Systematic endoscopic staging of mediastinum to guide radiotherapy planning in patients with locally advanced non-small-cell lung cancer (SEISMIC): an international, multicentre, single-arm, clinical trial.

BACKGROUND: Systematic mediastinal lymph node staging by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) improves accuracy of staging in patients with early-stage non-small-cell lung cancer (NSCLC). However, patients with locally advanced NSCLC commonly undergo only selective lymph node sampling. This study aimed to determine the proportion of patients with locally advanced NSCLC in whom systematic endoscopic mediastinal staging identified PET-occult lymph node metastases, and to describe the consequences of PET-occult disease on radiotherapy planning. METHODS: This prospective, international, multicentre, single-arm, international study was conducted at seven tertiary lung cancer centres in four countries (Australia, Canada, the Netherlands, and the USA). Patients aged 18 years or older with suspected or known locally advanced NSCLC underwent systematic endoscopic mediastinal lymph node staging before combination chemoradiotherapy or high-dose palliative radiotherapy. The primary endpoint was the proportion of participants with PET-occult mediastinal lymph node metastases shown following systematic endoscopic staging. The study was prospectively registered with Australian New Zealand Clinical Trials Registry, ACTRN12617000333314. FINDINGS: From Jan 30, 2018, to March 23, 2022, 155 patients underwent systematic endoscopic mediastinal lymph node staging and were eligible for analysis. 58 (37%) of patients were female and 97 (63%) were male. Discrepancy in extent of mediastinal disease identified by PET and EBUS-TBNA was observed in 57 (37% [95% CI 29-44]) patients. PET-occult lymph node metastases were identified in 18 (12% [7-17]) participants, including 16 (13% [7-19]) of 123 participants with clinical stage IIIA or cN2 NSCLC. Contralateral PET-occult N3 disease was identified in nine (7% [2-12]) of 128 participants staged cN0, cN1, or cN2. Identification of PET-occult disease resulted in clinically significant changes to treatment in all 18 patients. In silico dosimetry studies showed the median volume of PET-occult lymph nodes receiving the prescription dose of 60 Gy was only 10·1% (IQR 0·1-52·3). No serious adverse events following endoscopic staging were reported. INTERPRETATION: Our findings suggests that systematic endoscopic mediastinal staging in patients with locally advanced or unresectable NSCLC is more accurate than PET alone in defining extent of mediastinal involvement. Standard guideline-recommended PET-based radiotherapy planning results in suboptimal tumour coverage. Our findings indicate that systematic endoscopic staging should be routinely performed in patients with locally advanced NSCLC being considered for radiotherapy to accurately inform radiation planning and treatment decision making in patients with locally advanced NSCLC. FUNDING: None.

Assessment of Advanced Diagnostic Bronchoscopy Outcomes for Peripheral Lung Lesions: A Delphi Consensus Definition of Diagnostic Yield and Recommendations for Patient-centered Study Designs. An Official American Thoracic Society/American College of Chest Physicians Research Statement.

Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.

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.

Macrophage ACE2 is necessary for SARS-CoV-2 replication and subsequent cytokine responses that restrict continued virion release.

Macrophages are key cellular contributors to the pathogenesis of COVID-19, the disease caused by the virus SARS-CoV-2. The SARS-CoV-2 entry receptor ACE2 is present only on a subset of macrophages at sites of SARS-CoV-2 infection in humans. Here, we investigated whether SARS-CoV-2 can enter macrophages, replicate, and release new viral progeny; whether macrophages need to sense a replicating virus to drive cytokine release; and, if so, whether ACE2 is involved in these mechanisms. We found that SARS-CoV-2 could enter, but did not replicate within, ACE2-deficient human primary macrophages and did not induce proinflammatory cytokine expression. By contrast, ACE2 overexpression in human THP-1-derived macrophages permitted SARS-CoV-2 entry, processing and replication, and virion release. ACE2-overexpressing THP-1 macrophages sensed active viral replication and triggered proinflammatory, antiviral programs mediated by the kinase TBK-1 that limited prolonged viral replication and release. These findings help elucidate the role of ACE2 and its absence in macrophage responses to SARS-CoV-2 infection.

Safety and Feasibility of a Novel Externally Cooled Bronchoscopic Radiofrequency Ablation Catheter for Ablation of Peripheral Lung Tumours: A First-In-Human Dose Escalation Study.

