Walter Klepetko

Publications of Walter Klepetko

• Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: Results of a prospective, randomized international trial in lung transplantation.

  Authors: Hendrik Treede, Allan R Glanville, Walter Klepetko, Christina Aboyoun, Eik Vettorazzi, Raffael Lama, Carlos Bravo, Christiane Knoop, John-David Aubert, Hermann Reichenspurner

  The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 05/2012;

  BACKGROUND: Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation.BACKGROUND: Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS. METHODS: Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events. RESULTS: Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09). CONCLUSIONS: Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.

• Seroconversion and avidity maturation of cytomegalovirus-specific IgG in D(+)/R(-) lung transplant patients receiving different prophylactic anti-viral regimens.

  Authors: Heidrun Kerschner, Barbara Zweytick, Walter Klepetko, Theresia Popow-Kraupp, Elisabeth Puchhammer-Stöckl

  The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 04/2012;

• Long-term treatment, tolerability, and survival with sub-cutaneous treprostinil for severe pulmonary hypertension.

  Authors: Roela Sadushi-Koliçi, Nika Skoro-Sajer, Daniel Zimmer, Diana Bonderman, Michael Schemper, Walter Klepetko, Jutta Glatz, Johannes Jakowitsch, Irene Lang

  The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 04/2012;

  BACKGROUND: Randomized controlled trials have resulted in improved outcomes in pulmonary arterial hypertension; however, they are biased by stringent inclusion criteria, pre-specified patientBACKGROUND: Randomized controlled trials have resulted in improved outcomes in pulmonary arterial hypertension; however, they are biased by stringent inclusion criteria, pre-specified patient sub-sets, and study durations. In addition, common practice is to start oral therapies ahead of the more potent and titratable prostanoid therapies, despite advanced disease states at diagnosis. The objectives of our prospective registry were to evaluate long-term effects on functional class, 6-minute walking distance, hemodynamics, and survival, and also long-term tolerability of first-line sub-cutaneous treprostinil, a prostacyclin analog, in patients with severe pulmonary hypertension. METHODS: Data were collected from patients with functional class III/IV pre-capillary pulmonary hypertension (Dana Point groups 1 and 4; mean right arterial pressure ≥ 10 mmHg, and/or cardiac index ≤ 2.2 liters/min/m(2)). Treprostinil dose adjustments were driven by clinical symptoms and side effects. RESULTS: The study included 111 patients (1999 to 2010). Of these, 13 (12%) stopped treatment prematurely because of drug side effects, 11 (9.9%) underwent double lung transplantation, and 49 (44.1%) died of any cause (41 on treatment, 8 after early drug discontinuation). Overall survival rates at 1, 5, and 9 years were 84%, 53%, and 33%. In patients who were able to tolerate treatment > 6 months, survival rates were 57% at 9 years. CONCLUSION: First-line treatment of severe pre-capillary pulmonary hypertension with sub-cutaneous treprostinil is safe and efficacious over many years. If up-titration beyond 6 months is tolerated, effective doses are reached and outcomes are good.

• Removal of a large cement embolus from the right pulmonary artery 4 years after kyphoplasty: Consideration of thrombogenicity.

  Authors: Dagmar Kollmann, Konrad Hoetzenecker, Helmut Prosch, Hendrik J Ankersmit, Clemens Aigner, Shahrokh Taghavi, Walter Klepetko

  The Journal of thoracic and cardiovascular surgery. 04/2012; 143(4):e22-4.

• Discrimination of clinical stages in non-small cell lung cancer patients by serum HSP27 and HSP70: A multi-institutional case-control study.

  Authors: Matthias Zimmermann, Stefanie Nickl, Christopher Lambers, Stefan Hacker, Andreas Mitterbauer, Konrad Hoetzenecker, Anita Rozsas, Gyula Ostoros, Viktoria Laszlo, Helmut Hofbauer, Ferenc Renyi-Vamos, Walter Klepetko, Balazs Dome, Hendrik Jan Ankersmit

  Clinica chimica acta; international journal of clinical chemistry. 03/2012;

