Surgery for malignant pleural mesothelioma after radiotherapy (SMART): final results from a single-centre, phase 2 trial.

BACKGROUND: A novel approach for managing malignant pleural mesothelioma, surgery for mesothelioma after radiotherapy (SMART), consisting of a short accelerated course of high-dose, hemithoracic, intensity modulated radiotherapy (IMRT) followed by extrapleural pneumonectomy was developed. The aim of this study was to evaluate the clinical feasibility of the SMART protocol. METHODS: In this single-centre, phase 2 trial, patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, with histologically proven, resectable, cT1-3N0M0 disease who had previously untreated malignant pleural mesothelioma were eligible for inclusion. Patients received 25 Gy in five daily fractions over 1 week to the entire ipsilateral hemithorax with a concomitant 5 Gy boost to high risk areas followed by extrapleural pneumonectomy within 1 week. Adjuvant chemotherapy was offered to patients with ypN+ disease on final pathology. The primary endpoint was feasibility, which was defined as the number of patients with 30-day perioperative treatment-related death (grade 5 events) or morbidity (grade 3 or 4 events). A key secondary endpoint was cumulative incidence of distant recurrence. The final analysis was done on an intention-to-treat basis (including all eligible patients). This trial is registered with ClinicalTrials.gov, NCT00797719. FINDINGS: Between Nov 1, 2008, and Oct 31, 2019, 102 patients were enrolled onto the trial and 96 eligible patients were treated with SMART on protocol and included in the analysis. Extrapleural pneumonectomy was done at a median of 5 days (range 2-12) after completing IMRT. 47 (49%) patients had 30-day perioperative grade 3-4 events and one (1%) patient died within 30 days perioperatively (grade 5 event; pneumonia). After a median follow-up of 46·8 months (IQR 13·4-61·2), the 5-year cumulative incidence of distant recurrence was 62 (63·3% [95% CI 52·3-74·4]). The most common first sites of recurrence were the contralateral chest (33 [46%] of 72 patients) and the peritoneal cavity (32 [44%]). INTERPRETATION: Results from this study suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. However, minimising grade 4 events on the protocol is technically demanding and might affect survival beyond the post-operative period. FUNDING: Princess Margaret Hospital Foundation Mesothelioma Research Fund.

Performance of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for the Diagnosis of Isolated Mediastinal and Hilar Lymphadenopathy.

BACKGROUND: Although many studies have assessed the diagnostic utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the context of a specific disease, few studies have assessed the overall diagnostic yield, sensitivity, and negative predictive value in patients with isolated mediastinal and hilar lymphadenopathy (IMHL). OBJECTIVE: We evaluated the performance of EBUS-TBNA for diagnosing IMHL in a population with a high prevalence of concurrent or preexisting non-pulmonary malignancy. METHODS: A retrospective chart review of patients who underwent EBUS-TBNA from October 2008 to April 2014 was performed to identify patients with IMHL. Patients with known or suspected primary pulmonary malignancy were excluded. When available, EBUS-TBNA results were cross-referenced with further diagnostic investigation or clinical diagnosis based on follow-up. RESULTS: EBUS-TBNA was used to sample 765 lymph nodes from 350 patients. One hundred and fourteen (33.3%) patients had a concurrent or preexisting non-pulmonary malignancy. The overall yield of EBUS-TBNA for specific diagnosis was 300/350 (86%). The diagnostic yield for sarcoidosis, lymphoproliferative disease, metastatic lymphadenopathy from extrathoracic malignancy, and necrotizing granuloma was 123/149 (83%), 27/33 (82%), 20/25 (80%), and 13/19 (68%), respectively. Amongst 50 patients with non-diagnostic EBUS-TBNA, 25 yielded an insufficient sample and another 25 yielded only benign lymphoid material which was not representative of the underlying pathology. Overall, EBUS-TBNA had a sensitivity of 89%, a diagnostic yield of 86%, and a negative predictive value of 79%. CONCLUSION: For patients with isolated hilar or mediastinal lymphadenopathy and a high background prevalence of concurrent and preexisting non-pulmonary malignancy, EBUS-TBNA is a reliable first-line diagnostic investigation.

