelial malignancies (TEMs) are poorly understood. Consequently, there is a lack of efficacious targeted therapies and patient prognosis remains dismal, particularly for advanced TEMs. We sought to investigate protumorigenic mechanism relevant to this understudied cancer.Experimental Design: Recently established cell lines derived from thymic epithelial tumors were used as a model system. The antitumor activity of specific heat shock protein 90 (Hsp90) inhibitors was investigated by an analysis of cell viability, cell cycle, and apoptosis using MTT-assays and flow cytometry. Western blotting was used to investigate the altered expression of Hsp90 clients. Pharmacological inhibitors against select Hsp90 clients, as well as RNAi, were employed to test the relevance of each client independently. Tissue microarray analysis was performed to match the in vitro findings with observations obtained from patient-derived samples.Results: Hsp90 inhibition significantly reduces cell viability of thymic carcinoma cells, induces cell cycle arrest and apoptosis, and blocks invasiveness. Hsp90 inhibition triggers the degradation of multiple oncogenic clients, for example insulin-like growth factor 1 receptor (IGF-1R), CDK4, and the inactivation of PI3K/Akt and RAF/Erk signaling. Mechanistically, the IGF/IGF-1R–signaling axis contributes to the establishment of the antiapoptotic phenotype of thymic cancer cells. Finally, IGF-1R is overexpressed in advanced TEMs.Conclusions: We have unraveled a novel protumorigenic mechanism in TEMs, namely Hsp90-capacitated overexpression of IGF-1R, which confers apoptosis evasion in malignant thymic epithelial cells. Our data indicate that Hsp90 inhibition, which simultaneously blocks multiple cancer hallmarks, represents a therapeutic strategy in TEMs that may merit evaluation in clinical trials. Clin Cancer Res; 17(8); 2237–49. ©2011 AACR.

Purpose: Current staging methods are imprecise for predicting prognosis of early-stage non–small-cell lung cancer (NSCLC). We aimed to develop a gene expression profile for stage I and stage II NSCLC, allowing identification of patients with a high risk of disease recurrence within 2 to 3 years after initial diagnosis.Experimental Design: We used whole-genome gene expression microarrays to analyze frozen tumor samples from 172 NSCLC patients (pT1-2, N0-1, M0) from five European institutions, who had undergone complete surgical resection. Median follow-up was 89 months (range, 1.2-389) and 64 patients developed a recurrence. A random two thirds of the samples were assigned as the training cohort with the remaining samples set aside for independent validation. Cox proportional hazards models were used to evaluate the association between expression levels of individual genes and patient recurrence-free survival. A nearest mean analysis was used to develop a gene-expression classifier for disease recurrence.Results: We have developed a 72-gene expression prognostic NSCLC classifier. Based on the classifier score, patients were classified as either high or low risk of disease recurrence. Patients classified as low risk showed a significantly better recurrence-free survival both in the training set (P < 0.001; n = 103) and in the independent validation set (P < 0.01; n = 69). Genes in our prognostic signature were strongly enriched for genes associated with immune response.Conclusions: Our 72-gene signature is closely associated with recurrence-free and overall survival in early-stage NSCLC patients and may become a tool for patient selection for adjuvant therapy.

Supplemental Material and Methods. More detailed Material and Methods.

Table S1. Most regulated genes after PAEP knockdown in Affymetrix gene expression analyses.

Supplementary Figures S1-S8; Supplementary Methods; Supplementary Tables S1-S3.

Supplemental Figure Legends. Figure legends for the supplemental figures.

Supplementary Data from An Immune Response Enriched 72-Gene Prognostic Profile for Early-Stage Non–Small-Cell Lung Cancer

Purpose: In recent years, immune therapeutic strategies against non–small cell lung cancer (NSCLC) based on tissue-derived biomarkers, for example PD1/PD-L1 (CD274), have evolved as novel and promising treatment options. However, the crosstalk between tumor and immune cells is poorly understood. Glycodelin (gene name PAEP), initially described in the context of pregnancy and trophoblastic implantation, is a secreted immunosuppressive glycoprotein with an as-of-yet largely unknown function in lung cancer.Experimental Design: In this study, we characterized the expression and role of glycodelin in NSCLC through mRNA and protein expression analyses, functional knockdown experiments, and correlations with clinicopathologic parameters.Results: Glycodelin mRNA expression was significantly elevated in tumors (n = 336) compared with matched normal tissue (P < 0.0001). Overall survival (OS) was significantly reduced in NSCLC with high glycodelin mRNA levels in women but not in men. Glycodelin was detected in the sera of patients, and the levels correlated with recurrence and metastatic disease. Knockdown of glycodelin with siRNAs in NSCLC cell lines resulted in significant upregulation of immune system modulatory factors such as PDL1, CXCL5, CXCL16, MICA/B, and CD83 as well as proliferation stimulators EDN1 and HBEGF. Furthermore, decreased migration of tumor cells was observed.Conclusions: Altogether, the comprehensive characterization of glycodelin in NSCLC provides strong support for its use as a biomarker with immune modulatory function. Clin Cancer Res; 21(15); 3529–40. ©2015 AACR.

Genome-wide association studies (GWAS) have identified SNPs linked with lung cancer risk. Our aim was to discover the genes, non-coding RNAs, and regulatory elements within GWAS-identified risk regions that are deregulated in non-small cell lung carcinoma (NSCLC) to identify novel, clinically targetable genes and mechanisms in carcinogenesis. A targeted bisulphite-sequencing approach was used to comprehensively investigate DNA methylation changes occurring within lung cancer risk regions in 17 NSCLC and adjacent normal tissue pairs. We report differences in differentially methylated regions between adenocarcinoma and squamous cell carcinoma. Among the minimal regions found to be differentially methylated in at least 50% of the patients, 7 candidates were replicated in 2 independent cohorts (n = 27 and n = 87) and the potential of 6 as methylation-dependent regulatory elements was confirmed by functional assays. This study contributes to understanding the pathways implicated in lung cancer initiation and progression, and provides new potential targets for cancer treatment. This work was supported by the Deutsche Krebshilfe [70-2387; 70-2919, 106910]; National Institutes of Health [CA148127]; Deutsches Zentrum für Lungenforschung (DZL).

