An International Survey of Practices in the Investigation and Endoscopic Treatment of Peripheral Pulmonary Lesions amongst Interventional Bronchoscopists.

INTRODUCTION: The investigation of peripheral pulmonary lesions (PPLs) can be challenging. Several bronchoscopic modalities have been developed to reach and biopsy PPL but the level of adoption of these techniques by interventional pulmonologists (IPs) is unknown. This international survey was conducted to describe current practices in PPL investigation among IP. METHODS: This survey was sent to all members of the World Association for Bronchology and Interventional Pulmonology, Canadian Thoracic Society Procedures Assembly, AABIP, and the Groupe d'Endoscopie Thoracique et Interventionnel Francophone. The survey was composed of 48 questions and three clinical cases to establish a portrait of modalities used to investigate and treat PPL by IP around the world. RESULTS: Three hundred and twelve IP responded to the survey. Most of them practice in Europe (n = 122), North America (n = 97), and Asia (n = 49). Half of responders perform more than 100 endoscopic procedures for PPL annually. General anesthesia and conscious sedation are used in similar proportions (53% and 47%, respectively). Rapid on site evaluation (ROSE) is used when sampling PPL by 42%. Radial EBUS (69%), fluoroscopy (55%), and electromagnetic navigation (27%) are the most widely used techniques. Most IP combine techniques (89%). Robotic bronchoscopy (15%) and cone-beam CT (8%) are almost exclusively used in the USA where, respectively, 60% and 37% of respondents reported using these modalities. Ten percent of IP currently had access to endoscopic treatment modalities for PPL. However, half of the remaining IP plan to acquire an endoscopic treatment modality in the next 2 years. CONCLUSION: Available techniques and practices worldwide vary significantly regarding PPL investigation and treatment.

Molecular analysis of endobronchial ultrasound needle aspirates in patients with non-small cell lung cancer: Results from the SCOPE database.

OBJECTIVE: Molecular subtyping of non-small cell lung cancer (NSCLC) is critical in the diagnostic evaluation of patients with advanced disease. This study aimed to examine whether samples from endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) of intrathoracic lymph nodes and/or lung lesions are adequate for molecular analysis across various institutions. METHODS: We retrospectively reviewed all cases of linear EBUS-TBNA with a final bronchoscopic diagnosis of NSCLC entered in the Stather Canadian Outcomes registry for chest ProcEdures database. The primary outcome was specimen inadequacy rate for each molecular target, as defined by the local laboratory or pathologist. RESULTS: A total of 866 EBUS-TBNA procedures for NSCLC were identified. Specimen inadequacy rates were 3.8% for EGFR, 2.5% for ALK-1 and 3.5% for PD-L1. Largest target size was not different between adequate and inadequate specimens, and rapid onsite evaluation did not increase specimen adequacy rates. One centre using next-generation sequencing for EGFR had lower adequacy rates than 2 others using matrix-assisted laser desorption/ionization time-of-flight mass spectrophotometry. CONCLUSION: EBUS-TBNA specimens have a very low-specimen inadequacy rate for molecular subtyping of non-small cell lung cancer.

Tumor Shape-Specific Brachytherapy Implants by 3D-Printing, Precision Radioactivity Painting, and Biomedical Imaging.

In brachytherapy (BT), or internal radiation therapy, cancer is treated by radioactive implants. For instance, episcleral plaques (EPs) for the treatment of uveal melanoma, are designed according to generic population approximations. However, more personalized implants can enhance treatment precision through better adjustment of dose profiles to the contours of cancerous tissues. An original approach integrating biomedical imaging, 3D printing, radioactivity painting, and biomedical imaging, is developed as a workflow for the development of tumor shape-specific BT implants. First, computer-aided design plans of EP are prepared according to guidelines prescribed by the Collaborative Ocular Melanoma Study protocol. Polyetheretherketone (PEEK), a high-performance polymer suitable for permanent implants, is used to 3D-print plaques and the geometrical accuracy of the printed design is evaluated by imaging. The possibility to modulate the dose distribution in a tridimensional manner is demonstrated by painting the inner surfaces of the EPs with radioactive 103Pd, followed by dose profile measurements. The possibility to modulate dose distributions generated by these 3D-printed plaques through radioactivity painting is therefore confirmed. Ex vivo surgical tests on human eyeballs are performed as an assessment of manipulation ease. Overall, this work provides a solution for the fabrication of tumor-specific radioactive implants requiring higher dose precision.