Flexible 19-Gauge Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Needle: First Experience.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a well-established first-line invasive modality for mediastinal lymph node staging in lung cancer patients and in the diagnostic workup of patients with mediastinal adenopathy. With the current 21- and 22-gauge (G) EBUS-TBNA needles, the procedure can be limited by the degree of flexibility in the needle and the size of the lumen in tissue acquisition. OBJECTIVE: We report our initial experience with a first-generation flexible 19-G EBUS-TBNA (Flex 19G; Olympus Respiratory America, Redmond, WA, USA) needle with regards to efficacy and safety. METHODS: The Flex 19G EBUS-TBNA needle was used in 47 selected patients with enlarged hilar and/or mediastinal lymphadenopathy at 3 centers. The standard Olympus EBUS scope with a 2.2-mm working channel was used in all cases. RESULTS: The diagnostic yield of the Flex 19G needle according to clinical cytopathology reports was 89% (42/47). The diagnosis and their respective diagnostic yield with the Flex 19G EBUS-TBNA needle were malignancy 24/27 (89%), sarcoidosis 13/14 (93%), and reactive lymph node hyperplasia 5/6 (83%). The mean short axis of the sampled lymph nodes was 19 ± 9 mm. No complications occurred except for 1 instance of moderate bleeding, which did not require intervention beyond suctioning and subsequently resolved. All 13 patients diagnosed with adenocarcinoma by the 19-G needle had sufficient tissue for genetic testing. CONCLUSION: EBUS-TBNA using the first-generation Flex 19G needle is feasible and safe with promising diagnostic yield while providing a greater degree of flexion with the Olympus EBUS scope. Additional clinical evaluations are warranted.

Interventional pulmonology: focus on pulmonary diagnostics.

Interventional pulmonology (IP) allows comprehensive assessment of patients with benign and malignant airway, lung parenchymal and pleural disease. This relatively new branch of pulmonary medicine utilizes advanced diagnostic and therapeutic techniques to treat patients with pulmonary diseases. Endobronchial ultrasound revolutionized assessment of pulmonary nodules, mediastinal lymphadenopathy and lung cancer staging allowing minimally invasive, highly accurate assessment of lung parenchymal and mediastinal disease, with both macro- and microscopic tissue characterization including molecular signature analysis. High-spatial resolution, new endobronchial imaging techniques including autofluorescence bronchoscopy, narrow-band imaging, optical coherence tomography and confocal microscopy enable detailed evaluation of airways with increasing role in detection and treatment of malignancies arising in central airways. Precision in peripheral lesion localization has been increased through innovative navigational techniques including navigational bronchoscopy and electromagnetic navigation. Pleural diseases can be assessed with the use of non-invasive pleural ultrasonography, with high sensitivity and specificity for malignant disease detection. Medical pleuroscopy is a minimally invasive technique improving diagnostic safety and precision of pleural disease and pleural effusion assessment. In this review, we discuss the newest advances in diagnostic modalities utilized in IP, indications for their use, their diagnostic accuracy, efficacy, safety and challenges in application of these technologies in assessment of thoracic diseases.

Australasian Malignant PLeural Effusion (AMPLE)-3 trial: study protocol for a multi-centre randomised study comparing indwelling pleural catheter (±talc pleurodesis) versus video-assisted thoracoscopic surgery for management of malignant pleural effusion.

