Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid.

BACKGROUND: Malignant pleural effusions (MPE) are a common and fatal complication in cancers including lung or breast cancers, or malignant pleural mesothelioma (MPM). MPE animal models and immunotherapy trials in MPM patients previously suggested defects of the cellular immunity in MPE. However only few observational studies of the immune response were done in MPM patients, using questionable control groups (transudate…). METHODS: We compared T cell populations evaluated by flow cytometry from blood and pleural effusion of untreated patients with MPM (n = 58), pleural metastasis of adenocarcinoma (n = 30) or with benign pleural lesions associated with asbestos exposure (n = 23). Blood and pleural fluid were also obtained from healthy subjects, providing normal values for T cell populations. RESULTS: Blood CD4+ or CD8+ T cells percentages were similar in all groups of patients or healthy subjects. Whereas pleural fluid from healthy controls contained mainly CD8+ T cells, benign or malignant pleural effusions included mainly CD4+ T cells. Effector memory T cells were the main T cell subpopulation in pleural fluid from healthy subjects. In contrast, there was a striking and selective recruitment of central memory CD4+ T cells in MPE, but not of effector cells CD8+ T cells or NK cells in the pleural fluid as one would expect in order to obtain an efficient immune response. CONCLUSIONS: Comparing for the first time MPE to pleural fluid from healthy subjects, we found a local defect in recruiting effector CD8+ T cells, which may be involved in the escape of tumor cells from immune response. Further studies are needed to characterize which subtypes of effector CD8+ T cells are involved, opening prospects for cell therapy in MPE and MPM.

Efficacy predictors of lung volume reduction with Zephyr valves in a European cohort.

The Endobronchial Valve for Emphysema Palliation Trial (VENT) was a multi-centre, prospective, randomised, controlled trial conducted to evaluate the safety and effectiveness of unilateral endobronchial valve (EBV) treatment. The purpose of this analysis was to assess outcomes in the previously unreported European VENT study cohort. Patients with advanced emphysema were randomly assigned (2:1) to receive Zephyr® (Pulmonx Inc., Redwood City, CA, USA) EBV treatment (n = 111) or medical management (n = 60). At 6 months, EBV patients demonstrated a significant improvement compared with the controls for mean ± SD change in forced expiratory volume in 1 s (7 ± 20% versus 0.5 ± 19%; p = 0.067), cycle ergometry (2 ± 14 W versus -3 ± 10 W; p = 0.04) and St George's Respiratory Questionnaire (-5 ± 14 points versus 0.3 ± 13 points; p = 0.047). At 12 months, the magnitude of the difference between groups for change from baseline was of similar magnitude to the differences seen at 6 months. Rates for complications did not differ significantly. EBV patients with computed tomography (CT) scans suggestive of complete fissure and lobar occlusion had a mean ± SD lobar volume reduction of -80 ± 30% and >50% met minimal clinical difference thresholds. The degree of emphysema heterogeneity did not preclude excellent outcomes. Unilateral lobar volume reduction using EBV treatment is safe and superior clinical results correlated with CT suggestive of complete fissures and successful lobar occlusion. Emphysema heterogeneity was not critical for determining positive outcomes.

The internationalization of health care: the UZ Brussel model for international partnerships.

Globalization of health care, flat medicine, cross-boarder health care, medical tourism, are all terms describing some, but not all, aspects of a growing trend: patients seeking health care provision abroad, and health care providers travelling abroad for temporary or permanent health care delivery services. This trend is a complex, bilateral and multifaceted phenomenon, which in our opinion, cannot be sustained in a single, comprehensive description. Individual hospitals have the unique opportunity to develop a model for appropriate action. The specific model created by the university hospital UZ Brussel is presented here.

Reporting of Palliative Sedation and Use of Opioids at the End of Life in a Belgian University Hospital: A Pilot Study.