  INTRODUCTION: Lung cancer represents a major healthcare problem. Accordingly, there is an urgent need to identify serum biomarkers for early diagnosis of lung pathology. We have recently describedINTRODUCTION: Lung cancer represents a major healthcare problem. Accordingly, there is an urgent need to identify serum biomarkers for early diagnosis of lung pathology. We have recently described that patients with manifest COPD evidence elevated levels of heat shock proteins (HSPs). Based on these data, we speculated whether HSPs are also increased in patients with diagnosed lung cancer. METHODS: Serum levels of HSP27, phospho-HSP27 (pHSP27) and HSP70 in patients with non-small cell lung cancer (NSCLC) diagnosed at an early (stages I-II, n=37) or advanced (stages IIIA-IV, n=72) stage were determined by using ELISA. Healthy smokers (n=24), healthy never-smoker volunteers (n=33) and COPD patients (n=34) according to GOLD classification served as control population. RESULTS: Serum levels of HSP27 were elevated in patients with NSCLC diagnosed at an early or advanced stage when compared with both healthy control groups (P<0.005 and P<0.0001 respectively). Statistically significant differences were furthermore found between the groups of patients with early vs. advanced stage NSCLC (P=0.0021). Serum levels of HSP70 were also significantly elevated in patients with NSCLC diagnosed at an early or at an advanced stage when compared with either healthy control groups (P=0.0028 and P<0.0001 respectively). In univariate logistic regression models including healthy subjects and patients with NSCLC, HSP70 had an area under the curve (AUC) of 0.779 (P<0.0001) and HSP27 showed an AUC of 0.870 (P<0.0001). CONCLUSION: Our data suggest that serum HSP27 levels might serve as a possible tool to discriminate between early and advanced stages NSCLC.

• Increased Serum Levels of HSP27 as a Marker for Incipient Chronic Obstructive Pulmonary Disease in Young Smokers.

  Authors: Hendrik Jan Ankersmit, Stefanie Nickl, Eva Hoeltl, Michael Toepker, Christopher Lambers, Andreas Mitterbauer, Benedikt Kortuem, Matthias Zimmermann, Bernhard Moser, Christine Bekos, Barbara Steinlechner, Helmut Hofbauer, Walter Klepetko, Peter Schenk, Balazs Dome

  Respiration; international review of thoracic diseases. 03/2012;

  Background: Although chronic obstructive pulmonary disease (COPD) is amongst the leading causes of morbidity and mortality, no biomarkers for its early detection are known. We have recentlyBackground: Although chronic obstructive pulmonary disease (COPD) is amongst the leading causes of morbidity and mortality, no biomarkers for its early detection are known. We have recently demonstrated that COPD is accompanied by elevated serum heat shock protein (HSP) 27 levels as compared to a control population. Objectives: In an open prospective study, we investigated whether elevated HSP27 levels are associated with the early radiological signs of COPD, i.e. air trapping (AT), emphysema (E) and impaired lung function. Methods: In total, 120 apparently healthy smokers underwent lung function testing and serum sampling. Serum levels of HSP27, phospho-HSP27, CXCR2 chemokines and proteins related to inflammation, tissue remodeling and apoptosis were evaluated by ELISA. Of these 120 subjects, 94 voluntarily underwent a high-resolution computed tomography scan. Results: AT or AT and E were detected in 57.45%. Subjects with AT and E (n = 23) showed significantly higher HSP27 levels than those without any pathology [i.e. nothing abnormal detected (NAD)] (4,618 ± 1,677 vs. 3,282 ± 1,607 pg/ml; p = 0.0081). In a univariate logistic regression model including NAD and AT and E, the area under the curve of HSP27 in the receiver-operating-characteristic curve was 0.724, (0.594-0.854, 95% CI; p = 0.0033). Interestingly, proinflammatory IL-8 was elevated in those subjects with evidence of AT and E compared to those with AT and NAD. Lung function did not correlate with increased HSP27 levels or pathological radiological findings. Conclusions: HSP27 serum levels correlated with the early radiological signs of COPD, whereas lung function did not match with radiological findings or HSP27 serum levels. Serum HSP27 levels may serve as a potential marker to identify the early signs of COPD independent of lung function in young smokers.

• Primary lung transplantation after bridge with extracorporeal membrane oxygenation: a plea for a shift in our paradigms for indications.

  Authors: György Lang, Shahrokh Taghavi, Clemens Aigner, Ferenc Rényi-Vámos, Peter Jaksch, Victoria Augustin, Kazuhiro Nagayama, Bahil Ghanim, Walter Klepetko

  Transplantation. 03/2012; 93(7):729-36.