For early stage non-small cell lung cancer (NSCLC) retrospective data of functionally compromised patients undergoing segmentectomy showed equal outcomes for perioperative complications and quality of life (QoL) compared with lobectomy patients. However no prospectively randomized data comparing patients eligible for both procedures are available.We conducted a prospective, randomized, multicenter phase III trial and investigated perioperative complications and QoL in patients with NSCLC stage IA (7th edition) undergoing segmentectomy versus lobectomy. The EORTC Questionnaire Core-30 (QLQ C-30) supplemented by thirteen-item lung cancer-specific module (LC13) was assessed before surgery, at discharge, 6 weeks, 3, 6 and 12 months post-surgery.108 patients with verified or suspected NSCLC up to 2 cm diameter were enrolled, whereby 54 were assigned to lobectomy and 54 to segmentectomy. Due to nodal disease, tumor size and surgical reasons estimated during the operation, eight patients of the segmentectomy group received a lobectomy. In hospital and 90 days mortality was 0% in both groups. Perioperative complications were observed in 6 (11.3%) patients after segmentectomy and in 8 patients (14.8%) after lobectomy (p = 0.563), while the 90-day morbidity were 17% and 25.9% (9 and 14 patients), respectively (p = 0.452). Twelve months after surgery, there was a significant deterioration to the baselines of physical (p 0.001) and cognitive functioning (p = 0.025), dyspnea (p 0.001) and fatigue (p = 0.003) in the lobectomy group. Dyspnea showed a faster recovery in the segmentectomy compared to lobectomy group with statistical significance (p = 0.016 after 12 months).In patients with early-stage NSCLC, segmentectomy is associated with a statistically not significant lower perioperative morbidity and appears to provide a superior recovery in QoL compared with lobectomy patients.

Introduction This work was performed to develop and validate procedure-specific risk prediction for recurrence following resection for early-stage lung adenocarcinoma (ADC) and investigate risk prediction utility in identifying patients who may benefit from adjuvant chemotherapy (ACT). Methods In patients who underwent resection for small (≤2 cm) lung ADC (lobectomy, 557; sublobar resection, 352), an association between clinicopathologic variables and risk of recurrence was assessed by a competing risks approach. Procedure-specific risk prediction was developed based on multivariable regression for recurrence. External validation was conducted using cohorts (N = 708) from Japan, Taiwan, and Germany. The accuracy of risk prediction was measured using a concordance index. We applied the lobectomy risk prediction approach to a propensity score–matched cohort of patients with stage II-III disease (n = 316, after matching) with or without ACT and compared lung cancer–specific survival between groups among low- or high-risk scores. Results Micropapillary pattern, solid pattern, lymphovascular invasion, and necrosis were involved in the risk prediction following lobectomy, and micropapillary pattern, spread through air spaces, lymphovascular invasion, and necrosis following sublobar resection. Both internal and external validation showed good discrimination (concordance index in lobectomy and sublobar resection: internal, 0.77 and 0.75, respectively; and external, 0.73 and 0.79, respectively). In the stage II-III propensity score–matched cohort, among high-risk patients, ACT significantly reduced the risk of lung cancer–specific death (subhazard ratio 0.43, p = 0.001), but not among low-risk patients. Conclusions Procedure-specific risk prediction for patients with resected small lung ADC can be used to better prognosticate and stratify patients for further interventions.

PD-L1, as assessed by immunohistochemistry, is a predictive biomarker for immuno-oncology treatment in lung cancer. Different scoring methods have been used to assess its status, resulting in a wide range of positivity rates. We use the European Thoracic Oncology Platform Lungscape non-small cell lung carcinoma cohort to explore this issue. PD-L1 expression was assessed via immunohistochemistry on tissue microarrays (up to four cores per case), using the DAKO 28-8 immunohistochemistry assay, following a two-round external quality assessment procedure. All samples were analyzed under the same protocol. Cross-validation of scoring between tissue microarray and whole sections was performed in 10% randomly selected samples. Cutoff points considered: ≥1, 50 (primarily), and 25%. At the two external quality assessment rounds, tissue microarray scoring agreement rates between pathologists were: 73% and 81%. There were 2008 cases with valid immunohistochemistry tissue microarray results (50% all cores evaluable). Concordant cases at 1, 25, and 50% were: 85, 91, and 93%. Tissue microarray core results were identical for 70% of cases. Sensitivity of the tissue microarray method for 1, 25, and 50% was: 80, 78, and 79% (specificity: 90, 95, 98%). Complete agreement between tissue microarrays and whole sections was achieved for 60% of the cases. Highest sensitivity rates for 1% and 50% cutoffs were detected for higher number of cores. Underestimation of PD-L1 expression on small samples is more common than overestimation. We demonstrated that classification of PD-L1 on small biopsy samples does not represent the overall expression of PD-L1 in all non-small cell cancer carcinoma cases, although the majority of cases are ‘correctly’ classified. In future studies, sampling more and larger biopsies, recording the biopsy size and tumor load may permit further refinement, increasing predictive accuracy.

