The Prognostic Role of the Number of Involved Structures in Thymic Epithelial Tumors: Results from the ESTS Database.

BACKGROUND: The role of the number of involved structures (NIS) in thymic epithelial tumors (TETs) has been investigated for inclusion in future staging systems, but large cohort results still are missing. This study aimed to analyze the prognostic role of NIS for patients included in the European Society of Thoracic Surgeons (ESTS) thymic database who underwent surgical resection. METHODS: Clinical and pathologic data of patients from the ESTS thymic database who underwent surgery for TET from January 2000 to July 2019 with infiltration of surrounding structures were reviewed and analyzed. Patients' clinical data, tumor characteristics, and NIS were collected and correlated with CSS using Kaplan-Meier curves. The log-rank test was used to assess differences between subgroups. A multivariable model was built using logistic regression analysis. RESULTS: The final analysis was performed on 303 patients. Histology showed thymoma for 216 patients (71.3%) and NET/thymic carcinoma [TC]) for 87 patients (28.7%). The most frequently infiltrated structures were the pleura (198 cases, 65.3%) and the pericardium in (185 cases, 61.1%), whereas lung was involved in 96 cases (31.7%), great vessels in 74 cases (24.4%), and the phrenic nerve in 31 cases (10.2%). Multiple structures (range, 2-7) were involved in 183 cases (60.4%). Recurrence resulted in the death of 46 patients. The CSS mortality rate was 89% at 5 years and 82% at 10 years. In the univariable analysis, the favorable prognostic factors were neoadjuvant therapy, Masaoka stage 3, absence of metastases, absence of myasthenia gravis, complete resection, thymoma histology, and no more than two NIS. Patients with more than two NIS presented with a significantly worse CSS than patients with no more than two NIS (CSS 5- and 10-year rates: 9.5% and 83.5% vs 93.2% and 91.2%, respectively; p = 0.04). The negative independent prognostic factors confirmed by the multivariable analysis were incomplete resection (hazard ratio [HR] 2.543; 95% confidence interval [CI] 1.010-6.407; p = 0.048) and more than two NIS (HR 1.395; 95% CI 1.021-1.905; p = 0.036). CONCLUSIONS: The study showed that more than two involved structures are a negative independent prognostic factor in infiltrative thymic epithelial tumors that could be used for prognostic stratification.

Krebs von den Lungen 6 (KL-6) is a novel diagnostic and prognostic biomarker in pleural mesothelioma.

OBJECTIVES: Pleural mesothelioma (PM) is a rare disease with dismal outcome. Systemic treatment options include chemotherapy and immunotherapy, but biomarkers for treatment personalization are missing. The only FDA-approved diagnostic biomarker is the soluble mesothelin-related protein (SMRP). Krebs von den Lungen-6 (KL-6) is a human mucin 1 (MUC1) glycoprotein, which has shown diagnostic and prognostic value as a biomarker in other malignancies. The present study investigated whether KL-6 can serve as a diagnostic and/or prognostic biomarker in PM. MATERIALS AND METHODS: Using a fully-automated chemiluminescence enzyme immunoassay (CLEIA) for KL-6 and SMRP, pleural effusion samples from 87 consecutive patients with PM and 25 patients with non-malignant pleural disorders were studied. In addition, KL-6 and SMRP levels were determined in corresponding patient sera, and in an independent validation cohort (n = 122). MUC1 mRNA and protein expression, and KL-6 levels in cell line supernatants were investigated in PM primary cell lines in vitro. RESULTS: PM patients had significantly higher KL-6 levels in pleural effusion than non-malignant controls (AUC 0.78, p < 0.0001). Among PM patients, levels were highest in those with epithelioid or biphasic histologies. There was a strong positive correlation between pleural effusion levels of KL-6 and SMRP (p < 0.0001). KL-6 levels in sera similarly associated with diagnosis of PM, however, to a lesser extent (AUC 0.71, p = 0.008). PM patients with high pleural effusion KL-6 levels (≥303 IU/mL) had significantly better overall survival (OS) compared to those with low KL-6 levels (HR 0.51, p = 0.004). Congruently, high tumor cell MUC1 mRNA expression in primary cell lines associated with prolonged corresponding patient OS (HR 0.35, p = 0.004). These findings were confirmed in an independent validation cohort. CONCLUSION: This is the first study demonstrating KL-6 as a potential novel liquid-based diagnostic and prognostic biomarker in PM.