  BACKGROUND.: The introduction of the lung allocation score has brought lung transplantation (LTX) of patients on extracorporeal membrane oxygenation (ECMO) bridge into the focus of interest. WeBACKGROUND.: The introduction of the lung allocation score has brought lung transplantation (LTX) of patients on extracorporeal membrane oxygenation (ECMO) bridge into the focus of interest. We reviewed our institutional experience with ECMO as a bridge to LTX. METHODS.: Between 1998 and 2011, 38 patients (median age 30.1 years, range 13-66 years) underwent ECMO support with intention to bridge to primary LTX. The underlying diagnosis was cystic fibrosis (n=17), pulmonary hypertension (n=4), idiopathic pulmonary fibrosis (n=9), adult respiratory distress syndrome (n=4), hemosiderosis (n=1), bronchiolitis obliterans (n=1), sarcoidosis (n=1), and bronchiectasis (n=1). The type of extracorporeal bridge was venovenous (n=18), venoarterial (n=15), interventional lung assist (n=1), or a stepwise combination of them (n=4). The median bridging time was 5.5 days (range 1-63) days. The type of transplantation was double LTX (n=7), size-reduced double LTX (n=8), lobar LTX (n=16), split LTX (n=2), and lobar LTX after ex vivo lung perfusion (n=1). RESULTS.: Four patients died before transplantation. Thirty-four patients underwent LTX, of them eight patients died in the hospital after a median stay of 24.5 days (range 1-180 days). Twenty-six patients left the hospital and returned to normal life (median hospital stay=47.5 days; range 21-90 days). The 1-, 3-, and 5-year survival for all transplanted patients was 60%, 60%, and 48%, respectively. The 1-, 3-, and 5-year survival conditional on 3-month survival for patients bridged with ECMO to LTX (78%, 78%, and 63%) was not worse than for other LTX patients within the same period of time (90%, 80%, and 72%, respectively, P=0.09, 0.505, and 0.344). CONCLUSION.: Transplantation of patients bridged on ECMO to LTX is feasible and results in acceptable outcome.

• Genome-Wide miRNA Expression Profiling Identifies miR-9-3 and miR-193a as Targets for DNA Methylation in Non-Small Cell Lung Cancers.

  Authors: Gerwin Heller, Marlene Weinzierl, Christian Noll, Valerie Babinsky, Barbara Ziegler, Corinna Altenberger, Christoph Minichsdorfer, György Lang, Balazs Döme, Adelheid End-Pfützenreuter, Britt-Madeleine Arns, Yuliya Grin, Walter Klepetko, Christoph C Zielinski, Sabine Zöchbauer-Müller

  Clinical cancer research : an official journal of the American Association for Cancer Research. 03/2012;

  PURPOSE: The major aim of this study was to investigate the role of DNA methylation (referred to as methylation) on miRNA silencing in non-small cell lung cancers (NSCLC).EXPERIMENTAL DESIGN: WePURPOSE: The major aim of this study was to investigate the role of DNA methylation (referred to as methylation) on miRNA silencing in non-small cell lung cancers (NSCLC).EXPERIMENTAL DESIGN: We conducted microarray expression analyses of 856 miRNAs in NSCLC A549 cells before and after treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (Aza-dC) and with a combination of Aza-dC and the histone deacetylase inhibitor trichostatin A. miRNA methylation was determined in 11 NSCLC cell lines and in primary tumors and corresponding nonmalignant lung tissue samples of 101 patients with stage I-III NSCLC.RESULTS: By comparing microarray data of untreated and drug-treated A549 cells, we identified 33 miRNAs whose expression was upregulated after drug treatment and which are associated with a CpG island. Thirty (91%) of these miRNAs were found to be methylated in at least 1 of 11 NSCLC cell lines analyzed. Moreover, miR-9-3 and miR-193a were found to be tumor specifically methylated in patients with NSCLC. We observed a shorter disease-free survival of patients with miR-9-3 methylated lung squamous cell carcinoma (LSCC) than patients with miR-9-3 unmethylated LSCC by multivariate analysis [HR = 3.8; 95% confidence interval (CI), 1.3-11.2, P = 0.017] and a shorter overall survival of patients with miR-9-3 methylated LSCC than patients with miR-9-3 unmethylated LSCC by univariate analysis (P = 0.013).CONCLUSIONS: Overall, our results suggest that methylation is an important mechanism for inactivation of certain miRNAs in NSCLCs and that miR-9-3 methylation may serve as a prognostic parameter in patients with LSCC. Clin Cancer Res; 18(6); 1-11. ©2012 AACR.

• The receptor for advanced glycation endproducts and its ligands in patients with myasthenia gravis.

  Authors: Bernhard Moser, Christine Bekos, Fritz Zimprich, Stefanie Nickl, Walter Klepetko, Jan Ankersmit

  Biochemical and biophysical research communications. 03/2012; 420(1):96-101.

