Pulmonology Commons^™

Prognostic Significance Of Micropapillary Pattern And Risk Factors In Patients With Resected Stage I Lung Adenocarcinoma And Possible Benefit Of Adjuvant Therapy: A Real-World Multicenter Study, Jianjie Li, Yujia Chi, Bo Jia, Qiwen Zheng, Minghan Yuan, Jianjun Zhang, Aishen Zhou, Wei Sun, Yue Yang, Jun Zhao, Tongtong An, Yuyan Wang, Minglei Zhuo, Xue Yang, Hanxiao Chen, Jingjing Wang, Xiaoyu Zhai, Yidi Tai, Yuling He, Lingdong Kong, Xumeng Ji, Yiliang Liu, Nan Wu, Ken Onodera, Paul Van Schil, Mathew Thomas, Fan Yang, Ziping Wang

Faculty, Staff and Student Publications

Background: Micropapillary (MP) pattern has been identified as a negative prognostic factor in patients with lung adenocarcinoma, but it has not been recognized as a high-risk factor for patients with stage IB lung adenocarcinoma treated with adjuvant chemotherapy. This multicenter cohort study aimed to evaluate the prognostic value of histological subtypes for stage I lung adenocarcinoma and to determine the relative survival benefit of adjuvant chemotherapy for subgroups based on MP pattern.

Methods: This retrospective study included 412 patients with stage I lung adenocarcinoma [according the eighth edition of the tumor-node-metastasis (TNM) classification] with MP pattern who underwent complete surgical …

Delta-Like Ligand 3 (Dll3) Landscape In Pulmonary And Extra-Pulmonary Neuroendocrine Neoplasms, Alejandra G Serrano, Pedro Rocha, Cibelle Freitas Lima, Allison Stewart, Bingnan Zhang, Lixia Diao, Junya Fujimoto, Robert J Cardnell, Wei Lu, Khaja Khan, Beate Sable, Aaron R Ellison, Ignacio I Wistuba, Kyle F Concannon, Daniel M Halperin, Czerniak Bogdan, Kanishka Sircar, Miao Zhang, Kasey Cargill, Qi Wang, Ana Aparicio, Alexander Lazar, Sharia Hernandez, Jeannelyn Estrella, Preetha Ramalingam, Adel El-Naggar, Neda Kalhor, Carl M Gay, Lauren Averett Byers, Luisa M Solis Soto

Faculty, Staff and Student Publications

Delta-like Ligand 3 (DLL3) targeting therapies are promising in small cell lung cancer (SCLC) treatment. However, DLL3 expression in SCLC and other neuroendocrine neoplasms (NEN) is heterogeneous and not well characterized. We describe the landscape of DLL3 at the mRNA and protein levels across SCLC, large cell neuroendocrine carcinoma (LCNEC), and non-small cell lung cancer. Additionally, we explore its expression in extra-pulmonary NEN (EP-NEN) using a standardized DLL3 IHC assay. DLL3 expression is enriched in SCLC, LCNEC along with combined histology lung cancers. Moreover, we find a wide range of DLL3 expression in high-grade EP-NEN. We describe heterogenous DLL3 expression …

Multiregional Transcriptomic Profiling Provides Improved Prognostic Insight In Localized Non-Small Cell Lung Cancer, Chenyang Li, Thinh T Nguyen, Jian-Rong Li, Xingzhi Song, Junya Fujimoto, Latasha Little, Curtis Gumb, Chi-Wan B Chow, Ignacio I Wistuba, Andrew P Futreal, Jianhua Zhang, Shawna M Hubert, John V Heymach, Jia Wu, Christopher I Amos, Jianjun Zhang, Chao Cheng