BACKGROUND: Radiofrequency ablation (RFA) is an established modality for percutaneous ablation of non-small cell lung cancer (NSCLC) in medically inoperable patients but is underutilized clinically due to side effects. We have developed a novel, completely endobronchial RFA catheter with an externally cooled electrode. OBJECTIVES: The objective of this study was to establish the safety and feasibility of bronchoscopic RFA using a novel, externally cooled catheter for ablation of peripheral NSCLC. METHODS: Patients with stage I biopsy-confirmed NSCLC underwent bronchoscopic RFA of tumour 7 days prior to lobectomy. The RFA catheter was delivered bronchoscopically to peripheral NSCLC lesions, guided by radial endobronchial ultrasound, with positioning confirmed using intra-procedural cone beam CT. Pre-operative CT chest and histologic examination of resected specimens were used to establish distribution/uniformity of ablation and efficacy of tumour ablation. RESULTS: RFA in the first patient was complicated by dispersal of heated saline due to cough, resulting in ICU admission. The patient recovered fully and underwent uncomplicated lobectomy. Subsequently, the protocol was altered to mandate neuromuscular blockade with a pre-determined dose escalation, with algorithm-restricted energy (kJ) and irrigated saline volume (mL) constraints. A further 10 patients consented and seven underwent successful bronchoscopic RFA of peripheral NSCLC. No significant adverse events were noted. Ablation zone included tumour in all cases (proportion of tumour ablated ranged 8-72%), with uniform necrosis of tissue within ablation zones observed at higher energy levels. Ablation zone diameter correlated with RFA energy delivered (R2 = 0.553), with maximum long axis diameter of ablation zone 3.1 cm (22.9 kJ). CONCLUSION: Bronchoscopic RFA using an externally cooled catheter is feasible, appears safe, and achieves uniform ablation within the treatment zone. Uncontrolled escape of heated saline poses a major safety risk but can be prevented procedurally through neuromuscular blockade and by limiting irrigation.

Systematic endoscopic staging of mediastinum to determine impact on radiotherapy for locally advanced lung cancer (SEISMIC): protocol for a prospective single arm multicentre interventional study.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as the preferred method of mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). Selective (targeted) LN sampling is most commonly performed however studies in early stage NSCLC and locally advanced NSCLC confirm systematic EBUS-TBNA evaluation improves accuracy of mediastinal staging. This study aims to establish the rate of detection of positron emission tomography (PET)-occult LN metastases following systematic LN staging by EBUS-TBNA, and to determine the utility of systematic mediastinal staging for accurate delineation of radiation treatment fields in patients with locally advanced NSCLC. METHODS: Consecutive patients undergoing EBUS-TBNA for diagnosis/staging of locally advanced NSCLC will be enrolled in this international multi-centre single arm study. Systematic mediastinal LN evaluation will be performed, with all LN exceeding 6 mm to be sampled by TBNA. Where feasible, endoscopic ultrasound staging (EUS-B) may also be performed. Results of minimally invasive staging will be compared to FDG-PET. The primary end-point is proportion of patients in whom systematic LN staging identified PET-occult NSCLC metastases. Secondary outcome measures include (i) rate of nodal upstaging, (ii) false positive rate of PET for mediastinal LN assessment, (iii) analysis of clinicoradiologic risk factors for presence of PET-occult LN metastases, (iv) impact of systematic LN staging in patients with discrepant findings on PET and EBUS-TBNA on target coverage and dose to organs at risk (OAR) in patients undergoing radiotherapy. DISCUSSION: With specificity of PET of 90%, guidelines recommend tissue confirmation of positive mediastinal LN to ensure potentially early stage patients are not erroneously denied potentially curative resection. However, while confirmation of pathologic LN is routinely sought, the exact extent of mediastinal LN involvement in NSCLC in patient with Stage III NSCLC is rarely established. Studies examining systematic LN staging in early stage NSCLC report a significant discordance between PET and EBUS-TBNA. In patients with locally advanced disease this has significant implications for radiation field planning, with risk of geographic miss in the event of PET-occult mediastinal LN metastases. The SEISMIC study will examine both diagnostic outcomes following systematic LN staging with EBUS-TBNA, and impact on radiation treatment planning. TRIAL REGISTRATION: ACTRN12617000333314, ANZCTR, Registered on 3 March 2017.

EBUS versus EUS-B for diagnosing sarcoidosis: The International Sarcoidosis Assessment (ISA) randomized clinical trial.