  Myasthenia gravis (MG) is a T- and B-cell mediated autoimmune disorder affecting the neuromuscular junction. The receptor for advanced glycation endproducts (RAGE) plays a role in the amplificationMyasthenia gravis (MG) is a T- and B-cell mediated autoimmune disorder affecting the neuromuscular junction. The receptor for advanced glycation endproducts (RAGE) plays a role in the amplification of chronic inflammatory disorders and autoimmune diseases. We sought to investigate the role of RAGE and its ligands in the pathophysiology of MG. In this cross-sectional study we enrolled 42 patients with MG and 36 volunteers. We employed enzyme-linked immunosorbent assays to determine the concentration of soluble RAGE (sRAGE) and high mobility group box 1 (HMGB1) in serum of patients and volunteers. In a subpopulation of patients we measured the serum levels of endogenous secretory (es) RAGE and various RAGE ligands, such as S100B, S100A8 and advanced glycation endproducts (AGE-CML). Reported are means and standard error mean. We found significantly reduced levels of the soluble receptors sRAGE and esRAGE in patients with MG compared to volunteers without MG (sRAGE [pg/ml] 927.2±80.8 vs. 1400.1±92.4; p<0.001; esRAGE [pg/ml] 273.5±24.6 vs. 449.0±22.4; p<0.001). Further categorization of patients with MG according to the distribution of muscle involvement revealed the following sRAGE concentrations: generalized MG 999.4±90.8 and ocular MG 696.1±161.8 (vs. control; One-way ANOVA: p<0.001; Post hoc analysis: generalized vs. ocular MG: p=0.264, generalized MG vs. control: p=0.008, ocular MG vs. control: p=0.001). In patients with detectable antibodies specific for acetylcholine receptors (Anti-AChR positive) the sRAGE concentration was 970.0±90.2 compared to those without (seronegative) 670.6±133.1 (vs. control; One-way ANOVA: p<0.001; Post hoc analysis: Pos vs. Neg.: p=0.418, Pos vs. control: p=0.003, Neg. vs. control: p=0.008). We next investigated the role of RAGE ligands in MG. The concentrations of RAGE ligands in patients with MG and controls were as follows: (HMGB1 [ng/ml] 1.7±0.1 vs. 2.1±0.2; p=0.058; S100B [pg/ml] 22.5±22.5 vs. 14.4±9.2; p=0.698; S100A8 [pg/ml] 107.0±59.3 vs. 242.5±103.6; p=0.347; and AGE-CML [ng/ml] 1100.8±175.1 vs. 1399.8±132.8; p=0.179). Our data suggest a role for the RAGE pathway in the pathophysiology of MG. Further studies are warranted to elucidate more about this immunological axis in patients with MG.

• The PI3-kinase/mTOR-targeting drug NVP-BEZ235 inhibits growth and IgE-dependent activation of human mast cells and basophils.

  Authors: Katharina Blatt, Harald Herrmann, Irina Mirkina, Emir Hadzijusufovic, Barbara Peter, Sabine Strommer, Gregor Hoermann, Matthias Mayerhofer, Konrad Hoetzenecker, Walter Klepetko, Viviane Ghanim, Katharina Marth, Thorsten Füreder, Volker Wacheck, Rudolf Valenta, Peter Valent

  PloS one. 01/2012; 7(1):e29925.

  The phosphoinositide 3-kinase (PI3-kinase) and the mammalian target of rapamycin (mTOR) are two major signaling molecules involved in growth and activation of mast cells (MC) and basophils (BA). WeThe phosphoinositide 3-kinase (PI3-kinase) and the mammalian target of rapamycin (mTOR) are two major signaling molecules involved in growth and activation of mast cells (MC) and basophils (BA). We examined the effects of the dual PI3-kinase/mTOR blocker NVP-BEZ235 on growth of normal and neoplastic BA and MC as well as immunoglobulin E (IgE)-dependent cell activation. Growth of MC and BA were determined by measuring (3)H-thymidine uptake and apoptosis. Cell activation was determined in histamine release experiments and by measuring upregulation of CD63 and CD203c after challenging with IgE plus anti-IgE or allergen. We found that NVP-BEZ235 exerts profound inhibitory effects on growth of primary and cloned neoplastic MC. In the MC leukemia cell line HMC-1, NVP-BEZ235 showed similar IC(50) values in the HMC-1.1 subclone lacking KIT D816V (0.025 µM) and the HMC-1.2 subclone expressing KIT D816V (0.005 µM). Moreover, NVP-BEZ235 was found to exert strong growth-inhibitory effects on neoplastic MC in a xenotransplant-mouse model employing NMR1-Foxn1(nu) mice. NVP-BEZ235 also exerted inhibitory effects on cytokine-dependent differentiation of normal BA and MC, but did not induce growth inhibition or apoptosis in mature MC or normal bone marrow cells. Finally, NVP-BEZ235 was found to inhibit IgE-dependent histamine release in BA and MC (IC(50) 0.5-1 µM) as well as anti-IgE-induced upregulation of CD203c in BA and IgE-dependent upregulation of CD63 in MC. In summary, NVP-BEZ235 produces growth-inhibitory effects in immature neoplastic MC and inhibits IgE-dependent activation of mature BA and MC. Whether these potentially beneficial drug effects have clinical implications is currently under investigation.