Objectives To determine whether the tumor biomarkers cytokeratin 19 fragment (CYFRA 21-1) and carcinoembryonic antigen (CEA), which are prognostic in early-stage non-small cell lung cancer (NSCLC), can predict which patients benefit from adjuvant chemotherapy (CTx). Materials and methods Serum samples were collected preoperatively from patients with NSCLC who underwent resection. Samples were retrospectively analyzed for CYFRA 21-1 and CEA via electrochemiluminescence immunoassay. Recurrence-free survival (RFS) was compared for patients who received adjuvant CTx versus surgery alone, stratified based on the following prognostic classifications: (1) tumor stage (pT1‐2/N0 [stage I] or pT3/N0 or pT1‐2/N1 [stage II]), (2) biomarker-based risk score, (3) clinical characteristics. Absolute 2-year RFS rates were calculated via Kaplan-Meier estimations; statistical significance level: 0.05. Results 227 patients were included (stage I: 69%; male: 67%; median age 65 years); 70 received adjuvant CTx. Median duration of sample collection was 58.8 months. All high-risk patients (by all three prognostic classifications) who received adjuvant CTx had a longer RFS versus those who received surgery alone. In patients with squamous cell carcinoma (SCC) classified as high risk by all three prognostic classifications, there was a benefit from adjuvant CTx versus surgery alone (tumor stage hazard ratio [HR] 4.9, p = 0.004; biomarker levels HR 9.4, p = 0.002; clinical characteristics HR 9.0, p = 0.003). None of the prognostic classifications were able to predict a benefit from adjuvant CTx in patients with adenocarcinoma. Conclusion Baseline CYFRA 21-1 and CEA levels may provide further information to help clinicians decide which patients with SCC should receive adjuvant CTx. Further evaluation of these biomarkers is warranted.

In lung cancer a deregulation of Transforming Growth Factor-β (TGFβ) signaling has been observed. Yet, the impact of TGFβ in squamous cell carcinoma of the lung (LUSC) remained to be determined. We combined phenotypic and transcriptome-wide studies and showed that the stimulation of the LUSC cell line SK-MES1 with TGFβ results in an increase of migratory invasive properties. The analysis of the dynamics of gene expression by next-generation sequencing revealed that TGFβ stimulation orchestrates the upregulation of numerous motility- and actin cytoskeleton-related genes. Among these the non-muscle myosin 10 (MYO10) showed the highest upregulation in a LUSC patient cohort of the Cancer Genome Atlas (TCGA). Knockdown of MYO10 abrogated TGFβ-induced collagen gel invasion of SK-MES1 cells. The analysis of MYO10 mRNA expression in paired tissues of 151 LUSC patients with corresponding 80-month clinical follow-up data showed that the mRNA expression ratio of MYO10 in tumor and tumor-free tissue is prognostic for overall survival of LUSC patients and predictive for the response of these patients to adjuvant chemotherapy. Thus, MYO10 represents a new clinical biomarker for this aggressive disease and due to its role in cellular motility and invasion could serve as a potential molecular target for therapeutic interventions in patients with LUSC.

Zusammenfassung Hintergrund Die hypertherme intrathorakale Chemotherapie (HITHOC) wird seit mehreren Jahren an einigen thoraxchirurgischen Kliniken zusätzlich zur chirurgischen Zytoreduktion im Rahmen eines multimodalen Therapieansatzes zur Behandlung maligner Pleuratumoren angewendet. Genaue Zahlen zur HITHOC in Deutschland liegen bislang nicht vor. Material und Methode Deutschlandweite schriftliche Umfrage an den thoraxchirurgischen Kliniken bzw. Abteilungen zu Anzahl, Indikationen, technischer Durchführung, perioperativen Schutzmaßnahmen und Komplikationen der HITHOC. Ergebnis Insgesamt wurden 116 Kliniken angeschrieben. Die Rücklaufquote des Fragebogens lag bei 43% (n = 50). In 33 Kliniken wurde bisher keine HITHOC durchgeführt. Gründe hierfür sind mangelnde Ressourcen oder Erfahrung mit der HITHOC (n = 17), gefolgt von einer fehlenden Überzeugung bez. der Wirkung des Verfahrens (n = 8) verbunden mit einer zu hohen Komplikationsrate (n = 3). In 17 Kliniken wurden seit 2008 insgesamt 343 HITHOC-Prozeduren durchgeführt. Eine eigene Perfusionsmaschine besitzen 8 Kliniken, während sich die restlichen Kliniken die Maschine ausleihen. Indikationen stellten in allen Kliniken das maligne Pleuramesotheliom (n = 17), häufig Thymome mit pleuraler Aussaat (n = 11) und seltener die sekundäre Pleurakarzinose (n = 7) dar. Die HITHOC erfolgte in 16 Kliniken am geschlossenen Thorax, in den meisten Fällen bei 42 °C (n = 12) und für 60 Minuten (n = 15). Es wird immer Cisplatin entweder als Mono- (n = 9) oder in Kombinationstherapie (n = 8) verwendet. Alle Kliniken gaben als Ziel der HITHOC die Verbesserung der lokalen Tumorkontrolle sowie eine Verlängerung des rezidivfreien bzw. Gesamtüberlebens an. Über Komplikationen wird nur in wenigen Fällen berichtet. Schlussfolgerung Die HITHOC wird derzeit an mindestens 17 Kliniken in Deutschland weitgehend standardisiert mit entsprechenden perioperativen Maßnahmen und ohne schwerwiegende Komplikationen durchgeführt. Ziel ist die Verbesserung der lokalen Tumorkontrolle bei bösartigen Neubildungen der Pleura und einer damit verbundenen Verbesserung der Überlebenszeit bei guter Lebensqualität.

Objective To systematically evaluate the prognostic value of nutrition/inflammation-based markers for recurrence-free survival (RFS) in pN2-stage IIIA lung adenocarcinoma patients. Materials and methods Data from 156 patients who had pathologically confirmed pN2-stage IIIA primary lung adenocarcinoma and received complete surgical resection from 2010 to 2014 were retrospectively analyzed. The data for Glasgow prognostic score (GPS), modified GPS (mGPS), high-sensitivity mGPS, C-reactive protein/albumin ratio (CAR), neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and prognostic nutritional index were analyzed. Univariate and multivariate Cox proportional-hazards regression analyses were used to identify the prognostic factors associated with RFS. Results The optimal cutoff value for the CAR was set at 0.6. A significant correlation was found between the CAR and RFS (P = 0.001) by univariate analysis. Multivariate analysis between RFS and the factors selected from univariate analysis showed that ECOG performance status, pneumonectomy, multi-level N2, and high CAR were independent predictors of RFS. Conclusion The CAR was the best prognostic marker to predict tumor recurrence in pN2-stage IIIA lung adenocarcinoma patients among the 7 nutrition/inflammation-based markers. The preoperative CAR may identify patients with a high risk of postoperative tumor recurrence.