Background: Palliative sedation requires no formal registration in Belgium. For euthanasia, however, there are clear guidelines in certain countries, including mandatory registration and evaluation of cases. Official guidelines have been developed for palliative sedation, but research still shows unskilled use of sedation and unclear demarcation between palliative sedation and euthanasia. Registration could be used to avoid unskilled use of sedation and to avoid use or abuse of sedation to hasten the patient's death (described as "slow/passive euthanasia"). Objective: To evaluate the current practice of palliative sedation and use of opioids and sedatives at the end of life by using a registration document. Design: Retrospective observational study. Setting/Subjects: We included all in-hospital deaths at an academic hospital in Belgium of patients (age ≥18 years) who had received parenteral opioids, benzodiazepines, barbiturates, or other anesthetics during the last 24 hours. Measurements: We investigated indications for palliative sedation, patients' and physicians' characteristics, types of medication used, and the decision-making process with the patients and family. The questionnaires were collected between July 9 and November 25, 2016. The study was approved by the Biomedical Ethics Committee of UZ Brussel (B.U.N. 1432016293). Results: In a population of 124 patients, refractory symptoms were reported in 94.4%. All patients received parenteral opioids (intravenously). Benzodiazepines were used in 51.6%. In 75.8%, physicians reported no change in treatment plan during end of life. Hastening death by increasing analgesics and/or sedatives was mentioned in 19.3%. The treatment plan was discussed with patients in 26.6% of cases. In 6 cases, an explicit intention to hasten death was mentioned; in 36 cases, doses of opioids/sedatives may not have been strictly proportional to symptoms. Conclusion: This Belgian study shows that objective reporting of palliative sedation can be used as a tool to ensure good clinical practice where patients receive the most appropriate end-of-life care, avoiding abusive and injudicious or unskilled use of sedation.

Is Central Sensitisation the Missing Link of Persisting Symptoms after COVID-19 Infection?

Patients recovered from a COVID-19 infection often report vague symptoms of fatigue or dyspnoea, comparable to the manifestations in patients with central sensitisation. The hypothesis was that central sensitisation could be the underlying common aetiology in both patient populations. This study explored the presence of symptoms of central sensitisation, and the association with functional status and health-related quality of life, in patients post COVID-19 infection. Patients who were previously infected with COVID-19 filled out the Central Sensitisation Inventory (CSI), the Post-COVID-19 Functional Status (PCFS) Scale and the EuroQol with five dimensions, through an online survey. Eventually, 567 persons completed the survey. In total, 29.73% of the persons had a score of <40/100 on the CSI and 70.26% had a score of ≥40/100. Regarding functional status, 7.34% had no functional limitations, 9.13% had negligible functional limitations, 37.30% reported slight functional limitations, 42.86% indicated moderate functional limitations and 3.37% reported severe functional limitations. Based on a one-way ANOVA test, there was a significant effect of PCFS Scale group level on the total CSI score (F(4,486) = 46.17, p < 0.001). This survey indicated the presence of symptoms of central sensitisation in more than 70% of patients post COVID-19 infection, suggesting towards the need for patient education and multimodal rehabilitation, to target nociplastic pain.

Hospital at Home for Intrathecal Pump Refills: A Prospective Effectiveness, Safety and Feasibility Study.

Continuous Intrathecal Drug Delivery through an implanted pump is a well-known therapeutic option for the management of chronic pain and severe disabling spasticity. To have a successful therapy, pump refills need to be performed at regular time intervals after implantation. In line with the increased applications of Hospital at Home, these refill procedures might be performed at the patient's home. The aim of this pilot study is to evaluate the feasibility, safety, and effectiveness of intrathecal pump refill procedures at home. Twenty patients were included whereby pump refill procedures were conducted at the patient's home. To enable contact with the hospital, a video connection was set-up. Tele-ultrasound was used as post-refill verification. All procedures were successfully performed with complete patient satisfaction. Ninety-five percent of the patients felt safe during the procedure, and 95% of the procedures felt safe according to the physician. All patients indicated that they preferred their next refill at home. The median time consumption for the physician/nurse at the patient's home was 26 min and for the researcher at the hospital 15 min. In light of quality enhancement programs and personalized care, it is important to continue urgent pain management procedures in a safe way, even during a pandemic.

The utility of thoracoscopy in the diagnosis and management of pleural disease.

Recurrent and persistent pleural exudates are common in clinical practice, and in a large number of patients, thoracocentesis and blind pleural biopsy procedures do not provide a definitive diagnosis. In the Western world, the majority of these exudates are malignant. Thoracoscopy today remains the gold standard technique in providing diagnosis and management in these cases. Other common indications include diagnosis and management of recurrent or refractory benign exudates or transudates, pleural based tumors and pleural thickening, selected cases of pleural empyema, and recurrent spontaneous primary and secondary pneumothorax. Major advantages of this technique are ease of application, high diagnostic accuracy and therapeutic efficacy, low cost, and excellent safety record comparable with flexible bronchoscopy. Thoracoscopy should be part of the routine training curriculum of respiratory physicians.

Thoracoscopic findings and pharmacokinetics of inhaled fluorescein in a pig model.