• Lack of angiogenesis in experimental brain metastases.

  Authors: Edina Bugyik, Katalin Dezso, Lilla Reiniger, Viktória László, József Tóvári, József Tímár, Péter Nagy, Walter Klepetko, Balázs Döme, Sándor Paku

  Journal of neuropathology and experimental neurology. 11/2011; 70(11):979-91.

  Angiogenesis is believed to be essential for the growth of metastatic tumors in the brain. We analyzed the vascularization of tumors formed by 4 epithelial cell lines (C38, ZR75, HT25, and H1650) andAngiogenesis is believed to be essential for the growth of metastatic tumors in the brain. We analyzed the vascularization of tumors formed by 4 epithelial cell lines (C38, ZR75, HT25, and H1650) and a fibrosarcoma (HT1080) cell line injected into the brains of mice. No peritumoral angiogenesis was observed. Tumors apparently acquired their vasculature by incorporation of native vessels. Vessel density was lower, but vessel diameter and vascular cell proliferation were higher within all tumors versus those in the peritumoral tissue. There was an inverse correlation between the number of incorporated vessels and vascular cell proliferation. Epithelial tumors with pushing growth patterns had lower vessel density and elevated vascular cell proliferation compared with invasive tumors. The incorporated vessels retained their normal structure, with the exception of astrocyte foot processes that were replaced by tumor cells. Attachment to the vascular basement membrane led to the differentiation of the ZR75 breast cancer cells. In the HT1080 metastases, there was intussusceptive angiogenesis, that is, the fibrosarcoma cells that were attached to the vessel caused lumen splitting and filled the developing pillars. Branching angiogenesis was not observed either in the tumors or in control cerebral wounds. These data suggest that sprouting angiogenesis is not needed for the incipient growth of cerebral metastases and that tumor growth in this model is a result of incorporation of host vessels.

• Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice.

  Authors: Michael Seimetz, Nirmal Parajuli, Alexandra Pichl, Florian Veit, Grazyna Kwapiszewska, Friederike C Weisel, Katrin Milger, Bakytbek Egemnazarov, Agnieszka Turowska, Beate Fuchs [......] Peter Jaksch, Rio Dumitrascu, Holger Garn, Robert Voswinckel, Sawa Kostin, Werner Seeger, Ralph T Schermuly, Friedrich Grimminger, Hossein A Ghofrani, Norbert Weissmann

  Cell. 10/2011; 147(2):293-305.

  Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death worldwide. We report in an emphysema model of mice chronically exposed to tobacco smoke that pulmonary vascularChronic obstructive pulmonary disease (COPD) is one of the most common causes of death worldwide. We report in an emphysema model of mice chronically exposed to tobacco smoke that pulmonary vascular dysfunction, vascular remodeling, and pulmonary hypertension (PH) precede development of alveolar destruction. We provide evidence for a causative role of inducible nitric oxide synthase (iNOS) and peroxynitrite in this context. Mice lacking iNOS were protected against emphysema and PH. Treatment of wild-type mice with the iNOS inhibitor N(6)-(1-iminoethyl)-L-lysine (L-NIL) prevented structural and functional alterations of both the lung vasculature and alveoli and also reversed established disease. In chimeric mice lacking iNOS in bone marrow (BM)-derived cells, PH was dependent on iNOS from BM-derived cells, whereas emphysema development was dependent on iNOS from non-BM-derived cells. Similar regulatory and structural alterations as seen in mouse lungs were found in lung tissue from humans with end-stage COPD.

• Lung cancer in never smokers.

  Authors: Szilvia Torok, Balazs Hegedus, Viktoria Laszlo, Mir Alireza Hoda, Bahil Ghanim, Walter Berger, Walter Klepetko, Balazs Dome, Gyula Ostoros

  Future oncology (London, England). 10/2011; 7(10):1195-211.