// Yoshikane Yamauchi 1 , Seyer Safi 1 , Lena Orschiedt 2, 4 , Adriane Gardyan 2, 4, 5 , Stephan Brons 3, 4 , Juliane Rieber 2, 3, 4 , Nils H. Nicolay 2, 3, 4, 5 , Peter E. Huber 2, 4, 5 , Martin Eichhorn 1 , Hendrik Dienemann 1 , Felix J.F. Herth 6, 7 , Klaus-Josef Weber 2, 3, 4 , Jurgen Debus 2, 3, 4 , Hans Hoffmann 1 and Stefan Rieken 2, 3, 4 1 Department of Thoracic Surgery, Thorax Clinic, Heidelberg University, Heidelberg, Germany 2 Department of Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany 3 Heidelberg Ion Treatment Facility (HIT), Heidelberg, Germany 4 Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany 5 Department of Molecular and Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany 6 Pneumology and Critical Care Medicine, Thorax Clinic, Heidelberg University, Heidelberg, Germany 7 Translational Lung Research Center Heidelberg (TLRCH), Heidelberg, Germany, Member of the German Center for Lung Research (DZL) Correspondence to: Stefan Rieken, email: Stefan.Rieken@med.uni-heidelberg.de Keywords: mesothelioma, photon irradiation, carbon ion irradiation, CXCR4, SDF-1α Received: September 06, 2016 Accepted: June 10, 2017 Published: July 10, 2017 ABSTRACT Background: Low-dose photon irradiation has repeatedly been suspected to increase a risk of promoting local recurrence of disease or even systemic dissemination. The purpose of this study was to investigate the motility of malignant pleural mesothelioma (MPM) cell lines after low-doses of photon irradiation and to elucidate the mechanism of the detected phenotype. Methods: H28 and H226 MPM cells were examined in clonogenic survival experiments and migration assays with and without various doses of photon and carbon ion irradiation. C-X-C chemokine receptor type 4 (CXCR4), SDF-1α, β 1 integrin, α 3 integrin, and α 5 integrin expressions were analyzed by quantitative FACS analysis, ELISA and western blots. Apoptosis was assessed via Annexin-V-staining. Results: The migration of MPM cells was stimulated by both fetal bovine serum and by stromal cell-derived factor 1α (SDF-1α). Low doses of photon irradiation (1 Gy and 2 Gy) suppressed clonogenicity, but promoted migration of both H28 and H226 cells through the SDF-1α/CXCR4 pathway. Hypermigration was inhibited by the administration of CXCR4 antagonist, AMD3100. In contrast, corresponding doses of carbon ion irradiation (0.3 Gy and 1 Gy) suppressed clonogenicity, but did not promote MPM cell migration. Conclusion: Our findings suggest that the co-administration of photon irradiation and the CXCR4-antagonist AMD3100 or the use of carbon ions instead of photons may be possible solutions to reduce the risk of locoregional tumor recurrence after radiotherapy for MPM.

Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) shows a high potential for applications in histopathological diagnosis, and in particular for supporting tumor typing and subtyping. The development of such applications requires the extraction of spectral fingerprints that are relevant for the given tissue and the identification of biomarkers associated with these spectral patterns. We propose a novel data analysis method based on the extraction of characteristic spectral patterns (CSPs) that allow automated generation of classification models for spectral data. Formalin-fixed paraffin embedded (FFPE) tissue samples from N=445 patients assembled on 12 tissue microarrays were analyzed. The method was applied to discriminate primary lung and pancreatic cancer, as well as adenocarcinoma and squamous cell carcinoma of the lung. A classification accuracy of 100% and 82.8%, resp., could be achieved on core level, assessed by cross-validation. The method outperformed the more conventional classification method based on the extraction of individual m/z values in the first application, while achieving a comparable accuracy in the second. LC-MS/MS peptide identification demonstrated that the spectral features present in selected CSPs correspond to peptides relevant for the respective classification. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.

In 2011, the U.S. National Lung Cancer Screening Trial (NLST) reported a 20% reduction of lung cancer mortality after regular screening by low-dose computed tomography (LDCT), as compared to X-ray screening. The introduction of lung cancer screening programs in Europe awaits confirmation of these first findings from European trials that started in parallel with the NLST. The German Lung cancer Screening Intervention (LUSI) is a randomized trial among 4,052 long-term smokers, 50-69 years of age, recruited from the general population, comparing five annual rounds of LDCT screening (screening arm; n = 2,029 participants) with a control arm (n = 2,023) followed by annual postal questionnaire inquiries. Data on lung cancer incidence and mortality and vital status were collected from hospitals or office-based physicians, cancer registries, population registers and health offices. Over an average observation time of 8.8 years after randomization, the hazard ratio for lung cancer mortality was 0.74 (95% CI: 0.46-1.19; p = 0.21) among men and women combined. Modeling by sex, however showed a statistically significant reduction in lung cancer mortality among women (HR = 0.31 [95% CI: 0.10-0.96], p = 0.04), but not among men (HR = 0.94 [95% CI: 0.54-1.61], p = 0.81) screened by LDCT (pheterogeneity = 0.09). Findings from LUSI are in line with those from other trials, including NLST, that suggest a stronger reduction of lung cancer mortality after LDCT screening among women as compared to men. This heterogeneity could be the result of different relative counts of lung tumor subtypes occurring in men and women.

Intrapulmonale Rundherde stellen in der Regel einen Zufallsbefund im Rontgenbild oder Computertomogramm des Thorax dar. Sie sind definiert als relativ gut abgegrenzte Lasionen von bis zu 3 cm Durchmesser, die allseits von Lungengewebe umgeben sind. Die Wahrscheinlichkeit fur das Vorliegen eines malignen Tumors steigt mit ihrer Grose. Rundherde ab 1 cm Durchmesser bedurfen der aktiven Abklarung. Zur Behandlung solitarer maligner Tumoren steht fur Patienten ohne nennenswert erhohtes Operations- und Narkoserisiko der chirurgische Eingriff an erster Stelle. Patienten, die aus funktionellen Grunden fur einen solchen nicht geeignet sind, konnen mit Radiofrequenzablation (RFA) oder Einzeitbestrahlung (SBRT) behandelt werden. In diesen Fallen mussen vor Therapiebeginn die Malignitat nachgewiesen oder zumindest uber einen begrenzten Zeitraum eine Grosenzunahme der Lasion dokumentiert worden sein. In Bezug auf die lokale Tumorfreiheit ist die Operation unter den Voraussetzungen einer R0-Resektion den anderen Verfahren uberlegen.