Faculty, Staff and Student Publications

Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with …

Multi-Ancestry Gwas Meta-Analyses Of Lung Cancer Reveal Susceptibility Loci And Elucidate Smoking-Independent Genetic Risk, Bryan R Gorman, Sun-Gou Ji, Michael Francis, Anoop K Sendamarai, Yunling Shi, Poornima Devineni, Uma Saxena, Elizabeth Partan, Andrea K Devito, Jinyoung Byun, Younghun Han, Xiangjun Xiao, Don D Sin, Wim Timens, Jennifer Moser, Sumitra Muralidhar, Rachel Ramoni, Rayjean J Hung, James D Mckay, Yohan Bossé, Ryan Sun, Christopher I Amos, Va Million Veteran Program, Saiju Pyarajan

Faculty, Staff and Student Publications

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 …

Molecular Landscape Of Erbb2 Alterations In 3000 Advanced Nsclc Patients, Lingzhi Hong, Sonia Patel, Leylah M Drusbosky, Yuanyuan Xiong, Rongrong Chen, Ruixuan Geng, Simon Heeke, Monique Nilsson, Jia Wu, John V Heymach, Yingyi Wang, Jianjun Zhang, Xiuning Le

Faculty, Staff and Student Publications

ERBB2 (HER2) represents a newly recognized actionable oncogenic driver in non-small cell lung cancer (NSCLC), with approved targeted therapy available. Understanding the landscape of ERBB2 alterations and co-occurring mutations is essential for guiding treatment decisions. We conducted an analysis involving 3000 NSCLC patients with all types of ERBB2 alterations, drawn from two extensive retrospective cohorts: 1281 from Geneplus (Chinese) and 1719 from Guardant360 (the United States, US). The incidence of all types of ERBB2 alterations was found to be 5.6% in the Chinese group and 5.2% in the US group. In both cohorts, among oncogenic alterations of ERBB2, exon 20 …

Premalignant Progression In The Lung: Knowledge Gaps And Novel Opportunities For Interception Of Non-Small Cell Lung Cancer An Official American Thoracic Society Research Statement, Seyed Javad Moghaddam, Rajkumar Savai, Ramin Salehi-Rad, Shreoshi Sengupta, Michael N Kammer, Pierre Massion, Jennifer E Beane, Edwin J Ostrin, Carmen Priolo, Meredith A Tennis, Laura P Stabile, Alison K Bauer, Catherine R Sears, Eva Szabo, M Patricia Rivera, Charles A Powell, Humam Kadara, Brendan J Jenkins, Steven M Dubinett, A Mcgarry Houghton, Carla F Kim, Robert L Keith

Faculty, Staff and Student Publications

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the …

Overcoming Egfr-Tki Resistance By Targeting The Tumor Microenvironment, Jinsong Zhang, Natalie Vokes, Man Li, Jiachen Xu, Hua Bai, Jie Wang, Zhijie Wang, Jianjun Zhang

Faculty, Staff and Student Publications

Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer (NSCLC). Currently, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) stand as the recommended first-line therapy for advanced NSCLC harboring sensitive EGFR mutations. Nevertheless, most patients inevitably confront the challenge of drug resistance. This phenomenon arises not solely from intrinsic alterations within cancer cells but also from the intricate dynamics of the tumor microenvironment and the complex interactions that occur between cancer cells and their immediate surroundings. This review consolidates the current knowledge regarding EGFR-TKI resistance mechanisms, with a specific emphasis on unraveling the …

Inhibition Of Ulk1/2 And Kras G12c Controls Tumor Growth In Preclinical Models Of Lung Cancer, Phaedra C Ghazi, Kayla T O'Toole, Sanjana Srinivas Boggaram, Michael T Scherzer, Mark R Silvis, Yun Zhang, Madhumita Bogdan, Bryan D Smith, Guillermina Lozano, Daniel L Flynn, Eric L Snyder, Conan G Kinsey, Martin Mcmahon

Faculty, Staff and Student Publications

Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRASG12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRASG12C-driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients who do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRASG12C, efforts are underway to develop effective combination therapies. Here, we report that the inhibition of KRASG12C signaling increases autophagy in KRASG12C-expressing lung cancer …

