Inhibition of USP7 upregulates USP22 and activates its downstream cancer-related signaling pathways in human cancer cells.

Deubiquitinases (DUBs) play important roles in various human cancers and targeting DUBs is considered as a novel anticancer therapeutic strategy. Overexpression of ubiquitin specific protease 7 and 22 (USP7 and USP22) are associated with malignancy, therapy resistance, and poor prognosis in many cancers. Although both DUBs are involved in the regulation of similar genes and signaling pathways, such as histone H2B monoubiquitination (H2Bub1), c-Myc, FOXP3, and p53, the interdependence of USP22 and USP7 expression has never been described. In the study, we found that targeting USP7 via either siRNA-mediated knockdown or pharmaceutical inhibitors dramatically upregulates USP22 in cancer cells. Mechanistically, the elevated USP22 occurs through a transcriptional pathway, possibly due to desuppression of the transcriptional activity of SP1 via promoting its degradation upon USP7 inhibition. Importantly, increased USP22 expression leads to significant activation of downstream signal pathways including H2Bub1 and c-Myc, which may potentially enhance cancer malignancy and counteract the anticancer efficacy of USP7 inhibition. Importantly, targeting USP7 further suppresses the in vitro proliferation of USP22-knockout (USP22-Ko) A549 and H1299 lung cancer cells and induces a stronger activation of p53 tumor suppressor signaling pathway. In addition, USP22-Ko cancer cells are more sensitive to a combination of cisplatin and USP7 inhibitor. USP7 inhibitor treatment further suppresses in vivo angiogenesis and tumor growth and induced more apoptosis in USP22-Ko cancer xenografts. Taken together, our findings demonstrate that USP7 inhibition can dramatically upregulate USP22 in cancer cells; and targeting USP7 and USP22 may represent a more effective approach for targeted cancer therapy, which warrants further study. Video Abstract.

The value of perioperative physical activity in older patients undergoing surgery for lung cancer.

INTRODUCTION: With a median age at diagnosis of 70, lung cancer represents an enormous public health problem among older Americans. An estimated 19,000 people age 65 and older undergo lung cancer surgery annually in the US. Older adults undergoing lung cancer surgery are often frail with limited physiologic reserves, multi-morbidities, and functional impairments. Physical function, dyspnea, and quality of life return to baseline slower in older adults compared with younger adults after lung surgery. AREAS COVERED: In this review, we summarize available data about perioperative physical activity interventions that may improve outcomes for older adults undergoing lung cancer surgery. We also review the limitations of existing studies and discuss emerging data on the roles of telehealth and family caregiver inclusion in peri-operative physical activity interventions. EXPERT OPINION: We propose that future perioperative physical activity interventions in older adults undergoing lung cancer surgery should include a comprehensive geriatric assessment to guide personalized interventions. Interventions should be conceptually based, with a focus on enhancing self-efficacy, motivation, and adherence through classic behavior change strategies that are proven to impact outcomes. Finally, interventions should be designed with attention to feasibility and scalability. Exercise programs delivered via telehealth (telephone or tele-video) may improve access and convenience for patients.

Liquid Biopsy Screening for Early Detection of Lung Cancer: Current State and Future Directions.

Liquid biopsy (LB) is clinically utilized to detect minute amounts of genetic material or protein shed by cancer cells, most commonly cell free DNA (cfDNA), as a noninvasive precision oncology tool to assess genomic alterations to guide cancer therapy or to detect the persistence of tumor cells after therapy. LB is also being developed as a multi-cancer screening assay. The use of LB holds great promise as a tool to detect lung cancer early. Although lung cancer screening (LCS) with low-dose computed tomography (LDCT) substantially reduces lung cancer mortality in high-risk individuals, the ability of current LCS guidelines to reduce the public health burden of advanced lung cancer through early detection has been limited. LB may be an important tool to improve early lung cancer detection among all populations at risk for lung cancer. In this systematic review, we summarize the test characteristics, including sensitivity and specificity of individual tests, as they pertain to the detection of lung cancer.  We also address critical questions in the use of liquid biopsy for early detection of lung cancer including: 1. How might liquid biopsy be used to detect lung cancer early; 2. How accurate is liquid biopsy in detecting lung cancer early; and 3. Does liquid biopsy perform as well in never and light-smokers compared with current and former smokers.

Integration of artificial intelligence in lung cancer: Rise of the machine.