TROP2 expression and SN38 antitumor activity in malignant pleural mesothelioma cells provide a rationale for antibody-drug conjugate therapy.

OBJECTIVES: Malignant pleural mesothelioma (MPM) is an aggressive cancer which at large is not amenable to curative surgery. Despite the recent approval of immune checkpoint inhibitor therapy, the response rates and survival following systemic therapy is still limited. Sacituzumab govitecan is an antibody-drug conjugate targeting the topoisomerase I inhibitor SN38 to trophoblast cell-surface antigen 2 (TROP-2)-positive cells. Here we have explored the therapeutic potential of sacituzumab govitecan in MPM models. MATERIALS AND METHODS: TROP2 expression was analyzed in a panel of two well established and 15 pleural effusion derived novel lines by RT-QPCR and immunoblotting, TROP2 membrane-localization was studied by flow cytometry and immunohistochemistry. Cultured mesothelial cells and pneumothorax pleura served as controls. The sensitivity of MPM cell lines to irinotecan and SN38 was studied using cell viability, cell cycle, apoptosis and DNA damage assays. Drug sensitivity of cell lines was correlated with RNA expression of DNA repair genes. Drug sensitivity was defined as an IC50 below 5 nM in the cell viability assay. RESULTS: TROP2 expression was detected at RNA and protein level in 6 of the 17 MPM cell lines, but not in in cultured mesothelial control cells or in the mesothelial layer of the pleura. TROP2 was detectable on the cell membrane in 5 MPM lines and was present in the nucleus in 6 cell models. Ten of 17 MPM cell lines showed sensitivity to SN38 treatment, among those 4 expressed TROP2. High AURKA RNA expression and high proliferation rate correlated with sensitivity to SN38-induced cell death, DNA damage response, cell cycle arrest and cell death. Sacituzumab govitecan treatment effectively induced cell cycle arrest and cell death in TROP2-positive MPM cells. CONCLUSION: TROP2 expression and sensitivity to SN38 in MPM cell lines support biomarker-selected clinical exploration of sacituzumab govitecan in patients with MPM.

Prediction of malignant lymph nodes in NSCLC by machine-learning classifiers using EBUS-TBNA and PET/CT.

Accurate determination of lymph-node (LN) metastases is a prerequisite for high precision radiotherapy. The primary aim is to characterise the performance of PET/CT-based machine-learning classifiers to predict LN-involvement by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in stage-III NSCLC. Prediction models for LN-positivity based on [18F]FDG-PET/CT features were built using logistic regression and machine-learning models random forest (RF) and multilayer perceptron neural network (MLP) for stage-III NSCLC before radiochemotherapy. A total of 675 LN-stations were sampled in 180 patients. The logistic and RF models identified SUVmax, the short-axis LN-diameter and the echelon of the considered LN among the most important parameters for EBUS-positivity. Adjusting the sensitivity of machine-learning classifiers to that of the expert-rater of 94.5%, MLP (P = 0.0061) and RF models (P = 0.038) showed lower misclassification rates (MCR) than the standard-report, weighting false positives and false negatives equally. Increasing the sensitivity of classifiers from 94.5 to 99.3% resulted in increase of MCR from 13.3/14.5 to 29.8/34.2% for MLP/RF, respectively. PET/CT-based machine-learning classifiers can achieve a high sensitivity (94.5%) to detect EBUS-positive LNs at a low misclassification rate. As the specificity decreases rapidly above that level, a combined test of a PET/CT-based MLP/RF classifier and EBUS-TBNA is recommended for radiation target volume definition.

The clinical utility of cfRNA for disease detection and surveillance: A proof of concept study in non-small cell lung cancer.