Lung Cell Transplantation For Pulmonary Fibrosis, Irit Milman Krentsis, Yangxi Zheng, Chava Rosen, Sarah Y Shin, Christa Blagdon, Einav Shoshan, Yuan Qi, Jing Wang, Sandeep K Yadav, Esther Bachar Lustig, Elias Shetzen, Burton F Dickey, Harry Karmouty-Quintana, Yair Reisner

Faculty, Staff and Student Publications

Idiopathic pulmonary fibrosis is a major cause of death with few treatment options. Here, we demonstrate the therapeutic efficacy for lung fibrosis of adult lung cell transplantation using a single-cell suspension of the entire lung in two distinct mouse systems: bleomycin treatment and mice lacking telomeric repeat-binding factor 1 expression in alveolar type 2 (AT2) cells (SPC-Cre TRF1fl/fl), spontaneously developing fibrosis. In both models, the progression of fibrosis was associated with reduced levels of host lung progenitors, enabling engraftment of donor progenitors without any additional conditioning, in contrast to our previous studies. Two months after transplantation, engrafted progenitors …

Translational Modeling-Based Evidence For Enhanced Efficacy Of Standard-Of-Care Drugs In Combination With Anti-Microrna-155 In Non-Small-Cell Lung Cancer, Prashant Dogra, Vrushaly Shinglot, Javier Ruiz-Ramírez, Joseph Cave, Joseph D Butner, Carmine Schiavone, Dan G Duda, Ahmed O Kaseb, Caroline Chung, Eugene J Koay, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.

METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs.

RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg …

A Comparison Of Tracheal Intubation Using Direct Laryngoscope And Video Laryngoscope In The Sellick And Trendelenburg Position With That Using Direct Laryngoscope In The Supine Sniffing Position: A Randomized Controlled Trial, Yun-Jeong Chae, Jung-Yoon Moon, Min-Gyu Lee, Han-Bum Joe

Faculty, Staff and Student Publications

Background: Tracheal intubation in the Sellick and Trendelenburg position (ST position) can prevent pulmonary aspiration but increase the difficulty of tracheal intubation. We compared tracheal intubation using video and direct laryngoscopy in the ST position with direct laryngoscopy in the supine sniffing position to evaluate the overall intubation performance. Methods: One hundred and twenty patients were randomly assigned to three groups: direct laryngoscope in the supine sniffing position (control), direct laryngoscope in the ST position (ST direct), and video laryngoscope in the ST position (ST video). The primary outcome was the intubation time; secondary outcomes included the first …

Epigenome-Wide Association Study Of Lung Cancer Among Never Smokers In Two Prospective Cohorts In Shanghai, China, Mohammad L Rahman, Charles E Breeze, Xiao-Ou Shu, Jason Y Y Wong, Batel Blechter, Andres Cardenas, Xuting Wang, Bu-Tian Ji, Wei Hu, Qiuyin Cai, H Dean Hosgood, Gong Yang, Jianxin Shi, Jirong Long, Yu-Tang Gao, Douglas A Bell, Wei Zheng, Nathaniel Rothman, Qing Lan

Faculty, Staff and Student Publications

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted.

METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse …

The Calcineurin-Nfatc Pathway Modulates The Lipid Mediators In Bal Fluid Extracellular Vesicles, Thereby Regulating Microvascular Endothelial Cell Barrier Function, Manjula Karpurapu, Yunjuan Nie, Sangwoon Chung, Jiasheng Yan, Patrick Dougherty, Sonal Pannu, Jon Wisler, Ryan Harkless, Narasimham Parinandi, Evgeny Berdyshev, Dehua Pei, John W Christman