The goal of oncology is to provide the longest possible survival outcomes with the therapeutics that are currently available without sacrificing patients' quality of life. In lung cancer, several data points over a patient's diagnostic and treatment course are relevant to optimizing outcomes in the form of precision medicine, and artificial intelligence (AI) provides the opportunity to use available data from molecular information to radiomics, in combination with patient and tumor characteristics, to help clinicians provide individualized care. In doing so, AI can help create models to identify cancer early in diagnosis and deliver tailored therapy on the basis of available information, both at the time of diagnosis and in real time as they are undergoing treatment. The purpose of this review is to summarize the current literature in AI specific to lung cancer and how it applies to the multidisciplinary team taking care of these complex patients.

Surgical results of the Lung Cancer Mutation Consortium 3 trial: A phase II multicenter single-arm study to investigate the efficacy and safety of atezolizumab as neoadjuvant therapy in patients with stages IB-select IIIB resectable non-small cell lung cancer.

OBJECTIVE: Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery. METHODS: Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0. RESULTS: From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached. CONCLUSIONS: Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.

Transcription factor AP2 enhances malignancy of non-small cell lung cancer through upregulation of USP22 gene expression.

BACKGROUND: Ubiquitin-specific protease 22 (USP22), a putative cancer stem cell marker, is frequently upregulated in cancers, and USP22 overexpression is associated with aggressive growth, metastasis, and therapy resistance in various human cancers including lung cancer. However, USP22 gene amplification seldom occurs, and the mechanism underlying USP22 upregulation in human cancers remains largely unknown. METHODS: A luciferase reporter driven by a promoter region of USP22 gene was selectively constructed to screen against a customized siRNA library targeting 89 selected transcription factors to identify potential transcription factors (TFs) that regulate USP22 expression in human non-small cell lung cancers (NSCLC). Association of identified TFs with USP22 and potential role of the TFs were validated and explored in NSCLC by biological assays and immunohistochemistry analysis. RESULTS: Luciferase reporter assays revealed that SP1 and activating transcription factor 3 (ATF3) inhibit USP22 transcription, while transcription factor AP-2 Alpha/Beta (TFAP2A/2B) and c-Myc promote USP22 transcription. Binding site-directed mutagenesis and chromosome immunoprecipitation (ChIP) assays validated AP2α and AP2ß are novel TFs of USP22. Furthermore, overexpression of AP2A and AP2B significantly upregulates USP22 expression, and its target: Cyclin D1, concurrently enhances the proliferation, migration, and invasion of NSCLC A549 and H1299 cells in a partially USP22-dependent manner. Moreover, AP2 protein level correlated with USP22 protein in human NSCLC tissues. CONCLUSION: Our findings indicate AP2α and AP2ß are important transcription factors driving USP22 gene expression to promote the progression of NSCLC, and further support USP22 as a potential biomarker and therapeutic target for lung cancer. Video Abstract.

The impact of the COVID-19 pandemic on care delivery and quality of life in lung cancer surgery.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (COVID-19) pandemic and associated restrictions have altered the delivery of surgical care. The purpose of this study was to explore the impact of COVID-19 on care delivery and quality of life (QOL) from the perspectives of lung cancer surgery patients, family caregivers (FCGs), and thoracic surgery teams. METHODS: Patients/FCGs enrolled in a randomized trial of a self-management intervention for lung cancer surgery preparation/recovery were invited to participate in this qualitative study. Patients/FCGs data were collected separately 1-month postdischarge. Interviews were also conducted with thoracic surgery team members. Content analysis approaches were used to develop themes. RESULTS: Forty-one respondents including 19 patients, 18 FCGs, three thoracic surgeons, and one nurse practitioner participated in the study. Patient themes included isolation, psychological distress, delayed/impacted care, and financial impact. FCGs themes included caregiving challenges, worry about COVID-19, financial hardship, isolation, and physical activity limitations. Surgical team themes included witnessing patient/FCG's distress, challenges with telehealth, communication/educational challenges, and delays in treatment. CONCLUSIONS: COVID-19 had a varied impact on care delivery and QOL for lung cancer surgery dyads. Some dyads reported minimal impact, while others experienced added psychological distress, isolation, and caregiving challenges. Surgical teams also experienced challenges in the approach used to provide care.

A Lung Cancer Screening Education Program Impacts both Referral Rates and Provider and Medical Assistant Knowledge at Two Federally Qualified Health Centers.