BACKGROUND: Fluorescein-enhanced autofluorescence thoracoscopy (FEAT) reveals regions of abnormal fluorescence in patients with primary spontaneous pneumothorax and in normal subjects. Some of these lesions are undetectable by white light thoracoscopy and it has been hypothesized that they represent underlying pleural and/or parenchymal abnormalities. OBJECTIVES: In order to standardize and evaluate this novel technique, we developed an animal model. METHODS: Six pigs underwent thoracoscopy after the inhalation of nebulized sodium fluorescein by either volume-controlled mechanical ventilation or spontaneous ventilation. Pleural cavity and lung surface were inspected by white light thoracoscopy and FEAT during a period of 90 min. Fluorescence intensities were quantified in pleura and in blood. Regions of interest were examined postmortem for a histological assessment of the lesions. RESULTS: FEAT lesions were observed in all animals, with a maximum intensity of the lesions 20-30 min after the onset of fluorescein administration. The plasma concentrations of sodium fluorescein reached a maximum after approximately 20 min. The microscopic findings suggest that fluorescein accumulates in the subpleural space of better ventilated lung areas. CONCLUSIONS: This is the first animal model using FEAT. Valuable information has been gathered but further investigations are required to explain the phenomena observed in humans and pigs.

Safety of pleurodesis with talc poudrage in malignant pleural effusion: a prospective cohort study.

BACKGROUND: Talc is the most effective chemical pleurodesis agent for patients with malignant pleural effusion. However, concerns have arisen about the safety of intrapleural application of talc, after reports of development of acute respiratory distress syndrome in 1-9% of treated patients. Our aim was to establish whether use of large-particle-size talc is safe in patients with malignant pleural effusion. METHODS: We did a multicentre, open-label, prospective cohort study of 558 patients with malignant pleural effusion who underwent thoracoscopy and talc poudrage with 4 g of calibrated French large-particle talc in 13 European hospitals, and one in South Africa. The primary endpoint was the occurrence of acute respiratory distress syndrome after talc pleurodesis. FINDINGS: No patients developed acute respiratory distress syndrome (frequency 0%, one-sided 95% CI 0-0.54%). 11 (2%) patients died within 30 days. Additionally, seven patients had non-fatal post-thoracoscopy complications (1.2%), including one case of respiratory failure due to unexplained bilateral pneumothorax. INTERPRETATION: Use of large-particle talc for pleurodesis in malignant pleural effusion is safe, and not associated with the development of acute respiratory distress syndrome.

Pneumothorax.

Pneumothorax represents a common clinical problem. An overview of relevant and updated information on epidemiology, pathophysiology, and management of spontaneous (primary and secondary), catamenial, and traumatic (iatrogenic and noniatrogenic) pneumothorax is given.

Impact of interventional bronchoscopy on quality of life in malignant airway obstruction.

BACKGROUND: Interventional bronchoscopic procedures can re-establish airway patency in the majority of individuals suffering from endobronchial obstruction. However, literature provides limited data on the impact of these procedures on the individual's quality of life (QoL). OBJECTIVES: We evaluated the impact of interventional bronchoscopic procedures aimed at re-establishing airway patency on symptoms and QoL of individuals who do not receive concomitant chemotherapy or radiation therapy. METHODS: Over a 6-month period, we prospectively enrolled patients with symptomatic central airway obstruction related to malignancy and performed laser ablation, cryotherapy, and/or airway stenting in order to re-establish airway patency. QoL was evaluated by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire at one day before, 7 days after, and 1 month after procedure. Dyspnea was also assessed by the Borg scale before the procedure and one day after. RESULTS: Final analysis could be performed on 83% (20/24) of the participants. Improvement in airway diameter was achieved in all patients, and >80% patency was established in 80% (16/20) of the patients. Dyspnea scores had improved in 85% of participants (p = 0.01). Thirteen patients experienced an improvement in QoL, although QoL scores remained stable for the group as a whole. CONCLUSION: Endoscopic procedures can effectively reduce dyspnea associated with malignant central airway obstruction, but this may not always translate into improvements in overall QoL. Administration of QoL questionnaires is feasible, and may help identify domains contributing to patient's decline, and thereby improve overall patient care.

The prevalence of blebs or bullae among young healthy adults: a thoracoscopic investigation.