Faculty, Staff and Student Publications

Extracellular vesicles mediate intercellular communication by transporting biologically active macromolecules. Our prior studies have demonstrated that the nuclear factor of activated T cell cytoplasmic member 3 (NFATc3) is activated in mouse pulmonary macrophages in response to lipopolysaccharide (LPS). Inhibition of NFATc3 activation by a novel cell-permeable calcineurin peptide inhibitor CNI103 mitigated the development of acute lung injury (ALI) in LPS-treated mice. Although pro-inflammatory lipid mediators are known contributors to lung inflammation and injury, it remains unclear whether the calcineurin-NFATc pathway regulates extracellular vesicle (EV) lipid content and if this content contributes to ALI pathogenesis. In this study, EVs from mouse …

Age At Lung Cancer Diagnosis In Females Versus Males Who Never Smoke By Race And Ethnicity, Batel Blechter, Jason Y Y Wong, Li-Hsin Chien, Kouya Shiraishi, Xiao-Ou Shu, Qiuyin Cai, Wei Zheng, Bu-Tian Ji, Wei Hu, Mohammad L Rahman, Hsin-Fang Jiang, Fang-Yu Tsai, Wen-Yi Huang, Yu-Tang Gao, Xijing Han, Mark D Steinwandel, Gong Yang, Yihe G Daida, Su-Ying Liang, Scarlett L Gomez, Mindy C Derouen, W Ryan Diver, Ananya G Reddy, Alpa V Patel, Loïc Le Marchand, Christopher Haiman, Takashi Kohno, Iona Cheng, I-Shou Chang, Chao Agnes Hsiung, Nathaniel Rothman, Qing Lan

Faculty, Staff and Student Publications

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke.

METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes.

RESULTS: We found that among Chinese individuals diagnosed with lung cancer …

Omics-Based Profiles And Biomarkers Of Respiratory Infections: Are We There Yet?, Jezreel Pantaleon Garcia, Scott E Evans

Faculty, Staff and Student Publications

Descriptive omics-based clinical research provides valuable early steps in understanding host immune responses to respiratory pathogens in our global efforts to mitigate the impacts of severe respiratory infections with rapidly evolving technologies https://bit.ly/4bjJsvL

An Atlas Of Epithelial Cell States And Plasticity In Lung Adenocarcinoma, Guangchun Han, Ansam Sinjab, Zahraa Rahal, Anne M Lynch, Warapen Treekitkarnmongkol, Yuejiang Liu, Alejandra G Serrano, Jiping Feng, Ke Liang, Khaja Khan, Wei Lu, Sharia D Hernandez, Yunhe Liu, Xuanye Cao, Enyu Dai, Guangsheng Pei, Jian Hu, Camille Abaya, Lorena I Gomez-Bolanos, Fuduan Peng, Minyue Chen, Edwin R Parra, Tina Cascone, Boris Sepesi, Seyed Javad Moghaddam, Paul Scheet, Marcelo V Negrao, John V Heymach, Mingyao Li, Steven M Dubinett, Christopher S Stevenson, Avrum E Spira, Junya Fujimoto, Luisa M Solis, Ignacio I Wistuba, Jichao Chen, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver …

Biomarker-Directed Targeted Therapy Plus Durvalumab In Advanced Non-Small-Cell Lung Cancer: A Phase 2 Umbrella Trial, Benjamin Besse, Elvire Pons-Tostivint, Keunchil Park, Sylvia Hartl, Patrick M Forde, Maximilian J Hochmair, Mark M Awad, Michael Thomas, Glenwood Goss, Paul Wheatley-Price, Frances A Shepherd, Marie Florescu, Parneet Cheema, Quincy S C Chu, Sang-We Kim, Daniel Morgensztern, Melissa L Johnson, Sophie Cousin, Dong-Wan Kim, Mor T Moskovitz, David Vicente, Boaz Aronson, Rosalind Hobson, Helen J Ambrose, Sajan Khosla, Avinash Reddy, Deanna L Russell, Mohamed Reda Keddar, James P Conway, J Carl Barrett, Emma Dean, Rakesh Kumar, Marlene Dressman, Philip J Jewsbury, Sonia Iyer, Simon T Barry, Jan Cosaert, John V Heymach

Faculty, Staff and Student Publications

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance—which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment—and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure …

Development And Validation Of A Nomogram For Predicting Pulmonary Infection In Patients Receiving Immunosuppressive Drugs, Chuxuan Luo, Yue Zhang, Jiajie Zhang, Chen Jin, Xiaolan Ye, Yan Ren, Huajuan Shen, Maosheng Chen, Yiwen Li, Qiang He, Guangbiao Xu, Lina Shao

Faculty, Staff and Student Publications

Objective: Pulmonary infection (PI), a severe complication of immunosuppressive therapy, affects patients' prognosis. As part of this study, we aimed to construct a pulmonary infection prediction (PIP) model and validate it in patients receiving immunosuppressive drugs (ISDs). Methods: Totally, 7,977 patients being treated with ISDs were randomised 7:3 to the developing (n = 5,583) versus validation datasets (n = 2,394). Our predictive nomogram was established using the least absolute shrinkage and selection operator (LASSO) and multivariate COX regression analyses. With the use of the concordance index (C-index) and calibration curve, the prediction performance of the final model was …

Prioritizing Clinically Significant Lung Cancer Somatic Mutations For Targeted Therapy Through Efficient Ngs Data Filtering System, Jinlian Wang, Hui Li, Hongfang Liu

Faculty, Staff and Student Publications

In the realm of lung cancer treatment, where genetic heterogeneity presents formidable challenges, precision oncology demands an exacting approach to identify and hierarchically sort clinically significant somatic mutations. Current Next-Generation Sequencing (NGS) data filtering pipelines, while utilizing various external databases for mutation screening, often fall short in comprehensive integration and flexibility needed to keep pace with the evolving landscape of clinical data. Our study introduces a sophisticated NGS data filtering system, which not only aggregates but effectively synergizes diverse data sources, encompassing genetic variants, gene functions, clinical evidence, and an extensive body of literature. This system is distinguished by a …

Incidence And Risk Factors For Pneumonitis Associated With Checkpoint Inhibitors In Advanced Non-Small Cell Lung Cancer: A Single Center Experience, Mehmet Altan, Felipe Soto, Linda L Zhong, Fechukwu O Akhmedzhanov, Nathaniel R Wilson, Abdulrazzak Zarifa, Aya A Albittar, Vincent Yang, Jeff Lewis, Waree Rinsurongkawong, J Jack Lee, Vadeerat Rinsurongkawong, Jianjun Zhang, Don L Gibbons, Ara A Vaporciyan, Kristofer Jennings, Fareed Khawaja, Saadia A Faiz, Vickie R Shannon, Girish Shroff, Myrna C B Godoy, Naval G Daver, Saumil Gandhi, Tito R Mendoza, Aung Naing, Carrie Daniel-Macdougall, John V Heymach, Ajay Sheshadri

Faculty, Staff and Student Publications

INTRODUCTION: Immune checkpoint inhibitor (ICI) pneumonitis causes substantial morbidity and mortality. Estimates of real-world incidence and reported risk factors vary substantially.

METHODS: We conducted a retrospective review of 419 patients with advanced non-small cell lung cancer (NSCLC) who were treated with anti-PD-(L)1 with or without anti-CTLA-4 therapy. Clinical, imaging, and microbiological data were evaluated by multidisciplinary adjudication teams. The primary outcome of interest was grade ≥2 (CTCAEv5) pneumonitis. Clinicopathologic variables, tobacco use, cancer therapies, and preexisting lung disease were assessed for univariate effects using Cox proportional hazards models. We created multivariate Cox proportional hazards models to assess risk factors for …

Inflammatory Activity Of Epithelial Stem Cell Variants From Cystic Fibrosis Lungs Is Not Resolved By Cftr Modulators, Shan Wang, Suchan Niroula, Ashley Hoffman, Melika Khorrami, Melina Khorrami, Feng Yuan, Grace N Gasser, Soon Choi, Bovey Liu, Justin Li, Mark L Metersky, Matthew Vincent, Christopher P Crum, Richard C Boucher, Harry Karmouty-Quintana, Howard J Huang, Ajay Sheshadri, Burton F Dickey, Kalpaj R Parekh, John F Engelhardt, Frank D Mckeon, Wa Xian

