Faculty Bibliography

BACKGROUND:Advanced-stage non-small cell lung cancer treatment has evolved with the introduction of molecularly targeted therapy, immunotherapy and combination frontline therapies. Despite these advancements, most patients experience treatment failure, resulting in poor prognosis characterized by low median progression-free survival (PFS) and overall survival (OS). Second-line chemotherapy has demonstrated minimally improved survival compared to best supportive care. Exploring new mechanisms to enhance treatment response in this patient population is critical. OBJECTIVE:This retrospective study aims to assess if there is survival benefit in a cohort of patients with stage IV lung cancer who have failed previous systemic therapy treated with pulsed electrical fields (PEF) therapy compared to a propensity-matched cohort. METHODS:A retrospective review of patients treated with PEF at three academic institutions from January 1, 2023, to July 1, 2024, yielded 41 patients with progressive stage IV non-small cell lung cancer. Tumor response was evaluated by RECIST 1.1 criteria. A propensity matched cohort of 50 patients with advanced NSCLC undergoing systemic therapy was identified. Statistical analyses, including Kaplan-Meier survival estimates and Hazard ratios, were conducted. RESULTS:The PEF-treated cohort exhibited a 1-year PFS of 63.2 % and OS of 74.3 %. In contrast, the matched cohort demonstrated a 1-year PFS of 11.8 % and OS of 33 %. The hazard ratio for PFS in the PEF group was 3.66 (p < 0.0001) and for OS was 3.5 (p = 0.0007), indicating a significant survival advantage for patients receiving PEF. CONCLUSION/CONCLUSIONS:This study suggests that PEF therapy may be associated with significantly improved PFS and OS in patients with progressive stage IV non-small cell lung cancer compared to the matched cohort. Prospective controlled studies are required to confirm these preliminary findings, to better understand the mechanism of action of PEF, and to identify which patient populations would best benefit from this therapy.

How tumor microenvironment shapes lung adenocarcinoma (LUAD) precancer evolution remains poorly understood. Spatial immune profiling of 114 human LUAD and LUAD precursors reveals a progressive increase of adaptive response and a relative decrease of innate immune response as LUAD precursors progress. The immune evasion features align the immune response patterns at various stages. TIM-3-high features are enriched in LUAD precancers, which decrease in later stages. Furthermore, single-cell RNA sequencing (scRNA-seq) and spatial immune and transcriptomics profiling of LUAD and LUAD precursor specimens from 5 mouse models validate high TIM-3 features in LUAD precancers. In vivo TIM-3 blockade at precancer stage, but not at advanced cancer stage, decreases tumor burden. Anti-TIM-3 treatment is associated with enhanced antigen presentation, T cell activation, and increased M1/M2 macrophage ratio. These results highlight the coordination of innate and adaptive immune response/evasion during LUAD precancer evolution and suggest TIM-3 as a potential target for LUAD precancer interception.

BACKGROUND:It remains challenging to safely and reliably biopsy peripheral pulmonary lesions (PPLs). Robotic-assisted bronchoscopy (RAB) is gaining adoption for navigation to PPLs. However, evidence from large studies remains limited. RESEARCH QUESTION/OBJECTIVE:What is the clinical safety, navigational success, and diagnostic yield of RAB for biopsy of PPLs in a broad range of patients in a real-world setting? STUDY DESIGN AND METHODS/METHODS:This multicenter, prospective, single-arm study enrolled patients >21 years old with 8-50 mm lung lesions requiring bronchoscopic diagnosis. The primary endpoint was the incidence of the following device- or procedure-related events: (1) pneumothorax requiring intervention; (2) bleeding requiring intervention; or (3) respiratory failure. Secondary endpoints included individual components of the primary endpoint, procedure time, pneumothoraces, radial probe endobronchial ultrasound (R-EBUS) confirmation, conversion to an alternative biopsy procedure, complications, and diagnostic yield (DY). RESULTS:Among 715 patients at 21 sites, 679 met study criteria and underwent RAB (mean age 68.7, 55.4% female, 86.5% White, 77.5% current/past tobacco users). Mean (range) lesion size was 20.9 (7.0-63.0) mm; median (IQR) distance from pleural surface was 5 (0-16) mm. Most lesions were solid (n=587; 86.6%) and within the outer two-thirds of the lung (n=593; 87.5%). The primary endpoint was observed in 26 (3.8%) patients (19 pneumothorax, 7 bleeding, 0 respiratory failure). Users reported that RAB reached the lesion in 670/679 (98.7%) cases, and lesion location was confirmed with R-EBUS in 607/662 (91.7%) cases; sampling through the bronchoscope was performed in 675/679 (99.4%) cases. Prevalence of malignancy was 64.1% through 12 months. Adjudicated DY was 61.6% when calculated with the American Thoracic Society (ATS)/American College of Chest Physicians (ACCP) definition for strict reporting criteria. Sensitivity for malignancy was 78.8%. INTERPRETATION/CONCLUSIONS:This largest multicenter prospective study of RAB to date demonstrated that RAB-guided sampling of PPLs is safe and compares favorably to results from sizable non-robotic bronchoscopy studies. CLINICAL TRIAL REGISTRATION NUMBER/BACKGROUND:NCT04182815.