INTRODUCTION: Malignant pleural effusions (MPEs) are common. MPE causes significant breathlessness and impairs quality of life. Indwelling pleural catheters (IPC) allow ambulatory drainage and reduce hospital days and re-intervention rates when compared to standard talc slurry pleurodesis. Daily drainage accelerates pleurodesis, and talc instillation via the IPC has been proven feasible and safe. Surgical pleurodesis via video-assisted thoracoscopic surgery (VATS) is considered a one-off intervention for MPE and is often recommended to patients who are fit for surgery. The AMPLE-3 trial is the first randomised trial to compare IPC (±talc pleurodesis) and VATS pleurodesis in those who are fit for surgery. METHODS AND ANALYSIS: A multi-centre, open-labelled randomised trial of patients with symptomatic MPE, expected survival of ≥ 6 months and good performance status randomised 1:1 to either IPC or VATS pleurodesis. Participant randomisation will be minimised for (i) cancer type (mesothelioma vs non-mesothelioma); (ii) previous pleurodesis (vs not); and (iii) trapped lung, if known (vs not). Primary outcome is the need for further ipsilateral pleural interventions over 12 months or until death, if sooner. Secondary outcomes include days in hospital, quality of life (QoL) measures, physical activity levels, safety profile, health economics, adverse events, and survival. The trial will recruit 158 participants who will be followed up for 12 months. ETHICS AND DISSEMINATION: Sir Charles Gairdner and Osborne Park Health Care Group (HREC) has approved the study (reference: RGS356). Results will be published in peer-reviewed journals and presented at scientific meetings. DISCUSSION: Both IPC and VATS are commonly used procedures for MPE. The AMPLE-3 trial will provide data to help define the merits and shortcomings of these procedures and inform future clinical care algorithms. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry ACTRN12618001013257 . Registered on 18 June 2018. PROTOCOL VERSION: Version 3.00/4.02.19.

Plasma-first: accelerating lung cancer diagnosis and molecular profiling through liquid biopsy.

Introduction: Molecular profiling of tumor tissue is the gold standard for treatment decision-making in advanced non-small cell lung cancer (NSCLC). Results may be delayed or unavailable due to insufficient tissue, prolonged wait times for biopsy, pathology assessment and testing. We piloted the use of plasma testing in the initial diagnostic workup for patients with suspected advanced lung cancer. Methods: Patients with ⩽15 pack-year smoking history and suspected advanced lung cancer referred to the lung cancer rapid diagnostic program underwent plasma circulating-tumor DNA testing using a DNA-based mutation panel. Tissue testing was performed per standard of care, including comprehensive next-generation sequencing (NGS). The primary endpoint was time from diagnostic program referral to cancer treatment in stage IV NSCLC patients (Cohort A) compared to a contemporary cohort not enrolled in the study (Cohort B) and an historical pre-COVID cohort referred to the program between 2018 and 2019 (Cohort C). Results: From January to June 2021, 20 patients were enrolled in Cohort A; median age was 70.5 years (range 33-87), 70% were female, 55% Caucasian, 85% never smokers, and 75% were diagnosed with NSCLC. Seven had actionable alterations detected in plasma or tissue (4/7 concordant). Fusions, not tested in plasma, were identified by immunohistochemistry for three patients. Mean result turnaround time was 17.8 days for plasma NGS and 23.6 days for tissue (p = 0.10). Mean time from referral to treatment initiation was significantly shorter in cohort A at 32.6 days (SD 13.1) versus 62.2 days (SD 31.2) in cohort B and 61.5 days (SD 29.1) in cohort C, both p < 0.0001. Conclusion: Liquid biopsy in the initial diagnostic workup of patients with suspected advanced NSCLC can lead to faster molecular results and shorten time to treatment even with smaller DNA panels. An expansion study using comprehensive NGS plasma testing with faster turnaround time is ongoing (NCT04862924).

High-frequency oscillation in adults: a utilization review.