Faculty, Staff and Student Publications

Rationale

CFTR (cystic fibrosis transmembrane conductance regulator) modulator drugs restore function to mutant channels in patients with cystic fibrosis (CF) and lead to improvements in body mass index and lung function. Although it is anticipated that early childhood treatment with CFTR modulators will significantly delay or even prevent the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in patients with CF with established lung disease despite modulator therapy, underscoring the need to identify and ultimately target the sources of this inflammation in CF lungs.

Objectives

To determine whether CF lungs, like chronic obstructive pulmonary disease (COPD) …

Combining Clinical And Biological Data To Predict Progressive Pulmonary Fibrosis In Patients With Systemic Sclerosis Despite Immunomodulatory Therapy, Elizabeth R Volkmann, Holly Wilhalme, Shervin Assassi, Grace Hyun J Kim, Jonathan Goldin, Masataka Kuwana, Donald P Tashkin, Michael D Roth

Faculty, Staff and Student Publications

OBJECTIVE: Progressive pulmonary fibrosis (PPF) is the leading cause of death in systemic sclerosis (SSc). This study aimed to develop a clinical prediction nomogram using clinical and biological data to assess risk of PPF among patients receiving treatment of SSc-related interstitial lung disease (SSc-ILD).

METHODS: Patients with SSc-ILD who participated in the Scleroderma Lung Study II (SLS II) were randomized to treatment with either mycophenolate mofetil (MMF) or cyclophosphamide (CYC). Clinical and biological parameters were analyzed using univariable and multivariable logistic regression, and a nomogram was created to assess the risk of PPF and validated by bootstrap resampling.

RESULTS: Among …

Automated Cellular-Level Dual Global Fusion Of Whole-Slide Imaging For Lung Adenocarcinoma Prognosis, Songhui Diao, Pingjun Chen, Eman Showkatian, Rukhmini Bandyopadhyay, Frank R Rojas, Bo Zhu, Lingzhi Hong, Muhammad Aminu, Maliazurina B Saad, Morteza Salehjahromi, Amgad Muneer, Sheeba J Sujit, Carmen Behrens, Don L Gibbons, John V Heymach, Neda Kalhor, Ignacio I Wistuba, Luisa M Solis Soto, Jianjun Zhang, Wenjian Qin, Jia Wu

Faculty, Staff and Student Publications

Histopathologic whole-slide images (WSI) are generally considered the gold standard for cancer diagnosis and prognosis. Survival prediction based on WSI has recently attracted substantial attention. Nevertheless, it remains a central challenge owing to the inherent difficulties of predicting patient prognosis and effectively extracting informative survival-specific representations from WSI with highly compounded gigapixels. In this study, we present a fully automated cellular-level dual global fusion pipeline for survival prediction. Specifically, the proposed method first describes the composition of different cell populations on WSI. Then, it generates dimension-reduced WSI-embedded maps, allowing for efficient investigation of the tumor microenvironment. In addition, we introduce …

Heterogenous Lung Inflammation Ct Patterns Distinguish Pneumonia And Immune Checkpoint Inhibitor Pneumonitis And Complement Blood Biomarkers In Acute Myeloid Leukemia: Proof Of Concept, Muhammad Aminu, Naval Daver, Myrna C B Godoy, Girish Shroff, Carol Wu, Luis F Torre-Sada, Alberto Goizueta, Vickie R Shannon, Saadia A Faiz, Mehmet Altan, Guillermo Garcia-Manero, Hagop Kantarjian, Farhad Ravandi-Kashani, Tapan Kadia, Marina Konopleva, Courtney Dinardo, Sherry Pierce, Aung Naing, Sang T Kim, Dimitrios P Kontoyiannis, Fareed Khawaja, Caroline Chung, Jia Wu, Ajay Sheshadri

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint inhibitors (ICI) may cause pneumonitis, resulting in potentially fatal lung inflammation. However, distinguishing pneumonitis from pneumonia is time-consuming and challenging. To fill this gap, we build an image-based tool, and further evaluate it clinically alongside relevant blood biomarkers.