The role of dietary fiber in colon cancer prevention remains controversial. We investigated its impact on anti-tumor immunity and the gut microbiota in APCmin/+ mice infected with Enterotoxigenic Bacteroides fragilis. Mice were fed high-fiber, low-fiber, or chow diets, and tumor burden, survival, cytokines, microbiota, and metabolites were analyzed. Contrary to the belief that high fiber inhibits tumor progression, it had no significant impact compared to chow diet. However, the low-fiber diet significantly reduced tumor burden and improved survival. Mechanistically, high fiber increased pro-inflammatory cytokines and CD4+Foxp3+RORγt+IL-17A+ regulatory T cells, while low fiber enhanced anti-inflammatory cytokines and cytotoxic T-cells. High fiber enriched microbial taxa associated with IL-17A+RORγt+ Tregs and altered metabolites, including reduced tryptophan and increased short-chain fatty acids and bile acids. Low fiber produced opposite effects. These findings suggest that dietary fiber's effects on colon cancer depends on microbial infection and immune status, emphasizing the need for personalized dietary interventions in colon cancer management.

BACKGROUND:Risk of early-stage lung adenocarcinoma (LUAD) recurrence after surgical resection is significant, and post-recurrence median survival is approximately two years. Currently there are no commercially available biomarkers that predict recurrence. Here, we investigated whether microbial and host genomic signatures in the lung can predict recurrence. METHODS:In 91 early-stage (Stage IA/IB) LUAD-patients with extensive follow-up, we used 16s rRNA gene sequencing and host RNA-sequencing to map the microbial and host transcriptomic landscape in tumor and adjacent unaffected lung samples. RESULTS:23 out of 91 subjects had tumor recurrence over 5-year period. In tumor samples, LUAD recurrence was associated with enrichment with Dialister, Prevotella, while in unaffected lung, recurrence was associated with enrichment with Sphyngomonas and Alloiococcus. The strengths of the associations between microbial and host genomic signatures with LUAD recurrence were greater in adjacent unaffected lung samples than in the primary tumor. Among microbial-host features in the unaffected lung samples associated with recurrence, enrichment with Stenotrophomonas geniculata and Chryseobacterium were positively correlated with upregulation of IL-2, IL-3, IL-17, EGFR, HIF-1 signaling pathways among the host transcriptome. In tumor samples, enrichment with Veillonellaceae Dialister, Ruminococcacea, Haemophilus Influenza, and Neisseria were positively correlated with upregulation of IL-1, IL-6, IL17, IFN, and Tryptophan metabolism pathways. CONCLUSIONS:Overall, modeling suggested that a combined microbial/transcriptome approach using unaffected lung samples had the best biomarker performance (AUC=0.83). IMPACT/CONCLUSIONS:This study suggests that LUAD recurrence is associated with distinct pathophysiological mechanisms of microbial-host interactions in the unaffected lung rather than those present in the resected tumor.