BACKGROUND AND OBJECTIVE: Endosonography with intrathoracic nodal sampling is proposed as the single test with the highest granuloma detection rate in suspected sarcoidosis stage I/II. However, most studies have been performed in limited geographical regions. Studies suggest that oesophageal endosonographic nodal sampling has higher diagnostic yield than endobronchial endosonographic nodal sampling, but a head-to-head comparison of both routes has never been performed. METHODS: Global (14 hospitals, nine countries, four continents) randomized clinical trial was conducted in consecutive patients with suspected sarcoidosis stage I/II presenting between May 2015 and August 2017. Using an endobronchial ultrasound (EBUS) scope, patients were randomized to EBUS or endoscopic ultrasound (EUS)-B-guided nodal sampling, and to 22- or 25-G ProCore needle aspiration (2 × 2 factorial design). Granuloma detection rate was the primary study endpoint. Final diagnosis was based on cytology/pathology outcomes and clinical/radiological follow-up at 6 months. RESULTS: A total of 358 patients were randomized: 185 patients to EBUS-transbronchial needle aspiration (EBUS-TBNA) and 173 to EUS-B-fine-needle aspiration (FNA). Final diagnosis was sarcoidosis in 306 patients (86%). Granuloma detection rate was 70% (130/185; 95% CI, 63-76) for EBUS-TBNA and 68% (118/173; 95% CI, 61-75) for EUS-B-FNA (p = 0.67). Sensitivity for diagnosing sarcoidosis was 78% (129/165; 95% CI, 71-84) for EBUS-TBNA and 82% (115/141; 95% CI, 74-87) for EUS-B-FNA (p = 0.46). There was no significant difference between the two needle types in granuloma detection rate or sensitivity. CONCLUSION: Granuloma detection rate of mediastinal/hilar nodes by endosonography in patients with suspected sarcoidosis stage I/II is high and similar for EBUS and EUS-B. These findings imply that both diagnostic tests can be safely and universally used in suspected sarcoidosis patients.

Integrating endobronchial ultrasound bronchoscopy with molecular testing of immunotherapy biomarkers in non-small cell lung cancer.

Immunotherapy has transformed treatment of advanced non-small-cell lung cancer (NSCLC) patients leading to remarkable long-term survival benefit. However, only about 20% of advanced NSCLC patients typically respond to immune checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 pathway. The only validated biomarker for ICI therapy is the PD-L1 immunohistochemistry (IHC) test, which is considered an imperfect assay due to several variables including availability and integrity of tumour tissue, variability in staining/scoring techniques and heterogeneity in PD-L1 protein expression within and across tumour biopsies. Herein, we discuss integrating minimally invasive EBUS bronchoscopy procedures with novel molecular approaches to improve accuracy and sensitivity of PD-L1 testing. EBUS guided bronchoscopy facilitates repeated sampling of tumour tissue to increase the probability of detecting PD-L1 positive tumours. Since intra-tumoural PD-L1 (CD274) copy number is reported to be less heterogeneous than PD-L1 protein detection, quantifying PD-L1 transcript levels may increase detection of PD-L1 positive tumours. PD-L1 transcript levels show excellent concordance with PD-L1 IHC scoring and multiplex digital droplet PCR (ddPCR) assays that quantify absolute PD-L1 transcript copy number have been developed. ddPCR can also be automated for high throughput detection of low abundant variants with excellent sensitivity and accuracy to improve the broader application of diagnostic cut-off values. Optimizing diagnostic workflows that integrate optimal EBUS bronchoscopy procedures with emerging molecular ICI biomarker assays may improve the selection criteria for ICI therapy benefit.

Bronchoscopic Thermal Vapour Ablation for Localized Cancer Lesions of the Lung: A Clinical Feasibility Treat-and-Resect Study.

BACKGROUND: Bronchoscopic thermal vapour ablation (BTVA) is an established and approved modality for minimally invasive lung volume reduction in severe emphysema. Preclinical data suggest potential for BTVA in minimally invasive ablation of lung cancer lesions. OBJECTIVES: The objective of this study is to establish the safety, feasibility, and ablative efficacy of BTVA for minimally invasive ablation of lung cancers. METHODS: Single arm treat-and-resect clinical feasibility study of patients with biopsy-confirmed lung cancer. A novel BTVA for lung cancer (BTVA-C) system for minimally invasive treatment of peripheral pulmonary tumours was used to deliver 330 Cal thermal vapour energy via bronchoscopy to target lesion. Patients underwent planned lobectomy to complete oncologic care. Pre-surgical CT chest and post-resection histologic analysis were performed to evaluate ablative efficacy. RESULTS: Six patients underwent BTVA-C, and 5 progressed to planned lobectomy. Median procedure duration was 12 min. No major procedure-related complications occurred. All 5 resected lesions were part-solid lung adenocarcinomas with median solid component size 1.32±0.36 cm. Large uniform ablation zones were seen in 4 patients where thermal dose exceeded 3 Cal/mL, with complete/near-complete necrosis of target lesions seen in 2 patients. Tumour positioned within ablation zones demonstrated necrosis in >99% of cross-sectional area examined. CONCLUSION: BTVA of lung tumours is feasible and well tolerated, with preliminary evidence suggesting high potential for effective ablation of tumours. Thermal injury is well demarcated, and uniform tissue necrosis is observed within ablation zones receiving sufficient thermal dose per volume of lung. Treatment of smaller volumes and ensuring adequate thermal dose may be important for ablative efficacy.