BACKGROUND: To determine the prevalence of blebs or bullae using thoracoscopy in young healthy adults, and to compare patient characteristics among those with and without blebs. METHODS: Bilateral thoracoscopic evaluation of the lungs was performed in healthy individuals who were referred for thoracoscopic thoracic sympathectomy for essential hyperhidrosis. Participants were enrolled into a registry and followed for up to 9 years. RESULTS: Analysis was performed on 250 consecutive cases. Blebs were observed in 15 of 250 individuals (6%; male, n = 6; female, n = 9; mean age, 25.3 years; range, 15 to 51 years). Individuals with blebs had a significantly lower body mass index (BMI) [mean +/- SD, 20.7 +/- 2.4 kg/m(2) vs 22.7 +/- 3.4 kg/m(2); p = 0.027] when compared to individuals without blebs, whereas all other parameters were similar. Blebs were most prevalent among slim individuals (BMI < 22 kg/m(2)) who smoked (odds ratio, 5.9; 95% confidence interval, 1.19 to 29.20). CONCLUSION: Blebs were identified thoracoscopically in 6% of young healthy adults with no underlying lung disease. Low BMI in combination with smoking may have an important role in the development of pleural blebs in healthy young adults; however, these changes may not be responsible for future spontaneous pneumothoraces.

Tracheal stenosis: a flow dynamics study.

Patients referred for treatment of tracheal stenosis typically are asymptomatic until critical narrowing of the airway occurs, which then requires immediate intervention. To understand how tracheal stenosis affects local pressure drops and explore how a dramatic increase in pressure drop could possibly be detected at an early stage, a computational fluid dynamics (CFD) study was undertaken. We assessed flow patterns and pressure drops over tracheal stenoses artificially inserted into a realistic three-dimensional upper airway model derived from multislice computed tomography images obtained in healthy men. Solving the Navier-Stokes equations (with a Yang-shih k-epsilon turbulence model) for different degrees of tracheal constriction located approximately one tracheal diameter below the glottis, the simulated pressure drop over the stenosis (DeltaP) was seen to dramatically increase only when well over 70% of the tracheal lumen was obliterated. At 30 l/min, DeltaP increased from 7 Pa for a 50% stenosis to, respectively, 46 and 235 Pa for 80% and 90% stenosis. The pressure-flow relationship in the entire upper airway model (between mouth and end of trachea) in the flow range 0-60 l/min showed a power law relationship with best-fit flow exponent of 1.77 in the absence of stenosis. The exponent became 1.92 and 2.00 in the case of 60% and 85% constriction, respectively. The present simulations confirm that the overall pressure drop at rest is only affected in case of severe constriction, and the simulated flow dependence of pressure drop suggests a means of detecting stenosis at a precritical stage.

Fluorescein-enhanced autofluorescence thoracoscopy in patients with primary spontaneous pneumothorax and normal subjects.

RATIONALE: The exact site(s) and pathophysiology of air leakage in patients with primary spontaneous pneumothorax (PSP) are unknown. In one patient with PSP, fluorescein-enhanced autofluorescence thoracoscopy (FEAT) has shown areas of parenchymal abnormality unnoticed during white light thoracoscopy (WLT). OBJECTIVES: To prospectively perform and compare WLT and FEAT in patients with spontaneous pneumothorax and in normal subjects. METHODS: One-time FEAT and WLT inspection with systematic mapping of semiquantified lesions in 12 consecutive patients with PSP was compared with one-time FEAT and WLT during sequential bilateral thoracoscopy in 17 control subjects. RESULTS: WLT abnormalities (anthracosis, cobblestone malformation, and blebs/bullae) were more prevalent in PSP. FEAT, however, showed high-grade lesions in PSP only, which often were present at areas that were normal, or that only showed anthracosis at WLT. When blebs/bullae were present, bleb-associated FEAT abnormalities were only present in two. Actual fluorescein leakage was seen in two patients with PSP. CONCLUSIONS: Lungs in patients with PSP show significantly more abnormalities at WLT when compared with normal subjects. High-grade FEAT lesions were exclusively present in PSP, and predominantly at lung zones that appeared normal at white light inspection. These findings suggest that significant parenchymal abnormalities are not limited to lesions visible during WLT, such as blebs and bullae.

Design of the Endobronchial Valve for Emphysema Palliation Trial (VENT): a non-surgical method of lung volume reduction.

