Endobronchial Ultrasound Guided Transbronchial Needle Aspiration and PD-L1 Yields.

PURPOSE: Immunotherapy is a leading approach for treating advanced non-small cell lung cancer (NSCLC) by targeting the PD-1/PD-L1 checkpoint signaling pathway, particularly in tumors expressing high levels of PD-L1 (Jug et al. in J Am Soc Cytopathol 9:485-493, 2020; Perrotta et al. in Chest 158: 1230-1239, 2020). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive method to obtain tissue for molecular studies, including PD-L1 analysis, in unresectable tumors (Genova et al. in Front Immunol 12: 799455, 2021; Wang et al. in Ann Oncol 29: 1417-1422, 2018). This study aimed to assess the adequacy of PD-L1 assessment in EBUS-TBNA cytology specimens. METHODS: Data was collected retrospectively from patients who underwent EBUS-TBNA between 2017 and 2021 for suspected lung cancer biopsy. Samples positive for NSCLC were examined for PD-L1 expression. EBUS was performed by experienced practitioners, following institutional guidelines of a minimum of five aspirations from positively identified lesions. Sample adequacy for molecular testing was determined by the pathology department. RESULTS: The analysis involved 387 NSCLC cases (149 squamous cell, 191 adenocarcinoma, 47 unspecified). Of the 263 EBUS-TBNA specimens tested for PD-L1, 237 (90.1%) were deemed adequate. While 84% adhered to the protocol, adherence did not yield better results. Significantly higher PD-L1 adequacy was observed in squamous cell carcinomas (93.2%) compared to adenocarcinoma (87.6%). The number of aspirations and sedation type did not correlate with PD-L1 adequacy in either cancer type, but lesion size and location had a significant impact in adenocarcinomas. Adenocarcinoma exhibited higher PD-L1 expression (68%) compared to squamous cell carcinoma (48%). CONCLUSION: EBUS-TBNA offers high yields for assessing immunotherapy markers like PD-L1, with satisfactory adequacy regardless of NSCLC subtype, lesion size, or location.

Endobronchial Ultrasound Guided Transbronchial Needle Aspiration and Next Generation Sequencing Yields.

PURPOSE: The use of endobronchial ultrasound (EBUS) is standard practice for lung cancer diagnosis and staging. Next generation sequencing (NGS) for detection of genetic alterations is recommended in advanced, non-squamous, non-small-cell lung cancer (NSCLC). Existing protocols for NGS testing are minimal and reported yields vary. This study aimed to determine the yield of EBUS samples obtained for NGS using a sampling protocol at our institution and assess predictive factors to form collection protocols. METHODS: We reviewed EBUS bronchoscopies from 2016 to 2021 with non-squamous NSCLC diagnoses. For target lesions suspected to be malignant, the sampling protocol was: (a) two slides for on-site evaluation, (b) three to five fine needle aspirations rinsed into saline for immunohistochemical staining and in-house molecular markers, and (c) additional three to five rinses for NGS. Sufficiency for NGS processing was determined by the pathology department. RESULTS: Two hundred and seventy-eight non-squamous NSCLC samples were obtained by EBUS (205 adenocarcinoma; 73 not otherwise specified). EBUS was performed under general anesthesia in 75.5% of cases. The overall sample adequacy for NGS testing was 57.5%. Higher adequacy rates were observed when protocol was adhered to 66.0% versus 37.2% (p < 0.001). There was no statistically significant difference based on the size of the lesion or location of the sample. CONCLUSION: When a protocol of three to five dedicated needle rinses for NGS was followed, we nearly doubled our sample adequacy rate for NSG as compared to standard care. Studies are needed to determine the ideal collection and processing modality to preserve tissue samples for genetic sequencing.

Artificial Intelligence Tool for Assessment of Indeterminate Pulmonary Nodules Detected with CT.