BACKGROUND: Federally Qualified Health Centers (FQHCs) serve minority and low-socioeconomic populations and provide care to high-risk smokers. These centers frequently experience barriers, including low provider and medical assistant (MA) knowledge around lung cancer screening (LCS). Subsequent low LCS referral rates by providers at FQHCs limit utilization of LCS in eligible, high-risk, underserved patients. METHODS: Providers and MAs from two FQHCs participated in a LCS educational session. A pre-educational survey was administered at the start of the session and a post-educational survey at the end. The intervention included a presentation with education around non-small cell lung cancer, LCS, tobacco cessation, and shared-decision making. Both surveys were used to evaluate changes in provider and MA ability to determine eligible patients for LCS. The Pearson's Chi-squared test with Yates' continuity correction was used to measure the impact. RESULTS: A total of 29 providers and 28 MAs enrolled in the study from two FQHCs. There was an improvement, P < .009 and P < .015 respectively, in provider and MA confidence in identifying patients for LCS. Additionally, one year prior to the program, 9 low-dose computed tomography (LDCTs) were ordered at one of the FQHCs and 0 at the other. After the program, over 100 LDCTs were ordered at each FQHC. CONCLUSIONS: A targeted LCS educational program improves provider and MAs' ability to identify eligible LCS patients and is associated with an increase in the number of patients referred to LDCT at FQHCs.

The impact of income and education on lung cancer screening utilization, eligibility, and outcomes: a narrative review of socioeconomic disparities in lung cancer screening.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the US and worldwide. In particular, vulnerable populations such as those of low socioeconomic status (SES) are at the highest risk for and suffer the highest mortality from NSCLC. Although lung cancer screening (LCS) has been demonstrated to be a powerful tool to lower NSCLC mortality, it is underutilized by eligible smokers, and disparities in screening are likely to contribute to inequities in NSCLC outcomes. It is imperative that we collect and analyze LCS data focused on individuals of low socioeconomic position to identify and address barriers to LCS utilization and help close the gaps in NSCLC mortality along socioeconomic lines. Toward this end, this review aims to examine published studies that have evaluated the impact of income and education on LCS utilization, eligibility, and outcomes. We searched the PubMed, Ovid MEDLINE, and CINAHL Plus databases for all studies published from January 1, 2010, to October 21, 2020, that discussed socioeconomic-based LCS outcomes. The review reveals that income and education have impact on LCS utilization, eligibility, false positive rates and smoking cessation attempts; however, there is a lack of studies evaluating the impact of SES on LCS follow-up, stage at diagnosis, and treatment. We recommend the intentional inclusion of lower SES participants in LCS studies in order to clarify appropriate eligibility criteria, risk-based metrics and outcomes in this high-risk group. We also anticipate that low SES smokers and their providers will require increased support and education regarding smoking cessation and shared decision-making efforts.

The Association between Polluted Neighborhoods and TP53-Mutated Non-Small Cell Lung Cancer.

BACKGROUND: Poor patients often reside in neighborhoods of lower socioeconomic status (SES) with high levels of airborne pollutants. They also have higher mortality from non-small cell lung cancer (NSCLC) than those living in wealthier communities. We investigated whether living in polluted neighborhoods is associated with somatic mutations linked with lower survival rates, i.e., TP53 mutations. METHODS: In a retrospective cohort of 478 patients with NSCLC treated at a comprehensive cancer center between 2015 and 2018, we used logistic regression to assess associations between individual demographic and clinical characteristics, including somatic TP53 mutation status and environmental risk factors of annual average particulate matter (PM2.5) levels, and neighborhood SES. RESULTS: 277 patients (58%) had somatic TP53 mutations. Of those, 45% lived in neighborhoods with "moderate" Environmental Protection Agency-defined PM2.5 exposure, compared with 39% of patients without TP53 mutations. We found significant associations between living in neighborhoods with "moderate" versus "good" PM2.5 concentrations and minority population percentage [OR, 1.06; 95% confidence interval (CI), 1.04-1.08]. There was a significant association between presence of TP53 mutations and PM2.5 exposure (moderate versus good: OR, 1.66; 95% CI, 1.02-2.72) after adjusting for patient characteristics, other environmental factors, and neighborhood-level SES. CONCLUSIONS: When controlling for individual- and neighborhood-level confounders, we find that the odds of having a TP53-mutated NSCLC are increased in areas with higher PM2.5 exposure. IMPACT: The link between pollution and aggressive biology may contribute to the increased burden of adverse NSCLC outcomes in individuals living in lower SES neighborhoods.

Racial and socioeconomic disparities in lung cancer screening in the United States: A systematic review.

Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer deaths. Lung cancer screening (LCS) reduces NSCLC mortality; however, a lack of diversity in LCS studies may limit the generalizability of the results to marginalized groups who face higher risk for and worse outcomes from NSCLC. Identifying sources of inequity in the LCS pipeline is essential to reduce disparities in NSCLC outcomes. The authors searched 3 major databases for studies published from January 1, 2010 to February 27, 2020 that met the following criteria: 1) included screenees between ages 45 and 80 years who were current or former smokers, 2) written in English, 3) conducted in the United States, and 4) discussed socioeconomic and race-based LCS outcomes. Eligible studies were assessed for risk of bias. Of 3721 studies screened, 21 were eligible. Eligible studies were evaluated, and their findings were categorized into 3 themes related to LCS disparities faced by Black and socioeconomically disadvantaged individuals: 1) eligibility; 2) utilization, perception, and utility; and 3) postscreening behavior and care. Disparities in LCS exist along racial and socioeconomic lines. There are several steps along the LCS pipeline in which Black and socioeconomically disadvantaged individuals miss the potential benefits of LCS, resulting in increased mortality. This study identified potential sources of inequity that require further investigation. The authors recommend the implementation of prospective trials that evaluate eligibility criteria for underserved groups and the creation of interventions focused on improving utilization and follow-up care to decrease LCS disparities.

Improving Utilization of Lung Cancer Screening Through Incorporating a Video-Based Educational Tool Into Smoking Cessation Counseling.

BACKGROUND: Lung cancer screening (LCS) with low-dose computed tomography (LDCT) reduces lung cancer mortality in high-risk patients, but most of those eligible are not referred for screening, and most eligible smokers are not aware of LCS. Smoking cessation counseling may be an opportune time to educate smokers about LCS. Here we investigate the effect of LCS educational information on LDCT utilization and smoking cessation in LCS-eligible patients receiving smoking cessation counseling. PATIENTS AND METHODS: We randomized 1281 smokers aged 55-80 who underwent smoking cessation services to view a web-based educational video about LCS (n = 1026) or to receive usual care (n = 255). Outcomes included the utilization of chest computed tomographic (CT) scan during 6 months of follow-up, responses to survey questions, and patient-reported abstinence from smoking at 6 months. RESULTS: One hundred forty-six participants (14%) watched the video. Overall, 87 participants (8.5%) in the intervention group underwent any chest CT and 37 (3.6%) underwent LDCT compared to 22 (8.6%) and 11 (4.3%) in the control group during the 6-month follow-up period (P = .94 and .59, respectively). Among participants who completed watching the video, 27 (18.5%) underwent any chest CT and 13 (8.9%) underwent LDCT, compared to 22 (8.6%) and 11 (4.3%) in controls during follow-up (P = .0037 and .062, respectively). There was no difference in abstinence from smoking between groups. CONCLUSION: An LCS educational intervention may be effective in improving utilization of LDCT in eligible individuals who currently smoke at the time of smoking cessation counseling. Further research on the effect of LCS education in the context of smoking cessation counseling is needed.

Deterioration in Health-Related Quality of Life Diminishes Benefit of Lung Cancer Resection in Older Adults.

INTRODUCTION: Outcomes of oncologic resection are related to tumor biology and patient-reported health factors. However, data regarding changes in functional status and health-related quality of life (HRQOL) before and after lung surgery for older adults are lacking. PATIENTS AND METHODS: We identified lung cancer patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare Health Outcomes Survey (MHOS) linked database. HRQOL surveys captured physical/mental health, activity of daily living (ADLs), and medical comorbidities. Patients who underwent surgery with baseline prediagnosis HRQOL survey and postdiagnosis follow-up survey were selected. Patient, disease, and HRQOL measures were analyzed by Cox proportional hazards regression for overall and disease-specific survival. RESULTS: Overall, 138 patients were evaluated. Disease extent was localized for 75 (54%) and regional for 58 (42%). The cohort experienced an increase in the number of major comorbidities and declines in physical HRQOL, mental HRQOL, and ADLs. Median overall survival was 74 months. Decreased overall survival was independently associated with male sex (hazard ratio [HR] = 1.7, P = .03), more advanced disease (regional vs. localized: HR = 1.8, P = .01; distant vs. localized: HR = 2.1, P = .22), and decline in ADLs (HR = 1.8, P = .02). Decreased disease-specific survival was independently associated with male sex (HR = 2.2, P = .03), more advanced disease (regional vs. localized: HR = 2.9, P = .002; distant vs. localized: HR = 3.1, P = .22), and decline in mental HRQOL (odds ratio = 2.1, P = .02). CONCLUSION: The potential survival benefit of lung resection for malignancy is diminished by declines in physical and mental health. Among older surgical patients at risk for functional and HRQOL deterioration, identification and mitigation of such deterioration may optimize oncologic outcomes.