Gold-Enhanced Brachytherapy by a Nanoparticle-Releasing Hydrogel and 3D-Printed Subcutaneous Radioactive Implant Approach.

Brachytherapy (BT) is a widely used clinical procedure for localized cervical cancer treatment. In addition, gold nanoparticles (AuNPs) have been demonstrated as powerful radiosensitizers in BT procedures. Prior to irradiation by a BT device, their delivery to tumors can enhance the radiation effect by generating low-energy photons and electrons, leading to reactive oxygen species (ROS) production, lethal to cells. No efficient delivery system has been proposed until now for AuNP topical delivery to localized cervical cancer in the context of BT. This article reports an original approach developed to accelerate the preclinical studies of AuNP-enhanced BT procedures. First, an AuNP-containing hydrogel (Pluronic F127, alginate) is developed and tested in mice for degradation, AuNP release, and biocompatibility. Then, custom-made 3D-printed radioactive BT inserts covered with a AuNP-containing hydrogel cushion are designed and administered by surgery in mice (HeLa xenografts), which allows for measuring AuNP penetration in tumors (≈100 µm), co-registered with the presence of ROS produced through the interactions of radiation and AuNPs. Biocompatible AuNPs-releasing hydrogels could be used in the treatment of cervical cancer prior to BT, with impact on  the total amount of radiation needed per BT treatment, which will result in benefits to the preservation of healthy tissues surrounding cancer.

Transbronchial Lung Cryobiopsy and Surgical Lung Biopsy: A Prospective Multi-Centre Agreement Clinical Trial (CAN-ICE).

Rationale: Transbronchial cryobiopsy (TBCB) for the diagnosis of interstitial lung disease (ILD) has shown promising results, but prospective studies with matched surgical lung biopsy (SLB) have yielded conflicting results. Objectives: We aimed to assess within- and between-center diagnostic agreement between TBCB and SLB at both the histopathologic and multidisciplinary discussion (MDD) levels in patients with diffuse ILD. Methods: In a multicenter prospective study, we performed matched TBCB and SLB in patients referred for SLB. After a blinded review by three pulmonary pathologists, all cases were reviewed by three independent ILD teams in an MDD. MDD was performed first with TBCB, then with SLB in a second session. Within-center and between-center diagnostic agreement was evaluated using percentages and correlation coefficients. Measurements and Main Results: Twenty patients were recruited and underwent contemporaneous TBCB and SLB. Within-center diagnostic agreement between TBCB-MDD and SLB-MDD was reached in 37 of the 60 (61.7%) paired observations, resulting in a Cohen's κ value of 0.46 (95% confidence interval [CI], 0.29-0.63). Diagnostic agreement increased among high-confidence or definitive diagnoses on TBCB-MDD (21 of 29 [72.4%]), but not significantly, and was more likely among cases with SLB-MDD diagnoses of idiopathic pulmonary fibrosis than fibrotic hypersensitivity pneumonitis (13 of 16 [81.2%] vs. 16 of 31 [51.6%]; P = 0.047). Between-center agreement for cases was markedly higher for SLB-MDD (κ = 0.71 [95% CI, 0.52-0.89]) than TBCB-MDD (κ = 0.29 [95% CI, 0.09-0.49]). Conclusions: This study demonstrated moderate TBCB-MDD and SLB-MDD diagnostic agreement for ILD, while between-center agreement was fair for TBCB-MDD and substantial for SLB-MDD. Clinical trial registered with www.clinicaltrials.gov (NCT02235779).