Background Limited data are available regarding whether computer-aided diagnosis (CAD) improves assessment of malignancy risk in indeterminate pulmonary nodules (IPNs). Purpose To evaluate the effect of an artificial intelligence-based CAD tool on clinician IPN diagnostic performance and agreement for both malignancy risk categories and management recommendations. Materials and Methods This was a retrospective multireader multicase study performed in June and July 2020 on chest CT studies of IPNs. Readers used only CT imaging data and provided an estimate of malignancy risk and a management recommendation for each case without and with CAD. The effect of CAD on average reader diagnostic performance was assessed using the Obuchowski-Rockette and Dorfman-Berbaum-Metz method to calculate estimates of area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Multirater Fleiss κ statistics were used to measure interobserver agreement for malignancy risk and management recommendations. Results A total of 300 chest CT scans of IPNs with maximal diameters of 5-30 mm (50.0% malignant) were reviewed by 12 readers (six radiologists, six pulmonologists) (patient median age, 65 years; IQR, 59-71 years; 164 [55%] men). Readers' average AUC improved from 0.82 to 0.89 with CAD (P < .001). At malignancy risk thresholds of 5% and 65%, use of CAD improved average sensitivity from 94.1% to 97.9% (P = .01) and from 52.6% to 63.1% (P < .001), respectively. Average reader specificity improved from 37.4% to 42.3% (P = .03) and from 87.3% to 89.9% (P = .05), respectively. Reader interobserver agreement improved with CAD for both the less than 5% (Fleiss κ, 0.50 vs 0.71; P < .001) and more than 65% (Fleiss κ, 0.54 vs 0.71; P < .001) malignancy risk categories. Overall reader interobserver agreement for management recommendation categories (no action, CT surveillance, diagnostic procedure) also improved with CAD (Fleiss κ, 0.44 vs 0.52; P = .001). Conclusion Use of computer-aided diagnosis improved estimation of indeterminate pulmonary nodule malignancy risk on chest CT scans and improved interobserver agreement for both risk stratification and management recommendations. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Yanagawa in this issue.

Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion.

Malignant pleural effusion (MPE) is indicative of terminal malignancy with a uniformly fatal prognosis. Often, two distinct compartments of tumour microenvironment, the effusion and disseminated pleural tumours, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumour-associated myeloid cells with the tumour-promoting phenotype, impairing antitumour immunity. Here we developed a liposomal nanoparticle loaded with cyclic dinucleotide (LNP-CDN) for targeted activation of stimulators of interferon genes signalling in macrophages and dendritic cells and showed that, on intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both effusion and pleural tumours. Moreover, combination immunotherapy with blockade of programmed death ligand 1 potently reduced MPE volume and inhibited tumour growth not only in the pleural cavity but also in the lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.

Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10.

Chemo-immunotherapy is central to the treatment of small cell lung cancer (SCLC). Despite modest progress made with the addition of immunotherapy, current cytotoxic regimens display minimal survival benefit and new treatments are needed. Thymidylate synthase (TS) is a well-validated anti-cancer drug target, but conventional TS inhibitors display limited clinical efficacy in refractory or recurrent SCLC. We performed RNA-Seq analysis to identify gene expression changes in SCLC biopsy samples to provide mechanistic insight into the potential utility of targeting pyrimidine biosynthesis to treat SCLC. We identified systematic dysregulation of pyrimidine biosynthesis, including elevated TYMS expression that likely contributes to the lack of efficacy for current TS inhibitors in SCLC. We also identified E2F1-3 upregulation in SCLC as a potential driver of TYMS expression that may contribute to tumor aggressiveness. To test if TS inhibition could be a viable strategy for SCLC treatment, we developed patient-derived organoids (PDOs) from human SCLC biopsy samples and used these to evaluate both conventional fluoropyrimidine drugs (e.g., 5-fluorouracil), platinum-based drugs, and CF10, a novel fluoropyrimidine polymer with enhanced TS inhibition activity. PDOs were relatively resistant to 5-FU and while moderately sensitive to the front-line agent cisplatin, were relatively more sensitive to CF10. Our studies demonstrate dysregulated pyrimidine biosynthesis contributes to drug resistance in SCLC and indicate that a novel approach to target these pathways may improve outcomes.

The Effects of Health Disparities on Perceptions About Lung Cancer Screening (LCS): Survey Results of a Patient Sample.

Lung cancer screening (LCS) is currently advocated in a subset of current or former smokers with a thirty pack-year smoking history or higher. Studies report that few patients meeting the criteria for screening are undergoing LCS. We conducted a survey to assess if barriers to LCS (race, ethnicity, and socioeconomic status) affect the perceptions about LCS that could influence screening uptake. We did not detect different perceptions based on race, ethnicity, or socioeconomic status; however, our survey found that fewer barriers and more benefits to LCS may be perceived in patients who undergo other types of health screening and more benefits for those with internet capable devices.

