Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing.

Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

Interventional Pulmonology: Extending the Breadth of Thoracic Care.

Interventional pulmonary medicine has developed as a subspecialty focused on the management of patients with complex thoracic disease. Leveraging minimally invasive techniques, interventional pulmonologists diagnose and treat pathologies that previously required more invasive options such as surgery. By mitigating procedural risk, interventional pulmonologists have extended the reach of care to a wider pool of vulnerable patients who require therapy. Endoscopic innovations, including endobronchial ultrasound and robotic and electromagnetic bronchoscopy, have enhanced the ability to perform diagnostic procedures on an ambulatory basis. Therapeutic procedures for patients with symptomatic airway disease, pleural disease, and severe emphysema have provided the ability to palliate symptoms. The combination of medical and procedural expertise has made interventional pulmonologists an integral part of comprehensive care teams for patients with oncologic, airway, and pleural needs. This review surveys key areas in which interventional pulmonologists have impacted the care of thoracic disease through bronchoscopic intervention.

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.

Multidisciplinary Management of Adult Patients with Chylothorax: A Consensus Statement.

The management of chylothorax remains challenging given the limited evidence and significant heterogeneity in practice. In addition, there are no practical guidelines on the optimal approach to manage this complex condition. We convened an international group of 27 experts from 20 institutions across five countries and 4 specialties (Pulmonary, Interventional Radiology, Thoracic Surgery & Nutrition) with experience and expertise in managing adult patients with chylothorax. We performed a literature and internet search for reports addressing 7 clinically relevant questions pertaining to the management of adult patients with chylothorax. This consensus statement, consisting of best practice statements based on expert consensus addressing these 7 PICO questions, was formulated by a systematic and rigorous process involving the evaluation of published evidence, augmented with provider experience. Panel members participated in the development of the final best practice statements using the modified Delphi technique. Our consensus statement aims to offer guidance in clinical decision making when managing patients with chylothorax while also identifying gaps in knowledge and inform future research.

Safety and utility of indwelling pleural catheters in lung transplant recipients.

INTRODUCTION: The safety and efficacy of indwelling pleural catheters (IPCs) in lung allograft recipients is under-reported. METHODS: We performed a multicenter, retrospective analysis between 1/1/2010 and 6/1/2022 of consecutive IPCs placed in lung transplant recipients. Outcomes included incidence of infectious and non-infectious complications and rate of auto-pleurodesis. RESULTS: Seventy-one IPCs placed in 61 lung transplant patients at eight centers were included. The most common indication for IPC placement was recurrent post-operative effusion. IPCs were placed at a median of 59 days (IQR 40-203) post-transplant and remained for 43 days (IQR 25-88). There was a total of eight (11%) complications. Infection occurred in five patients (7%); four had empyema and one had a catheter tract infection. IPCs did not cause death or critical illness in our cohort. Auto-pleurodesis leading to the removal of the IPC occurred in 63 (89%) instances. None of the patients in this cohort required subsequent surgical decortication. CONCLUSIONS: The use of IPCs in lung transplant patients was associated with an infectious complication rate comparable to other populations previously studied. A high rate of auto-pleurodesis was observed. This work suggests that IPCs may be considered for the management of recurrent pleural effusions in lung allograft recipients.

Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.

Translating the transcriptome into tools for the early detection and prevention of lung cancer.

Despite advances in the management of lung cancer, this disease remains a significant global health burden with survival rates that have not significantly improved in decades. The mortality reduction achieved by low-dose helical CT (LDCT) screening of select high-risk patients is challenged by the high false positive rate of this screening modality and the potential for morbidity associated with follow-up diagnostic evaluation in patients with high risk for iatrogenic complications. The diagnostic dilemma of the indeterminate nodule incidentally identified on diagnostic or screening CT has created a need for reliable biomarkers capable of distinguishing benign from malignant disease. Furthermore, there is an urgent need to develop molecular biomarkers to supplement clinical risk models in order to identify patients at highest risk for having an early stage lung cancer that may derive the greatest benefit from LDCT screening, as well as identifying patients at high-risk for developing lung cancer that may be candidates for emerging chemopreventive strategies. Evolving bioinformatic techniques and the application of these algorithms to analyse the transcriptomic changes associated with lung cancer promise translational discoveries that can bridge these large clinical gaps. The identification of lung cancer associated transcriptomic alterations in readily accessible tissue sampling sites offers the potential to develop early diagnostic and risk stratification strategies applicable to large populations. This review summarises the challenges associated with the early detection, screening and chemoprevention of lung cancer with an emphasis on how genomic information encapsulated by the transcriptome can facilitate future innovations in these clinical settings.

Explor-A-Thora: A Novel Three-Dimensionally Printed Pleural Simulator.