Patienten mit einer diffusen Atemwegsinstabilitat bei einer Tracheobronchomalazie oder eines „Excessive dynamic Airway Collapse“ sind typischerweise hoch symptomatisch mit einer ausgepragten Belastungsdyspnoe, rezidivierenden bronchopulmonalen Infekten und qualendem therapieresistentem Hustenreiz. Silikonstents erreichen eine unmittelbare Symptomkontrolle, sind jedoch aufgrund der typischen, mit einer Stentbehandlung verbundenen Komplikationen i. d. R. keine Option fur eine Dauerbehandlung. Das Ziel der Operation ist die langstreckige und dauerhafte Stabilisierung der Trachea und beider Hauptbronchien durch Raffung und Verstarkung des Paries membranaceus mit einem Polypropylennetz. Die Operation ist eine geeignete Therapieoption fur Patienten mit dokumentiert schwerer Tracheobronchomalazie und sie ist schlussendlich die einzige Therapie, durch die eine dauerhafte Symptomkontrolle erreicht werden kann. Der Erfolg der Operation hangt allerdings von vielen Faktoren ab und erfordert eine enge interdisziplinare Zusammenarbeit.

Background Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. Methods Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N = 12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. Results Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR = 0.48, 95%CI = 0.30–0.75, p = 0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR = 0.68, 95%CI = 0.61–0.77, p = 4.9 ∗ 10–10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. Conclusion We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7 years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke., Highlights • CHRNA5 rs16969968 confers risk for earlier lung cancer diagnosis, but quitting produces benefit regardless of genotype. • Smokers can cut their risk of lung cancer in half and delay its onset by 7 years among those diagnosed. • Precision prevention allows clinicians to provide personalized health benefits of smoking cessation. This is a report on whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. We determined that quitting smoking is highly beneficial in reducing lung cancer risk levels for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Although CHRNA5 rs16969968 increases risk for earlier lung cancer by 4 years, quitting produces essentially the same benefit for smokers with either high or low genetic risks. Smokers can cut their risk of lung cancer in half and delay its onset by 7 years among those diagnosed. These results are important for smokers to prevent cancer. On average, smokers at all genetic risk levels can largely eliminate their elevated risk for lung cancer by quitting smoking.

Growth patterns of pulmonary adenocarcinoma (ADC) have high prognostic impact and are accepted as a novel classification system for this entity. However, specifically for the papillary pattern, divergent data with respect to prevalence, clinical associations, and prognostic impact have been reported. By evaluating 674 resected pulmonary ADCs containing 308 cases with a papillary component and 101 papillary predominant cases, we documented differences in the morphologic composition of papillary growth patterns and delineated 3 different types. The different types were correlated with pathologic and clinical data including survival. Type 3 papillary cases with any or predominant papillary growth were associated with extensive spread through alveolar spaces, high proliferation, higher stage, low rates of EGFR mutations, and smoking, whereas type 1 papillary tumors showed the opposite associations. The subclassification of papillary growth revealed type-specific associations for overall and disease-free survival (disease-free survival type 1: 67.1 mo, type 2: 56.8 mo, type 3: 49.9 mo, P=0.025). The presence of any papillary type 3 pattern was a predominant pattern independent predictor of worse overall survival (hazard ratio=2.5, P=0.02). For a future grading system of lung ADC, categorization of papillary growth in 1 single category might not be adequate, as this pattern contains a heterogenous mix of tumors with a divergent prognosis. We suggest that papillary pattern types should be separated to further improve the prognostic power of ADC growth pattern analysis.

// Arne Warth 1, # , Volker Endris 1 , Albrecht Stenzinger 1 , Roland Penzel 1 , Alexander Harms 1 , Thomas Duell 2 , Amir Abdollahi 3, + , Michael Lindner 4 , Peter Schirmacher 1 , Thomas Muley 5, # , Hendrik Dienemann 6, # , Ludger Fink 7, # , Alicia Morresi-Hauf 8 , Nicole Pfarr 1, 10, § , Wilko Weichert 1, 9, 10, +, § 1 Institute of Pathology, Heidelberg University, Heidelberg, Germany 2 Department of Pneumology and Thoracic Oncology, Asklepios Hospital, Munich-Gauting, Germany 3 Department of Radiation Oncology, Heidelberg University, Heidelberg, Germany 4 Department of Thoracic Surgery, Asklepios Hospital, Munich-Gauting, Germany 5 Translational Research Unit, Thoraxklinik at Heidelberg University, Heidelberg, Germany 6 Department of Thoracic Surgery, Thoraxklinik at Heidelberg University, Heidelberg, Germany 7 Institute of Pathology, Wetzlar, Germany 8 Institute of Pathology, Asklepios Hospital, Munich-Gauting, Germany 9 National Center for Tumor Diseases (NCT), Heidelberg, Germany 10 Institute of Pathology, Technical University (TUM), Munich, Germany # Translational Lung Research Centre Heidelberg, Member of the German Center for Lung Research (DZL-TLRC) + Member of the German Cancer Consortium (DKTK) § shared senior authorship Correspondence to: Arne Warth, email: arne.warth@med.uni-heidelberg.de Wilko Weichert, email: wilko.weichert@tum.de Keywords: lung cancer, molecular evolution, driver mutations, therapy Received: November 06, 2015 Accepted: March 28, 2016 Published: April 20, 2016 ABSTRACT Background: Large scale sequencing efforts defined common molecular alterations in non-small cell lung cancer (NSCLC) and revealed potentially druggable mutations. Yet, systematic data on the changes of the respective molecular profiles under standard therapy in NSCLC are limited. Results: 14 out of 68 observed coding mutations (21%) and 6 out of 33 (18%) copy number variations (CNV) were lost or gained during therapy. Mutational and CNV changes clustered in 6/37 (16%) and 3/37 (8%) patients. Changes in clinically relevant mutations were rare but present in single cases for genes such as BRAF and PIK3CA . The type of radiochemotherapy but not the duration of therapy impacted on the frequency of mutational changes. Methods: We established a lung cancer specific next-generation sequencing panel covering ~7500 hotspots of 41 genes frequently mutated in NSCLC and performed ultradeep multigene sequencing of 37 corresponding pre- and post-therapeutic formalin fixed paraffin-embedded specimens to discover mutational changes and copy number variations under neo-adjuvant radio- (RTX) and/or chemotherapy (CTX). Conclusion: We unraveled changes in common driver gene candidates in NSCLC under neo-adjuvant therapy. Our data shed first light on the genetic changes of NSCLC under conventional therapy and might be taken into account when the relevance of sequential biopsy approaches is discussed.