  Lung cancer in never smokers (LCINS) is the seventh leading cause of death among solid tumors. The main risk factor for lung cancer is smoking; however, approximately 15% of lung cancer patients haveLung cancer in never smokers (LCINS) is the seventh leading cause of death among solid tumors. The main risk factor for lung cancer is smoking; however, approximately 15% of lung cancer patients have never smoked. LCINS is more frequent in women, irrespective of geographical location, nevertheless, the highest incidence has been found in South-East Asia. The histological incidence of adenocarcinoma is higher in the group of never smokers than squamous cell carcinoma. There is a familial clustering of lung cancer that is more pronounced in never smokers, where the family history was associated with an increased risk. Genome-wide association studies identified certain chromosomal aberrations in LCINS. Furthermore, the oncogenic mutation pattern is distinct in nonsmoking patients: activating mutations of EGFR or anaplastic lymphoma kinase are more frequent. The etiology of LCINS includes several environmental factors as well, such as environmental tobacco smoke, viral and hormonal factors, a variety of pulmonary diseases and certain occupational exposures. It is now established that EGFR-tyrosine kinase inhibitor treatment (erlotinib and geftinib) in lung cancer is more effective in LCINS, owing to the higher incidence of EGFR mutation in nonsmokers. Despite the growing body of information on LCINS in recent years there is a need to further investigate the pathogenesis of this particular lung cancer. Future studies on LCINS should try to tackle the issues of prevention, early diagnosis and the exploration of novel therapeutic targets to combat lung cancer disease.

• A new mechanism for pillar formation during tumor-induced intussusceptive angiogenesis: inverse sprouting.

  Authors: Sándor Paku, Katalin Dezso, Edina Bugyik, József Tóvári, József Tímár, Péter Nagy, Viktoria Laszlo, Walter Klepetko, Balázs Döme

  The American journal of pathology. 09/2011; 179(3):1573-85.

  One of the hallmarks of intussusceptive angiogenesis is the development of intraluminal connective tissue pillars. The exact mechanism of pillar formation has not yet been elucidated. By usingOne of the hallmarks of intussusceptive angiogenesis is the development of intraluminal connective tissue pillars. The exact mechanism of pillar formation has not yet been elucidated. By using electron and confocal microscopy, we observed intraluminal nascent pillars that contain a collagen bundle covered by endothelial cells (ECs) in the vasculature of experimental tumors. We proposed a new mechanism for the development of these pillars. First, intraluminal endothelial bridges are formed. Second, localized dissolution of the basement membrane occurs and a bridging EC attaches to a collagen bundle in the underlying connective tissue. A pulling force is then exerted by the actin cytoskeleton of the ECs via specific attachment points, which contain vinculin, to the collagen bundle, resulting in suction and subsequent transport of the collagen bundle into and through the vessel lumen. Third, the pillar matures through the immigration of connective tissue cells and the deposition of new collagenous connective tissue. The proposed simple mechanism generates a connection between the processes of endothelial bridging and intussusceptive angiogenesis and identifies the source of the force behind pillar formation. Moreover, it ensures the rapid formation of pillars from pre-existing building blocks and the maintenance of EC polarity. To describe it, we coined the term inverse sprouting.

• Extracorporeal membrane oxygenation support for resection of locally advanced thoracic tumors.

  Authors: György Lang, Shahrokh Taghavi, Clemens Aigner, Ruben Charchian, Jose Ramon Matilla, Atsushi Sano, Walter Klepetko

  The Annals of thoracic surgery. 07/2011; 92(1):264-70.

  The international experience with resection of advanced thoracic malignancies performed with extracorporeal membrane oxygenation (ECMO) support is limited. We examined our results to assess the risksThe international experience with resection of advanced thoracic malignancies performed with extracorporeal membrane oxygenation (ECMO) support is limited. We examined our results to assess the risks and benefits of this approach. We retrospectively analyzed all patients with thoracic malignancies who underwent tumor resection with ECMO support in our department between 2001 and 2010. Nine patients (aged 21 to 71 years; mean, 54.8±7.5 years) underwent complex tracheobronchial resections (n=6) or resections of greater thoracic vessels (n=3) under venoarterial (VA) ECMO support. In 7 patients the underlying pathologic condition was non-small cell lung cancer, in 1 patient it was carcinoid tumor, and in 1 patient it was synovial sarcoma. The indication for extracorporeal support was complex tracheobronchial reconstruction (n=5), resection of the descending aorta (n=2), and resection of the inferior vena cava (n=1). ECMO cannulation was central (n=4), peripheral (n=4), or combined (n=1). Mean time on bypass was 110±19 minutes (range 40 to 135 minutes). A complete resection (R0) was achieved in 8 patients (89%). One patient died perioperatively as a result of hepatic necrosis. Eight patients were discharged from the hospital after 7 to 42 days (median, 10 days). Median time in the intensive care unit was 1 day (range, 0 to 36 days). The only complication related to the use of ECMO was a lymphatic fistula in the groin. Mean follow-up time was 38±42 months (range, 9 to 111 months). The actuarial 3-month survival was 88.9%, and the 1-year, 3-year, and 5-year survival was 76.7%. Based on this experience, we consider VA ECMO support to be a safe alternative to cardiopulmonary bypass (CPB) for advanced general thoracic operations.

• Forequarter amputation combined with chest wall resection: a single-center experience.