OBJECTIVES/OBJECTIVE:To evaluate the clinical significance of low-field MRI lung opacity severity. METHODS:Retrospective cross-sectional analysis of post-acute Covid-19 patients imaged with low-field MRI from 9/2020 through 9/2022, and within 1 month of pulmonary function tests (PFTs), 6-min walk test (6mWT), and symptom inventory (SI), and/or within 3 months of St. George Respiratory Questionnaire (SGRQ) was performed. Univariate and correlative analyses were performed with Wilcoxon, Chi-square, and Spearman tests. The association between disease and demographic factors and MR opacity severity, PFTs, 6mWT, SI, and SGRQ, and association between MR opacity severity with functional and patient-reported outcomes (PROs), was evaluated with mixed model analysis of variance, covariance and generalized estimating equations. Two-sided 5 % significance level was used, with Bonferroni multiple comparison correction. RESULTS:81 MRI exams in 62 post-acute Covid-19 patients (median age 57, IQR 41-64; 25 women) were included. Exams were a median of 8 months from initial illness. Univariate analysis showed lung opacity severity was associated with decreased %DLCO (ρ = -0.55, P = .0125), and lung opacity severity quartile was associated with decreased %DLCO, predicted TLC, FVC, and increased FEV1/FVC. Multivariable analysis adjusting for sex, initial disease severity, and interval from Covid-19 diagnosis showed MR lung opacity severity was associated with decreased %DLCO (P < .001). Lung opacity severity was not associated with PROs. CONCLUSION/CONCLUSIONS:Low-field MRI lung opacity severity correlated with decreased %DLCO in post-acute Covid-19 patients, but was not associated with PROs.

Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies.

OBJECTIVES/UNASSIGNED:The destruction of the World Trade Center (WTC) towers in New York City on September 11, 2001 (9/11), released approximately 1 million tons of pulverized particulate matter throughout southern Manhattan and areas in Brooklyn, exposing community members and responders to high levels of potentially toxic environmental particles. Asbestos exposure was a health concern because of its use in certain sections of the WTC towers. Malignant mesothelioma, originating from the lining cells (mesothelium) of the peritoneal and pleural cavities, is one complication associated with asbestos exposure. METHODS/UNASSIGNED:The WTC Environmental Health Center (WTC EHC) is a treatment and surveillance program for community members (Survivors) exposed to WTC dust and fumes. RESULTS/UNASSIGNED:In this report, we describe four cases of mesothelioma in the WTC EHC as of July 1st, 2023. Two of our patients have been diagnosed with peritoneal mesothelioma and two patients have been diagnosed with pleural mesothelioma. CONCLUSION/UNASSIGNED:Given the known delay in the development of mesotheliomas after asbestos exposure, we provide information on these early mesothelioma cases to enhance the understanding of the adverse health effects of WTC exposures on the local community.

Recent statistics on lung cancer, including the steady decline of advanced diseases and the dramatically increasing detection of early-stage diseases and indeterminate pulmonary nodules, mark the significance of a comprehensive understanding of early lung carcinogenesis. Lung adenocarcinoma (ADC) is the most common histologic subtype of lung cancer, and atypical adenomatous hyperplasia is the only recognized preneoplasia to ADC, which may progress to adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and eventually to invasive ADC. Although molecular evolution during early lung carcinogenesis has been explored in recent years, the progress has been significantly hindered, largely due to insufficient materials from ADC precursors. Here, we employed state-of-the-art deep learning and artificial intelligence techniques to robustly segment and recognize cells on routinely used hematoxylin and eosin histopathology images and extracted 9 biology-relevant pathomic features to decode lung preneoplasia evolution. We analyzed 3 distinct cohorts (Japan, China, and United States) covering 98 patients, 162 slides, and 669 regions of interest, including 143 normal, 129 atypical adenomatous hyperplasia, 94 AIS, 98 MIA, and 205 ADC. Extracted pathomic features revealed progressive increase of atypical epithelial cells and progressive decrease of lymphocytic cells from normal to AAH, AIS, MIA, and ADC, consistent with the results from tissue-consuming and expensive molecular/immune profiling. Furthermore, pathomics analysis manifested progressively increasing cellular intratumor heterogeneity along with the evolution from normal lung to invasive ADC. These findings demonstrated the feasibility and substantial potential of pathomics in studying lung cancer carcinogenesis directly from the low-cost routine hematoxylin and eosin staining.

Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.