The objective includes radiofrequency ablation (RFA) of a cancerous nodule results in immunogenic cell death. Tumor antigens are presented and the inflammatory environment may help stimulate adaptive and innate antitumor immunity. The objective of this study was to investigate the immune response following RFA and subsequent surgical resection in early stage non–small cell lung cancer (NSCLC). In methods, a single-session approach of computed tomography-guided tumor biopsy with immediate frozen section (and proof of NSCLC) was performed followed by RFA of the tumor in 4 patients with a solitary pulmonary nodule. Blood samples were collected before RFA and 3 days thereafter. All patients underwent radical surgical resection by video-assisted thoracoscopic lobectomy 8 days following RFA. In results, intense infiltrations of CD4+ and CD8+ lymphocytes were found along the perimeter of the RFA-treated tumor tissue, whereas the central tumor areas remained devoid of lymphocytes. In the peripheral blood, the frequency of proinflammatory, immunostimulatory IFNγ-secreting, and immunostimulatory BDCA-3+/B7-H3- dendritic cells increased after RFA. Furthermore, a significant increase in T-cell proliferation was detected in T-cell assays after RFA and tumor resection. In this article, a local and systemic immune response subsequent to RFA and complete surgical resection in patients with NSCLC was identified for the first time. Treatment of patients with NSCLC with RFA and surgery leads to an activated and highly T–cell-stimulatory phenotype of dendritic cells, which may promote long-term immunity against NSCLC. The data suggest that the RFA-induced necrotic tumor debris can serve as an in situ antigen source to induce an autologous antitumor immune response.

Myeloid-derived suppressor cell (MDSC) expansion has been found to play a role in disease progression in patients with cancer. However, the characteristics of MDSCs in lung cancer are poorly understood.We prospectively investigated MDSCs and inflammatory factors in tumor and peripheral blood samples from patients with resectable non-small cell lung cancer and studied their correlations with the disease prognosis.A complex analysis of MDSC subsets and inflammatory mediators was performed using flow cytometry and a Bio-Plex assay.A significant increase in the frequency of circulating monocytic (M)-MDSCs was observed in the patients with non-small cell lung cancer compared with the healthy donors (HDs). Moreover, the frequencies of M- and polymorphonuclear (PMN)-MDSCs were higher in tumors than in the peripheral blood of the same patients. This accumulation was associated with elevated concentrations of inflammatory mediators involved in MDSC migration to and activation in the tumor microenvironment. An analysis of the MDSC immunosuppressive pattern showed increased programmed death-ligand 1 expression on circulating cells from patients compared with HDs. Tumor PMN-MDSCs displayed higher programmed death-ligand 1 expression levels than the same cells in the peripheral blood. The frequency of CCR5 (C-C chemokine receptor 5) expression on circulating M-MDSCs was significantly higher in the patients than in the HDs. Clinical data analysis revealed negative correlations between recurrence-free survival and the frequencies of PMN-MDSCs and CCR5Our findings suggest that the level of MDSCs in the peripheral blood but not in tumor tissues predicts recurrence after surgery.