  Authors: Patrick Nierlich, Philipp Funovics, Martin Dominkus, Oskar Aszmann, Manfred Frey, Walter Klepetko

  The Annals of thoracic surgery. 06/2011; 91(6):1702-8.

  Forequarter amputation combined with chest wall resection is a rarely performed procedure. Six patients were treated for advanced malignancies with this operation in our institution since 1993.Forequarter amputation combined with chest wall resection is a rarely performed procedure. Six patients were treated for advanced malignancies with this operation in our institution since 1993. Uncontrollable pain, lymphedema, loss of function of the affected limb and, in some patients, localized ulceration of the tumor at the time of presentation, provided the indication for the operation. All patients underwent radical amputation of the upper limb and the structures of the shoulder girdle, in combination with resection of the thoracic chest wall in an extent of 2 to 7 ribs. Chest wall reconstruction was achieved by implantation of a polytetrafluoroethylene patch (n=5) or a combination of a metal implant (Stratos System R, MedXpert GmbH, Heitersheim, Germany) and a polytetrafluoroethylene patch (n=1). Myocutaneous coverage of the defects was achieved by use of pedicled flaps from adjacent tissue (n=3) or by free myocutaneous flaps harvested from the amputated forearm (n=3). No perioperative mortality occurred; however, significant morbidity was seen after the use of the free forearm flaps based on occurring vascular problems. All 3 patients had to undergo surgical revision of the flap. Survival ranged from 5 to 50 months (median=23.5 months) with 3 patients still alive at the time of this investigation. Forequarter amputation in combination with chest wall resection is a feasible and potentially curative treatment for malignant tumors of the shoulder girdle with invasion of the chest wall. The operation results in immediate palliation and long-term survival can be obtained in selected cases.

• Effects of reclassification from the TNM-6 into the TNM-7 staging system in bronchoplastic resection for non-small cell lung cancer.

  Authors: Thomas Klikovits, Adelheid End, Gunther Riedl, Michaela Stiebler, Gerhard Dekan, Walter Klepetko

  Interactive cardiovascular and thoracic surgery. 06/2011; 13(1):29-34.

  In 2007, the International Association for the Study of Lung Cancer proposed changes to the sixth edition of the lung cancer stage classification system, which were adopted by the UnionIn 2007, the International Association for the Study of Lung Cancer proposed changes to the sixth edition of the lung cancer stage classification system, which were adopted by the Union Internationale Contre le Cancer in 2009 (TNM-7). Using historic patient data, the effects of reclassification from the TNM-6 to the TNM-7 system were researched within a single institution. We retrospectively reclassified the pathological records of 145 patients who underwent bronchoplastic resection for non-small cell lung cancer between 1991 and 2004, by applying the new TNM-7 classification for lung cancer. A comparison between the previous and the new system was conducted. Out of 145 patients, 49 (33.8%) were reclassified into a new stage, 42 (85.7% of reclassified cases) being allocated to a lower and seven (14.3%) being assigned to a higher stage. Most of the patients switched from stage IIB to IIA (n=31, 63.3%). The application of the new TNM-7 staging system resulted in a more accurate stratification of five-year survival curves. The newly revised TNM classification for lung cancer appears to be superior in defining different prognostic groups for this cohort and should lead to an improvement in stage specific tumor therapy.

• Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry.

  Authors: Eckhard Mayer, David Jenkins, Jaroslav Lindner, Andrea D'Armini, Jaap Kloek, Bart Meyns, Lars Bo Ilkjaer, Walter Klepetko, Marion Delcroix, Irene Lang, Joanna Pepke-Zaba, Gerald Simonneau, Philippe Dartevelle

  The Journal of thoracic and cardiovascular surgery. 03/2011; 141(3):702-10.

  Pulmonary endarterectomy is a curative surgical treatment option for the majority of patients with chronic thromboembolic pulmonary hypertension. The current surgical management and postoperativePulmonary endarterectomy is a curative surgical treatment option for the majority of patients with chronic thromboembolic pulmonary hypertension. The current surgical management and postoperative outcome of patients enrolled in an international registry on chronic thromboembolic pulmonary hypertension were investigated. The registry included newly diagnosed (≤6 months) consecutive patients with chronic thromboembolic pulmonary hypertension from February 2007 to January 2009. A total of 679 patients were registered from 1 Canadian and 26 European centers, of whom 386 (56.8%) underwent surgery. The median age of patients undergoing surgery was 60 years, and 54.1% were male. Previous pulmonary embolism was confirmed for 79.8% of patients. Perioperative complications occurred in 189 patients (49.2%): infection (18.8%), persistent pulmonary hypertension (16.7%), neurologic (11.2%) or bleeding (10.2%) complications, pulmonary reperfusion edema (9.6%), pericardial effusion (8.3%), need for extracorporeal membrane oxygenation (3.1%), and in-hospital mortality due to perioperative complications (4.7%). Documented 1-year mortality was 7%. Preoperative exercise capacity was predictive of 1-year mortality. Postoperative pulmonary vascular resistance predicted in-hospital and 1-year mortality. In patients evaluated within 1 year after surgery, the median pulmonary vascular resistance had decreased from 698 to 235 dyn x s x cm(-5) (95% confidence limit, 640-874 and 211-255, respectively, n = 70) and the median 6-minute walk distance had increased from 362 to 459 m (95% confidence limit, 340-399 and 440-473, respectively, n = 168). New York Heart Association functional class improved with most patients progressing from class III/IV to class I/II. Pulmonary endarterectomy is associated with a low in-hospital mortality rate and improvements in hemodynamics and exercise capacity.