BACKGROUND: Lung volume reduction surgery is effective at improving lung function, quality of life, and mortality in carefully selected individuals with advanced emphysema. Recently, less invasive bronchoscopic approaches have been designed to utilize these principles while avoiding the associated perioperative risks. The Endobronchial Valve for Emphysema PalliatioN Trial (VENT) posits that occlusion of a single pulmonary lobe through bronchoscopically placed Zephyr endobronchial valves will effect significant improvements in lung function and exercise tolerance with an acceptable risk profile in advanced emphysema. METHODS: The trial design posted on Clinical trials.gov, on August 10, 2005 proposed an enrollment of 270 subjects. Inclusion criteria included: diagnosis of emphysema with forced expiratory volume in one second (FEV1) < 45% of predicted, hyperinflation (total lung capacity measured by body plethysmography > 100%; residual volume > 150% predicted), and heterogeneous emphysema defined using a quantitative chest computed tomography algorithm. Following standardized pulmonary rehabilitation, patients were randomized 2:1 to receive unilateral lobar placement of endobronchial valves plus optimal medical management or optimal medical management alone. The co-primary endpoint was the mean percent change in FEV1 and six minute walk distance at 180 days. Secondary end-points included mean percent change in St. George's Respiratory Questionnaire score and the mean absolute changes in the maximal work load measured by cycle ergometry, dyspnea (mMRC) score, and total oxygen use per day. Per patient response rates in clinically significant improvement/maintenance of FEV1 and six minute walk distance and technical success rates of valve placement were recorded. Apriori response predictors based on quantitative CT and lung physiology were defined. CONCLUSION: If endobronchial valves improve FEV1 and health status with an acceptable safety profile in advanced emphysema, they would offer a novel intervention for this progressive and debilitating disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00129584.

Successful treatment of a giant emphysematous bulla by bronchoscopic placement of endobronchial valves.

Surgical bullectomy is the treatment of choice for giant emphysematous bulla. We report a case of successful nonsurgical treatment with bronchoscopic placement of one-way endobronchial valves that are currently under investigation for the treatment of end-stage emphysema. In patients who are poor surgical candidates, this noninvasive bronchoscopic treatment may represent a valuable alternative.

Bronchopleural fistulas: an overview of the problem with special focus on endoscopic management.

A bronchopleural fistula (BPF) is a communication between the pleural space and the bronchial tree. Although rare, BPFs represent a challenging management problem and are associated with high morbidity and mortality. By far, the postoperative complication of pulmonary resection is the most common cause, followed by lung necrosis complicating infection, persistent spontaneous pneumothorax, chemotherapy or radiotherapy (for lung cancer), and tuberculosis. The treatment of BPF includes various surgical and medical procedures, and of particular interest is the use of bronchoscopy and different glues, coils, and sealants. Localization of the fistula and size may indicate potential benefits of surgical vs endoscopic procedures. In high-risk surgical patients, endoscopic procedures may serve as a temporary bridge until the patient's clinical status is improved, while in other patients endoscopic procedures may be the only option. Therapeutic success has been variable, and the lack of consensus suggests that no optimal therapy is available; rather, the current therapeutic options seem to be complementary, and the treatment should be individualized.

Removal of covered self-expandable metallic airway stents in benign disorders: indications, technique, and outcomes.

STUDY OBJECTIVES: To describe the technique and outcome of removal of self-expandable metallic airway stents (SEMAS) in a series of patients who underwent stenting for benign airway stenoses. DESIGN AND SETTING: A retrospective cohort analysis of patients with benign airway disorders treated with SEMAS between 1997 and 2003, who presented with an indication for stent removal in a tertiary-care hospital, and referral interventional pulmonology clinic. PATIENTS AND METHODS: During the study period, 49 SEMAS were inserted in 39 patients for treatment of benign airway disorders. Ten of these 39 patients (25.6%), bearing 12 covered stents, presented with an indication for stent removal. Data of these cases were extracted from electronic files kept in our institution archive. RESULTS: Indications for stent removal included excessive or recurrent granuloma formation (five cases), recurrence of stenosis after stent failure (one case), stent fracture (two cases), and accomplishment of treatment (two cases). In all of these cases, covered versions of SEMAS had been placed either in the trachea or in a main bronchus. In contrast to many previous reports, these stents proved to be absolutely retrievable even if some difficulties were encountered. In all cases, however, removal was successful without major complications. All patients resumed normal spontaneous ventilation postoperatively, and follow-up was uneventful. Average duration of stenting before removal was 16.2 +/- 17.5 months (+/- SD) [range, 1 to 60 months]. CONCLUSIONS: We conclude that although placement of SEMAS is assumed to be permanent in patients with benign airway disorders, an indication for stent removal is often observed (25.6% in our series). The covered SEMAS can be effectively and safely removed if needed without major sequelae. Nevertheless, new technical improvements in metallic stent design and materials may help reinforce the concept of a retrievable metallic airway stent, which may offer significant clinical advantages.

