Cone Beam Computed Tomography-guided Navigation Bronchoscopy with Augmented Fluoroscopy for the Diagnosis of Peripheral Pulmonary Nodules: a step-by-step guide.

Introduction Cone Beam CT-guided Navigation Bronchoscopy (CBCT-NB) with Augmented Fluoroscopy (AF) guidance represents a minimally invasive endobronchial technique for diagnosing small, peripheral pulmonary lesions. This approach is characterized by its high diagnostic accuracy and low complication risk. Current pilot trials are exploring the application of localized therapies using this innovative approach. This reportaims to provide a detailed procedural guide for performing CBCT-NB with AF guidance as the only tool for navigation and image guided biopsy. Methods We outline the procedural steps involved in the CBCT-NB procedure for diagnosing peripheral pulmonary lesions, supported by specific intra-procedural clinical video footage. The steps include (1) preprocedural considerations, (2) a detailed procedural workflow encompassing navigation to the target lesion, (3) position confirmation and tissue acquisition, and (4) postprocedural follow-up. Conclusion CBCT-NB with AF guidance is a safe and precise stand-alone navigation modality that offers high-resolution real-time 3D imaging, enhancing the diagnosis and potential treatment of peripheral pulmonary nodules.

Radiation Principles, Protection, and Reporting for Interventional Pulmonology: A World Association of Bronchology and Interventional Pulmonology White Paper.

The use and availability of diverse advanced X-ray based imaging and guidance systems in the field of interventional pulmonology are rapidly growing. This popularity links inextricably to an increase in ionizing radiation use. Knowing ionizing radiation is hazardous, knowledge and competent use of X-ray imaging and guidance systems are important. The globally implemented As Low As Reasonably Achievable (ALARA) principle demands careful attention to minimize radiation exposure while achieving the precise goals of the intervention and imaging therein. To allow careful and targeted weighing of risk against reward while using X-ray based equipment, proper background knowledge of physics as well as imaging system aspects are needed. This white paper summarizes the principles of ionizing radiation which are crucial to enhance awareness and interpretation of dosimetric quantities. Consecutively, a consensus on standards for reporting radiation exposure in interventional pulmonology procedures is indicated to facilitate comparisons between different systems, approaches and results. Last but not least, it provides a list of practical measures, considerations and tips to optimize procedural imaging as well as reduce radiation dose to patients and staff.

Proposed quality indicators and recommended standard reporting items in performance of EBUS bronchoscopy: An official World Association for Bronchology and Interventional Pulmonology Expert Panel consensus statement.

BACKGROUND: Since their introduction, both linear and radial endobronchial ultrasound (EBUS) have become an integral component of the practice of Pulmonology and Thoracic Oncology. The quality of health care can be measured by comparing the performance of an individual or a health service with an ideal threshold or benchmark. The taskforce sought to evaluate quality indicators in EBUS bronchoscopy based on clinical relevance/importance and on the basis that observed significant variation in outcomes indicates potential for improvement in health care outcomes. METHODS: A comprehensive literature review informed the composition of a comprehensive list of candidate quality indicators in EBUS. A multiple-round modified Delphi consensus process was subsequently performed with the aim of reaching consensus over a final list of quality indicators and performance targets for these indicators. Standard reporting items were developed, with a strong preference for items where evidence demonstrates a relationship with quality indicator outcomes. RESULTS: Twelve quality Indicators are proposed, with performance targets supported by evidence from the literature. Standardized reporting items for both radial and linear EBUS are recommended, with evidence supporting their utility in assessing procedural outcomes presented. CONCLUSION: This statement is intended to provide a framework for individual proceduralists to assess the quality of EBUS they provide their patients through the identification of clinically relevant, feasible quality measures. Emphasis is placed on outcome measures, with a preference for consistent terminology to allow communication and benchmarking between centres.

Accuracy and Reproducibility of Endoscopic Ultrasound B-Mode Features for Observer-Based Lymph Nodal Malignancy Prediction.