Protocol to Improve Genotyping of Non-Small-Cell Lung Cancer Diagnosed Using EBUS-TBNA.

OBJECTIVES: Targeted therapies for non-small-cell lung cancers (NSCLCs) are based on the presence of driver mutations such as epidermal growth factor receptor (EGFR) and the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation. Endobronchial ultrasound-guided-transbronchial needle aspiration (EBUS-TBNA) is a first-line modality for diagnosing and staging NSCLC. A quality improvement protocol maximizing tissue acquisition for molecular analysis has not been previously described. METHODS: We instituted a standardized protocol designed from a multidisciplinary meeting of the pulmonology, oncology, and pathology departments for the acquisition and on-site processing of samples obtained through EBUS-TBNA to improve the yield for genetic analysis of EGFR and ALK testing. RESULTS: Preprotocol there were 50 NSCLCs (29 adenocarcinomas) and postprotocol there were 109 NSCLCs (52 adenocarcinomas). A statistically significant increase in yield for molecular analysis was seen in both EGFR (36% preprotocol and 80% postprotocol, P < 0.01) and ALK (41% preprotocol and 80% postprotocol, P < 0.01). There was no difference in complications preprotocol and postprotocol. CONCLUSIONS: Implementation of a standardized protocol with EBUS-TBNA was associated with an increase in adequacy for molecular genetic analysis in NSCLC.

False-positive screens and lung cancer risk in the National Lung Screening Trial: Implications for shared decision-making.

Objectives Low-dose computed tomography lung cancer screening has been shown to reduce lung cancer mortality but has a high false-positive rate. The precision medicine approach to low-dose computed tomography screening assesses subjects' benefits versus harms based on their personal lung cancer risk, where harms include false-positive screens and resultant invasive procedures. We assess the relationship between lung cancer risk and the rate of false-positive LDCT screens. Methods The National Lung Screening Trial randomized high-risk subjects to three annual screens with low-dose computed tomography or chest radiographs. Following the completion of National Lung Screening Trial, the Lung CT Screening Reporting and Data System (Lung-RADS) classification system was developed and retrospectively applied to National Lung Screening Trial low-dose computed tomography findings. The rate of false-positive screens (by Lung-RADS) and the resultant invasive procedures were examined as a function of lung cancer risk estimated by a model. Results Of 26,722 subjects randomized to the low-dose computed tomography arm, 26,309 received a baseline screen and were included in the analysis. The proportion with any false positive over three screening rounds increased from 12.9% to 25.9% from lowest to highest risk decile, and the proportion with an invasive procedure following a false positive also significantly increased from 0.7% to 2.0% from lowest to highest risk decile. Conclusion These findings indicate a need for personalized low-dose computed tomography lung cancer screening decision aids to accurately convey the benefits to harm trade-off.

Bronchoscopy Safety in Patients With Chronic Obstructive Lung Disease.

BACKGROUND: Flexible bronchoscopy is a safe and minimally invasive diagnostic tool used by pulmonologists, but few studies have prospectively compared outcomes in patients with objectively defined obstructive lung disease to those without obstruction. METHODS: We determined whether complications in patients undergoing moderate sedation bronchoscopy differ in those without obstruction compared with chronic obstructive pulmonary disease (COPD). We prospectively followed all patients undergoing moderate sedation bronchoscopy in an inpatient or outpatient setting. RESULTS: Over 12 months, data were collected prospectively in 258 patients. A total o 151 patients had pulmonary function testing with classification of COPD according to GOLD Criteria. Sixty-seven of those patients (44%) had COPD: 6 mild (9%), 29 moderate (42%), 27 severe (41%), and 5 very severe (8%). COPD patients were more likely to receive outpatient inhaled corticosteroids and long-acting bronchodilators and anticholinergics (P<0.001) as would be clinically appropriate. Among all patients with COPD, there were 13% minor complications and 5% major complications, with no deaths. Respiratory complications occurred more often in patients with severe to very severe COPD (22%) compared with patients without COPD (6%) (P=0.018). When adjusted for age, body mass index, and use of home oxygen, this difference was still significant (P=0.045). CONCLUSION: Bronchoscopy is generally safe with few complications in most patients with COPD. Patients with objectively confirmed severe to very severe COPD had more frequent respiratory complications than patients without COPD. The risks were not prohibitively high, but should be taken into consideration for COPD patients undergoing moderate sedation flexible bronchoscopy.