Endoscopic transoesophageal fine-needle aspiration with convex probe bronchoscope for diagnosis of coeliac lymphadenopathy.

EUS-B-FNA is a feasible and accurate technique for diagnosis of extrathoracic lesions https://bit.ly/34TFMR8.

Teaching Radial Endobronchial Ultrasound with a Three-Dimensional-printed Radial Ultrasound Model.

BACKGROUND: Peripheral pulmonary lesion (PPL) incidence is rising because of increased chest imaging sensitivity and frequency. For PPLs suspicious for lung cancer, current clinical guidelines recommend tissue diagnosis. Radial endobronchial ultrasound (R-EBUS) is a bronchoscopic technique used for this purpose. It has been observed that diagnostic yield is impacted by the ability to accurately manipulate the radial probe. However, such skills can be acquired, in part, from simulation training. Three-dimensional (3D) printing has been used to produce training simulators for standard bronchoscopy but has not been specifically used to develop similar tools for R-EBUS. OBJECTIVE: We report the development of a novel ultrasound-compatible, anatomically accurate 3D-printed R-EBUS simulator and evaluation of its utility as a training tool. METHODS: Computed tomography images were used to develop 3D-printed airway models with ultrasound-compatible PPLs of "low" and "high" technical difficulty. Twenty-one participants were allocated to two groups matched for prior R-EBUS experience. The intervention group received 15 minutes to pretrain R-EBUS using a 3D-printed model, whereas the nonintervention group did not. Both groups then performed R-EBUS on 3D-printed models and were evaluated using a specifically developed assessment tool. RESULTS: For the "low-difficulty" model, the intervention group achieved a higher score (21.5 ± 2.02) than the nonintervention group (17.1 ± 5.7), reflecting 26% improvement in performance (P = 0.03). For the "high-difficulty" model, the intervention group scored 20.2 ± 4.21 versus 13.3 ± 7.36, corresponding to 52% improvement in performance (P = 0.02). Participants derived benefit from pretraining with the 3D-printed model, regardless of prior experience level. CONCLUSION: 3D-printing can be used to develop simulators for R-EBUS education. Training using these models significantly improves procedural performance and is effective in both novice and experienced trainees.

Impact of general social distancing measures on incidence of influenza in Australia.

General social distancing measures enacted for control of the #SARSCoV2 pandemic have achieved a profound reduction in incidence of #influenza in Australia https://bit.ly/3hXjOkl.

Transoesophageal Fine Needle Aspiration of Pleural Metastasis Using EBUS Scope.

Endoscopic ultrasound using convex endobronchial ultrasound probe (EUS-B) is an evolving diagnostic technique. We present a case of successful EUS-B biopsy of pleural metastasis in a patient with lung adenocarcinoma. This was an accurate, uncomplicated procedure and demonstrates the feasibility of EUS-B for pleural lesions.

Bronchoscopic treatments for early-stage peripheral lung cancer: Are we ready for prime time?

Lung cancer is the leading cause of cancer-related death worldwide and surgical lobectomy remains the preferred therapy for patients with early-stage NSCLC. Medical comorbidities and advanced age preclude resection in many patients and minimally invasive ablative therapies are needed for treatment. Stereotactic ablative radiation is established as an effective modality in this patient group, although may be contraindicated in some patients with prior radiation exposure, comorbidities or centrally positioned tumours. Percutaneous ablative methods are available, although are frequently associated with significant complications. Numerous endoscopic ablative techniques are under evaluation. With a more favourable safety profile and the ability to provide diagnosis and staging information potentially within a single procedure, there is a strong rationale for development of bronchoscopic ablative modalities. In the following article, the authors aim to explore the role bronchoscopic ablation may play in treatment of peripheral lung tumours, and to describe a pathway to establishing these modalities as part of routine care. The current status of several bronchoscopic ablative options is discussed in detail.