Background: For procedural education, the shift from the traditional apprenticeship model to simulation-based mastery has become increasingly accepted as the gold standard and has underscored the importance of high-fidelity, cost-effective training options. However, cost-effective pleural procedure simulators providing both realistic haptic feedback and ultrasound compatibility are lacking. Objective: We aimed to create a pleural procedure simulator with characteristics of human tissue, at low cost and with ultrasound compatibility. Methods: This work used design-based research principles and a collaborative rapid iteration approach in collaboration with the University of California, San Francisco, Makers Lab and design-based researchers at the University of California, Berkeley, which led to the creation of a three-dimensionally printed pleural procedure simulator. Results: The needs assessment indicated significant discomfort with pleural procedures and a request for more accessible simulation opportunities. Iterative prototyping resulted in a three-dimensionally printed rib cage and a series of innovations in the fluid pocket and skin layers to provide realistic tactile feedback and ultrasound imaging compatibility. The final model costs significantly less than commercial simulators, with durable components and replaceable parts that can be reused multiple times. Conclusion: The development of a low-cost, high-fidelity pleural procedure simulator addresses the current limitations of commercially available pleural simulators. By integrating three-dimensional printing technology and easily accessible materials, we were able to produce a simulator that closely replicates the feel of human tissue, allows ultrasound use, and is adaptable for different patient anatomies and clinical scenarios. This novel simulator is a scalable solution to elevate the standard of procedural education and ultimately positively affect patient care.

Impact of a Dedicated Pleural Clinic on Indwelling Pleural Catheter Related Outcomes: A Retrospective Single Center Experience.

BACKGROUND: Recurrent pleural effusions are a major cause of morbidity and frequently lead to hospitalization. Indwelling pleural catheters (IPCs) are tunneled catheters that allow ambulatory intermittent drainage of pleural fluid without repeated thoracentesis. Despite the efficacy and safety of IPCs, data supporting postplacement follow-up is limited and variable. Our study aims to characterize the impact of a dedicated pleural clinic (PC) on patient outcomes as they relate to IPCs. METHODS: Patients who underwent IPC placement between 2015 and 2021 were included in this retrospective study. Differences in outcomes were analyzed between patients with an IPC placed and managed by Interventional Pulmonology (IP) through the PC and those placed by non-IP services (non-PC providers) before and after the PC implementation. RESULTS: In total, 371 patients received IPCs. Since the implementation of the PC, there was an increase in ambulatory IPC placement (31/133 pre-PC vs. 96/238 post-PC; P =0.001). There were fewer admissions before IPC placement (18/103 vs. 43/133; P =0.01), and fewer thoracenteses per patient (2.7±2.5 in PC cohort vs. 4±5.1 in non-PC cohort; P <0.01). The frequency of pleurodesis was higher in the PC cohort (40/103 vs. 41/268; P <0.001). A Fine and Gray competing risks model indicated higher likelihood of pleurodesis in the PC cohort (adjusted subhazard ratio 3.8, 95% CI: 2.5-5.87). CONCLUSION: Our experience suggests that the implementation of a dedicated PC can lead to improved patient outcomes including fewer procedures and admissions before IPC placement, and increased rates of pleurodesis with IPC removal.

Real-World Perspectives and Practices for Pneumonitis/Interstitial Lung Disease Associated With Trastuzumab Deruxtecan Use in Human Epidermal Growth Factor Receptor 2-Expressing Metastatic Breast Cancer.

Trastuzumab deruxtecan (T-DXd) is an antibody drug conjugate with a topoisomerase I payload that targets the human epidermal growth factor receptor 2 (HER2). T-DXd is approved for patients with previously treated HER2-positive or HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/ISH-) metastatic/unresectable breast cancer (BC). In a second-line HER2-positive metastatic BC (mBC) population (DESTINY-Breast03 [ClinicalTrials.gov identifier: NCT03529110]), T-DXd demonstrated significantly improved progression-free survival (PFS) over ado-trastuzumab emtansine (12-month rate: 75.8% v 34.1%; hazard ratio, 0.28; P < .001), and in patients with HER2-low mBC treated with one prior line of chemotherapy (DESTINY-Breast04 [ClinicalTrials.gov identifier: NCT03734029]), T-DXd demonstrated significantly longer PFS and overall survival than physician's choice chemotherapy (10.1 v 5.4 months; hazard ratio, 0.51; P < .001, and 23.4 v 16.8 months; hazard ratio, 0.64; P < .001, respectively).Interstitial lung disease (ILD) is an umbrella term used for a group of diseases characterized by lung injury including pneumonitis, which can lead to irreversible lung fibrosis. ILD is a well-described adverse event associated with certain anticancer therapies, including T-DXd. An important part of T-DXd therapy for mBC consists of monitoring for and managing ILD. Although information on ILD management strategies is included in the prescribing information, additional information on patient selection, monitoring, and treatment can be beneficial in routine clinical practice. The objective of this review is to describe real-world, multidisciplinary clinical practices and institutional protocols used for patient selection/screening, monitoring, and management related to T-DXd-associated ILD.

Education for Tobacco Use Disorder Treatment: Current State, Evidence, and Unmet Needs.

