Felix Herth

AURKA, DLGAP5, TPX2, KIF11 and CKAP5: Five specific mitosis-associated genes correlate with poor prognosis for non-small cell lung cancer patients

The growth of a tumor depends to a certain extent on an increase in mitotic events. Key steps during mitosis are the regulated assembly of the spindle apparatus and the separation of the sister chromatids. The microtubule-associated protein Aurora kinase A phosphorylates DLGAP5 in order to correctly segregate the chromatids. Its activity and recruitment to the spindle apparatus is regulated by TPX2. KIF11 and CKAP5 control the correct arrangement of the microtubules and prevent their degradation. In the present study, we investigated the role of these five molecules in non-small cell lung cancer (NSCLC). We analyzed the expression of the five genes in a large cohort of NSCLC patients (n=362) by quantitative real-time PCR. Each of the genes was highly overexpressed in the tumor tissues compared to corresponding normal lung tissue. The correlation of the expression of the individual genes depended on the histology. An increased expression of AURKA, DLGAP5, TPX2, KIF11 and CKAP5 was associated with poor overall survival (P=0.001–0.065). AURKA was a significant prognostic marker using multivariate analyses (P=0.006). Immunofluorescence studies demonstrated that the five mitosis-associated proteins co-localized with the spindle apparatus during cell division. Taken together, our data demonstrate that the expression of the mitosis-associated genes AURKA, DLGAP5, TPX2, KIF11 and CKAP5 is associated with the prognosis of NSCLC patients.

Glycodelin: A New Biomarker with Immunomodulatory Functions in 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.

Optical coherence tomography detects structural abnormalitiesof the nasal mucosa in patients with cystic fibrosis

BACKGROUNDnChronic inflammation and remodeling of the airways remain a hallmark of cystic fibrosis (CF). However, knowledge of the associated mucosal micro-anatomical changes is limited. We evaluated the potential of optical coherence tomography (OCT) for in vivo imaging of the upper airway mucosa in CF patients.nnnMETHODSnA flexible OCT probe was used for cross-sectional imaging of the nasal mucosa in 25 CF patients and 25 healthy controls.nnnRESULTSnOCT images showed mucosal details including epithelium, basement membrane, lamina propria with seromucinous glands, and underlying cartilaginous structures. Mean nasal mucosa and epithelial layer thickness were increased in CF compared to controls. In CF patients, antibiotic therapy was associated with reduced nasal mucosa thickening.nnnCONCLUSIONSnOCT detected mucosal changes associated with upper airway inflammation and response to antibiotic therapy in CF patients. OCT may be a useful tool for quantitative in vivo assessment of structural changes of the airway mucosa.

Direct nodal sampling by echoendoscopy in lung cancer: the clinician’s expectations: Direct nodal sampling by echoendoscopy in lung cancer

BackgroundMediastinal lymph node staging for lung cancer remains one of the most important factors to determine patient outcome.MethodsNoninvasive imaging techniques such as CT, MRI, PET and PET-CT provide some answers but no tissue diagnosis.ResultsThe development of endo-oesophageal (EUS) and endobronchial ultrasound (EBUS) with fine-needle aspiration has provided the clinician with a tool to investigate the mediastinum and the adrenal gland with a safe, minimally invasive procedure that can be performed on an outpatient basis.ConclusionThe aim of this article was to give radiologists an overview of the techniques of EUS and EBUS and their role in the staging of lung cancer patients.

Targeted deep sequencing of effusion cytology samples is feasible, informs spatiotemporal tumor evolution, and has clinical and diagnostic utility

During the course of disease, many cancer patients eventually present with metastatic disease including peritoneal or pleural spread. In this context, cytology specimens derived from ascites or pleural effusion may help to differentiate malignant from benign conditions and sometimes yield diagnosis of a malignancy. However, even when supported by immunohistochemistry, cytological interpretation can be challenging, especially if tumor cellularity is low. Here, we investigated whether targeted deep sequencing of formalin‐fixed and paraffin embedded (FFPE) cytology specimens of cancer patients is feasible, and has diagnostic and clinical impact. To this end, a cohort of 20 matched pairs was compiled, each comprising a cytology sample (FFPE cell block) and at least one biopsy/surgical resection specimen serving as benchmark. In addition, 5 non‐malignant effusions were sequenced serving as negative‐controls. All samples yielded sufficient libraries and were successfully subjected to targeted sequencing employing a semiconductor based next‐generation sequencing platform. Using gene panels of different size and composition, including the Oncomine Comprehensive Assay, for targeted sequencing, somatic mutations were detected in the tissue of all 20 cases. Of these, 15 (75%) harbored mutations that were also detected in the corresponding cytology samples. In four of these cases (20%), additional private mutations were detected in either cytology or tissue samples, reflecting spatiotemporal tumor evolution. Of the five remaining cases, three (15%) showed wild type alleles in cytology material whereas tumor tissue had mutations in interrogated genes. Two cases were discordant, showing different private mutations in the cytology and in the tissue sample, respectively. In summary, sequencing of cytology specimens (FFPE cell block) reflecting spatiotemporal tumor evolution is feasible and yields adjunct genetic information that may be exploitable for diagnostics and therapy.

Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis

Neutrophil elastase (NE) is a key risk factor for severity of cystic fibrosis (CF) lung disease. Recent studies identified increased NE activity on the surface of airway neutrophils from CF-like mice and patients with CF. However, the role of surface-bound NE in CF lung disease remains unknown. We determined the relationship between surface-bound NE activity and severity of lung disease in CF. Surface-bound NE activity was measured on sputum neutrophils from 35 CF patients and eight healthy controls using novel lipidated Förster resonance energy transfer reporters and correlated with free NE activity, neutrophil counts, interleukin-8, myeloperoxidase and antiproteases in sputum supernatant, and with lung function parameters. Surface-bound NE activity was increased in CF compared to healthy controls (p<0.01) and correlated with free NE activity (p<0.05) and other inflammation markers (p<0.001). Surface-bound and free NE activity correlated with forced expiratory volume in 1u2005s % predicted (p<0.01 and p<0.05), but only surface-bound NE activity correlated with plethysmographic functional residual capacity % pred (p<0.01) in patients with CF. We demonstrate that surface-bound NE activity on airway neutrophils correlates with severity of lung disease in patients with CF. Our results suggest that surface-bound NE activity may play an important role in the pathogenesis and serve as novel biomarker in CF lung disease. Surface-bound elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis http://ow.ly/SRcT30iziHe

EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK+ non-small cell lung cancer: Christopoulos et al.

In order to identify anaplastic lymphoma kinase‐driven non‐small cell lung cancer (ALK+ NSCLC) patients with a worse outcome, who might require alternative therapeutic approaches, we retrospectively analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK fusion variants V1, V2 and V3 as detected by next‐generation sequencing or reverse transcription‐polymerase chain reaction (nu2009=u200967). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy. EML4‐ALK fusion variants V1, V2 and V3 were found in 39%, 10% and 51% of cases, respectively. Patients with V3‐driven tumors had more metastatic sites at diagnosis than cases with the V1 and V2 variants (mean 3.3 vs. 1.9 and 1.6, pu2009=u20090.005), which suggests increased disease aggressiveness. Furthermore, V3‐positive status was associated with earlier failure after treatment with first and second‐generation ALK TKI (median progression‐free survival [PFS] by RECIST in the first line 7.3 vs. 39.3 months, pu2009=u20090.01), platinum‐based combination chemotherapy (median PFS 5.4 vs. 15.2 months for the first line, pu2009=u20090.008) and cerebral radiotherapy (median brain PFS 6.1 months vs. not reached for cerebral radiotherapy during first‐line treatment, pu2009=u20090.028), and with inferior overall survival (39.8 vs. 59.6 months in median, pu2009=u20090.017). Thus, EML4‐ALK fusion variant V3 is a high‐risk feature for ALK+ NSCLC. Determination of V3 status should be considered as part of the initial workup for this entity in order to select patients for more aggressive surveillance and treatment strategies.

Recommendations for the use of endoscopic lung volume reduction in South Africa: Role in the treatment of emphysema.

Emphysema is a very common cause of morbidity and mortality in South Africa (SA). Therapeutic options in severe emphysema are limited. Endoscopic lung volume reduction (ELVR) is increasingly being used internationally for the treatment of advanced emphysema in a subset of patients with advanced disease, aiming to obtain the same functional advantages as surgical lung volume reduction while reducing risks and costs. In addition to endobronchial valves, ELVR using endobronchial coils is now available in SA. The high cost of these interventions underscores the need for careful patient selection to best identify those who may or may not benefit from ELVR-related procedures. The Assembly on Interventional Pulmonology of the South African Thoracic Society appointed a committee comprising both local and international experts to extensively review all relevant evidence and provide advice on the use of ELVR in SA based on published evidence, expert opinion and local access to the various devices.

The role of endobronchial ultrasound (EBUS) in radiographically occult mediastinal disease and the future of EBUS

Lung cancer remains a common cancer worldwide. The normal mediastinum on imaging often requires further clarification prior to potentially curative surgery. In this article we review the indications for endobronchial ultrasound (EBUS) and compare it with radiological imaging. We evaluate recent publications on EBUS as a means to evaluate CT and PET negative mediastinal lymph nodes. We also discuss the role of a combined approach of oesophageal ultrasound (EUS) with EBUS for staging of the mediastinum and evaluate the future of EBUS in lung cancer. Transbronchial needle forceps biopsy is a new approach to obtain a larger histological specimen under ultrasound guidance and may be used for immunohistochemistry analysis. In the future EBUS may also offer treatment options as outlined in this article.

Brustwandtumor — immer ein Tumorrezidiv?

Bei einem Patienten wurde fünf Monate nach Operation und adjuvanter Chemotherapie eines NSCLC eine Raumforderung der Thoraxwand mit ossärer Destruktion der Rippen und pulmonalen Rundherden festgestellt. Wie wichtig eine aktuelle histologische Sicherung ist, zeigt der Fallbericht.