Till Plönes

Serum level of CC-chemokine ligand 18 is increased in patients with non-small-cell lung cancer and correlates with survival time in adenocarcinomas.

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.

Simultaneous Multi-Antibody Staining in Non-Small Cell Lung Cancer Strengthens Diagnostic Accuracy Especially in Small Tissue Samples

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 entitys 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.

mRNA and miRNA analyses in cytologically positive endobronchial ultrasound-guided transbronchial needle aspiration: implications for molecular staging in lung cancer patients.

Lung cancer is highly aggressive and tends to metastasize early. Therefore, accurate mediastinal staging is important for therapeutic decision making. Endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) has emerged as a minimally invasive procedure for mediastinal lymph node sampling and cancer staging. Classical EBUS‐TBNA cytology has been combined with molecular staging techniques to improve sensitivity and specificity. This study aimed to assess mRNA integrity in samples acquired by EBUS‐TBNA in the clinics. As proof‐of‐principle experiments, we also investigated whether stable miRNA could be detected in these samples.

Spontaneous regression of non-small cell lung cancer after biopsy of a mediastinal lymph node metastasis: a case report

IntroductionSpontaneous regression of cancer is defined as a complete or partial, temporary or permanent disappearance of tumor in the absence of specific therapy. With only a few cases reported, spontaneous regression is extremely rare in primary lung cancer. Regarding spontaneous regression in lung cancer, recent investigations revealed the role of immunological mechanisms, thus indicating potential treatment options by specific immunotherapy in the future.Case presentationA 76-year-old Caucasian man with progressive dyspnea presented to our hospital. A computed tomography scan revealed a tumor mass in the upper lobe of his right lung and enlarged mediastinal lymph nodes. A biopsy of a paratracheal lymph node by mediastinoscopy disclosed metastatic lung cancer. By immunohistochemical findings the tumor was classified as large cell carcinoma. Diagnosed with clinical stage IIIA non-small cell lung cancer, a neoadjuvant therapy concept was indicated. However, before starting chemoradiation, a computed tomography scan showed a regression of both the tumor mass in the upper lobe of his right lung and the mediastinal lymphadenopathy. As a repeated computed tomography scan showed further regression, we agreed with our patient to perform routine follow-up instead of starting therapy. To date, no relapse has been reported.ConclusionsGiven the circumstances that regression started after the biopsy and involved both the tumor in the upper lobe of his right lung and the mediastinal lymph node metastases, an immune response is a reasonable explanation for the observed spontaneous regression in this case.

Molecular Pathology and Personalized Medicine: The Dawn of a New Era in Companion Diagnostics—Practical Considerations about Companion Diagnostics for Non-Small-Cell-Lung-Cancer

Companion diagnostics (CDx) have become a major tool in molecular pathology and assist in therapy decisions in an increasing number of various cancers. Particularly, the developments in lung cancer have been most impressing in the last decade and consequently lung cancer mutation testing and molecular profiling has become a major business of diagnostic laboratories. However, it has become difficult to decide which biomarkers are currently relevant for therapy decisions, as many of the new biomarkers are not yet approved as therapy targets, remain in the status of clinical studies, or still have not left the experimental phase. The current review is focussed on those markers that do have current therapy implications, practical implications arising from the respective companion diagnostics, and thus is focused on daily practice.

Roflumilast-N-oxide Induces Surfactant Protein Expression in Human Alveolar Epithelial Cells Type II

Surfactant proteins (SPs) are important lipoprotein complex components, expressed in alveolar epithelial cells type II (AEC-II), and playing an essential role in maintenance of alveolar integrity and host defence. Because expressions of SPs are regulated by cyclic adenosine monophosphate (cAMP), we hypothesized that phosphodiesterase (PDE) inhibitors, influence SP expression and release. Analysis of PDE activity of our AEC-II preparations revealed that PDE4 is the major cAMP hydrolysing PDE in human adult AEC-II. Thus, freshly isolated human AEC-II were stimulated with two different concentrations of the PDE4 inhibitor roflumilast-N-oxide (3 nM and 1 µM) to investigate the effect on SP expression. SP mRNA levels disclosed a large inter-individual variation. Therefore, the experiments were grouped by the basal SP expression in low and high expressing donors. AEC-II stimulated with Roflumilast-N-oxide showed a minor increase in SP-A1, SP-C and SP-D mRNA mainly in low expressing preparations. To overcome the effects of different basal levels of intracellular cAMP, cyclooxygenase was blocked by indomethacin and cAMP production was reconstituted by prostaglandin E2 (PGE2). Under these conditions SP-A1, SP-A2, SP-B and SP-D are increased by roflumilast-N-oxide in low expressing preparations. Roflumilast-N-oxide fosters the expression of SPs in human AEC-II via increase of intracellular cAMP levels potentially contributing to improved alveolar host defence and enhanced resolution of inflammation.

Intrapulmonary aspergilloma in an old tuberculous cavity with access to the bronchial system

to the bronchial system Alberto Lopez-Pastorini*, Till Plones, Corinna Ludwig and Erich Stoelben Department of Thoracic Surgery, University Medical Center Witten/Herdecke, Lung Clinic Merheim, Campus Cologne, Germany * Corresponding author. Department of Thoracic Surgery, University Medical Center Witten/Herdecke, Lung Clinic Merheim, Campus Cologne, Ostmerheimerstr. 200, 51109 Cologne, Germany. Tel: +49-221-89078640; fax: +49-221-89073048; e-mail: lopeza@kliniken-koeln.de; albvalelopez@yahoo.de (A. Lopez-Pastorini). Received 11 September 2013; accepted 16 October 2013

Fatal migration of an endobronchial stent into the pulmonary artery.

A 64-year-old woman was referred to our department with progressive dyspnoea and haemoptysis. Half a year ago a metallic endobronchial stent was inserted in the left main bronchus due to a benign stenosis after sleeve resection for lung cancer. A CT showed the stent with erosion of the left pulmonary artery and newly diagnosed pulmonary metastasis (figure 1). We decided to perform a palliative pneumonectomy for symptom control. Intraoperative findings …

Idiopathic pulmonary ossification

Herein, we report a 50-year-old smoker with chronic cough and no other pre-existing conditions in his medical history. Lung function tests and laboratory findings were normal. The computed tomography showed a bilateral reticulonodular pattern with calcifications (Fig. 1). We performed a thoracoscopic biopsy. Histopathological examination revealed a pulmonary ossification of unknown aetiology (Fig. 2).

Bilateral pneumothoraces, pneumomediastinum and subcutaneous emphysema as a rare complication of endoscopic cholangiopancreatography

A 67-year-old woman underwent endoscopic cholangiopancreatography (ERCP) for elective exchange of a bile duct stent. The ductus hepaticus communis was stented because of a bilary stricture of unknown aetiology for the first time half a year ago. Multiple previous performed ERCPs were without any complications and show no unexpected findings. The previously placed stent was extracted and replaced by a new …