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1.  Preoperative mediastinal lymph node staging for non-small cell lung cancer: 2014 update of the 2007 ESTS guidelines 
Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with potentially resectable non-small cell lung cancer (NSCLC) is of paramount importance. In 2007, the European Society of Thoracic Surgeons (ESTS) published an algorithm on preoperative mediastinal staging integrating imaging, endoscopic and surgical techniques. Over the last years more evidence of the different mediastinal staging technique has become available. Therefore, a revision of the ESTS guidelines was needed. In case of CT-enlarged or PET-positive mediastinal lymph nodes, tissue confirmation is indicated. Endosonography (EBUS/EUS) with fine needle aspiration is the first choice (when available) since it is minimally invasive and has a high sensitivity to rule in mediastinal nodal disease. If negative, surgical staging with nodal dissection or biopsy is indicated. Video-assisted mediastinoscopy is preferred over mediastinoscopy. The combined use of endoscopic staging and surgical staging results in the highest accuracy. When there are no enlarged lymph nodes on CT and when there is no uptake in lymph nodes on PET or PET-CT, direct surgical resection with systematic nodal dissection is indicated for tumors ≤3 cm located in the outer third of the lung. In central tumors or N1 nodes, preoperative mediastinal staging is indicated. The choice between endoscopic staging with EBUS/EUS and fine needle aspiration or video-assisted mediastinoscopy depends on local expertise to adhere to minimal requirements for staging. For tumors larger than 3 cm, preoperative mediastinal staging is advised, mainly in adenocarcinoma with high SUV uptake.
PMCID: PMC4367702  PMID: 25806304
Lung cancer; preoperative staging; surgical staging; endoscopic staging
2.  Local effects of high-powered neodymium-doped yttrium aluminium garnet laser systems on the pulmonary parenchyma: an experimental study on the isolated perfused pig lung lobe 
Neodymium-doped yttrium aluminium garnet (Nd:YAG) laser systems (with a power output up to 100 W, wavelength 1318 nm) have been introduced into clinical practice for resecting lung metastases. However, the extent of the local effect on the lung parenchyma and the role of the application time are unknown. All experiments were performed on normothermal, whole-blood-perfused paracardiac pig lung lobes (n = 6). Lobes were not ventilated during the laser application. The laser itself was clamped into a hydraulic feed system that moves horizontally at two different constant rates (10 and 20 mm/s). A 30-mm focus distance from the pulmonary parenchyma was maintained at all times. At each feed rate, the laser was applied thrice along a horizontal path using laser power outputs of 40, 60 and 100 W. After lasering, we recruited the lungs via a ventilation tube using pressures of up to 40 cm H2O and tested lung tightness. Both a gross inspection and a histological examination revealed larger coagulation zones for higher power outputs and lower laser feed rates. Exposure to higher outputs for shorter application times reduced the laser effect. When lungs were manually recruited, all lungs were airtight up to a pressure of 40 mmHg. Reducing the exposure time reduces local tissue coagulation even when the laser power output is increased.
PMCID: PMC3397735  PMID: 22535543
Nd:YAG laser; Laser power output; Application time; Lung parenchyma
3.  Venous thoracic outlet syndrome caused by a congenital rib malformation 
Venous thoracic outlet syndrome (VTOS) represents a rare disorder. Hypertrophy of the anterior scalene musculature is the cause of the compression syndrome in most cases. To our knowledge, we describe the first reported case worldwide of a venous compression syndrome caused by a congenital malformation of the 1st and 2nd ribs. Treatment by transaxillary partial rib resection was necessary and a very good postoperative result was achieved.
PMCID: PMC3397736  PMID: 22544354
Venous thoracic outlet; Subclavian venous thrombosis; Rib malformation
4.  Simultaneous Multi-Antibody Staining in Non-Small Cell Lung Cancer Strengthens Diagnostic Accuracy Especially in Small Tissue Samples 
PLoS ONE  2013;8(2):e56333.