Retrospective Assessment of Complementary Liquid Biopsy on Tissue Single-Gene Testing for Tumor Genotyping in Advanced NSCLC.

Biomarker testing is key for non-small cell lung cancer (NSCLC) management and plasma based next-generation sequencing (NGS) is increasingly characterized as a non-invasive alternative. This study aimed to evaluate the value of complementary circulating tumor DNA (ctDNA) NGS on tissue single-gene testing (SGT). Ninety-one advanced stage NSCLC patients with tumor genotyping by tissue SGT (3 genes) followed by ctDNA (38 genes amplicon panel) were included. ctDNA was positive in 47% (n = 43) and identified a targetable biomarker in 19 patients (21%). The likelihood of positivity on ctDNA was higher if patients had extra-thoracic disease (59%) or were not under active treatment (59%). When compared to SGT, ctDNA provided additional information in 41% but missed a known alteration in 8%. Therapeutic change for targeted therapy based on ctDNA occurred in five patients (5%), while seven patients with missed alterations on ctDNA had EGFR mutations or ALK fusions. The median turnaround time of ctDNA was 10 days (range 6-25), shorter (p = 0.002) than the cumulative delays for the tissue testing trajectory until biomarker availability (13 d; range 7-1737). Overall, the results from this study recapitulate the potential and limitations of ctDNA when used complementarily to tissue testing with limited biomarker coverage.

An unusual isolated anterior mediastinal lesion.

Malignant pleural mesothelioma (MPM) is an infrequent tumour of poor prognosis with a strong association with asbestos exposure. Pleural effusion or thickening is the most common radiological finding. Thoracoscopic biopsy is the diagnostic modality of choice. In our report, we present the case of a career welder who consulted with vocal cord palsy and an atypical anterior mediastinal lesion. An EBUS-TBNA-guided biopsy and a thorough cytological assessment led to an unexpected diagnosis of epithelioid MPM. A localized anterior mediastinal lesion is an extremely infrequent presentation of MPM that deserves clinical recognition.

Safety of Bronchoscopy after Acute Coronary Syndrome.

BACKGROUND: Bronchoscopy is a safe procedure which is frequently performed for the investigation of respiratory diseases. Current guidelines recommend to delay bronchoscopy for 4-6 weeks after acute coronary syndrome (ACS), as this period is theoretically considered at risk for new onset of ACS. We therefore aimed to evaluate the safety and the tolerance of bronchoscopy in patients with ACS (≤30 days) and to compare outcomes with matched controls. METHODS: All consecutive patients who had a bronchoscopy performed in the first 30 days after an ACS in the bronchoscopy suite were included. A group of patients with ACS who did not undergo bronchoscopy (controls) were also included and matched for age, sex, type of ACS, and severity of ACS (GRACE score). RESULTS: Of the 13,646 patients who underwent bronchoscopy between 2010 and 2019, 2,181 had an history of ACS and among those, 87 patients had an ACS (19 with STEMI, 52 with NSTEMI, and 16 unstable angina). Mean interval between ACS and bronchoscopy was of 10.1 ± 8.9 days. Systolic blood pressure and heart rate significantly increased and oxygen saturation significantly decreased during bronchoscopy. The most frequent adverse event was desaturation which occurred in 26% of patients. Reinfarction rate (1.1% vs. 2.3% p = 1.00) and all-cause 30-day mortality (2.3% vs. 4.6%; p = 0.68) were similar in patients who underwent bronchoscopy and in matched controls (n = 87). CONCLUSION: Our study reinforces the safety of bronchoscopy after ACS. When clinically indicated with potential benefits outweighing risks, ACS should not contraindicate bronchoscopy.