BACKGROUND: CT scans are used in routine clinical practice for the diagnosis and treatment surveillance of non-small cell lung cancer (NSCLC). However, more sensitive methods are desirable. Liquid biopsy analyses of RNA and DNA can offer more sensitive diagnostic approaches. Cell-free RNA (cfRNA) has been described in several malignancies, but its clinical utility has not previously been explored. METHODS: We evaluated the clinical utility of cfRNA for early detection and surveillance of tumor disease in a proof-of-concept study. Using real-time-droplet digital polymerase chain reaction we characterized a candidate transcript (MORF4L2) in plasma samples from 41 advanced stage, 38 early stage NSCLC and 39 healthy samples. We compared its diagnostic performance with tumor markers and evaluated its utility for disease monitoring. RESULTS: MORF4L2 cfRNA was more abundant in patients than in healthy donors (p < 0.0001). Using the Youden index approach (cutoff value of 537 copies/ml was established) with a sensitivity of 0.73 (95% CI: 0.61-0.82) and a specificity of 0.87 (95% CI: 0.73-0.96). Positive and negative predictive values of 0.92 (95% CI: 0.83-0.95) and 0.59 (95% CI: 0.47-0.83) were achieved. Combination of cfRNA and Cyfra21-1 improved its predictive value from 89.5% to 94.7%. Low baseline MORF4L2 levels were associated with better overall survival (HR:0.25, 95% CI: 0.09-0.7, p = 0.009) and progression-free survival for patients treated with tyrosine kinase inhibitors (p = 0.011) and chemotherapy (p = 0.019). MORF4L2 profile between baseline and follow-up mirrored radiological response and tumor dynamics better than tumor markers. cfRNA transcripts allowed monitoring tumor dynamics in patients without tumor-reported genetic alterations. CONCLUSION: Our data support clinical utility of cfRNA for detection and surveillance of NSCLC. Further studies with larger cohorts are required.

The pathological oral cavity as a preventable source of postoperative pneumonia in thoracic surgery: a prospective observational study.

Background: Pneumonia after thoracic surgery considerably contributes to perioperative morbidity and mortality. So far, the forced expiratory volume in one second and diffusing capacity of the lungs for carbon dioxide are the most common validated prognosticators to estimate individual risk. Beyond functional parameters, modifiable risk factors for respiratory complications like pneumonia are poorly investigated in a prospective way. Thus, we aimed to assess the impact of oral health status in patients undergoing thoracic surgery and its correlation to perioperative outcomes. Methods: A prospective observational study included adult patients undergoing elective thoracic surgery from October 2, 2018 to April 29, 2020. The day before surgery, patients were examined by a dentist. Oral health status (caries, periodontal disease, tooth loss, and regular dental visits) was correlated with perioperative outcomes. Results: During the study period, 230 consecutive patients were included. Oral health status was poor in the study population. Postoperative complications were associated with active caries [odds ratio (OR) 2.5, P<0.03]. Patients with frequent dental visits and treated teeth had a lower risk for postoperative complications compared with patients without regular visits (OR 0.3, P<0.02). Patients with a high burden of caries had a significantly increased risk for pneumonia (OR 7.9, P<0.002). The forced expiratory volume in one second was a significant prognosticator for postoperative complications; however, no association between the forced expiratory volume in one second and oral health parameters was observed. Conclusions: A pathological oral health status is a modifiable factor predicting postoperative complications and pneumonia. A prospective randomized interventional study is warranted to clarify whether an improvement in oral health status can lead to a reduction of perioperative risk.

Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer.

BACKGROUND: Radiology is the current standard for monitoring treatment responses in lung cancer. Limited sensitivity, exposure to ionizing radiations and related sequelae constitute some of its major limitation. Non-invasive and highly sensitive methods for early detection of treatment failures and resistance-associated disease progression would have additional clinical utility. METHODS: We analyzed serially collected plasma and paired tumor samples from lung cancer patients (61 with stage IV, 48 with stages I-III disease) and 61 healthy samples by means of next-generation sequencing, radiological imaging and droplet digital polymerase chain reaction (ddPCR) mutation and methylation assays. RESULTS: A 62% variant concordance between tumor-reported and circulating-free DNA (cfDNA) sequencing was observed between baseline liquid and tissue biopsies in stage IV patients. Interestingly, ctDNA sequencing allowed for the identification of resistance-mediating p.T790M mutations in baseline plasma samples for which no such mutation was observed in the corresponding tissue. Serial circulating tumor DNA (ctDNA) mutation analysis by means of ddPCR revealed a general decrease in ctDNA loads between baseline and first reassessment. Additionally, serial ctDNA analyses only recapitulated computed tomography (CT) -monitored tumor dynamics of some, but not all lesions within the same patient. To complement ctDNA variant analysis we devised a ctDNA methylation assay (methcfDNA) based on methylation-sensitive restriction enzymes. cfDNA methylation showed and area under the curve (AUC) of > 0.90 in early and late stage cases. A decrease in methcfDNA between baseline and first reassessment was reflected by a decrease in CT-derive tumor surface area, irrespective of tumor mutational status. CONCLUSION: Taken together, our data support the use of cfDNA sequencing for unbiased characterization of the molecular tumor architecture, highlights the impact of tumor architectural heterogeneity on ctDNA-based tumor surveillance and the added value of complementary approaches such as cfDNA methylation for early detection and monitoring.

