Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platform.

Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients' molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency.

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Early lung ultrasound assessment for the prognosis of patients hospitalized for COVID-19 pneumonia. A pilot study.

OBJECTIVE: SARS CoV-2 is an epidemic viral infection that can cause mild to severe lung involvement. Newly apprehended knowledge on thoracic imaging abnormalities and the growing clinical experience on the evolution of this disease make the radiographic follow-up of hospitalized patients relevant. The value of consecutive bedside lung ultrasonography in the follow-up of hospitalized patients with SARS CoV-2 pneumonia and its correlation with other clinical and laboratory markers needs to be evaluated. METHODS: We assessed 39 patients [age: 64 y(60.1-68.7)] with confirmed SARS CoV-2 pneumonia. A total of 24 patients were hospitalized until the follow-up test, 9 were discharged early and 6 required a transfer to critical care unit. Two ultrasound scans of the lung were performed on day 1 and 4 of patients' hospitalization. Primary endpoint was the magnitude of association between a global lung ultrasound score (LUS) and clinical and laboratory markers. Secondary endpoint was the association between the evolution of LUS with the corresponded changes in clinical and laboratory outcomes during hospitalization period. RESULTS: LUS score on admission was higher among the deteriorating patients and significantly (P=0.038-0.0001) correlated (Spearman's rho) with the levels of C-reactive protein (0.58), lymphocytes (-0.33), SpO2 (-0.48) and oxygen supplementation (0.48) upon admission. The increase in LUS score between the two scans was significantly correlated (0.544, P=0.006) with longer hospital stay. CONCLUSION: Lung ultrasound assessment can be a useful as an imaging modality for SARS CoV-2 patients. Larger studies are needed to further investigate the predictive role of LUS in the duration and the outcome of the hospitalization of these patients.

Endoscopic advanced imaging of the respiratory tract: exploring probe-based confocal laser endomicroscopy in emphysema.

: Probe-based confocal laser endomicroscopy (pCLE) was performed in 15 patients with emphysema and 15 healthy subjects to visualise small airways in a direct and dynamic way. Morphometry shows that the median cross-sectional area of the alveolar openings at the level of the alveolar ducts is significantly larger in emphysema (7.2×104 µm2) as compared with healthy subjects (5.2×104 µm2) (p=0.0002). Normalised autofluorescence intensity histograms show a decrease in median autofluorescence intensity (mAFI) in emphysema (p=0.001). mAFI correlates well with Tiffeneau index (r=0.66, p=0.007, 95% CI 0.21 to 0.88). Autofluorescence intensity in emphysema correlates with corresponding data of CT-based quantification. pCLE-based morphometry and autofluorescence intensity analysis in emphysema is able to detect regional changes inside the 'quiet zone'. TRIAL REGISTRATION NUMBER: Results, NCT01204970.

Metabolic phenotyping of human blood plasma: a powerful tool to discriminate between cancer types?

BACKGROUND: Accumulating evidence has shown that cancer cell metabolism differs from that of normal cells. However, up to now it is not clear whether different cancer types are characterized by a specific metabolite profile. Therefore, this study aims to evaluate whether the plasma metabolic phenotype allows to discriminate between lung and breast cancer. PATIENTS AND METHODS: The proton nuclear magnetic resonance spectrum of plasma is divided into 110 integration regions, representing the metabolic phenotype. These integration regions reflect the relative metabolite concentrations and were used to train a classification model in discriminating between 80 female breast cancer patients and 54 female lung cancer patients, all with an adenocarcinoma. The validity of the model was examined by permutation testing and by classifying an independent validation cohort of 60 female breast cancer patients and 81 male lung cancer patients, all with an adenocarcinoma. RESULTS: The model allows to classify 99% of the breast cancer patients and 93% of the lung cancer patients correctly with an area under the curve (AUC) of 0.96 and can be validated in the independent cohort with a sensitivity of 89%, a specificity of 82% and an AUC of 0.94. Decreased levels of sphingomyelin and phosphatidylcholine (phospholipids with choline head group) and phospholipids with short, unsaturated fatty acid chains next to increased levels of phospholipids with long, saturated fatty acid chains seem to indicate that cell membranes of lung tumors are more rigid and less sensitive to lipid peroxidation. The other discriminating metabolites are pointing to a more pronounced response of the body to the Warburg effect for lung cancer. CONCLUSION: Metabolic phenotyping of plasma allows to discriminate between lung and breast cancer, indicating that the metabolite profile reflects more than a general cancer marker. CLINICAL TRIAL REGISTRATION NUMBER: NCT02362776.