Endobronchial Ultrasound Transbronchial Needle Aspiration With a 19-Gauge Needle vs 21- and 22-Gauge Needles for Mediastinal Lymphadenopathy.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is commonly used to evaluate mediastinal lymphadenopathy. Studies focusing on malignant lymphadenopathy have compared 21- and 22-gauge (21G and 22G, respectively) needles and have not identified an advantage of one needle size over the other in terms of diagnostic yield. RESEARCH QUESTION: Does the 19-gauge (19G) EBUS needle offer greater diagnostic yield and sensitivity vs the 21G and 22G EBUS needles for a diagnosis of sarcoidosis, lymphoma, or mediastinal lymphadenopathy not yet diagnosed? STUDY DESIGN AND METHODS: This study retrospectively examined records of 730 patients from the Stather Canadian Outcomes Registry for Chest Procedures (SCOPE) database who underwent EBUS-TBNA for a diagnosis of suspected sarcoidosis, lymphoma, or mediastinal lymphadenopathy not yet diagnosed. A propensity score analysis of two groups was performed. One group comprised patients undergoing EBUS-TBNA with a 19G needle, the other with a 21G or 22G needle. Cases for analysis were selected with a 1:2 ratio of 19G vs 21/22G using logistic regression and random matching with all eligible 19G cases included. RESULTS: There were 137 patients (312 targets) in the 19G group and 274 patients (631 targets) in the 21/22G group in the propensity score analysis. The diagnostic yield was 107 of 137 (78.1%) in the 19G group vs 194 of 274 (70.8%) in the 21/22G group (difference, 7.3%; 95% CI, -1.9 to 15.6; P = .116). The sensitivity of EBUS-TBNA for sarcoidosis was 80 of 83 (96.4%) in the 19G group vs 150 of 156 (96.2%) in the 21/22G group (difference, 0.24%; 95% CI, -6.6 to 85.1; P = .93). In patients with a final diagnosis of lymphoma, EBUS was diagnostic in 10 of 13 (76.9%) in the 19G group vs 12 of 12 (100%) in the 21/22G group (difference, 23.1%; 95% CI, -5.4 to 50.3; P = .08). INTERPRETATION: The study did not identify an advantage of the 19G EBUS needle over the 21/22G EBUS needles for diagnostic yield nor sensitivity for sarcoidosis or lymphoma.

Dilation versus laser resection in subglottic stenosis: protocol for a prospective international multicentre randomised controlled trial (AERATE trial).

INTRODUCTION: Subglottic stenosis (SGS) is a rare condition that results from progressive narrowing of the upper airways. Outcomes and treatment options depend on the benign or complex nature of the stenosis. Treatment options for SGS include surgery and endoscopic techniques. The main endoscopic techniques used are dilation and laser resection. Observational and retrospective studies suggest that endoscopic laser resection may be more effective than dilation. We, therefore, aimed to compare the effectiveness of dilation and laser resection in preventing recurrence of SGS. METHODS AND ANALYSIS: AERATE (dilAtion vs laser Endoscopic Resection in subglottic trAcheal sTEnosis) is a multicentre, investigator-initiated, randomised controlled trial, comparing endoscopic dilation to endoscopic laser resection for simple benign SGS (less than 1 cm long without underlying cartilaginous damage) referred for endoscopic treatment (first treatment or recurrence). The study will be conducted in three centres in France and one in Canada with other centres from France and Canada expected to join. The primary outcome is the recurrence rate of stenosis at 2 years. Recurrence is defined as having a new onset of symptoms along with a stenosis of more than 40% (confirmed by bronchoscopy) requiring a new procedure. A sample size of 100 patients is calculated for the primary endpoint assuming a 10% recurrence rate in the laser resection group and 33% in the dilation group with a statistical significance level of 5%, a power of 80%. ETHICS AND DISSEMINATION: This study is approved by local and national ethics committees as required. Results will be published, and trial data will be made available. TRIAL REGISTRATION NUMBER: NCT04719845.

A Three-Dimensional Printable Hydrogel Formulation for the Local Delivery of Therapeutic Nanoparticles to Cervical Cancer.