Patterns of nodal spread in stage III NSCLC: importance of EBUS-TBNA and 18F-FDG PET/CT for radiotherapy target volume definition.

PURPOSE: The aim of this study was to compare the pattern of intra-patient spread of lymph-node (LN)-metastases within the mediastinum as assessed by 18F-FDG PET/CT and systematic endobronchial ultrasound-guided transbronchial-needle aspiration (EBUS-TBNA) for precise target volume definition in stage III NSCLC. METHODS: This is a single-center study based on our preceding investigation, including all consecutive patients with initial diagnosis of stage IIIA-C NSCLC, receiving concurrent radiochemotherapy (12/2011-06/2018). Inclusion criteria were curative treatment intent, 18F-FDG PET/CT and EBUS-TBNA prior to start of treatment. The lymphatic drainage was classified into echelon-1 (ipsilateral hilum), echelon-2 (ipsilateral LN-stations 4 and 7) and echelon-3 (rest of the mediastinum, contralateral hilum). The pattern of spread was classified according to all permutations of echelon-1, echelon-2, and echelon-3 EBUS-TBNA findings. RESULTS: In total, 180 patients were enrolled. Various patterns of LN-spread could be identified. Skip lesions with an involved echelon distal from an uninvolved one were detected in less than 10% of patients by both EBUS-TBNA and PET. The pattern with largest asymmetry was detected in cases with EBUS-TBNA- or PET-positivity at all three echelons (p < 0.0001, exact symmetry test). In a multivariable logistic model for EBUS-positivity at echelon-3, prognostic factors were PET-positivity at echelon-3 (Hazard ratio (HR) = 12.1; 95%-CI: 3.2-46.5), EBUS-TBNA positivity at echelon-2 (HR = 6.7; 95%-CI: 1.31-31.2) and left-sided tumor location (HR = 4.0; 95%-CI: 1.24-13.2). There were significantly less combined ipsilateral upper (LN-stations 2 and 4) and lower (LN-station 7) mediastinal involvements (16.8% of patients) with EBUS-TBNA than with PET (38.9%, p < 0.0001, exact symmetry test). EBUS-TBNA detected a lobe specific heterogeneity between the odds ratios of LN-positivity in the upper versus lower mediastinum (p = 0.0021, Breslow-Day test), while PET did not (p = 0.19). CONCLUSION: Frequent patterns of LN-metastatic spread could be defined by EBUS-TBNA and PET and discrepancies in the pattern were seen between both methods. EBUS-TBNA showed more lobe and tumor laterality specific patterns of LN-metastases than PET and skipped lymph node stations were rare. These systematic relations offer the opportunity to further refine multi-parameter risk of LN-involvement models for target volume delineation based on pattern of spread by EBUS-TBNA and PET.

HDAC Inhibition Induces Cell Cycle Arrest and Mesenchymal-Epithelial Transition in a Novel Pleural-Effusion Derived Uterine Carcinosarcoma Cell Line.

Objective: Uterine carcinosarcoma (UCS) is a rare but highly aggressive malignancy with biphasic growth pattern. This morphology can be attributed to epithelial-mesenchymal transition (EMT) that often associates with tumor invasion and metastasis. Accordingly, we analyzed a novel patient-derived preclinical model to explore whether EMT is a potential target in UCS. Methods: A novel UCS cell line (PF338) was established from the malignant pleural effusion of a 59-year-old patient at time of disease progression. Immunohistochemistry was performed in primary and metastatic tumor lesions. Oncogenic mutations were identified by next-generation sequencing. Viability assays and cell cycle analyses were used to test in vitro sensitivity to different standard and novel treatments. E-cadherin, ß-catenin and pSMAD2 expressions were measured by immunoblot. Results: Whereas immunohistochemistry of the metastatic tumor showed a predominantly sarcomatous vimentin positive tumor that has lost E-cadherin expression, PF338 cells demonstrated biphasic growth and carried mutations in KRAS, PIK3CA, PTEN and ARID1A. PF338 tumor cells were resistant to MEK- and TGF-ß signaling-inhibition but sensitive to PIK3CA- and PARP-inhibition and first-line chemotherapeutics. Strikingly, histone deacetylase (HDAC) inhibition markedly reduced cell viability by inducing a dose-dependent G0/1 arrest and led to mesenchymal-epithelial transition as evidenced by morphological change and increased E-cadherin and ß-catenin expression. Conclusions: Our data suggest that HDAC inhibition is effective in a novel UCS cell line by interfering with both viability and differentiation. These findings emphasize the dynamic manner of EMT/MET and epigenetics and the importance of molecular profiling to pave the way for novel therapies in UCS.