MATERIALS AND METHODS: We studied CT images from 97 patients with pneumonia and 29 patients with pneumonitis from acute myeloid leukemia treated with ICIs. We developed a CT-derived signature using a habitat imaging algorithm, whereby infected lungs are segregated into clusters ("habitats"). We validated the model and compared it with a clinical-blood model to determine whether imaging can add …

Design Of A Phase Iii, Double-Blind, Randomised, Placebo-Controlled Trial Of Bi 1015550 In Patients With Progressive Pulmonary Fibrosis (Fibroneer-Ild), Toby M Maher, Shervin Assassi, Arata Azuma, Vincent Cottin, Anna-Maria Hoffmann-Vold, Michael Kreuter, Justin M Oldham, Luca Richeldi, Claudia Valenzuela, Marlies S Wijsenbeek, Carl Coeck, Christina Schlecker, Florian Voss, Daniel Wachtlin, Fernando J Martinez

Faculty, Staff and Student Publications

INTRODUCTION: Progressive pulmonary fibrosis (PPF) includes any diagnosis of progressive fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). However, disease progression appears comparable between PPF and IPF, suggesting a similar underlying pathology relating to pulmonary fibrosis. Following positive results in a phase II study in IPF, this phase III study will investigate the efficacy and safety of BI 1015550 in patients with PPF (FIBRONEER-ILD).

METHODS AND ANALYSIS: In this phase III, double-blind, placebo-controlled trial, patients are being randomised 1:1:1 to receive BI 1015550 (9 mg or 18 mg) or placebo twice daily over at least 52 weeks, …

Association Between Duration Of Smoking Abstinence Before Non-Small-Cell Lung Cancer Diagnosis And Survival: A Retrospective, Pooled Analysis Of Cohort Studies, Aline F Fares, Yao Li, Mei Jiang, M Catherine Brown, Andrew C L Lam, Reenika Aggarwal, Sabine Schmid, Natasha B Leighl, Frances A Shepherd, Zhichao Wang, Nancy Diao, Angela S Wenzlaff, Juntao Xie, Takashi Kohno, Neil E Caporaso, Curtis Harris, Hongxia Ma, Matthew J Barnett, Leticia Ferro Leal, G Fernandez-Tardon, Mónica Pérez-Ríos, Michael P A Davies, Fiona Taylor, Ben Schöttker, Paul Brennan, David Zaridze, Ivana Holcatova, Jolanta Lissowska, Beata Świątkowska, Dana Mates, Milan Savic, Hermann Brenner, Angeline Andrew, Angela Cox, John K Field, Alberto Ruano-Ravina, Sanjay S Shete, Adonina Tardon, Ying Wang, Loic Le Marchand, Rui Manuel Reis, Matthew B Schabath, Chu Chen, Hongbing Shen, Brid M Ryan, Maria Teresa Landi, Kouya Shiraishi, Jie Zhang, Ann G Schwartz, Ming S Tsao, David C Christiani, Ping Yang, Rayjean J Hung, Wei Xu, Geoffrey Liu

Faculty, Staff and Student Publications

BACKGROUND: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival.

METHODS: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed …

Pathologist-Initiated Reflex Testing For Biomarkers In Non-Small-Cell Lung Cancer: Expert Consensus On The Rationale And Considerations For Implementation, J R Gosney, L Paz-Ares, P Jänne, K M Kerr, N B Leighl, M D Lozano, U Malapelle, T Mok, B S Sheffield, A Tufman, I I Wistuba, S Peters

Faculty, Staff and Student Publications

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.