Cervical cancer is the fourth most common malignancy among women. Compared to other types of cancer, therapeutic agents can be administrated locally at the mucosal vaginal membrane. Thermosensitive gels have been developed over the years for contraception or for the treatment of bacterial, fungal, and sexually transmitted infections. These formulations often carry therapeutic nanoparticles and are now being considered in the arsenal of tools for oncology. They can also be three-dimensionally (3D) printed for a better geometrical adjustment to the anatomy of the patient, thus enhancing the local delivery treatment. In this study, a localized delivery system composed of a Pluronic F127-alginate hydrogel with efficient nanoparticle (NP) release properties was prepared for intravaginal application procedures. The kinetics of hydrogel degradation and its NP releasing properties were demonstrated with ultrasmall gold nanoparticles (∼80% of encapsulated AuNPs released in 48 h). The mucoadhesive properties of the hydrogel formulation were assayed by the periodic acid/Schiff reagent staining, which revealed that 19% of mucins were adsorbed on the gel's surface. The hydrogel formulation was tested for cytocompatibility in three cell lines (HeLa, CRL 2616, and BT-474; no sign of cytotoxicity revealed). The release of AuNPs from the hydrogel and their accumulation in vaginal membranes were quantitatively measured in vitro/ex vivo with positron emission tomography, a highly sensitive modality allowing real-time imaging of nanoparticle diffusion (lag time to start of permeation of 3.3 h, 47% of AuNPs accumulated in the mucosa after 42 h). Finally, the potential of the AuNP-containing Pluronic F127-alginate hydrogel for 3D printing was demonstrated, and the geometrical precision of the 3D printed systems was measured by magnetic resonance imaging (<0.5 mm precision; deviation from the design values <2.5%). In summary, this study demonstrates the potential of Pluronic F127-alginate formulations for the topical administration of NP-releasing gels applied to vaginal wall therapy. This technology could open new possibilities for photothermal and radiosensitizing oncology applications.

Outcomes Following Surgical Lung Biopsy for Interstitial Lung Diseases: A Monocenter Experience.

BACKGROUND: Surgical lung biopsy (SLB) is considered in the investigation of interstitial lung diseases (ILDs) when a complete clinical evaluation and a multidisciplinary discussion (MDD) do not allow the clinician to make a confident diagnosis. Owing to the risk of the procedure, an appropriate assessment of the risk/benefit ratio prior to the intervention is recommended. We aimed to assess the postoperative outcomes and diagnostic yield of SLB for the investigation of ILD in a tertiary care institution. METHODS: We conducted a retrospective cohort study of consecutive subjects who underwent a SLB for the investigation of ILD in our center from 2009 to 2020. The postoperative mortality and complications rates as well as the diagnostic yield of the procedure were assessed. RESULTS: Of the 1,805 patients newly investigated for ILD in our center from 2009 to 2020, 71 (3.93%) underwent a SLB. At days 30 and 90, the mortality rates were 0 and 2.8%, whereas 4.3 and 7.6% patients experienced an acute ILD exacerbation, respectively. In addition, 4 (5.8%) patients experienced infectious complications and 5 (7.0%) presented prolonged air leaks (all within 30 days). A definite pathological diagnosis was made in 47 (66.2%) patients. Following postoperative MDD, a confident diagnosis was made in 61 patients (85.9%) and resulted in a change of therapy in 49 (69.0%) patients. CONCLUSION: SLB for the diagnosis of unclassifiable ILDs is associated with low mortality but significant morbidity. However, it results in a confident diagnosis and a change in therapy in the majority of patients.

A Prediction Model to Optimize Invasive Mediastinal Staging Procedures for Non-small Cell Lung Cancer in Patients With a Radiologically Normal Mediastinum: The Quebec Prediction Model.