Torque Teno Virus load in lung cancer patients correlates with age but not with tumor stage.

BACKGROUND: Torque teno virus (TTV) is a ubiquitous non-pathogenic virus, which is suppressed in immunological healthy individuals but replicates in immune compromised patients. Thus, TTV load is a suitable biomarker for monitoring the immunosuppression also in lung transplant recipients. Since little is known about the changes of TTV load in lung cancer patients, we analyzed TTV plasma DNA levels in lung cancer patients and its perioperative changes after lung cancer surgery. MATERIAL AND METHODS: Patients with lung cancer and non-malignant nodules as control group were included prospectively. TTV DNA levels were measured by quantiative PCR using DNA isolated from patients plasma and correlated with routine circulating biomarkers and clinicopathological variables. RESULTS: 47 patients (early stage lung cancer n = 30, stage IV lung cancer n = 10, non-malignant nodules n = 7) were included. TTV DNA levels were not detected in seven patients (15%). There was no significant difference between the stage IV cases and the preoperative TTV plasma DNA levels in patients with early stage lung cancer or non-malignant nodules (p = 0.627). While gender, tumor stage and tumor histology showed no correlation with TTV load patients below 65 years of age had a significantly lower TTV load then older patients (p = 0.022). Regarding routine blood based biomarkers, LDH activity was significantly higher in patients with stage IV lung cancer (p = 0.043), however, TTV load showed no correlation with LDH activity, albumin, hemoglobin, CRP or WBC. Comparing the preoperative, postoperative and discharge day TTV load, no unequivocal pattern in the kinetics were. CONCLUSION: Our study suggest that lung cancer has no stage dependent impact on TTV plasma DNA levels and confirms that elderly patients have a significantly higher TTV load. Furthermore, we found no uniform perioperative changes during early stage lung cancer resection on plasma TTV DNA levels.

PROGNOSTIC VALUE OF POST-INDUCTION CHEMOTHERAPY VOLUMETRIC PET/CT PARAMETERS FOR STAGE IIIA/B NON-SMALL CELL LUNG CANCER PATIENTS RECEIVING DEFINITIVE CHEMORADIOTHERAPY.

Purpose/Objective(s): The aim of this follow-up analysis of the ESPATUE phase-3 trial was to explore the prognostic value of post-induction chemotherapy PET metrics in patients with stage III non-small cell lung cancer (NSCLC) who were assigned to receive definitive chemoradiotherapy. Materials/Methods: All eligible patients stage IIIA (cN2) and stage IIIB of the trial received induction chemotherapy consisting of 3 cycles of cisplatin/paclitaxel and chemoradiotherapy up to 45 Gy/1.5 Gy per fraction twice-a-day, followed by a radiation-boost with 2 Gy once per day with concurrent cisplatin/vinorelbine. The protocol definition prescribed a total dose of 65-71 Gy. 18F-FDG-PET/CT (PETpre) was performed at study entry and before concurrent chemoradiotherapy (interim-PET; PETpost). Interim PETpost metrics and known prognostic clinical parameters were correlated in uni- and multivariable survival analyses. Leave-one-out cross-validation was used to show internal validity. Results: Ninety-two patients who underwent 18F-FDG-PET/CT after induction chemotherapy were enrolled. Median MTVpost value was 5.9 ml. Altogether 85 patients completed the whole chemoradiation with the planned total dose of 60-71 Gy. In univariable proportional hazard analysis, each of the parameters MTVpost, SUVmax(post) and TLGmax(post) was associated with overall survival (P < 0.05). Multivariable survival analysis, including clinical and post-induction PET parameters, found TLGmax(post) (hazard ratio: 1.032 (95%-CI: 1.013-1.052) per 100 ml increase) and total radiation dose (hazard ratio: 0.930 (0.902-0.959) per Gray increase) significantly related with overall survival in the whole group of patients, and also in patients receiving a total dose ≥ 60 Gy. The best leave-one-out cross-validated 2 parameter classifier contained TLGmax(post) and total radiation dose. TLGmax(post) was associated with time to distant metastases (P = 0.0018), and SUVmax(post) with time to loco-regional relapse (P = 0.039) in multivariable analysis of patients receiving a total dose ≥ 60 Gy. Conclusion: Post-induction chemotherapy PET parameters demonstrated prognostic significance. Therefore, an interim 18F-FDG-PET/CT is a promising diagnostic modality for guiding individualized treatment intensification.