The inner and outer of our thorax: silicone breast implants and pulmonary alveolar proteinosis.

Pulmonary alveolar (phospholipo)proteinosis (PAP) is a rare lung disease, predominantly autoimmune in nature. This case report describes a patient with insidious dyspnoea since 5 years and a milky appearance of her bronchoalveolar fluid, leading to the diagnosis of PAP. The onset of symptoms coincided with an exchange of her silicone breast implants. Giant cell reaction in axillary adenopathies pointed towards silicone leakage. Adjuvants, such as silicone, might boost pre-existing antigen reactions of the immune system, potentially leading to autoimmune phenomena.

2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease.

Probe-based confocal laser endomicroscopy of the respiratory tract: a data consistency analysis.

BACKGROUND: Probe-based confocal laser endomicroscopy is a novel imaging tool in the field of respiratory medicine. It enables a real-time and bedside qualitative characterization at the level of small airways but due to a relatively small field of view the reliability of quantification remains uncertain. METHODS: Twenty-six lung transplant recipients were subjected to two consecutive alveoloscopic imaging procedures within a median time interval of 90 days to analyze test-retest reliability. Only patients in a stable clinical condition were analyzed. We studied alveolar duct diameter, elastic fiber thickness at the alveolar level, the number of autofluorescent cells at the level of the alveolar space, the diameter of autofluorescent alveolar cells and their autofluorescence intensity. RESULTS: Intraclass correlation coefficients ranged from 0.56 for elastic fiber thickness, 0.62 for alveolar duct diameter, 0.29 for alveolar cell diameter, 0.74 for cellularity to 0.78 for alveolar cell autofluorescence. CONCLUSION: Probe-based confocal laser endomicroscopy enables imaging and quantitative measurements at the level of small airways and alveolar ducts. Test-retest reliability is good for cellularity and autofluorescence quantification but only moderate for morphometric analysis of elastic fibers and alveolar ducts.

Clinical factors predictive of long-term survival in advanced non-small cell lung cancer.

PURPOSE: While the overall prognosis of non-molecularly selected advanced non-small cell lung cancer (NSCLC) patients is poor, a subset of these patients has durable survival. We examined which clinical factors might be predictive for this favourable outcome. PATIENTS AND METHODS: Long-term NSCLC survivors (LTS, i.e. >2 years) were retrieved from all our out- and in-patient contacts in a 6 month period (March-August 2009). LTS records were compared with a group of short-term survivors (STS). Both baseline clinical factors (sex, age, smoking status, weight loss, performance status, co-morbidity, histological subtype, place and number of metastasis) and treatment-related features (number and type of therapeutic lines, response, duration of treatment-free interval) were compared. RESULTS: 31 LTS were retrieved (stage IV patients with potentially radical treatment options, e.g. solitary brain or adrenal metastasis, were excluded), and compared with 34 STS. In the LTS group, median survival was 53 months, with 47% of patients alive at 5 years, in the STS patients this was 9.7 months, with 24% alive at 1-year. Baseline factors had little predictive value, but response to 1st line therapy (P = 0.0001), response duration (P = 0.009), and the number of systemic lines (P = 0.0023) were of importance. CONCLUSION: These data confirm the existence of LTS in patients with advanced NSCLC. There are very little clinical factors at the time of diagnosis that help to distinguish future LTS from STS patients. Factors related to the effect of 1st line treatment are important, and further prospects of patients achieving a 2-year survival are in general quite good.

Screening and early detection of lung cancer.