Sedation for Bronchoscopy and Complications in Obese Patients.

BACKGROUND: Bronchoscopy is a safe and minimally invasive diagnostic tool, but no studies have reported prospectively on sedation and outcomes in patients with objectively defined obesity. OBJECTIVES: The purpose of the study is to determine if obese patients require more sedation or had more procedural complications during bronchoscopy under moderate sedation than non-obese patients. METHODS: We evaluated complications and sedation requirements in non-obese versus obese patients, defined by multiple criteria including body mass index (BMI), neck circumference, abdominal height, and Mallampati scores. RESULTS: Data were collected prospectively in 258 patients undergoing bronchoscopy under moderate sedation. By varying criteria, there were the following proportions of obese patients: 30% by BMI >30, 39% by neck circumference >40 cm, and 35% by abdominal height >22 cm in males and >20 cm in females. Sedative and analgesic dosing was not clinically significantly higher in obese patients than in non-obese patients. There was no difference in complications or procedural success based on obesity criteria. Hemoglobin oxygen desaturations occurred more often during bronchoscopy in patients with increasing Mallampati scores (p = 0.04), but this had no effect on bronchoscopy time or successful completion of the procedure. A subset of patients with previous polysomnogram-proven obstructive sleep apnea were more likely to have earlier termination of their procedure (15.8%) than patients with no diagnosed sleep apnea (2.3%; p = 0.002). CONCLUSION: In this prospective assessment of patients with obesity, we found neither clinically significant differences in sedation needs nor increases in complications in obese versus non-obese patients using a variety of indices of obesity.

Negative Predictive Value of Granulomas on EBUS-TBNA in Suspected Extrathoracic Malignancy.

PURPOSE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a well-established diagnostic tool for lung cancer, sarcoidosis, and suspected metastatic extrathoracic malignancy. EBUS-TBNA carries a high diagnostic yield, but its negative predictive value (NPV) requires further clarification. METHODS: We reviewed EBUS-TBNA at our cancer center from 2008 to 2015. We identified negative diagnostic samples for adenopathy suspected to represent metastatic disease from extrathoracic malignancy. RESULTS: We reviewed 529 EBUS-TBNAs. Ninety patients underwent EBUS-TBNA sampling of the hilum and/or mediastinum (121 nodes, 14 masses) for suspected extrathoracic malignancy. Thirty-seven patients had negative samples (lymph node, granulomas or non-diagnostic specimens). The overall NPV was 98 %. Granulomas (11 patients, 25 nodes) seen on histology had a 100 % NPV, including those that were FDG-PET (fluorodeoxyglucose positron emission tomography) avid (n = 14 nodes). CONCLUSION: Negative EBUS-TBNA in patients with extrathoracic malignancy and suspected secondary hilar or mediastinal metastases can infer a high NPV especially if granulomas are seen on histology. Larger prospective investigations are needed to confirm the high NPV of EBUS-TBNA with granulomas in extrathoracic malignancies.

Outpatient Chronic Obstructive Pulmonary Disease Management: Going for the GOLD.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States with a burden of $50 billion in direct health care costs. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines airflow obstruction as spirometry where the ratio of forced expiratory volume in the first second to forced vital capacity after bronchodilation is less than 0.70. The guidelines also provided graded recommendations on current therapy for COPD. Treatment can be guided based on severity of disease and severity of symptoms. We review the GOLD guidelines to provide an overview of treatment modalities aimed at improving lung function, reducing hospitalization, and reducing mortality.

Training in and experience with endobronchial ultrasound.