Histological subclassification of non-small cell lung cancer (NSCLC) has growing therapeutic impact. In advanced cancer stages tissue specimens are usually bioptically collected. These small samples are of extraordinary value since molecular analyses are gaining importance for targeted therapies. We therefore studied the feasibility, diagnostic accuracy, economic and prognostic effects of a tissue sparing simultaneous multi-antibody assay for subclassification of NSCLC. Of 265 NSCLC patients tissue multi arrays (TMA) were constructed to simulate biopsy samples. TMAs were stained by a simultaneous bi-color multi-antibody assay consisting of TTF1, Vimentin, p63 and neuroendocrine markers (CD56, chromogranin A, synaptophysin). Classification was based mainly on the current proposal of the IASLC with a hierarchical decision tree for subclassification into adenocarcinoma (LAC), squamous cell carcinoma (SCC), large cell neuroendocrine carcinoma (LCNEC) and NSCLC not otherwise specified. Investigation of tumor heterogeneity showed an explicit lower variation for immunohistochemical analyses compared to conventional classification. Furthermore, survival analysis of our combined immunohistochemical classification revealed distinct separation of each entity's survival curve. This was statistically significant for therapeutically important subgroups (p = 0.045). As morphological and molecular cancer testing is emerging, our multi-antibody assay in combination with standardized classification delivers accurate and reliable separation of histomorphological diagnoses. Additionally, it permits clinically relevant subtyping of NSCLC including LCNEC. Our multi-antibody assay may therefore be of special value, especially in diagnosing small biopsies. It futher delivers substantial prognostic information with therapeutic consequences. Integration of immunohistochemical subtyping including investigation of neuroendocrine differentiation into standard histopathological classification of NSCLC must, therefore, be considered.
PMCID: PMC3572034  PMID: 23418554
5.  CC-Chemokine Ligand 18 Induces Epithelial to Mesenchymal Transition in Lung Cancer A549 Cells and Elevates the Invasive Potential 
PLoS ONE  2013;8(1):e53068.
Lung cancer is one of the leading causes of cancer related death worldwide with more than a million deaths per year. The poor prognosis is due to its high aggressiveness and its early metastasis. Although the exact mechanisms are still unknown, the process of epithelial to mesenchymal transition (EMT) seems to be involved in these neoplastic processes. We already demonstrated that serum levels of CCL18, a primate specific chemokine, are highly elevated in patients with lung cancer and correlate with their survival time of patients with adenocarcinoma of the lung. Therefore, we hypothesized that CCL18 may be directly involved in pathological processes of lung cancer, e.g. EMT. We investigated the effect of CCL18 on A549, an adenocarcinoma cell line of the lung, on EMT and other cell functions like proliferation, chemotaxis, invasion, chemoresistance and proliferation. Exposure of A549 lung cancer cells to CCL18 in various concentrations decreases the epithelial marker E-cadherin, whereas FSP-1, a marker of the mesenchymal phenotype increases. Accordingly, CCL18 induced the transcriptional EMT regulator SNAIL1 in a dose dependent fashion. In contrast, an increasing CCL18 concentration was associated with a decline of cell proliferation rate. In addition, CCL18 induced chemotaxis of these cells and increased their chemoresistance. Therefore, CCL18 may be an interesting therapeutic target for NSCLC.
PMCID: PMC3548837  PMID: 23349697
6.  Serum Level of CC-Chemokine Ligand 18 Is Increased in Patients with Non-Small-Cell Lung Cancer and Correlates with Survival Time in Adenocarcinomas 
PLoS ONE  2012;7(7):e41746.
CC-chemokine ligand 18 (CCL18) is mainly expressed by alternatively activated macrophages and DCs and plays an important role in lung fibrosis, arthritis and other diseases. Here CCL18 was measured in sera of 31 healthy volunteers and 170 patients with lung cancer and correlated these data with histology, tumor stage and clinical parameters. Mean CCL18 serum level of the patients with non-small-cell lung cancer was 150(857) ng/ml vs. 32(61) ng/ml in the healthy control group. Patient groups differ significantly according their histology (adenocarcinoma 143(528) ng/ml vs squamous cell carcinoma 187(857) ng/ml, p<0.02). In addition, we found a significant difference between patients with lower versus higher T-stage (p<0.003). Receiver operating characteristic (ROC) analyses revealed a cutoff point of 83 ng/ml (area under the curve (AUC): 0.968; p<0.0001) to discriminate between healthy controls and non-small-cell lung cancer patients. ROC analyses to discriminate between patients, who died because of cancer related death and those who died for other reasons did not lead to a valid AUC. To stratify the tumor patients, a criterion value plot was performed leading to a point of equal sensitivity and specificity (54%) of 162 ng/ml. Patients with a CCL18 serum level higher than 160 ng/ml had a mean survival time of 623 days. In contrast, those in patients with a baseline level between 83 ng/ml and 160 ng/ml the mean survival time was 984 days (p<0.005). Survival-analysis revealed in adenocarcinoma a mean survival of 1152 days in the group below 83 ng/ml. In the median group the mean survival time was 788 days and in the group with the highest levels the mean survival time was 388 days (p<0.001). In contrast, we found no correlation between the FEV1 and the CCL18 baseline level. In conclusion, in patients suffering from adenocarcinoma increased serum CCL18 levels predict a diminished survival time.