The greatest news of the past year in this field was the first large-scale early detection trial that could prove a 20% reduction in lung cancer-related mortality by screening high-risk individuals with low-dose computed tomography (LDCT). Several expert groups and medical societies have assessed the data and concluded that LDCT screening for lung cancer is, however, not ready for large-scale population-based implementation. Too many open questions remain, such as definition of the at-risk population, timing and intervals of screening, optimal method of acquisition and interpretation of the images, how to handle (false) positive findings, and especially cost-effectiveness in relation to other lung cancer prevention strategies, mainly smoking cessation. Further analyses and several ongoing European trials are eagerly awaited. Much hope also resides in the use of biomarkers, as their use in, e.g., blood or exhaled air may provide more easy-to-use tests to better stratify high-risk populations for screening studies. While exciting research is ongoing in this domain--e.g. with microRNAs--none of the tests has yet reached sufficient validation for clinical use. Early central lung cancers are more difficult to visualise by CT. For these patients, standard bronchoscopy, complemented by autofluoresence endoscopy, has been studied in different screening and follow-up settings.

Learning curve in tracheal allotransplantation.

The first vascularized tracheal allotransplantation was performed in 2008. Immunosuppression was stopped after forearm implantation and grafting of the recipient mucosa to the internal site of the transplant. Nine months after forearm implantation, the allograft was transplanted to the tracheal defect on the radial blood vessels. Since then, four additional patients have undergone tracheal allotransplantation, three (patients 2-4) for long-segment stenosis and one (patient 5) for a low-grade chondrosarcoma. Our goal was to reduce the time between forearm implantation and orthotopic transplantation and to determine a protocol for safe withdrawal of immunosuppressive therapy. Following forearm implantation, all transplants became fully revascularized over 2 months. Withdrawal of immunosuppression began 4 months after graft implantation and was completed within 6 weeks in cases 2-4. Repopulation of the mucosal lining by recipient cells, to compensate for the necrosis of the donor mucosa, was not complete. This resulted in partial loss of the allotransplant in patients 2-4. In patient 5, additional measures promoting recipient cell repopulation were made. The trachea may be used as a composite tissue allotransplant after heterotopic revascularization in the forearm. Measures to maximize recipient cell repopulation may be important in maintaining the viability of the transplant after cessation of immunosuppression.

Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial.

OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of endosonography (followed by surgical staging if endosonography was negative), compared with standard surgical staging alone, in patients with non-small cell lung cancer (NSCLC) who are otherwise candidates for surgery with curative intent. DESIGN: A prospective, international, open-label, randomised controlled study, with a trial-based economic analysis. SETTING: Four centres: Ghent University Hospital, Belgium; Leuven University Hospitals, Belgium; Leiden University Medical Centre, the Netherlands; and Papworth Hospital, UK. INCLUSION CRITERIA: known/suspected NSCLC, with suspected mediastinal lymph node involvement; otherwise eligible for surgery with curative intent; clinically fit for endosonography and surgery; and no evidence of metastatic disease. EXCLUSION CRITERIA: previous lung cancer treatment; concurrent malignancy; uncorrected coagulopathy; and not suitable for surgical staging. INTERVENTIONS: Study patients were randomised to either surgical staging alone (n = 118) or endosonography followed by surgical staging if endosonography was negative (n = 123). Endosonography diagnostic strategy used endoscopic ultrasound-guided fine-needle aspiration combined with endobronchial ultrasound-guided transbronchial needle aspiration, followed by surgical staging if these tests were negative. Patients with no evidence of mediastinal metastases or tumour invasion were referred for surgery with curative intent. If evidence of malignancy was found, patients were referred for chemoradiotherapy. MAIN OUTCOME MEASURES: The main clinical outcomes were sensitivity (positive diagnostic test/nodal involvement during any diagnostic test or thoracotomy) and negative predictive value (NPV) of each diagnostic strategy for the detection of N2/N3 metastases, unnecessary thoracotomy and complication rates. The primary economic outcome was cost-utility of the endosonography strategy compared with surgical staging alone, up to 6 months after randomisation, from a UK NHS perspective. RESULTS: Clinical and resource-use data were available for all 241 patients, and complete utilities were available for 144. Sensitivity for detecting N2/N3 metastases was 79% [41/52; 95% confidence interval (CI) 66% to 88%] for the surgical arm compared with 94% (62/66; 95% CI 85% to 98%) for the endosonography strategy (p = 0.02). Corresponding NPVs were 86% (66/77; 95% CI 76% to 92%) and 93% (57/61; 95% CI 84% to 97%; p = 0.26). There were 21/118 (18%) unnecessary thoracotomies in the surgical arm compared with 9/123 (7%) in the endosonography arm (p = 0.02). Complications occurred in 7/118 (6%) in the surgical arm and 6/123 (5%) in the endosonography arm (p = 0.78): one pneumothorax related to endosonography and 12 complications related to surgical staging. Patients in the endosonography arm had greater EQ-5D (European Quality of Life-5 Dimensions) utility at the end of staging (0.117; 95% CI 0.042 to 0.192; p = 0.003). There were no other significant differences in utility. The main difference in resource use was the number of thoracotomies: 66% patients in the surgical arm compared with 53% in the endosonography arm. Resource use was similar between the groups in all other items. The 6-month cost of the endosonography strategy was £9713 (95% CI £7209 to £13,307) per patient versus £10,459 (£7732 to £13,890) for the surgical arm, mean difference £746 (95% CI -£756 to £2494). The mean difference in quality-adjusted life-year was 0.015 (95% CI -0.023 to 0.052) in favour of endosonography, so this strategy was cheaper and more effective. CONCLUSIONS: Endosonography (followed by surgical staging if negative) had higher sensitivity and NPVs, resulted in fewer unnecessary thoracotomies and better quality of life during staging, and was slightly more effective and less expensive than surgical staging alone. Future work could investigate the need for confirmatory mediastinoscopy following negative endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the diagnostic accuracy of EUS-FNA or EBUS-TBNA separately and the delivery of both EUS-FNA or EBUS-TBNA by suitably trained chest physicians. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 97311620. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 18. See the HTA programme website for further project information.