OBJECTIVES: High-frequency oscillation is used for adults with acute lung injury/acute respiratory distress syndrome. Given the uncertain benefits, our objective was to describe contemporary patient selection, high-frequency oscillation utilization, and outcomes. DESIGN: Utilization review. SETTING: Ten academic centers (Ontario, Canada; January 1, 2005-January 31, 2007). PATIENTS: We included 190 consecutive adults treated with high-frequency oscillation and retrospectively abstracted data on patient demographics, gas exchange, hemodynamics, settings during conventional ventilation and high-frequency oscillation, adjunctive therapies, and outcomes. We used logistic regression to explore associations with oxygenation response and hemodynamic and ventilatory complications (2 hrs after high-frequency oscillation initiation) and mortality. Continuous data are reported as mean (sd) or median (quartile 1, quartile 3). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients (60.0% male; mean age, 52; sd 17) had predominantly acute lung injury/acute respiratory distress syndrome (89.8%) and were severely ill (mean Acute Physiology and Chronic Health Evaluation II score, 28; sd, 9) and hypoxemic (mean Pao2/Fio2, 80; sd, 42). High-frequency oscillation was started a median of 2 (1, 8) days after intubation and continued for a median of 3 (2, 7) days. During high-frequency oscillation, adjunctive treatments (neuromuscular blockade, 75.6%; recruitment maneuvers, 49.5%; nitric oxide, 34.0%; steroids, 63.1%) and new barotrauma or chest tube placement (23.5%) were common. Ten patients (5.3%) had technical complications; five required a new ventilator. Reasons for stopping high-frequency oscillation included death or withdrawal of life support (39.1%), significant improvement in respiratory failure (37.6%), and inadequate improvement (23.3%). One hundred and twenty-eight of 189 patients died in hospital. Most (62.5%) had a positive oxygenation response after 2 hrs of high-frequency oscillation (mean absolute increase in PaO2/FiO2, 22 [SD, 54]; 95% confidence interval of mean 14-31). A minority had lower PaO2/FiO2 (32.5%) or a hemodynamic (27.5%) or ventilatory (30.5%) complication. Older age, Acute Physiology and Chronic Health Evaluation II score, and Paco2 before high-frequency oscillation were independently associated with mortality. CONCLUSIONS: Most patients treated with high-frequency oscillation have acute respiratory distress syndrome and severe hypoxemia that modestly improves 2 hrs after high-frequency oscillation application. However, oxygenation worsens in some patients, complications are common, and mortality is high.

Developing a National, Simulation-Based, Surgical Skills Bootcamp in General Thoracic Surgery.

BACKGROUND: The use surgical simulation across all subspecialties has gained widespread adoption in the last decade. A number of factors, including the small number of trainees, identified gaps in surgical skill training from cross-sectional surveys, increased national collaboration, and support from the national specialty committee identified a need to construct a surgical skills "bootcamp" in thoracic surgery in Canada. OBJECTIVE: The goals of the surgical skills bootcamp, as identified by the residency training program directors and the national specialty committee were to create a national, centralized, simulation-based skills workshop that focused on key foundational procedures within thoracic surgery, particularly those identified as areas of weakness by former residents; to smooth the transition to intraoperative teaching; to provide exposure to important but not necessarily universally available procedures such as advanced endoscopy; to teach non-medical expert competencies, and lastly to provide a venue for networking for residents across the country. DESIGN: The curriculum committee has constructed a 3.5 day curriculum, with a focus on hands-on skills simulation, as well as lectures, on a breadth of topics including benign esophageal disorders, lung cancer staging, minimally invasive lung surgery, crisis management and advanced bronchoscopy and endoscopy. All residents across the country attend as well as faculty from a variety of institutions. SETTING: The course is hosted centrally at the University of Toronto, Ontario over 3.5 days. A combination of auditorium and both animal and human operating room facilities are utilized. METHODS: A needs-assessment based on a formal meeting of the program directors, as well feedback from surveys identified the target areas for curriculum development. A committee of interested faculty developed the content as well as the local construct and logistics required. Iterative feedback has evolved the duration and content over the initial 3 years. RESULTS: Through formal resident feedback, national subspecialty committee review, and program director meetings the support for the bootcamp has been overwhelmingly positive. Specific resident feedback for structure, content and specific simulations has been favorable, but has also been used to modify the program. CONCLUSION: In response to identified weaknesses in training, with the support of the national specialty committee, the residency program directors, and the faculty at the University of Toronto, an intensive simulation based thoracic surgery bootcamp has successfully been created for Canadian thoracic surgery residents.

The role of endobronchial ultrasound-guided transbronchial needle aspiration in stereotactic body radiation therapy for non-small cell lung cancer.