PMCID: PMC3404958  PMID: 22848587
7.  Initial experience with a synthetic sealant PleuraSeal™ after pulmonary resections: a prospective study with retrospective case matched controls 
The objective of this study was to evaluate postoperative outcome and efficacy of a hydrogel tissue sealant for prevention of alveolar leakage after open lung resections.
20 consecutive patients were enrolled in the PleuraSeal™ sealant group (PSG) and case matched with 20 retrospective controls (CG) with standard treatment. Assessment of postoperative air leakage was performed until chest tube removal. Patients were followed until 30 days after discharge.
At end of surgery, 100% in the PSG and 0% in the CG were air leak free (p < 0.001). Duration of postoperative chest tube suction was shorter in PSG (p < 0.001), and air leak chest tube was removed earlier (p = 0.03). Limitation for chest tube removal due to a pulmonary leak was 35% in CG and 5% in PSG (p = 0.04). Patients remaining air leak free thru discharge was 95% and 15% for PSG and CG (p < 0.001).
The study demonstrated a superior efficacy of PleuraSeal™ sealant compared with standard surgical treatment for sustained sealing of postoperative air leakage and causes shorter air leak chest tube duration.
PMCID: PMC2898668  PMID: 20553612
8.  Lactate-Dehydrogenase 5 is overexpressed in non-small cell lung cancer and correlates with the expression of the transketolase-like protein 1 
Diagnostic Pathology  2010;5:22.
As one of the five Lactate dehydrogenase (LDH) isoenzymes, LDH5 has the highest efficiency to catalyze pyruvate transformation to lactate. LDH5 overexpression in cancer cells induces an upregulated glycolytic metabolism and reduced dependence on the presence of oxygen. Here we analyzed LDH5 protein expression in a well characterized large cohort of primary lung cancers in correlation to clinico-pathological data and its possible impact on patient survival.
Primary lung cancers (n = 269) and non neoplastic lung tissue (n = 35) were tested for LDH5 expression by immunohistochemistry using a polyclonal LDH5 antibody (ab53010). The results of LDH5 expression were correlated to clinico-pathological data as well as to patient's survival. In addition, the results of the previously tested Transketolase like 1 protein (TKTL1) expression were correlated to LDH5 expression.
89.5% (n = 238) of NSCLC revealed LDH5 expression whereas LDH5 expression was not detected in non neoplastic lung tissues (n = 34) (p < 0.0001). LDH5 overexpression was associated with histological type (adenocarcinoma = 57%, squamous cell carcinoma = 45%, large cell carcinoma = 46%, p = 0.006). No significant correlation could be detected with regard to TNM-stage, grading or survival. A two sided correlation between the expression of TKTL1 and LDH5 could be shown (p = 0.002) within the overall cohort as well as for each grading and pN group. A significant correlation between LDH5 and TKTL1 within each histologic tumortype could not be revealed.
LDH5 is overexpressed in NSCLC and could hence serve as an additional marker for malignancy. Furthermore, LDH5 correlates positively with the prognostic marker TKTL1. Our results confirm a close link between the two metabolic enzymes and indicate an alteration in the glucose metabolism in the process of malignant transformation.
PMCID: PMC2861018  PMID: 20385008
9.  Gene expression profiles of lung adenocarcinoma linked to histopathological grading and survival but not to EGF-R status: a microarray study 
BMC Cancer  2010;10:77.
Several different gene expression signatures have been proposed to predict response to therapy and clinical outcome in lung adenocarcinoma. Herein, we investigate if elements of published gene sets can be reproduced in a small dataset, and how gene expression profiles based on limited sample size relate to clinical parameters including histopathological grade and EGFR protein expression.
Affymetrix Human Genome U133A platform was used to obtain gene expression profiles of 28 pathologically and clinically annotated adenocarcinomas of the lung. EGFR status was determined by fluorescent in situ hybridization and immunohistochemistry.
Using unsupervised clustering algorithms, the predominant gene expression signatures correlated with the histopathological grade but not with EGFR protein expression as detected by immunohistochemistry. In a supervised analysis, the signature of high grade tumors but not of EGFR overexpressing cases showed significant enrichment of gene sets reflecting MAPK activation and other potential signaling cascades downstream of EGFR. Out of four different previously published gene sets that had been linked to prognosis, three showed enrichment in the gene expression signature associated with favorable prognosis.
In this dataset, histopathological tumor grades but not EGFR status were associated with dominant gene expression signatures and gene set enrichment reflecting oncogenic pathway activation, suggesting that high immunohistochemistry EGFR scores may not necessarily be linked to downstream effects that cause major changes in gene expression patterns. Published gene sets showed association with patient survival; however, the small sample size of this study limited the options for a comprehensive validation of previously reported prognostic gene expression signatures.