BACKGROUND: Endoscopic ultrasound routinely guides lymph node evaluation for the staging of a known or suspected lung cancer. Characteristics seen on B-mode imaging might help the observer decide on the lymph nodes of risk. The influence of nodal size on the predictivity of these characteristics and the agreement with which operators can combine these for malignancy risk prediction is to be determined. OBJECTIVES: We evaluated (1) if prospectively scored individual B-mode ultrasound features predict malignancy when further divided by size and (2) assessed if observers were able to reproducibly agree on still lymph node image malignancy risk. METHODS: Lymph nodes as visualized by EBUS were prospectively scored for B-mode characteristics. Still B-mode images were furthermore collected. After collection, a repeated scoring of a subset of lymph nodes was retrospectively performed (n = 11 observers). RESULTS: Analysis of 490 lymph nodes revealed the short axis size is an objective measure for stratifying risk of malignancy (ROC area under the curve 0.78). With ≥8-mm size, 210/237 malignant lymph nodes were correctly identified (89% sensitivity, 46% specificity, 61% PPV, and 81% NPV). Secondary addition of B-mode features in <8-mm nodes had limited value. Retrospective analysis of intra- and interobserver scoring furthermore revealed significant disagreement. CONCLUSIONS: Lymph nodes of ≥8-mm size and preferably even smaller should be aspirated regardless of other B-mode features. Observer disagreement in scoring both small and large lymph nodes suggests it is infeasible to include subjective features for stratification. Future research should focus on (integrating) other (semi)quantitative values for improving prediction.

Predictive Value of Endobronchial Ultrasound Strain Elastography in Mediastinal Lymph Node Staging: The E-Predict Multicenter Study Results.

BACKGROUND: Systematic assessment of lymph node status by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is indicated in (suspected) lung cancer. Sampling is herein guided by nodal size and FDG-PET characteristics. Ultrasound strain elastography (SE) might further improve risk stratification. By imaging tissue deformation over time, SE computes relative tissue strain. In several tissues, a lower strain (deformation) has been associated with a higher likelihood of malignancy. OBJECTIVES: To assess if EBUS-SE can independently help predict malignancy, and when combined with size and FDG uptake information. METHODS: This multicenter (n = 5 centers) prospective trial included patients with suspected or proven lung cancer using a standardized measurement protocol. Cytopathology combined with surgery or follow-up imaging (>6 months) were used as reference standard. RESULTS: Between June 2016 and July 2018, 327 patients and 525 lymph nodes were included (mean size 12.3 mm, malignancy prevalence 0.48). EBUS-SE had an overall AUC of 0.77. A mean strain <115 (range 0-255) showed 90% sensitivity, 43% specificity, 60% positive predictive value, and 82% negative predictive value. Combining EBUS-SE (<115) with size (<8 mm) and FDG-PET information into a risk stratification algorithm increased the accuracy. Combining size and SE showed that the 48% a priori chance of malignancy changed to 11 and 70% in double negative or positive nodes, respectively. In the subset where FDG-PET was available (n = 370), triple negative and positive nodes went from a 42% a priori chance of malignancy to 9 and 73%, respectively. CONCLUSIONS: EBUS-SE can help predict lymph node malignancy and may be useful for risk stratification when combined with size and PET information.

Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci.

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study.

BACKGROUND: Retrospective studies suggest that low molecular weight heparin may delay the development of metastasis in patients with resected NSCLC. METHODS: Multicentre phase 3 study with patients with completely resected NSCLC who were randomised after surgery to receive chemotherapy with or without nadroparin. The main exclusion criteria were R1/2 and wedge/segmental resection. FDG-PET was required. The primary endpoint was recurrence-free survival (RFS). RESULTS: Among 235 registered patients, 202 were randomised (nadroparin: n = 100; control n = 102). Slow accrual enabled a decrease in the number of patients needed from 600 to 202, providing 80% power to compare RFS with 94 events (α = 0.05; 2-sided). There were no differences in bleeding events between the two groups. The median RFS was 65.2 months (95% CI, 36-NA) in the nadroparin arm and 37.7 months (95% CI, 22.7-NA) in the control arm (HR 0.77 (95% CI, 0.53-1.13, P = 0.19). FDG-PET SUVmax ≥10 predicted a greater likelihood of recurrence in the first year (HR 0.48, 95% CI 0.22-0.9, P = 0.05). CONCLUSIONS: Adjuvant nadroparin did not improve RFS in patients with resected NSCLC. In this study, a high SUVmax predicted a greater likelihood of recurrence in the first year. CLINICAL TRIAL REGISTRATION: Netherlands Trial registry: NTR1250/1217.

Optimal Endobronchial Ultrasound Strain Elastography Assessment Strategy: An Explorative Study.

