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Additional file 1. Supplementary Figures.

Introduction and background: A complete resection is the cornerstone in the treatment of early stage non-small cell lung cancer (NSCLC). Over the last decades survival after surgery improved due to better preoperative staging, better postoperative care, multimodal treatment and the increase of lung parenchyma sparing surgical techniques, resulting in relative less pneumonectomies. Recently, minimally invasive techniques, both for staging and treatment have been introduced. The LLCG research group previously reported on the role of endoscopic ultrasound in the staging of NSCLC, particular in patients with PET-CT suspect mediastinal nodes. An endoscopic ultrasound, if negative followed by mediastinoscopy, results in higher sensitivity to detect mediastinal disease. However, in a subset of patients with positive hilar lymph nodes on imaging further research is necessary to determine the optimal technique for invasive mediastinal staging. After initial hesitancy, VATS anatomical resections are now widespread. In expert centers, up to 90% of resections for stage I NSCLC are performed by VATS. In literature, better quality of life, less pain, early drainage removal and shorter hospital stay are reported. However, there remain concerns about major intra-operative complications. Furthermore, one can question whether intra-operative nodal dissection and staging is equivalent and the role of VATS anatomical resections after induction treatment is largely unknown. General Hypothesis: Minimal invasive surgical techniques are oncologic suitable for staging and treatment of NSCLC patients provided correct patient selection and experience of the multidisciplinary team. Methodology: In a prospective multicenter study we will analyze the sensitivity of invasive preoperative nodal staging in patients NSCLC with hilar nodal disease (Study I). The risk of intra-operative major complications during VATS anatomical resections will be evaluated using a large multi center patient cohort (Study II). We will describe our technique to minimize the risk of intraoperative complications (Study III). In a retrospective study we will evaluate on our patient data the efficacy of nodal dissection and intraoperative nodal staging in VATS lobectomy for NSCLC (Study IV). In a last study we will analyze the feasibility and efficacy of VATS resections after induction therapy for NSCLC (Study V) The value of surgical mediastinal staging in clinical N1 lung cancer. (Aster III) ClinicalTrials.gov: NCT 02222194 CTC Leuven: S56397 Objective and Rationale: In patients with NSCLC and clinical (PET or CT) positive N1 nodal disease, the guidelines of the European Society of Thoracic Surgeons propose mediastinal staging by echo-endoscopy OR mediastinoscopy. Recent data show a sensitivity of less than 50% for echo-endoscopy to detect N2 disease in cN1 NSCLC patients, while prevalence of mediastinal nodal disease was 24%. Our hypothesis is that video-assisted mediastinoscopy (VAM) will have a higher accuracy in this setting. We plan to perform a prospective multicentric observational study to measure the sensitivity of mediastinal staging by VAM in cN1 operable and resectable NSCLC patients. Study design: Multicentric prospective observational study Methods: Video assisted mediastinoscopy. If negative, followed by anatomical resection and lymphadenectomy in accordance to the ESTS guidelines. Timing: EC approved. Data accrual 2015-2017, 200 patients in 10 centers 2.Analysis of the most common major intraoperative complications during video-assisted thoracoscopic surgery (VATS) anatomical resections ClinicalTrials.gov: NCT02031809 CTC Leuven: S56280 / ML10233 Objective: Multicentric evaluation of the frequency and nature of intraoperative major complications during video assisted thoracoscopic (vats) anatomical resections. The purpose is to quantify these major complications, discuss the steps that can be taken to prevent and treat these events. Rationale: Vats lobectomy is becoming the standard of care for early stage lung cancer. Several studies have shown feasibility and safety in dedicated centers. Compared to thoracotomy the procedure results in at least equal oncologic results and survival. Most series do not publish their early experience. They are retrospective and report on lobectomies and segmentectomies, excluding the live-saving pneumonectomies. They are potentially ignoring the intention-to-treat principle, excluding conversions. Based on scarce existing literature and conference worst-case presentations a pattern of the most common intraoperative major complications can be drawn. In Europe, a large percentage of high-volume-centers have now successfully implemented a vats lobectomy program. To be aware of potential hazards is the best way to avoid them. In this era with low-volume-centers switching into vats anatomical resections, it is therefore important to focus on potentially life-threatening complications. Study design: Multicentric Retrospective analysis Methods: Six European centers submit their series of consecutive anatomical lung resections intended to be performed by VATS. Conversions to thoracotomy, vascular injuries and major intraoperative complications are studied in relation to the surgeons’ experience. Major complications include immediately