PMCID: PMC2843676  PMID: 20196851
10.  The role of a pseudocapsula in thymic epithelial tumors: outcome and correlation with established prognostic parameters. Results of a 20-year single centre retrospective analysis 
Treatment of thymoma is often based on observation of only a few patients. Surgical resection is considered to be the most important step. Role of a pseudocapsula for surgery, its clinical significance and outcome compared with established prognostic parameters is discussed which has not been reported so far.
84 patients with thymoma underwent resection and analysis was carried out for clinical features, prognostic factors and long-term survival.
Fifteen patients were classified in WHO subgroup A, 21 in AB, 29 in B and 19 patients in C. Forty two patients were classified in Masaoka stage I, 19 stage II, 9 stage III and 14 stage IV. Encapsulated thymoma was seen in 40, incomplete or missing capsula in 44 patients. In 71 complete resections, local recurrence was 5%. 5-year survival was 88.1%. Thymomas with pseudocapsula showed a significant better survival (94.9% vs. 61.1%, respectively) (p = 0.001) and was correlated with the absence of nodal or distant metastasis (p = 0.04 and 0.001, respectively). Presence of pseudocapsula as well as the Masaoka and WHO classification, and R-status were of prognostic significance. R-status and Masaoka stage appeared to be of independent prognostic significance in multivariate analysis.
Intraoperative presence of an encapsulated tumor is a good technical marker for the surgeon to evaluate resectability and estimate prognosis. Although the presence of a capsula is of strong significance in the univariate analysis, it failed in the multivariate analysis due to its correlation with clinical Masaoka stage. Masaoka stage has a stronger relevance than WHO classification to determinate long-term outcome.
PMCID: PMC2717064  PMID: 19604398
11.  Neuroendocrine differentiation and neuroendocrine morphology as two different patterns in large-cell bronchial carcinomas: outcome after complete resection 
In 1999, large-cell neuroendocrine carcinoma of the lung was introduced by the World Health Organization (WHO) as a new tumor entity in the group of non-small cell, epithelial tumors, a differentiated classification of neuroendocrine tumors of the lung not existing until this time. Scientific knowledge on prognosis and therapy of these tumors, especially between those with neuroendocrine morphology only and those showing additional expression of neuroendocrine markers, is fragmentary. In this analysis, we studied the clinical behavior and the prognosis of these two rare tumor entities.
Patients and Methods
The analysis comprises 12 patients of a total of 2053, who underwent thoracotomy for non small-cell lung carcinoma between 1997 and 2005 in the Department of Thoracic Surgery at the University Hospital of Freiburg. Clinical data, pathological examinations as well as complete follow-up were reviewed from large-cell carcinoma with neuroendocrine morphology only (n=4) and from large-cell carcinoma expressing neuroendocrine markers (n=8).
The median survival of patients with neuroendocrine morphology was 30 months (11–96 months). In the patient group showing the expression of neuroendocrine markers, the median survival time was 20 months (2–26 months). Tumor recurrences occurred in the group with neuroendocrine morphology, without exception, in the form of distant metastases and in the group with neuroendocrine markers as intrapulmonary metastases.
Large-cell neuroendocrine carcinomas of the lung show aggressive behavior with a poor prognosis. Expression of neuroendocrine markers markedly reduce tumor-free interval as well as survival and might influence the site of metastases.
PMCID: PMC1570460  PMID: 16953887
12.  The Hematopoietic System–specific Minor Histocompatibility Antigen HA-1 Shows Aberrant Expression in Epithelial Cancer Cells 
Allogeneic stem cell transplantation (SCT) can induce curative graft-versus-tumor reactions in patients with hematological malignancies and solid tumors. The graft-versus-tumor reaction after human histocompatibility leukocyte antigen (HLA)-identical SCT is mediated by alloimmune donor T cells specific for polymorphic minor histocompatibility antigens (mHags). Among these, the mHag HA-1 was found to be restricted to the hematopoietic system. Here, we report on the HA-1 ribonucleic acid expression by microdissected carcinoma tissues and by single disseminated tumor cells isolated from patients with various epithelial tumors. The HA-1 peptide is molecularly defined, as it forms an immunogenic peptide ligand with HLA-A2 on the cell membrane of carcinoma cell lines. HA-1–specific cytotoxic T cells lyse epithelial tumor cell lines in vitro, whereas normal epithelial cells are not recognized. Thus, HA-1–specific immunotherapy combined with HLA-identical allogeneic SCT may now be feasible for patients with HA-1+ carcinomas.
PMCID: PMC2193937  PMID: 12163564
stem cell transplantation; graft-versus-tumor; carcinomas; cytotoxic T cells; minimal residual disease

Results 1-12 (12)