BACKGROUND: Diagnosing mediastinal and hilar lymphadenopathy and staging lung cancer with endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) are on the rise, but uncertainty surrounds the optimal number of cases needed to achieve acceptable yields. OBJECTIVES: To determine the threshold at which EBUS-TBNA reaches adequate yields among trainees and skilled bronchoscopists. METHODS: We reviewed all EBUS-TBNAs performed at our medical center since implementing the use of EBUS (n = 222). RESULTS: EBUS-TBNAs were performed in 222 patients (344 nodes). The percentage of adequate specimens sampled (diagnostic specimens or nodal tissue) rose from 66% in 2008 to 90% in 2012 (p < 0.01) and cancer yield improved from 34% in 2008 to 48% in 2012 (p < 0.01). Attending physicians who performed an average of more than 10 procedures per year had higher yields compared to those who performed fewer than 10 procedures per year (86 vs. 68%, p < 0.01). The yield of trainees also improved with every 10 procedures (79, 90 and 95%, p < 0.001) and that of attending physicians with experience (1-25 procedures: 78% yield, 26-50 procedures: 87% yield and 50+ procedures: 90% yield; p < 0.01). Among trainees, failure rates declined steadily. CONCLUSION: EBUS-TBNA yield (malignant and benign) increases with increasing experience amongst experienced bronchoscopists and trainees as early as the first 20-25 procedures. Pulmonary trainees had a rapid decline in failure rates. These findings suggest that in an academic environment a minimum of 20-25 procedures is needed to achieve acceptable yields.

Argon plasma coagulation and electrosurgery for benign endobronchial tumors.

BACKGROUND: Benign endobronchial tumors are a rare entity capable of causing significant symptoms. Endobronchial tumor destruction has the potential for relieving symptoms while sparing the patient from invasive surgical resection. Although Nd:YAG laser has been successfully used, other less costly approaches such as argon plasma coagulation (APC) and electrocautery, may be effective alternatives for the bronchoscopic treatment of benign endobronchial tumors. METHODS: A retrospective medical chart review was conducted at a single academic center in the United States from the period of January 2005 through December 2011 to collect a minimum of 10 cases for review. Eligibility criteria included diagnosis of a benign endobronchial tumor and age over 18 years. Our institution's pathology database was searched by specific benign tumor and the results were further refined based on an endobronchial location. The bronchoscopic procedure log was also searched and identified procedures were cross referenced with the medical record to confirm eligibility. RESULTS: Ten patients with pathologically confirmed benign endobronchial tumors were identified. All patients achieved tumor regression with APC in combination with electrocautery or cryotherapy. Majority of the procedures (75%) were performed with flexible bronchoscopy and 55% were performed under moderate sedation. CONCLUSIONS: APC is an effective method for tumor devitalization and reduction in tumor size, making it a viable and less costly therapeutic option for the treatment of benign endobronchial tumors.

Conventional and endobronchial ultrasound-guided transbronchial needle aspiration: complementary procedures.

OBJECTIVE: The diagnosis of mediastinal and hilar lymphadenopathy and staging lung cancer with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are on the rise. Most reports have demonstrated high yields with EBUS-TBNA and superiority of this procedure over conventional TBNA (cTBNA), but the relative roles of these procedures remain undefined. We present a comprehensive comparison of EBUS-TBNA to cTBNA. METHODS: We reviewed all of the bronchoscopies performed at our medical center from January 2009 through December 2010. We collected data on 82 EBUS-TBNAs and 209 cTBNAs performed. A cost analysis was subsequently performed. RESULTS: EBUS-TBNA was performed more often in patients with known prior cancer and suspicion of recurrence or staging compared with cTBNA (42% vs 18%, P < 0.001). cTBNA was more likely to be performed in patients suspected of having malignancy and needing diagnostic specimens (70% vs 46%, P = 0.009). The overall yield in which a diagnostic specimen or lymphoid tissue was obtained was not different in each group: EBUS 84% vs cTBNA 86% (P = 0.75). The cancer yield was 57% in cTBNAs compared with 44% in EBUS-TBNAs (P < 0.0001), with EBUS-TBNA more often targeting smaller nodes (mean 15 ± 7 mm vs 21 ± 11 mm; P < 0.0001) and paratracheal sites (67% vs 49%, P = 0.003). Per-procedure cost using a Medicare scale was higher for EBUS than it was for cTBNA ($1195 vs $808; P < 0.001). CONCLUSIONS: EBUS-TBNA and cTBNA are complementary bronchoscopic procedures, and the appropriate diagnostic modality can be selected in a cost-effective manner based upon the primary indication for TBNA, lymph node size, and lymph node location.