life-threatening complications (e.g. blood loss of more than 2 liters), injury to proximal airway or other organs, or complications leading to unplanned additional anatomical resections. Results: The result section will include the indication of surgery, intraoperative deaths, in-hospital mortality, 90-day mortality, conversion rate to open surgery and the reason for conversion, i.e. for oncologic or technical reasons or complications. The rate of vascular injuries will be reported and in what percentage this resulted in a conversion. The peroperative major complications will be reported. A panel of experienced minimal invasive surgeons will discuss these cases. Recommendations will be submitted for publication. Relation between surgeon experience and indication, conversion rate, vascular injuries and major complications will be investigated. Timing: EC approved, Collection of data: 2015, 3000 patients expected, publication 2016. VATS tunnel technique: a plea for a ‘fissure first, hilum last’ approach with staplers in the fissureless patient CTC Leuven: S57657 Objective: To minimize airleak, many vats surgeons use a “fissureless” technique, dividing the hilar bronchovascular structures first and the main part of the fissure last with staplers. We describe an alternative fissureless technique, opening the fissure completely with staplers at an early stage of vats anatomical lung resections in a cohort of consecutive patients. Rationale: By making a tunnel between the bronchovascular structures and parenchyma from anterior to posterior, one can open the oblique fissure completely with staplers at an early stage of an anatomical lung resection. This combines the advantages of both the ‘fissureless’ hilum first technique and classic fissure first dissection, i.e. minimal airleak and optimal anatomical overview before bronchovascular structures are divided. This may result in a safer operation with more attention to the intrapulmonary lymphadenectomy. Study Design: Retrospective cohort analysis Methods: Based on a prospectively managed single institution database patients that were planned for VATS anatomical resection between 10/2009 and 12/2014 will be included. Robotic assisted cases, middle lobe resections, upper trisegmentectomies and individual segmentectomies are excluded. The patients are consecutive divided in 4 groups: first 50 learning curve (LC), “hilum first, fissure last” (HF), a mixed transition group, “fissure first, hilum last” (FF). Conversion rate, operation time duration of drainage, hospital stay, Airleak(>5days), incidence of vascular injuries and major peroperative complications and postoperative complications will be compared between HF and FF. Timing: Publication 2015 4.Should tumor location be considered when comparing N1 upstaging between VATS and open surgery for clinical stage I NSCLC? ClinicalTrials.gov: NCT01985659 CTC Leuven: S50634 Objective: Systematic nodal dissection (of both mediastinal, hilar and interlobar lymph nodes) is an essential component of a complete resection for NSCLC. There are some concerns that mainly hilar and interlobar nodal dissection might be less optimal in VATS lung resections. Optimal nodal dissection may lead to nodal upstaging (higher pathological than clinicalm disease). Therefore nodal upstaging is a quality indicator for thoracic surgery. We investigate the impact of primary tumor location on nodal upstaging in clinical stage I (cStage-I; TNM 7) NSCLC as this was not included in already published large retrospective series that showed lower N1 upstaging after VATS resections. Study design: Retrospective multivariate analysis Methods: Consecutive patients operated for cStage-I NSCLC are selected from our prospectively managed surgical database. Tumor location is classified as central or peripheral based on endobronchial visibility during videobronchoscopy. A nodal station mapping is drawn for each patient. The number of investigated lymph node stations will be compared between VATS and open resections. A binary logistic regression model including tumor location, surgical technique, cStage-I, gender and histology will be performed to find variables with significant impact on nodal upstaging (pN1). Timing: EC pending. Data accrual 2015, 400 patients, Publication 2016 5.Feasibility and results of VATS resections after induction therapy for single level N2 disease Introduction: Surgery after induction chemotherapy for stage IIIA-N2 NSCLC can be performed with acceptable mortality and morbidity. Baseline single level N2 disease is an independent prognostic factor for survival. No data are available on the feasibility to perform these operations by minimal invasive techniques. Objective: Feasibility of VATS lung resections after induction therapy Study Design: Multicentric prospective observational study Methods: Data of consecutive patients operated for stage IIIA-N2 NSCLC of different European centers are analyzed. Inclusion criteria: patients with baseline resectable pathology proven stage IIIAN2 NSCLC and single positive ipsilateral mediastinal lymphnode position before induction chemo(radio) therapy intended to undergo a VATS resection. Endpoints: Conversion rate to open surgery, number of lymph node positions removed, peroperative complications, hospital stay, 90-day mortality Timing: Design 2015, accrual 2015-2016, publication 2017 status: published