Effectiveness of thoracoscopic talc pleurodesis in the management of complicated spontaneous pneumothorax.

BACKGROUND: Complicated (recurring or persistent) spontaneous pneumothorax requires intervention either by surgical or nonsurgical pleurodesis or other interventions. As for high-risk patients, aggressive interventions may be associated with morbidity, the safety and effectiveness of less aggressive alternative interventions like thoracoscopic talc pleurodesis (TTP) should be evaluated. METHODS: Data were extracted on patients who had undergone TTP for complicated spontaneous pneumothorax at Interventional Clinic, University Hospital, Brussels, Belgium. The complications, length of hospital stay, and success rate over a 24-month period were studied. RESULTS: A total of 41 TTP procedures were performed for 25 (61%) cases of primary spontaneous pneumothorax and for 16 (39%) cases of secondary spontaneous pneumothorax. Twenty-four cases were first episodes, whereas it was a recurrence in 17. Of 4 patients with blebs/bullae, 2 had recurrence after TTP.No patient had acute respiratory distress syndrome or any other serious complication after TTP. Recurrence rates after TTP in primary and secondary spontaneous pneumothorax were 9.5% and 25% at 24 months, respectively. The mean length of hospital stay after TTP was 3±3.2 days. CONCLUSIONS: TTP is a safe and effective intervention in complicated spontaneous pneumothorax.

Definition of gross tumor volume in lung cancer: inter-observer variability.

BACKGROUND AND PURPOSE: To determine the inter-observer variation in gross tumor volume (GTV) definition in lung cancer, and its clinical relevance. MATERIALS AND METHODS: Five clinicians involved in lung cancer were asked to define GTV on the planning CT scan of eight patients. Resulting GTVs were compared on the base of geometric volume, dimensions and extensions. Judgement of invasion of lymph node (LN) regions was evaluated using the ATS/LCSG classification of LN. Clinical relevance of the variation was studied through 3D-dosimetry of standard conformal plans: volume of critical organs (heart, lungs, esophagus, spinal cord) irradiated at toxic doses, 95% isodose volumes of GTVs, normal tissue complication probabilities (NTCP) and tumor control probabilities (TCP) were compared for evaluation of observer variability. RESULTS: Before evaluation of observer variability, critical review of planning CT scan led to up- (two cases) and downstaging (one case) of patients as compared to the respective diagnostic scans. The defined GTVs showed an inter-observer variation with a ratio up to more than 7 between maximum and minimum geometric content. The dimensions of the primary tumor had inter-observer ranges of 4.2 (transversal), 7.9 (cranio-caudal) and 5.4 (antero-posterior) cm. Extreme extensions of the GTVs (left, right, cranial, caudal, anterior and posterior) varied with ranges of 2.8-7.3 cm due to inter-observer variation. After common review, only 63% of involved lymph node regions were delineated by the clinicians (i.e. 37% are false negative). Twenty-two percent of drawn in lymph node regions were accepted to be false positive after review. In the conformal plans, inter-observer ranges of irradiated normal tissue volume were on average 12%, with a maximum of 66%. The probability (in the population of all conformal plans) of irradiating at least 95% of the GTV with at least 95% of the nominal treatment dose decreased from 96 to 88% when swapping the matched GTV with an unmatched one. The average (over all patients) inter-observer range in NTCP varied from 5% (spinal cord) to 20% (ipsilateral lung), whereas the maximal ranges amounted 16% (spinal cord) to 45% (heart). The average TCP amounted 51% with an average range of 2% (maximally 5%) in case of matched GTVs. These values shifted to 42% (average TCP) with an average range of 14% (maximally 31%) when defining unmatched GTVs. Four groups of causes are suggested for the large inter-observer variation: (1) problems of methodology; (2) impossible differentiation between pathologic structures and tumor; or (3) between normal structures and tumor, and (4); lack of knowledge. Only the minority of these can be resolved objectively. For most of the causal factors agreements have to be made between clinicians, intra- and inter-departmentally. Some of the factors will never be unequivocally solved. CONCLUSIONS: GTV definition in lung cancer is one of the cornerstones in quality assurance of radiotherapy. The large inter-observer variation in GTV definition jeopardizes comparison between clinicians, institutes and treatments.