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.

[Perioperative Targeted Therapy for Operable, Early Stage NSCLC]. / Zielgerichtete Systemtherapie beim operablen Lungenkarzinom.

Non-small cell lung cancer (NSCLC) is characterized by high recurrence rates in the early stages. In a German cohort, recurrence-free survival after 5 years was 62% (stage IA1), 40.7% (stage IIA) and 28% (stage IIIA). In addition to the perioperative use of immune checkpoint inhibitors, targeted tumor therapy is also making inroads as an innovation from the palliative setting into the early stages. Of particular relevance is the use of the EGFR inhibitor osimertinib, which has been shown to improve overall survival in the adjuvant setting. In this practice-oriented review, we briefly describe the current status of adjuvant targeted therapy and the associated testing and provide an outlook on further developments.

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.

A Prospective Study Investigating Blood Patch Pleurodesis for Postoperative Air Leaks After Pulmonary Resection.

BACKGROUND: Prolonged air leaks (PALs) after lung resection are one of the most common complications in thoracic surgery. Several options are available to treat PALs. The autologous blood patch pleurodesis is commonly used but has not been thoroughly investigated. MATERIALS AND METHODS: We conducted a prospective randomized study including all consecutive patients with PALs after pulmonary resections. Patients were randomized to either having received pleurodesis by injecting 100 mL autologous blood at d 5 and 6 (Group A) or being placed under observation (Group B). Patients from either group undergoing revisions were further investigated by a post hoc analysis and formed Group C. RESULTS: A total of 24 patients were included: 10 patients were randomized to group A and 14 to group B. Six patients (3 from each group) underwent surgical revision and were included in Group C. Groups A and B did not differ in baseline characteristics. The median time to drainage removal was 9 d (range: 5-23 d) in Group A; 9 d (range: 2-20 d) in Group B; and 6 d in Group C (range: 3-10 d), (A/B versus C, P < 0.04; A versus B was not significant). CONCLUSIONS: There is no evidence indicating a benefit for blood patch pleurodeses in patients undergoing lung resections and presenting with postoperative PALs for more than 5 d. An early operative closure of postoperative air leakage seems to be more effective.

Effectiveness of Robotic Lobectomy-Outcome and Learning Curve in a High Volume Center.

BACKGROUND: Robotic surgery has been developed as a sophisticated tool to expand possibilities in minimal invasive surgery. The learning curve for this method is short in various surgical fields; however, limited data exist on the learning curve in robotic thoracic surgery. METHODS: This study analyzes a single center experience of robotic lobectomies using a prospectively kept database. Perioperative data and outcome of patients during the learning curve were compared with patients operated with increased institutional experience. The learning curve was defined as the initial 20 lobectomies. RESULTS: Sixty-four robotic lobectomies were performed between January 2014 and February 2017. Indications, preoperative lung functions, comorbidities, patient age, and tumor stage were comparable between patients operated during the learning curve and thereafter. The mean operative time could be significantly reduced after the learning curve (286 ± 86 vs. 211 ± 62 minutes; p = 0.0003). The conversion rate dropped from 4 of 20 (20%) during the learning curve to 2 of 44 (4.5%, p = 0.07) thereafter. Chest tube duration (4.3 ± 2.9 vs. 3.8 ± 2.1 days) and hospital stay (8.3 ± 3.4 vs. 7.9 ± 4.5 days) were not different in the two phases. The number of resected lymph nodes increased from 11.2 ± 6.8 to 13.9 ± 6.5 (p = 0.0797). Lymph node upstaging was achieved in 8 (12.9%) cases. Ninety-day mortality was 0%, and 2-year overall survival was 83%. CONCLUSIONS: Robotic thoracic surgery can be safely performed and trained with low complication rates and contributes to the extension of minimal invasive thoracic surgery. The initial learning curve in our experience is overcome after 20 cases. However, to become proficient in more advanced procedures and to further reduce operative time, additional training is required. Prospective studies are required to clearly determine the role of robotic surgery in comparison to the video-assisted thoracoscopic surgery (VATS) procedures.

Same-day Routine Chest-X Ray After Thoracic Surgery is Not Necessary!

