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Objectives Implementation of tyrosine kinase inhibitors (TKI) and other targeted therapies was a main advance in thoracic oncology with survival gains ranging from several months to years for non-small-cell lung cancer (NSCLC) patients. High-throughput comprehensive molecular profiling is of key importance to identify patients that can potentially benefit from these novel treatments. Material and Methods Next-generation sequencing (NGS) was performed on 4500 consecutive formalin-fixed, paraffin-embedded specimens of advanced NSCLC (n = 4172 patients) after automated extraction of DNA and RNA for parallel detection of mutations and gene fusions, respectively. Results and Conclusion Besides the 24.9 % (n = 1040) of cases eligible for approved targeted therapies based on the presence of canonical alterations in EGFR exons 18–21, BRAF, ROS1, ALK, NTRK, and RET, an additional n = 1260 patients (30.2 %) displayed rare or non-canonical mutations in EGFR (n = 748), BRAF (n = 135), ERBB2 (n = 30), KIT (n = 32), PIK3CA (n = 221), and CTNNB1 (n = 94), for which targeted therapies could also be potentially effective. A systematic literature search in conjunction with in silico evaluation identified n = 232 (5.5 %) patients, for which a trial of targeted treatment would be warranted according to available evidence (NCT level 1, i.e. published data showing efficacy in the same tumor entity). In conclusion, a sizeable fraction of NSCLC patients harbors rare or non-canonical alterations that may be associated with clinical benefit from currently available targeted drugs. Systematic identification and individualized management of these cases can expand applicability of precision oncology in NSCLC and extend clinical gain from established molecular targets. These results can also inform clinical trials.

Objectives With the objective of simultaneous bronchoscopic biopsy and ablation of malignant solitary pulmonary nodules, we have developed a flexible monopolar radiofrequency (RF) catheter that can be deployed through the working channel of most bronchoscopes. Materials and Methods Fresh tumor specimens were heated in a water bath to 37 °C, and the RF catheter was inserted into the tumors within the specimen. Temperature sensors were positioned 3 mm, 5 mm and 7 mm from the electrode to measure the temperature of the surrounding tissue every 1 s. The ablation was conducted by applying RF energy for 8 min. The ablated specimens were evaluated by cutting the tissue samples along the top of the device and measuring the ablation zones. Results Five ablations were performed in 3 specimens. All of the ablation zones had a major axis length (along the electrode axis) between 18.9 mm and 22.8 mm and a minor axis length (perpendicular to the major axis) between 13.3 mm and 18.0 mm. The temperature data showed that all of the temperature sensors detected 60 °C or higher. These results demonstrate that the RF catheter was capable of generating ablation zones that were locally contained in ex vivo human cancerous lung specimens and that incorporated the tumor tissues. Conclusion We present the results of a benchtop study demonstrating the local control of ablation achieved using the RF device. This study suggests that the ex vivo ablation of lung malignancy with a new bronchoscopic RF catheter is feasible and that in vivo tumor ablation with this method in humans merits further study.

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.

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.

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.

The outcome of resectable non-small cell lung cancer (NSCLC) is critically determined by metastatic spread: About 30–50% of early-stage NSCLC patients encounter tumour recurrence within 5 years after surgery. A biomarker-driven stratification of early-stage lung cancer with a high risk of recurrence may improve therapy management and patient care. The aim of this study was to identify microRNAs (miRNAs) in serum of patients associated with early relapse in pulmonary adenocarcinoma. Serum samples were collected from 204 patients before surgery. miRNA screening was done using qRT-PCR based low-density arrays (664 miRNAs) comparing adenocarcinoma patients ( n =40) with and without recurrence 24 months after surgery. Selected miRNAs associated with disease recurrence were validated in an independent patient cohort ( n =114). miRNAs were also measured in advanced adenocarcinoma patients ( n =29), and individuals with benign pulmonary diagnosis ( n =21). Circulating miR-142-3p ( p =0.005) and miR-29b ( p =0.01) were identified in the screening and confirmed in the validation cohort to be increased in sera of early-stage adenocarcinoma patients suffering from recurrence within 24 months. Elevated miRNA levels were exclusively observed in the group of high-risk patient diagnosed for operable adenocarcinoma compared with benign diagnosis or advanced tumour disease. The differentiation between pulmonary adenocarcinoma patients with low and high risk for recurrence was improved by accounting for both miR-142-3p levels and tumour stage ( p =0.007; AUC=0.78). In conclusion, circulating miR-142-3p was found to be associated with a high risk of recurrence in early-stage lung adenocarcinoma patients, and a putative serum marker for risk assessment.

Background Cancer-associated fibroblasts (CAF) play a vital role in lung cancer initiation and progression. Although mesenchymal stem cells (MSC) are considered progenitor cells of fibroblasts and show cancer modulating abilities themselves, analyses on their presence and properties in lung cancer are lacking so far. Methods We performed a comparative molecular and functional analysis of MSC derived from non-small cell lung cancer (NSCLC) and corresponding normal lung tissue (NLT) of a total of 15 patients. MSC were identified and selected according to their mesenchymal multilineage differentiation capability and surface marker profile. Results Compared to NLT-MSC, NSCLC-MSC showed accelerated growth kinetics and reduced sensitivity to cisplatin. Karyotyping, comparative genomic hybridization and multiplex fluorescence in situ hybridization revealed no chromosomal aberrations. However, gene expression profiling of NSCLC- and NLT-MSC indicated variable expression of 62 genes involved in proliferation, DNA repair, apoptosis, extracellular matrix synthesis, tissue remodeling and angiogenesis. Differential expression of the selected candidate genes butyrylcholinesterase , clusterin and quiescin Q6 sulfhydryl oxidase 1 was validated by quantitative real-time PCR and, on protein level, by immunohistochemical analyses of original tumor tissue. Upon exposure to tumor cell-conditioned medium or transforming growth factor-β , both, NSCLC-MSC and NLT-MSC acquired expression of α-smooth muscle actin ( α-SMA ), a major characteristics of CAF. Conclusions This study indicates that NSCLC tissue contains MSC with specific molecular and functional properties. These cells might represent a progenitor reservoir for CAF and thus crucially contribute to lung cancer progression.

Various techniques are used for diagnosing mesothelioma including clinical investigation, transthoracic ultrasound, X-ray, computed tomography (CT), sonographic support puncture and thorascoscopy with biopsy. Whereas ultrasound examination of a normal lung is of limited value, it can be very useful in identifying pleural pathological processes. The presence of pleural effusion can substantially enhance the usefulness of ultrasound investigations: the liquid of the pleural effusion acts as an acoustic window and can enable the detection of intrapleural and intrapulmonal processes. Highly soluble transducers can be used to visualise pathological findings at the chest wall, enabling the recognition of pleural effusions and the diagnosis of pleural thickening, tumour tissue and abscesses. Further evidence for diagnosis can be obtained with ultrasound-guided puncture, using one of three techniques: sonographic supported puncture, sonographic-guided puncture without puncture assistance, and sonographic-guided puncture with puncture assistance. Complications such as bleeding, infection and local tumour cell propagation can arise.

Summary Conventional transbronchial needle aspiration (TBNA) is a valuable procedure but remains underutilised. Recently, imaging guidance such as CT fluoroscopy has created considerable interest. As CT fluoroscopy is cumbersome and exposes patients and staff to radiation, endosonographic imaging may be a better choice in providing guidance for TBNA or FNA in enlarged mediastinal lymph nodes. Real-time imaging during the procedure is helpful and increases the yield.