BACKGROUND: In lung cancer staging, mediastinal lymph nodes are currently aspirated using endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) based on size and FDG-PET avidity. EBUS strain elastography (SE) is a new technique that may help predict the presence of malignancy. However, a standardized assessment strategy for EBUS-SE measurement is lacking. OBJECTIVES: The aim of this study was to determine the optimal assessment strategy for investigating the predictive value of EBUS-SE in mediastinal lymph nodes. METHODS: Two qualitative visual analogue scale strain scores and two semiquantitative strain elastography measurements (a strain histogram and strain ratio) were acquired in 120 lymph nodes of 63 patients with (suspected) lung cancer. The dataset was randomized into an 80% training dataset to determine cut-off values. Performance was consecutively tested on the remaining 20% and the overall dataset. RESULTS: The semiquantitative mean histogram scoring strategy with a cut-off value of 78 (range 0-255) showed the best and most reproducible performance in prediction of malignancy with 93% overall sensitivity, 75% specificity, 69% positive predictive value, 95% negative predictive value, and 82% accuracy. Combining the EBUS-SE mean histogram scoring outcome with PET-CT information increased the post-test probability of disease in relevant clinical scenarios, having a positive test likelihood ratio of 4.16 (95% CI 2.98-8.13) and a negative test likelihood ratio of 0.14 (95% CI 0.04-2.81) in suspicious lymph nodes based on FDG-PET or CT imaging. CONCLUSIONS: EBUS-SE can potentially help predict lymph node malignancy in patients with lung cancer. The best semiquantitative assessment method is the mean strain histogram technique.

EUS Needle Identification Comparison and Evaluation study (with videos).

BACKGROUND AND AIMS: EUS-guided FNA or biopsy sampling is widely practiced. Optimal sonographic visualization of the needle is critical for image-guided interventions. Of the several commercially available needles, bench-top testing and direct comparison of these needles have not been done to reveal their inherent echogenicity. The aims are to provide bench-top data that can be used to guide clinical applications and to promote future device research and development. METHODS: Descriptive bench-top testing and comparison of 8 commonly used EUS-FNA needles (all size 22 gauge): SonoTip Pro Control (Medi-Globe); Expect Slimline (Boston Scientific); EchoTip, EchoTip Ultra, EchoTip ProCore High Definition (Cook Medical); ClearView (Conmed); EZ Shot 2 (Olympus); and BNX (Beacon Endoscopic), and 2 new prototype needles, SonoCoat (Medi-Globe), coated by echogenic polymers made by Encapson. Blinded evaluation of standardized and unedited videos by 43 EUS endoscopists and 17 radiologists specialized in GI US examination who were unfamiliar with EUS needle devices. RESULTS: There was no significant difference in the ratings and rankings of these needles between endosonographers and radiologists. Overall, 1 prototype needle was rated as the best, ranking 10% to 40% higher than all other needles (P < .01). Among the commercially available needles, the EchoTip Ultra needle and the ClearView needle were top choices. The EZ Shot 2 needle was ranked statistically lower than other needles (30%-75% worse, P < .001). CONCLUSIONS: All FNA needles have their inherent and different echogenicities, and these differences are similarly recognized by EUS endoscopists and radiologists. Needles with polymeric coating from the entire shaft to the needle tip may offer better echogenicity.

High definition bronchoscopy: a randomized exploratory study of diagnostic value compared to standard white light bronchoscopy and autofluorescence bronchoscopy.

BACKGROUND: Videobronchoscopy is an essential diagnostic procedure for evaluation of the central airways and pivotal for the diagnosis and staging of lung cancer. Technological improvements have resulted in high definition (HD) images with advanced real time image enhancement techniques (i-scan). OBJECTIVES: In this study we aimed to explore the sensitivity of HD+ i-scan bronchoscopy for detection of epithelial changes like vascular abnormalities and suspicious preinvasive lesions, and tumors. METHODS: In patients scheduled for a therapeutic or diagnostic procedure under general anesthesia videos of the bronchial tree were made using 5 videobronchoscopy modes in random order: normal white light videobronchoscopy (WLB), HD-bronchoscopy (HD), HD bronchoscopy with surface enhancement technique (i-scan1), HD with surface- and tone enhancement technique (i-scan2) and dual mode autofluorescence videobronchoscopy (AFB). The videos were scored in random order by two independent and blinded expert bronchoscopists. RESULTS: In 29 patients all videos were available for analysis. Vascular abnormalities were scored most frequently in HD + i-scan2 bronchoscopy (1.33 ± 0.29 abnormal or suspicious sites per patient) as compared to 0.12 ± 0.05 site for AFB (P = 0.003). Sites suspicious for preinvasive lesions were most frequently reported using AFB (0.74 ± 0.12 sites per patient) as compared to 0.17 ± 0.06 for both WLB and HD bronchoscopy (P = 0.003). Tumors were detected equally by all modalities. The preferred modality was HD bronchoscopy with i-scan (tone- plus surface and surface enhancement in respectively 38% and 35% of cases P = 0.006). CONCLUSIONS: This study shows that high definition bronchoscopy with image enhancement technique may result in better detection of subtle vascular abnormalities in the airways. Since these abnormalities may be related to preneoplastic lesions and tumors this is of clinical relevance. Further investigations using this technique relating imaging to histology are warranted.