Why a chest physician should be interested in abdominal pain.

A 37-year-old woman presented at casualty with a 1-day history of progressive spontaneous left iliac fossa pain. She was having her menstruations for 4 days. She had no respiratory symptoms. Her medical history consisted of laparoscopic surgery for endometriosis and ovarian cysts. A very small right basal pneumothorax with visualisation of a hypervascular nodular lesion on the right diaphragm was incidentally noticed on the right diaphragm. We suspected here a catamenial pneumothorax. During video-assisted thoracoscopy the surgeon observed in the centrum tendineum of the diaphragm a small and a large perforation with partial intrathoracic herniation of the liver, but without visible diaphragmatic or pleural endometriosis. The surgeons converted to a small anterior thoracotomy in order to reinforce the large perforation with interrupted non-absorbable sutures and plication of the smaller perforation, and finally performed a mechanical pleural abrasion with a surgical pad.

Endobronchial ultrasound-guided transbronchial needle biopsy for M1 staging of extrathoracic malignancies.

BACKGROUND: extrathoracic malignancies metastasize to the mediastinum and/or pulmonary hilum. Mediastinoscopy and thoracoscopy are standard to obtain tissue proof of metastatic spread but are invasive. Endobronchial ultrasound with real-time-guided transbronchial fine-needle aspiration (EBUS-TBNA) is a minimally invasive alternative for surgical staging of lung cancer. METHODS: we analysed the test characteristics of EBUS-TBNA in consecutive patients with a suspicion of mediastinal or hilar metastases of various extrathoracic malignancies. RESULTS: ninety-two patients with concurrent (n = 33) or previously diagnosed and treated (n = 59) extrathoracic malignancies were evaluated. EBUS-TBNA detected mediastinal or hilar metastatic spread in 52 patients (57%) [metastasis of extrathoracic tumour in 40 (44%) and second malignancies (lung cancer) in 12 (13%)]. Subsequent surgical staging showed malignancy in another nine patients. With EBUS-TBNA, an alternate diagnosis was found in four. Sensitivity and negative predictive value for mediastinal or hilar metastatic spread were 85% [95% confidence interval (CI) 73-93] and 76% (95% CI 59-88). EBUS-TBNA prevented an invasive surgical procedure in 61% of the patients. One patient had a respiratory arrest during EBUS-TBNA; abortion lead to full recovery without further intervention. CONCLUSIONS: EBUS-TBNA is a minimally invasive method for M staging of patients with extrathoracic malignancies to confirm mediastinal or hilar spread. EBUS-TBNA therefore may qualify as an alternative for surgical staging.