Background: Tobacco use is undertreated in the medical setting. One driver may be inadequate tobacco use disorder treatment (TUDT) training for clinicians in specialties treating tobacco-dependent patients. Objective: We sought to evaluate the current state of TUDT training for diverse professionals and how these skills are assessed in credentialing exams. Methods: We performed a focused review of current educational practices, evidence-based strategies, and accreditation exam contents focused on TUDT. Results: Among medical students, participants in reviewed studies reported anywhere from 45 minutes to 3 hours of TUDT training throughout their 4-year programs, most often in the form of didactic sessions. Similarly, little TUDT training was reported at the post-graduate (residency, fellowship, continuing medical education) levels, and reported training was typically delivered as time-based (expected hours of instruction) rather than competency-based (demonstration of mastery) learning. Multiple studies evaluated effective TUDT curricula at varied stages of training. More effective curricula incorporated longitudinal sessions and active learning, such as standardized patient encounters or proctored patient visits. Knowledge of TUDT is minimally evaluated on certification exams. For example, the American Board of Internal Medicine blueprint lists TUDT as <2% of one subtopic on both the internal medicine and pulmonary exams. Conclusion: TUDT training for most clinicians is minimal, does not assess competency, and is minimally evaluated on certification exams. Effective, evidence-based TUDT training incorporating active learning should be integrated into medical education at all levels, with attention paid to inclusion on subsequent certifying exams.

Use of tunneled pleural catheters in chronic empyema: Two case reports and brief review of the literature.

The incidence of empyema is increasing worldwide, which, coupled with the aging global population, makes the non-surgical management of pleural space infections increasingly important. Despite this, there remains no consensus for management of chronic empyema in those patients who are not surgical candidates and do not get adequate source control with chest tube and intra-pleural lytic therapy, particularly for patients with non-expandable lungs. We reviewed the literature regarding non-surgical management of chronic empyema and present two cases that support the use of pleuroscopy in conjunction with tunneled pleural catheters for management of chronic empyema in non-surgical candidates.

Erector Spinae Plane Block: A Novel Anesthetic Approach for Pleuroscopy.

BACKGROUND: Anesthesia and analgesia for thoracic procedures, specifically pleuroscopy, present unique challenges given the spectrum of underlying pulmonary disease and susceptibility to respiratory complications. This study describes efforts to reduce postoperative pain and minimize opioid analgesia after thoracoscopic procedures through the use of erector spinae plane block (ESPB). METHODS: This is a single center, retrospective case series of all patients who underwent rigid pleuroscopy with ESPB plus monitored anesthesia care (MAC) from November 2018 through September 2020. The primary outcome measures were postoperative pain scores and analgesic medication requirements. RESULTS: Twenty-six patients underwent pleuroscopy with ESPB plus MAC. Average intraoperative and postoperative opioid consumption in oral morphine equivalents were 18.4±15.8 and 11.2±19.6 mg, respectively. There was no significant difference between average preoperative and postoperative subjective numerical pain scores (P=0.221). There were no complications associated with ESPB. CONCLUSION: This case series demonstrates the feasibility of utilizing single shot ESPB in combination with MAC as the primary anesthetic for thoracoscopic procedures.

Bleeding Risk With Combination Intrapleural Fibrinolytic and Enzyme Therapy in Pleural Infection: An International, Multicenter, Retrospective Cohort Study.

BACKGROUND: Combination intrapleural fibrinolytic and enzyme therapy (IET) has been established as a therapeutic option in pleural infection. Despite demonstrated efficacy, studies specifically designed and adequately powered to address complications are sparse. The safety profile, the effects of concurrent therapeutic anticoagulation, and the nature and extent of nonbleeding complications remain poorly defined. RESEARCH QUESTION: What is the bleeding complication risk associated with IET use in pleural infection? STUDY DESIGN AND METHODS: This was a multicenter, retrospective observational study conducted in 24 centers across the United States and the United Kingdom. Protocolized data collection for 1,851 patients treated with at least one dose of combination IET for pleural infection between January 2012 and May 2019 was undertaken. The primary outcome was the overall incidence of pleural bleeding defined using pre hoc criteria. RESULTS: Overall, pleural bleeding occurred in 76 of 1,833 patients (4.1%; 95% CI, 3.0%-5.0%). Using a half-dose regimen (tissue plasminogen activator, 5 mg) did not change this risk significantly (6/172 [3.5%]; P = .68). Therapeutic anticoagulation alongside IET was associated with increased bleeding rates (19/197 [9.6%]) compared with temporarily withholding anticoagulation before administration of IET (3/118 [2.6%]; P = .017). As well as systemic anticoagulation, increasing RAPID score, elevated serum urea, and platelets of < 100 × 109/L were associated with a significant increase in bleeding risk. However, only RAPID score and use of systemic anticoagulation were independently predictive. Apart from pain, non-bleeding complications were rare. INTERPRETATION: IET use in pleural infection confers a low overall bleeding risk. Increased rates of pleural bleeding are associated with concurrent use of anticoagulation but can be mitigated by withholding anticoagulation before IET. Concomitant administration of IET and therapeutic anticoagulation should be avoided. Parameters related to higher IET-related bleeding have been identified that may lead to altered risk thresholds for treatment.