Distress in suspected lung cancer patients following rapid and standard diagnostic programs: a prospective observational study.

OBJECTIVE: Timeliness may influence emotional distress during the diagnostic phase of suspected lung cancer patients. We performed a prospective observational study to compare distress and quality of life (QoL) in two medical centres with a Rapid Outpatient Diagnostic Program (RODP) and two using conventional Stepwise Diagnostic Approach (SDA) on the basis of trained nurse-led care. METHODS: Outpatients with radiological suspicion of lung cancer completed the Hospital Anxiety and Depression Scale (HADS), European Organization for Research and Treatment of Cancer 30-item Quality of Life Questionnaire (QLQ-C30) and its 13-item Lung Cancer specific module (QLQ-LC13) upon first visit, 2 days later, thereafter weekly for 5 weeks and after 3 months. RESULTS: The 72 SDA patients and 121 RODP patients had a mean pre-diagnostic HADS-total score of 13.5 (SD 7.6); 63.4% had a score ≥10. Baseline QLQ-C30 global QoL was 61.6 (SD 22.7) exceeding reference values for lung cancer patients. Generalized least square models showed a significant centre by time interaction effect: during the first 6 weeks, HADS-total scores decreased in RODP patients (13.8-11.9) but sustained in SDA patients (13.1-13.6), whereas QoL showed no relevant changes. Times to diagnosis and discussion of therapy plan for RODP patients were 7 and 11 days shorter, respectively. CONCLUSIONS: Suspected lung cancer patients had high baseline distress levels. A decrease over time was found in RODP compared with SDA patients. QoL did not change relevantly. Albeit observational, these data indicate that patients experience less distress in rapid diagnostic programs than in stepwise diagnostic evaluation.

Guideline for the acquisition and preparation of conventional and endobronchial ultrasound-guided transbronchial needle aspiration specimens for the diagnosis and molecular testing of patients with known or suspected lung cancer.

RATIONALE: Conventional transbronchial needle aspiration (TBNA) and endobronchial ultrasound (EBUS)-TBNA are widely accepted tools for the diagnosis and staging of lung cancer and the initial procedure of choice for staging. Obtaining adequate specimens is key to provide a specific histologic and molecular diagnosis of lung cancer. OBJECTIVES: To develop practice guidelines on the acquisition and preparation of conventional TBNA and EBUS-TBNA specimens for the diagnosis and molecular testing of (suspected) lung cancer. We hope to improve the global unification of procedure standards, maximize the yield and identify areas for research. METHODS: Systematic electronic database searches were conducted to identify relevant studies for inclusion in the guideline [PubMed and the Cochrane Library (including the Cochrane Database of Systematic Reviews)]. MAIN RESULTS: The number of needle aspirations with both conventional TBNA and EBUS-TBNA was found to impact the diagnostic yield, with at least 3 passes needed for optimal performance. Neither needle gauge nor the use of miniforceps, the use of suction or the type of sedation/anesthesia has been found to improve the diagnostic yield for lung cancer. The use of rapid on-site cytology examination does not increase the diagnostic yield. Molecular analysis (i.e. EGFR, KRAS and ALK) can be routinely performed on the majority of cytological samples obtained by EBUS-TBNA and conventional TBNA. There does not appear to be a superior method for specimen preparation (i.e. slide staining, cell blocks or core tissue). It is likely that optimal specimen preparation may vary between institutions depending on the expertise of pathology colleagues.

Estimating lung function from computed tomography at the patient and lobe level using machine learning.