For several years, hyperthermic intrathoracic chemotherapy (HITHOC) has been performed in a few departments for thoracic surgery in a multimodality treatment regime in addition to surgical cytoreduction. Specific data about HITHOC in Germany are still lacking.Survey in written form to all departments of thoracic surgery in Germany. The objective is the evaluation of HITHOC with respect to number, indications, technique, perioperative protection measure and complications.A total of 116 departments of thoracic surgery were contacted, with a return rate of 43% (n = 50). HITHOC was not performed in 33 departments, due to lack of resources or experience (n = 17), missing efficacy of the procedure (n = 8) and fear of excessive complication rates (n = 3). Since 2008, a total of 343 HITHOC procedures have been performed in 17 departments. Eight departments have their own perfusion machine, whereas the remaining departments borrow the perfusion machine. Indications were malignant pleural mesothelioma in all departments (n = 17), thymoma with pleural spread (n = 11) and secondary pleural carcinosis (n = 7). The HITHOC was performed in nearly all departments after closing the chest (n = 16), with a temperature of 42 °C (n = 12) and for 60 minutes (n = 15). Cisplatin was always used, either alone (n = 9) or in combination (n = 8). In all the participating departments, the aims of the HITHOC were improvement in local tumor control and prolonged recurrence-free and overall survival. Relevant HITHOC-associated complications were low.HITHOC is performed in at least 17 departments of thoracic surgery in Germany, and is widely standardised with protective measures and a low rate of complications. The aims of the HITHOC are improvement in local tumor control in pleural malignancies combined with prolonged overall survival and better quality of life.Die hypertherme intrathorakale Chemotherapie (HITHOC) wird seit mehreren Jahren an einigen thoraxchirurgischen Kliniken zusätzlich zur chirurgischen Zytoreduktion im Rahmen eines multimodalen Therapieansatzes zur Behandlung maligner Pleuratumoren angewendet. Genaue Zahlen zur HITHOC in Deutschland liegen bislang nicht vor.Deutschlandweite schriftliche Umfrage an den thoraxchirurgischen Kliniken bzw. Abteilungen zu Anzahl, Indikationen, technischer Durchführung, perioperativen Schutzmaßnahmen und Komplikationen der HITHOC.Insgesamt wurden 116 Kliniken angeschrieben. Die Rücklaufquote des Fragebogens lag bei 43% (n = 50). In 33 Kliniken wurde bisher keine HITHOC durchgeführt. Gründe hierfür sind mangelnde Ressourcen oder Erfahrung mit der HITHOC (n = 17), gefolgt von einer fehlenden Überzeugung bez. der Wirkung des Verfahrens (n = 8) verbunden mit einer zu hohen Komplikationsrate (n = 3). In 17 Kliniken wurden seit 2008 insgesamt 343 HITHOC-Prozeduren durchgeführt. Eine eigene Perfusionsmaschine besitzen 8 Kliniken, während sich die restlichen Kliniken die Maschine ausleihen. Indikationen stellten in allen Kliniken das maligne Pleuramesotheliom (n = 17), häufig Thymome mit pleuraler Aussaat (n = 11) und seltener die sekundäre Pleurakarzinose (n = 7) dar. Die HITHOC erfolgte in 16 Kliniken am geschlossenen Thorax, in den meisten Fällen bei 42 °C (n = 12) und für 60 Minuten (n = 15). Es wird immer Cisplatin entweder als Mono- (n = 9) oder in Kombinationstherapie (n = 8) verwendet. Alle Kliniken gaben als Ziel der HITHOC die Verbesserung der lokalen Tumorkontrolle sowie eine Verlängerung des rezidivfreien bzw. Gesamtüberlebens an. Über Komplikationen wird nur in wenigen Fällen berichtet.Die HITHOC wird derzeit an mindestens 17 Kliniken in Deutschland weitgehend standardisiert mit entsprechenden perioperativen Maßnahmen und ohne schwerwiegende Komplikationen durchgeführt. Ziel ist die Verbesserung der lokalen Tumorkontrolle bei bösartigen Neubildungen der Pleura und einer damit verbundenen Verbesserung der Überlebenszeit bei guter Lebensqualität.

A major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency, leading to accumulation of numerous mutations at repetitive DNA sequence stretches (microsatellites), known as high-level microsatellite instability (MSI-H). In colorectal cancer, MSI-H tumors show a clinical behavior different from microsatellite-stable (MSS) tumors. Data about the prevalence of MSI among non-small cell lung cancer (NSCLC) are conflicting, and clinical relevance of MSI is largely unknown. We analyzed a series of 480 pulmonary adenocarcinomas (ADC) for MSI using a sensitive mononucleotide marker panel (BAT25, BAT26, and CAT25). Positive cases were further analyzed by immunohistochemical staining for DNA mismatch repair proteins. Results were correlated with clinicopathological variables. MSI-H was detected in 4/480 (0.8 %) cases. In none of these, a background of Lynch syndrome was found. Three of the patients developed a metachronous carcinoma (esophagus, pancreas, and kidney). All MSI-H cases were stage I and occurred in smokers/ex-smokers. Mutations were found in EGFR (n = 2), KRAS (n = 1), or BRAF (n = 1). MSI-H neoplasms had a higher proliferative activity (38.7 %) than MSS neoplasms (28.3 %). Mean overall survival for MSS and MSI-H cases was 64.8 (CI 60.4-69.1) and 47.1 (CI 21-73.2) months, respectively. When specific mononucleotide marker panels are applied, the MSI-H phenotype is rare and predominantly found in early stage ADC of smokers. However, the frequency of MSI-H is in the range of other relevant molecular alterations. In the era of precision therapy, associations with distinct clinicopathological variables merit further investigation.

NUT (nuclear protein in testis) carcinomas are exceedingly rare neoplasms with specific molecular alterations and often follow a devastating course. Thus, a precise early diagnosis is of utmost importance. Known from the sinonasal region for years, the new 2015 WHO classification now also recognizes the existence of this entity in the thorax, specifically the lungs and the mediastinum. However, yet available data on this entity are sparse. Here, we report on a 31 years old female patient with an aggressively growing tumor localized in the median line that was initially sampled by endobronchial ultrasound-guided transbronchial biopsies. Pathological assessment of the biopsy specimens revealed a NUT carcinoma with typical morphological characteristics and an uncommon NUT translocation variant with a NSD3-NUT fusion. Diagnosis was further confirmed in the subsequent resection specimen. We describe specific clinical, histomorphological, and molecular characteristics of this tumor and provide a comprehensive review of the current literature on these rare neoplasms.

Molecular profiling of non-small cell lung cancers (NSCLC) has a strong impact on clinical decision making and current oncological therapies. Besides detection of activating mutations in EGFR, analysis of ALK and ROS1 gene rearrangements has come into focus for targeted therapies. Targeted massive parallel sequencing (MPS) has been established for routine diagnostic profiling of the most prevalent oncogenic mutations in NSCLC, but not for the detection of gene rearrangements yet. Here, we present and evaluate an MPS-based panel sequencing approach which simultaneously detects ALK, ROS1, and RET fusions as well as somatic mutations in a single multiplex assay using formalin-fixed paraffin-embedded (FFPE) tissue. To this end, we first evaluated sensitivity and specificity of the fusion assay retrospectively by employing it to a set of 50 NSCLC with known gene fusions (n = 35) and with no gene fusions (n = 15). The sensitivity and specificity of the MPS assay for the detection of known fusions was 100%. In a second prospective phase, we implemented the approach of parallel mutation and gene fusion detection in our routine diagnostic workflow to assess performance of the test in a diagnostic outreach setting. Our prospective screening of 109 NSCLC samples revealed four gene fusions all of which were confirmed by FISH. In conclusion, our approach facilitates simultaneous high-throughput detection of gene fusions and somatic mutations in NSCLC samples and is able to replace conventional methods.