Early stage non-small-cell lung cancer: challenges in staging and adjuvant treatment: evidence-based staging.

Staging of non-small-cell lung cancer is a multidisciplinary process involving imaging, endoscopic and surgical techniques. Accuracy is vital in order to avoid false-positive interpretations leading to a false stage III or IV diagnosis in early stage patients, or false-negative findings leading to a false early stage diagnosis in patients with mediastinal lymph node disease. CT scan offers great anatomical detail of tumour spread, but radiological imaging lacks information on the biological nature of the lesions. The latter is brought in by 2-[fluorine-18] fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) scan as a metabolic imaging tool, which, however, has clearly lower spatial resolution. Therefore, contemporary staging relies on the combination of both, preferably in a fusion PET-CT scan. Absence of suspected lymph node metastasis on both CT and PET has a high negative predictive value, and these patients may in general proceed to surgery. In most others, tissue confirmation of the locoregional lymph node status is needed. The historical standard of mediastinoscopy is nowadays complemented by endoscopic techniques by the bronchial or esophageal approach. Each of these techniques remains important in modern staging algorithms. A practical scheme for rational staging in clinical practice is discussed.

Diagnostic bronchoscopy: state of the art.

Since the introduction of the flexible fibreoptic bronchoscope in the late 1960s there have been relatively few technological advances for three decades, aside from the development of a white light video bronchoscope with a miniature charge-coupled device built in its tip replacing the fibreoptics. White light flexible videobronchoscopy with its ancillary devices (forceps biopsy, bronchial brushing, bronchoalveolar lavage, bronchial washings and transbronchial needle aspiration) has long been the only established diagnostic bronchoscopic technique. With the advances in microtechnology over the past two decades, recent technical developments such as autofluorescence bronchoscopy and endoscopic ultrasound allow better evaluation of endobronchial, mediastinal and parenchymal lesions.

The value of endoscopic ultrasound after bronchoscopy to diagnose thoracic sarcoidosis.

A clinicoradiological presentation of thoracic sarcoidosis requires histopathology in order to establish the diagnosis. Flexible bronchoscopy has a reasonable diagnostic yield and is the procedure of first choice for diagnosis. Endoscopic ultrasound (endoscopic ultrasound-guided fine needle aspiration/endobronchial ultrasound-guided transbronchial needle aspiration) can help in the diagnosis of sarcoidosis. An implementation strategy of endoscopic ultrasound for the diagnosis of sarcoidosis following negative flexible bronchoscopy results was examined prospectively in 15 clinics. A total of 137 patients (92 males; median age 43 yrs) were included, and sarcoidosis was found in 115 (84%). Alternative diagnoses were tuberculosis, lymphangitis carcinomatosa, pneumoconiosis and alveolitis. All patients were sent for flexible bronchoscopy, which was performed in 121 (88%), resulting in a definite diagnosis in 57 (42%). A total of 80 patients were sent for endoscopic ultrasound, which could be performed in 72 (90%), yielding a definite diagnosis in 47 (59%). Endoscopic ultrasound following negative flexible bronchoscopy avoided a surgical procedure in 47 out of 80 patients. The sensitivity of flexible bronchoscopy for sarcoidosis was 45% (95% confidence interval 35-54%), but 62% (50-72%) if biopsy specimens were taken. The sensitivity of endoscopic ultrasound following negative flexible bronchoscopy results was 71% (58-82%). With this strategy, 97 out of 115 (84% (76-90%)) of proven sarcoidosis was diagnosed using endoscopy. This large prospective implementation study (trial number NCT00888212; ClinicalTrials.gov) shows that endoscopic ultrasound is valuable for diagnosing sarcoidosis after negative flexible bronchoscopy results.