Insights into immunometabolism: A dataset correlating the 18FDG PET/CT maximum standard uptake value of the primary tumor with the CCL18 serum level in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the western world [1]. Despite multiple therapeutic and diagnostic advances, the overall survival is low and recurrence of NSCLC is a common problem with different treatment regimens. The inclusion of 18fluorine fluorodeoxyglucose (18FDG) positron emission tomography (PET) in combination with computed tomography (CT) in clinical practice was revolutionary for the staging of NSCLC [2]. 18FDG-PET/CT provides morphological, functional, and metabolic information about the tumor, which is usually highly, metabolically active. Due to the increased glucose uptake, 18FDG is actively accumulatedin the tumor tissues, resulting in an increased standardized uptake value (SUV). The tumor tissue itself consists of neoplastic cells, extracellular matrix, fibroblasts, and various immune cells. These immune cells include tumor-infiltrating lymphocytes, regulatory T cells, and macrophages. Macrophages have different activation patterns and play an essential role in inflammation and cancer. In particular, tumor-associated macrophages (TAMs) are a specialized group of alternatively activated or M2 macrophages. TAMs release several chemokines that are different from those released by classically activated macrophages found in an inflammatory environment. One of the most important chemokines released by TAMs is CC-chemokine ligand 18 (CCL18). Although CCL18 is present in healthy subjects, its levels are significantly elevated in the serum of patients with NSCLC. It correlates with overall survival and tumor stage in several malignant diseases [3,4]. A recurring problem is that increased glucose metabolism can be found in the inflammatory tissue, which can also lead to an increased SUV in 18FDG PET/CT, lowering its oncological specificity [5]. In a previous study, we demonstrated that serum CCL18 levels can be used to differentiate between patients with NSCLC and healthy subjects [3]. Hence, we investigated the correlation between serum CCL18 levels and the maximum standardized uptake value (SUVmax) of the primary tumor using 18FDG-PET/CT. We found a significant correlation between the SUVmax of the primary tumor and the serum CCL18 level. The data are important because they can be used to draw conclusions about immunometabolism. Furthermore, they can serve as basis for future prospective clinical studies.

DNA methylation of PTGER4 in peripheral blood plasma helps to distinguish between lung cancer, benign pulmonary nodules and chronic obstructive pulmonary disease patients.

BACKGROUND/INTRODUCTION: In contrast to patients who present with advanced stage lung cancer and associated poor prognosis, patients with early-stage lung cancer may be candidates for curative treatments. The results of the NELSON lung cancer screening trial are expected to stimulate the development and implementation of a lung cancer screening strategy in most countries. Widespread use of chest computed tomography scans will also result in the detection of solitary pulmonary nodules. Because reliable biomarkers to distinguish between malignant and benign lesions are lacking, tissue-based histopathological diagnostics remain the gold standard. In this study, we aimed to establish a test to assess the predictive ability of DNA hypermethylation of SHOX2 and PTGER4 in plasma to discriminate between patients with 1.) lung cancer, 2.) benign lesions, and 3.) patients with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: We retrospectively analysed SHOX2 and PTGER4 methylation in 121 prospectively collected plasma samples of patients with lung cancer (group 1A), benign lesions (group 1B), and COPD without nodules (group 2). RESULTS: PTGER4 DNA hypermethylation was more frequently observed in patients with lung cancer than in controls (p = 0.0004). Results remained significant after correction for tumour volume, smoking status, age, and eligibility for the NELSON trial. CONCLUSIONS: Detection of methylated PTGER4 in plasma DNA may serve as a biomarker to support clinical decision-making in patients with pulmonary lesions at lung cancer screening in high-risk populations. Further exploration in prospective studies is warranted.