Pulmonary cystic echinococcosis is a very rare disease in Germany. It is caused by the larvae of the dog tapeworm (echinococcus granulosus). The liver is the most affected organ, followed by the lungs. Surgery remains the main therapeutic approach for pulmonary CE. Whenever possible, parenchyma-preserving lung surgery should be preferred over anatomic lung resections. To ensure best therapeutic results, surgery needs to be performed under precise consideration of important infectiological aspects and patients should be treated in specialised centres based on interdisciplinary consensus. In addition to surgical aspects, this review summarises special infectiological features of this disease, which are crucial to the surgical approach.

Tumor spread, in general, is the most important factor determining outcome in almost all malignant tumors. Lung tumors are unique with respect to potential routes for tumor dissemination, as apart from vascular, nodal, and distant spread of tumor cells, tumor spread through air spaces (STAS) might also occur. However, morphologic criteria for STAS and its prognostic impact have not been defined yet. We evaluated a series of 569 resected pulmonary adenocarcinomas (ADCs) for predefined morphologic criteria of limited and extensive STAS and correlated our findings with clinical, morphologic, molecular, and outcome data. Limited (21.6%) or extensive (29%) STAS was present in roughly half of all ADCs. The presence and type of STAS was tightly linked to specific growth patterns (P

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D-imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development. What's new? Cellular membranes are subject to extensive modification in cancer, often with marked alterations in phospholipid metabolism. The extent and nature of those changes are not fully known, however, particularly for non-small cell lung cancer (NSCLC). In this study, lipidomics analysis of phospholipid profiles uncovered dramatic differences between NSCLC and normal lung tissue. The differences were confirmed via 2D-imaging lipidomics in tissue sections. Lipid markers capable of discriminating between tumor and normal tissue and between different NSCLC subtypes were identified. The observed alterations in NSCLC phospholipid profiles may be biologically significant. Grant sponsor: EU FP7 (to J.Sw., M.M., T.M. and M.T.); Grant number: Canceralia EU-259737; Grant sponsor: Research Foundation-Flanders (FWO) (to J.Sw.); Grant number: G.0691.12; Grant sponsor: KU Leuven (to J.Sw.); Grant number: GOA/11/2009; Grant sponsor: Foundation Fournier Majoie (FFM) (to J.Sw.); Grant sponsor: Stichting tegen Kanker (to J.Sw.); Grant number: F/2014/324; Grant sponsor: Agency for Innovation by Science and Technology IWT-Flanders (to E.M. and J.D.; recipients of a fellowship); Grant sponsor: Olle Engkvist foundation (Sweden) (to S.B.); Grant sponsor: National Institutes of Health (to J.Sp., R.V. and R.M.C.); Grant numbers: NIH/NIGMS R01 GM058008-14 and NIH/NIGMS P41 GM103391-03

BackgroundA novel classification of pulmonary adenocarcinoma (ADC) distinguishing five growth patterns has been established by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. There is evidence that an additional cribriform pattern associates with a distinct clinical behavior.MethodsWe evaluated the predominant growth pattern of 674 resected ADC as recommended by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society, including the cribriform pattern. The predominant pattern type was correlated with clinical, molecular, and survival data.ResultsTwo hundred forty-eight (36.8%) of the pulmonary ADC were solid, 207 (30.6%) were acinar, 101 (15%) were papillary, 55 (8.2%) were micropapillary, 35 (5.2%) were lepidic, and 28 cases (4.2%) were cribriform predominant (cpADC). Minor cribriform components were frequently observed (28.6% of all cases). cpADC showed the second highest proliferative capacity of all patterns, no somatic mutations in the epidermal growth factor receptor (p = 0.001) and a high rate of KRAS mutations. Overall survival (OS) of patients with cpADC (mean OS: 62.7 months) ranged in between survival times of patients with acinar (mean OS: 71.3 months) and solid predominant ADC (mean OS: 54.5 months); cpADC was associated with the worst disease-free survival (DFS) of all patterns (mean DFS: 36.9 months). Both associations were confirmed by multivariate analysis (p < 0.01 for both OS and DFS). Hazard ratios for cpADC were 1.72 for OS and 2.99 for DFS, with lepidic predominant ADC set as reference (hazard ratio: 1).ConclusionsOur data support the introduction of cpADC as a novel category into future morphology based on pulmonary ADC classifications. Further international studies are required to validate the reported clinicopathological associations of the cribriform pattern.

A chest tube is used to drain the contents of the pleural space to reconstitute the physiologic pressures within the pleural space and to allow the lungs to fully expand. Indications for chest tube placement include pneumothorax, hemothorax, pleural effusion, pleural empyema, and major thoracic surgery. The most appropriate site for chest tube placement is the 4th or 5th intercostal space in the mid- or anterior- axillary line. Attention to technique in placing the chest tube is vital to avoid complications from the procedure. Applying the step-by-step technique presented, placement of a chest tube is a quick and safe procedure. Complications - frequently occurring when the tube is inserted with a steel trocar - include hemothorax, dislocation, lung lacerations, and injury to organs in the thoracic or abdominal cavity."

Die Lunge stellt die haufigste Lokalisation einer Fernmetastasierung durch solide Malignome dar. Diese Metastasierung ist gleichbedeutend mit limitierten Therapieoptionen und meist infauster Prognose. Der Lungenmetastasenchirurgie kommt, abgesehen von palliativen und diagnostischen Eingriffen, bei Nachweis einer isolierten pulmonalen Filialisierung auch im Rahmen kurativer Behandlungskonzepte Bedeutung zu. Eine sorgsame klinische und radiologische Diagnostik sind zur Evaluation potenzieller Kandidaten fur eine Operation essenziell. Daten aus prospektiv randomisierten Studien fehlen bislang, jedoch konnte eine Vielzahl von retrospektiven Analysen einen Uberlebensvorteil durch radikale Lungenmetastasenresektion bei bestimmten Tumorentitaten dokumentieren. Voraussetzungen fur eine Prognoseverbesserung oder gar Heilung sind die chirurgische Expertise sowie eine differenzierte interdisziplinare Indikationsstellung und Patientenselektion unter Berucksichtigung bekannter Pradiktoren.