Emt Activates Exocytotic Rabs To Coordinate Invasion And Immunosuppression In Lung Cancer, Guan-Yu Xiao, Xiaochao Tan, Bertha L Rodriguez, Don L Gibbons, Shike Wang, Chao Wu, Xin Liu, Jiang Yu, Mayra E Vasquez, Hai T Tran, Jun Xu, William K Russell, Cara Haymaker, Younghee Lee, Jianjun Zhang, Luisa Solis, Ignacio I Wistuba, Jonathan M Kurie

Faculty, Staff and Student Publications

Epithelial-to-mesenchymal transition (EMT) underlies immunosuppression, drug resistance, and metastasis in epithelial malignancies. However, the way in which EMT orchestrates disparate biological processes remains unclear. Here, we identify an EMT-activated vesicular trafficking network that coordinates promigratory focal adhesion dynamics with an immunosuppressive secretory program in lung adenocarcinoma (LUAD). The EMT-activating transcription factor ZEB1 drives exocytotic vesicular trafficking by relieving Rab6A, Rab8A, and guanine nucleotide exchange factors from miR-148a-dependent silencing, thereby facilitating MMP14-dependent focal adhesion turnover in LUAD cells and autotaxin-mediated CD8

Predicting Benefit From Immune Checkpoint Inhibitors In Patients With Non-Small-Cell Lung Cancer By Ct-Based Ensemble Deep Learning: A Retrospective Study, Maliazurina B Saad, Lingzhi Hong, Muhammad Aminu, Natalie I Vokes, Pingjun Chen, Morteza Salehjahromi, Kang Qin, Sheeba J Sujit, Xuetao Lu, Elliana Young, Qasem Al-Tashi, Rizwan Qureshi, Carol C Wu, Brett W Carter, Steven H Lin, Percy P Lee, Saumil Gandhi, Joe Y Chang, Ruijiang Li, Michael F Gensheimer, Heather A Wakelee, Joel W Neal, Hyun-Sung Lee, Chao Cheng, Vamsidhar Velcheti, Yanyan Lou, Milena Petranovic, Waree Rinsurongkawong, Xiuning Le, Vadeerat Rinsurongkawong, Amy Spelman, Yasir Y Elamin, Marcelo V Negrao, Ferdinandos Skoulidis, Carl M Gay, Tina Cascone, Mara B Antonoff, Boris Sepesi, Jeff Lewis, Ignacio I Wistuba, John D Hazle, Caroline Chung, David Jaffray, Don L Gibbons, Ara Vaporciyan, J Jack Lee, John V Heymach, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

BACKGROUND: Only around 20-30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg, PD-L1) are limited by suboptimal performance, tissue availability, and tumour heterogeneity, radiographic images might holistically capture the underlying cancer biology. We aimed to investigate the application of deep learning on chest CT scans to derive an imaging signature of response to immune checkpoint inhibitors and evaluate its added value in the clinical context.

METHODS: In this retrospective modelling study, 976 patients with metastatic, EGFR/ALK negative NSCLC treated with immune checkpoint inhibitors at MD Anderson and Stanford were enrolled from …

Redox-Dependent Activation Of Lung Epithelial Stat3 Is Required For Inducible Protection Against Bacterial Pneumonia, Vikram V Kulkarni, Yongxing Wang, Jezreel Pantaleon Garcia, Scott E Evans

Faculty, Staff and Student Publications

The lung epithelium is dynamic, capable of considerable structural and functional plasticity in response to pathogen challenges. Our laboratory has demonstrated that an inhaled combination of a Toll-like receptor (TLR) 2/6 agonist and a TLR9 agonist (Pam2ODN) results in robust protection against otherwise lethal pneumonias. We have previously shown that intact epithelial TLR signaling and generation of multisource epithelial reactive oxygen species (ROS) are required for inducible protection. Further investigating the mechanisms underlying this phenomenon of inducible resistance, reverse-phase protein array analysis demonstrated robust STAT3 (signal transducer and activator of transcription 3) phosphorylation following treatment of lung epithelial cells. We …