OBJECTIVE: To evaluate the diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in stereotactic body radiation therapy (SBRT) candidates and compare with computed tomography (CT) and positron emission tomography (PET). METHODS: Inclusion criteria for this single institutional retrospective study were 1) biopsy-proven or suspicious NSCLC with diameter <6 cm; 2) no distant metastasis; 3) EBUS-TBNA staging between April 2008 and November 2014; 4) SBRT eligible. CT and PET positive nodes were defined as short axis ≧1 cm and standardized uptake value ≧2.5, respectively. Node positive by clinical-pathologic confirmation (NPCP) was defined as confirmed malignancy by EBUS-TBNA or recurrence in hilar or mediastinal lymph nodes within one year after SBRT. The survival after SBRT was compared between radiologically node-positive, but EBUS-TBNA negative, patients (Case) and a matched cohort (tumor size; radiation dose; operability) who underwent SBRT without EBUS-TBNA staging (Control). RESULTS: There were 35 eligible patients (mean age 77 ±â€¯8.2; mean diameter 2.5 ±â€¯1.0 cm). Thirty were medically inoperable. Twenty out of 24 patients with radiologically positive node(s) were negative by EBUS-TBNA. All eleven radiologically negative patients were N0 following EBUS-TBNA. Thirty-one patients underwent SBRT. Per-person based sensitivity/specificity of CT, PET and EBUS-TBNA for NPCP were 42.9/64.3%, 100/64.3% and 57.1/100%, respectively. A 1:4 match was obtained. Regional failure-free survival (p = 0.71; HR = 0.88 95%CI 0.45-1.74) and disease-free survival (p = 0.77; HR = 1.10 95%CI 0.58-2.11) of the Case were not significantly different from the Control. CONCLUSION: Patients with radiographically positive lymph nodes can be considered for EBUS-TBNA and may remain candidates for SBRT.

High Dose Rate Brachytherapy as a Treatment Option in Endobronchial Tumors.

Purpose. To report our experience with high dose rate endobronchial brachytherapy (HDR-EBBT) and to assess its efficacy and tolerability with possibility of its use in selected cases with curative intent. Method. Retrospective review of patients with endobronchial tumors treated at our institution in 2007-2013 with HDR-EBBT. Subjective response and treatment related toxicity were extracted from patients' records. Clinical response was evaluated by chest CT +/- bronchoscopy 2-3 months after treatment. Local control (LC) and overall survival (OS) were analyzed. Results. Overall 23 patients were identified. Ten patients were treated with curative intent, in 8 of them HDR-EBBT was combined with external beam radiotherapy. Short term palliation was as follows: dyspnea (13/15), cough (12/14), and hemoptysis (3/3). Seventeen patients were evaluated, of whom 9 (53%) showed complete response. Four patients developed local failure (only 1 of them treated with curative intent) and were salvaged with HDR-EBBT (n = 1), chemotherapy (n = 2), and laser (n = 1). Among patients treated with curative intent, the 2-year LC and OS were 89% and 67%, respectively, and 2 out of 4 deaths were cancer-related. Late toxicity included bronchial stenosis (n = 1). Only 1 patient had fatal hemoptysis and postmortem examination indicated local recurrence. Conclusion. HDR-EBBT is promising treatment with tolerable complication if used in properly selected patients.

The role of endobronchial ultrasound/esophageal ultrasound for evaluation of the mediastinum in lung cancer.

The introduction: of ultrasound-based, minimally invasive techniques (Endobronchial Ultrasound guided Transbronchial Needle Aspiration (EBUS-TBNA) and Esophageal Ultrasound guided Fine Needle Aspiration) has revolutionized care of patients with lung cancer needing mediastinal lymph node sampling. When combined, the techniques offer safe and accurate assessment of mediastinum, with accuracy surpassing that of the pervious gold standard - cervical mediastinoscopy. EBUS-TBNA can be used for mediastinal restaging in both, patients with suspected recurrence following treatment for primary lung cancer and followingneoadjuvant therapy in preparation for definitive surgical intervention. Both EBUS-TBNA and esophageal ultrasound guided fine needle aspiration techniques have been shown to provide sufficient material for molecular and DNA testing, extending their role beyond initial evaluation of the mediastinum to help direct and personalize medical treatment and predict response to therapy. In the future, assessing sonographic features of lymph nodesmay become useful in predicting nodal metastasis, further increasing the sensitivity of these techniques for detection of metastatic disease.