• Right-sided approach for management of left-main-bronchial stump problems.

  Authors: Paula Moreno, György Lang, Sharouk Taghavi, Clemens Aigner, Gabriel Marta, Angela De Palma, Walter Klepetko

  European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 03/2011; 40(4):926-30.

  Although the incidence of bronchopleural fistula (BPF) has decreased in the past decades, it remains a serious complication following pulmonary resection. The management of left-sided bronchial stumpAlthough the incidence of bronchopleural fistula (BPF) has decreased in the past decades, it remains a serious complication following pulmonary resection. The management of left-sided bronchial stump fistulas is difficult and depends on the choice of the approach. In contrast to several surgical procedures published in the past, herein we report our experience managing five left-main-bronchial stump (LMBS) problems through a right thoracotomy route. Five women, who underwent left pneumonectomy and later developed BPF, were managed with this novel procedure at our Institution. BPF appeared between 12 days and 24 years after pneumonectomy. Diagnosis of BPF or bronchoesophageal fistula (BEF) was made by computed tomography (CT) scan and fiberoptic bronchoscopy. Through a right posterolateral thoracotomy incision, the LMBS was re-stapled and covered with pedicled flaps in all cases. In patient #4, carinal resection was performed also, with temporary extracorporeal membrane oxygenation (ECMO) application. The main results are depicted in the table. In all cases, encircling of the LMBS and stapling at the level of the carina was performed without difficulties. In patients #1, #2 and #3, resection of the bronchial stump remnant was also done and, in patient #4, carinal resection was also performed. All patients are doing well, with no evidence of recurrence of fistula. We advocate the right posterolateral thoracotomy route for the management of left-sided BPFs as an alternative to transternal transpericardial and transthoracic closures. It is a safe, feasible and time-efficient approach that provides control of central structures and avoids previously manipulated or infected operative fields.

• Sporadic desmoid tumors of the chest: long-term follow-up of 28 multimodally treated patients.

  Authors: Zoltán Mátrai, László Tóth, Zoltán Szentirmay, Ferenc Rényi Vámos, Walter Klepetko, Pál Vadász, István Kenessey, Miklós Kásler

  European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 03/2011; 40(5):1170-6.

  Desmoids of the chest are extremely rare borderline tumors. Radical surgical resection is considered to be the primary treatment. Achieving negative margins is often a challenge. Cases with positiveDesmoids of the chest are extremely rare borderline tumors. Radical surgical resection is considered to be the primary treatment. Achieving negative margins is often a challenge. Cases with positive surgical margins are associated with high risk of local recurrence. A retrospective multicenter review was undertaken of 28 patients who underwent surgery for sporadically appearing desmoids of the chest between 1988 and 2008. Clinico-pathological data were investigated in detail. Authors have statistically analyzed the relationships between gender, age, tumor size, radicality of the first surgery, impact of the pharmacologic treatment, estrogen receptor positivity, and the development of local recurrences after a median follow-up period of 104 months. Primary surgery was radical in 14 patients (50%). Mean pathologic diameter was 72.14mm. Wide surgical excision was performed in 27 primary cases, out of which 10 cases (37%) were full- and 17 cases (63%) partial-thickness chest wall resections. Synthetic mesh stabilization was used in nine cases and soft tissue coverage in six patients. Morbidity rate was 25%. Recurrences were found in 63% of the cases, with a mean time of 30.5 months to first recurrences. Our investigation confirmed that microscopically free surgical margin of the first tumor resection significantly affected local tumor control. Because the radicality of the first surgical resection is of essential importance for long-time local control of chest desmoids, accurate preoperative diagnostics and well-planned aggressive surgical resection of the primary tumor is recommended. Due to the low incidence of desmoids, multicentric randomized investigations would be mandatory to establish evidence-based protocol for desmoid tumors.