INTRODUCTION: Performing a routine postoperative chest X-ray (CXR) after general thoracic surgery is daily practice in many thoracic surgery departments. The quality, frequency of pathological findings and the clinical consequences have not been well evaluated. Furthermore, exposure to ionising radiation should be restricted to a minimum and therefore routine practice can be questioned. METHODS: As a hospital standard, each patient was given a routine CXR after opening of the pleura and inserting a chest tube. From October 2015 to March 2016, each postoperative patient with a routine CXR was included in a prospective database, including film quality, pathological findings, clinical and laboratory results and cardiorespiratory monitoring, as well as clinical consequences. RESULTS: 546 patients were included. Risk factors for postoperative complications were obesity in 50 patients (9.2%), emphysema in 127 patients (23.3%), coagulopathy in 34 patients (6.2%), longer operation time (more than two hours) in 242 patients (44.3%) and previous lung irradiation in 29 (5.3%) of patients. Major lung resections were performed in 191 patients (35.9%). 263 (48.2%) patients had procedures with minimally invasive access. The quality of the X-ray film was insufficient in 8.2% of patients. 90 (16.5%) of CXRs were found to show pathological findings, with a trend for more pathological findings after open surgery (55/283; 19.4%) compared to minimally invasive surgery (35/263; 13.3%) (p = 0.064). 11 (2.0%) patients needed a surgical or clinical intervention during postoperative observation; this corresponds to 12.2% of patients with a pathological finding on CXR. Nine of these 11 patients were clinically symptomatic and only two (0.37%) patients were asymptomatic with a relevant pneumothorax. CONCLUSIONS: Our study cannot support routine postoperative CXR after general thoracic procedures and we believe that restriction to clinically symptomatic cases should be a safe option.

Air in the insufflation tube may cause fatal embolizations in laparoscopic surgery: an animal study.

BACKGROUND: The aim of this study was to evaluate the risk of an air embolization with the volume of the insufflation tube during induction of laparoscopy. A further objective was to determine the LD50 of air in young piglets. METHODS: End-tidal carbon dioxide pressure ([Formula: see text]), pulmonary arterial pressure (P pa), heart rate (f c), and mean arterial pressure (P a carot) were measured in 17 piglets divided into three groups: group 1 (n = 6), bolus application (CO2 embolization, followed by air embolization, 2 mL/kg each), group 2 (n = 7), continuous air embolization (30 min, 0.2 mL/kg/min), and group 3 (n = 4), continuous CO2 embolization (30 min, 0.4 mL/kg/min). RESULTS: All animals survived CO2 embolism. Air embolization as a bolus (2 mL/kg) or with an accumulated volume of 3.1 mL/kg led to death. Decreases in [Formula: see text] indicated air or massive CO2 embolization only. There was a good correlation between [Formula: see text] and P pa in case of air embolization (r = -0.80, p < 0.0001). In contrast, no dependency was recognized during CO2 embolism (r = -0.17, p = 0.2). CONCLUSIONS: In order to minimize the lethal risk of gas embolization, the insufflation system has to be completely filled with CO2 before connecting to the patient.

Acute fibrinous and organizing pneumonia associated with influenza A/H1N1 pneumonia after lung transplantation.

BACKGROUND: Immunocompromised patients, particularly after lung transplantation, are at high risk to develop atypical forms of pulmonary infections including influenza A/H1N1. Acute Fibrinous and Organizing Pneumonia (AFOP) is a special histological pattern in acute respiratory failure with high mortality. CASE PRESENTATION: We describe a 66-year-old woman with double lung transplantation in August 2009 due to end stage pulmonary fibrosis. After prolonged weaning and subsequent promising course, she developed atypical pneumonia with diffuse pulmonary infiltrates in both lungs in January 2010. Infection with influenza A/H1N1 virus was verified. The patient rapidly suffered from respiratory insufficiency and died eight days after this diagnosis. The post-mortem revealed especially in the lower parts of the lungs the classical histological pattern of pure AFOP. Molecular analyses of lung tissue were positive for influenza A/H1N1. CONCLUSION: To our knowledge we present the first case of AFOP triggered by viral infection, here proven to be influenza virus A/H1N1. Thus, also in the setting of viral infection the highly deadly differential diagnosis of AFOP must be considered.

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.

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.

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.

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.

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.