BACKGROUND: Current guideline-recommended criteria for invasive mediastinal staging in patients with a radiologically normal mediastinum fail to identify a significant proportion of patients with occult mediastinal disease (OMD), despite it leading to a large number of invasive staging procedures. RESEARCH QUESTION: Which variables available before surgery predict the probability of OMD in patients with a radiologically normal mediastinum? STUDY DESIGN AND METHODS: We identified all cTxN0/N1M0 non-small cell lung cancer tumors staged by CT imaging and PET with CT imaging in our institution between 2014 and 2018 who underwent gold standard surgical lymph node dissection or were demonstrated to have OMD before surgery by invasive mediastinal staging techniques and divided them into a derivation and an independent validation cohort to create the Quebec Prediction Model (QPM), which allows calculation of the probability of OMD. RESULTS: Eight hundred three patients were identified (development set, n = 502; validation set, n = 301) with a prevalence of OMD of 9.1%. The developed prediction model included largest mediastinal lymph node size (P < .001), tumor centrality (P = .23), presence of cN1 disease (P = .29), and lesion standardized uptake value (P = .09). Using a calculated probability of more than 10% as a threshold to identify OMD, this model had a sensitivity, specificity, positive predictive value, and negative predictive value in the derivation cohort of 73.9% (95% CI, 58.9%-85.7%), 81.1% (95% CI, 77.2%-84.6%), 28.3% (95% CI, 23.4%-33.8%), and 96.8% (95% CI, 95.0%-98.1%), respectively. It performed similarly in the validation cohort (P = .77, Hosmer-Lemeshow test; P = .5163, Pearson χ2 and unweighted sum-of-squares statistics; and P = .0750, Stukel score test) and outperformed current guideline-recommended criteria in identifying patients with OMD (area under the receiver operating characteristic curve [AUC] for American College of Chest Physicians guidelines criteria, 0.65 [95% CI, 0.59-0.71]; AUC for European Society of Thoracic Surgeons guidelines criteria, 0.60 [95% CI, 0.54-0.67]; and AUC for the QPM, 0.85 [95% CI, 0.80-0.90]). INTERPRETATION: The QPM allows the clinician to integrate available information from CT and PET imaging to minimize invasive staging procedures that will not modify management, while also minimizing the risk of unforeseen mediastinal disease found at surgery.

A role for magnetic susceptibility in synthetic computed tomography.

PURPOSE: Radiotherapy treatment planning based on magnetic resonance imaging (MRI) benefits from increased soft-tissue contrast and functional imaging. MRI-only planning is attractive but limited by the lack of electron density information required for dose calculation, and the difficulty to differentiate air and bone. MRI can map magnetic susceptibility to separate bone from air. A method is introduced to produce synthetic CT (sCT) through automatic voxel-wise assignment of CT numbers from an MRI dataset processed that includes magnetic susceptibility mapping. METHODS: Volumetric multi-echo gradient echo datasets were acquired in the heads of five healthy volunteers and fourteen patients with cancer using a 3 T MRI system. An algorithm for CT synthesis was designed using the volunteer data, based on fuzzy c-means clustering and adaptive thresholding of the MR data (magnitude, fat, water, and magnetic susceptibility). Susceptibility mapping was performed using a modified version of the iterative phase replacement algorithm. On patient data, the algorithm was assessed by direct comparison to X-ray computed tomography (CT) scans. RESULTS: The skull, spine, teeth, and major sinuses were clearly distinguished in all sCT, from healthy volunteers and patients. The mean absolute CT number error between X-ray CT and sCT in patients ranged from 78 and 134 HU. CONCLUSION: Susceptibility mapping using MRI can differentiate air and bone for CT synthesis. The proposed method is automated, fast, and based on a commercially available MRI pulse sequence. The method avoids registration errors and does not rely on a priori information, making it suitable for nonstandard anatomy.

Performance and safety of diagnostic procedures in superior vena cava syndrome.

Standard bronchoscopy and EBUS-TBNA have good diagnostic yield and are relatively safe procedures in the setting of SVCS. However, complications may arise from the underlying malignancy and its proximity to central vital structures. https://bit.ly/37HXFUY.