Impact of EBUS-TBNA in addition to [18F]FDG-PET/CT imaging on target volume definition for radiochemotherapy in stage III NSCLC.

PURPOSE/INTRODUCTION: [18F]FDG-PET/CT is the standard imaging-technique for radiation treatment (RT) planning in locally advanced non-small cell lung cancer (NSCLC). The purpose of this study was to examine the additional value of endobronchial-ultrasound transbronchial needle aspiration (EBUS-TBNA) to standard PET/CT for mediastinal lymph-node (LN) staging and its impact on clinical target volume (CTV). MATERIALS AND METHODS: All consecutive patients with primary stage III NSCLC who underwent [18F]FDG-PET/CT and EBUS-TBNA prior to RT were analyzed from 12/2011 to 06/2018. LN-stations were assessed by an expert-radiologist and a nuclear medicine-physician. CTV was evaluated by two independent radiation oncologists. LNs were grouped with increasing distance along the lymphatic chains from primary tumor into echelon-1 (ipsilateral hilum), echelon-2 (LN-station 7 and ipsilateral 4), and echelon-3 (remaining mediastinum and contralateral hilum). RESULTS: A total of 675 LN-stations of which 291 were positive for tumor-cells, were sampled by EBUS-TBNA in 180 patients. The rate of EBUS-positive LNs was 43% among all sampled LNs. EBUS-positivity in EBUS-probed LNs decreased from 85.8% in echelon-1 LNs to 42.4%/ 9.6% in echelon-2/ -3 LNs, respectively (p < 0.0001, Fisher's exact test). The false discovery rate of PET in comparison with EBUS results rose from 5.3% in echelon-1 to 32.9%/ 69.1% in echelon-2/ -3 LNs, respectively (p < 0.0001, Fisher's exact test). Sensitivity and specificity of FDG-PET/CT ranged from 85 to 99% and 67 to 80% for the different echelons. In 22.2% patients, EBUS-TBNA finding triggered changes of the treated CTV, compared with contouring algorithms based on FDG-avidity as the sole criterion for inclusion. CTV was enlarged in 6.7% patients due to EBUS-positivity in PET-negative LN-station and reduced in 15.5% by exclusion of an EBUS-negative but PET-positive LN-station. CONCLUSION: The false discovery rate of [18F]FDG-PET/CT increased markedly with distance from the primary tumor. Inclusion of systematic mediastinal LN mapping by EBUS-TBNA in addition to PET/CT has the potential to increase accuracy of target volume definition, particularly in echelon-3 LNs. EBUS-TBNA is recommended as integral part of staging for radiochemotherapy in stage III NSCLC.

Minimal-invasive approach reduces cardiopulmonary complications in elderly after lung cancer surgery.

BACKGROUND: The number of elderly patients undergoing lung resection for lung cancer is continuously increasing. This study investigates the risk factors for postoperative complications in elderly lung cancer patients and the role of surgical approach in early postoperative outcome. METHODS: We reviewed all consecutive patients who underwent anatomical resection for early stage T1/2 lung cancer in a curative intent between January 2016 and November 2018 at our institution. Clinical data, postoperative complications, hospital stay and 30- and 90-day mortality were prospectively collected. RESULTS: A total of 505 (278 male) patients were included. One hundred ninety patients (38%) were ≥70 years of age. Forty-eight percent (n=241) had thoracotomy, 52% (n=264) were operated with video-assisted or robot-assisted thoracoscopy. Major cardiopulmonary complications were observed in 4.2% (n=21) patients. There was no significant difference in major cardiopulmonary complication rate following minimally invasive surgery between patients above or below 70 years of age (4.3% vs. 2.5%, P=0.47). In contrast, major cardiopulmonary complication rate was significantly higher in elderly thoracotomy patients than in patients below 70 years of age (9.9% vs. 2.6%, P=0.035). Elderly patients operated minimally invasive had a significantly shorter hospital stay compared to open approach (8.1 vs. 11.9 days, P<0.0001). Thirty- and 90-day mortality was comparable with 1.4% and 1.5%, respectively. CONCLUSIONS: Pulmonary resection for lung cancer in elderly patients is safe and can be performed with a low morbidity and mortality. However, our results indicate that minimal invasive surgery leads to reduced postoperative complications especially in elderly and should be the preferred approach.