BACKGROUND: Automated estimation of Pulmonary function test (PFT) results from Computed Tomography (CT) could advance the use of CT in screening, diagnosis, and staging of restrictive pulmonary diseases. Estimating lung function per lobe, which cannot be done with PFTs, would be helpful for risk assessment for pulmonary resection surgery and bronchoscopic lung volume reduction. PURPOSE: To automatically estimate PFT results from CT and furthermore disentangle the individual contribution of pulmonary lobes to a patient's lung function. METHODS: We propose I3Dr, a deep learning architecture for estimating global measures from an image that can also estimate the contributions of individual parts of the image to this global measure. We apply it to estimate the separate contributions of each pulmonary lobe to a patient's total lung function from CT, while requiring only CT scans and patient level lung function measurements for training. I3Dr consists of a lobe-level and a patient-level model. The lobe-level model extracts all anatomical pulmonary lobes from a CT scan and processes them in parallel to produce lobe level lung function estimates that sum up to a patient level estimate. The patient-level model directly estimates patient level lung function from a CT scan and is used to re-scale the output of the lobe-level model to increase performance. After demonstrating the viability of the proposed approach, the I3Dr model is trained and evaluated for PFT result estimation using a large data set of 8 433 CT volumes for training, 1 775 CT volumes for validation, and 1 873 CT volumes for testing. RESULTS: First, we demonstrate the viability of our approach by showing that a model trained with a collection of digit images to estimate their sum implicitly learns to assign correct values to individual digits. Next, we show that our models can estimate lobe-level quantities, such as COVID-19 severity scores, pulmonary volume (PV), and functional pulmonary volume (FPV) from CT while only provided with patient-level quantities during training. Lastly, we train and evaluate models for producing spirometry and diffusion capacity of carbon mono-oxide (DLCO) estimates at the patient and lobe level. For producing Forced Expiratory Volume in one second (FEV1), Forced Vital Capacity (FVC), and DLCO estimates, I3Dr obtains mean absolute errors (MAE) of 0.377 L, 0.297 L, and 2.800 mL/min/mm Hg respectively. We release the resulting algorithms for lung function estimation to the research community at https://grand-challenge.org/algorithms/lobe-wise-lung-function-estimation/ CONCLUSIONS: I3Dr can estimate global measures from an image, as well as the contributions of individual parts of the image to this global measure. It offers a promising approach for estimating PFT results from CT scans and disentangling the individual contribution of pulmonary lobes to a patient's lung function. The findings presented in this work may advance the use of CT in screening, diagnosis, and staging of restrictive pulmonary diseases as well as in risk assessment for pulmonary resection surgery and bronchoscopic lung volume reduction.

Diagnostic yield of cone beam CT based navigation bronchoscopy in patients with metastatic lesions: A propensity score matched case-control study.

BACKGROUND: Cone beam CT based Navigation Bronchoscopy (CBCT-NB) has predominantly been investigated as a diagnostic tool in (suspected) primary lung cancers. Small metastatic lesions are clinically considered more challenging to diagnose, but no study has explored the yield of navigation bronchoscopy in patients with pulmonary metastatic lesions (ML) compared to primary lung cancers (PL), correcting for known lesion characteristics affecting diagnostic yield. MATERIALS AND METHODS: This is a single-center, retrospective, propensity score-matched case-control study. We matched a subset of patients who underwent CBCT-NB and received a final diagnosis of pulmonary metastases of solid tumors between December 2017 and 2021 against confirmed primary lung cancer lesions subjected to CBCT-NB in the same time period. The lesions were propensity score matched based on known characteristics affecting yield, including location (upper lobe, lower lobe), size, bronchus sign, and lesion solidity. RESULTS: Fifty-six metastatic pulmonary lesions (mean size 14.7 mm) were individually case-matched to a selection of 297 available primary lung cancer lesions. Case-matching revealed non-significant differences in navigation success rate (PL: 89.3 % vs. ML: 82.1 %, 95%CI on differences: -21.8 to +7.5) and yield (PL: 60.7 % vs. ML: 55.4 %, 95%CI on differences: -25.4 to +14.7). The overall complication rate was comparable (5.4 % in PL vs. 5,4 % in ML). CONCLUSION: After matching primary and metastatic lesions based on CT assessable lesions characteristics, CBCT-NB showed no clinically relevant or significantly different navigation success or yield in either group. We recommend a careful assessment of CT characteristics to determine procedural difficulty rather than selecting based on the suspicion of lesion origin.

Minimally Invasive Sampling of Mediastinal Lesions.

This narrative review examines the existing literature on minimally invasive image-guided sampling techniques of mediastinal lesions gathered from international databases (Medline, PubMed, Scopus, and Google Scholar). Original studies, systematic reviews with meta-analyses, randomized controlled trials, and case reports published between January 2009 and November 2023 were included. Four authors independently conducted the search to minimize bias, removed duplicates, and selected and evaluated the studies. The review focuses on the recent advancements in mediastinal sampling techniques, including EBUS-TBNA, EUS-FNA and FNB, IFB, and nodal cryobiopsy. The review highlights the advantages of an integrated approach using these techniques for diagnosing and staging mediastinal diseases, which, when used competently, significantly increase diagnostic yield and accuracy.