Readmission and complications after robotic surgery: experience of 10,000 operations at a comprehensive cancer center.

Evaluation of safety is of paramount importance with adoption of novel surgical technology. Although robotic surgery has become widely used in oncologic surgery, analysis of safety is lacking in comparison to traditional techniques. Standardized assessment of robotic surgical outcomes and adverse events following oncologic surgery is necessary for quality improvement with innovative technology. Between 2003 and 2016, 10,013 unique robotic operations were performed in 9,858 patients. Our prospectively maintained database was retrospectively reviewed for hospital readmissions and Clavien-Dindo grade ≥ 2 complications within 30 days. Multivariable logistic regression was used to identify predictors of surgical complications and hospital readmissions. Cases were stratified by discipline: genitourinary (n = 8240), gynecologic (n = 857), thoracic (n = 457), gastrointestinal (n = 322), hepatobiliary (n = 60), ear/nose/throat (n = 44) and general (n = 33). Intraoperative complications occurred in 42 surgeries (0.4%). Postoperative complications occurred in 946 patients [9.4%, highest grade 2 (n = 574), 3 (n = 288), 4 (n = 72), 5 (n = 10)]. Most frequent complications were ileus (154, 16.3%), anemia (91, 9.6%), cardiac arrhythmia (62, 6.6%), deep vein thrombosis/pulmonary embolus (47, 5.0%), wound infection (45, 4.8%) and urinary leak (43, 4.5%). 405 patients (4.0%) required readmission. Most common causes for hospital readmission were ileus (44, 10.9%), urinary leak (23, 5.7%), urinary tract infection (23, 5.7%), intra-abdominal abscess/fluid collection (23, 5.7%), and small bowel obstruction (19, 4.7%). On multivariable analysis, longer operative time and older age predicted complications and readmissions (p ≤ 0.02). Robotic-assisted surgery appears a safe for oncologic surgery with acceptable hospital readmission and complication rates. Older age and longer operative time were associated with complications and readmission.

G9a Promotes Invasion and Metastasis of Non-Small Cell Lung Cancer through Enhancing Focal Adhesion Kinase Activation via NF-κB Signaling Pathway.

Potential roles of euchromatic histone methyltransferase 2 (EHMT2 or G9a) in invasion and metastasis are not well understood in non-small cell lung cancer (NSCLC). Here, we investigated the effect and underlying mechanisms of G9a and therapeutic implications of targeting G9a in the invasion and metastasis of NSCLC. Overexpression of G9a significantly enhanced in vitro proliferation and invasion, while knockdown of G9a drastically suppressed in vivo growth and metastasis of A549 and H1299 NSCLC cells. Knockdown or inhibition of G9a significantly decreased the expression of focal adhesion kinase (FAK) protein and activation of FAK pathway. In addition, defactinib, a potent FAK inhibitor, partially abolished the G9a-enhanced invasion in these NSCLC cells. Furthermore, targeting G9a was found to suppress NF-κB transcriptional activity in NSCLC cells through stabilizing NF-κB inhibitor alpha (IκBα), while an NF-κB inhibitor Parthenilide partially abolished the G9a-enhanced FAK activation, which suggests that G9a-enhanced invasion and activation of FAK is mediated by elevated NF-κB activity. Notably, a strong positive correlation between the IHC staining of G9a and phosphorylated FAK proteins was identified in H1299 xenografts and 159 cases of NSCLC tissues (R = 0.408). IMPLICATIONS: The findings of this study strongly demonstrate that G9a may promote invasion and metastasis of NSCLC cells by enhancing FAK signaling pathway via elevating NF-κB transcriptional activity, indicating potential significance and therapeutic implications of these pathways in the invasion and metastasis of NSCLCs that overexpress G9a protein.

Cetuximab-Triptolide Conjugate Suppresses the Growth of EGFR-Overexpressing Lung Cancers through Targeting RNA Polymerase II.

To overcome poor pharmacokinetics and toxicity of triptolide (TPL), a natural compound that exhibits potent anticancer activities, we developed a novel antibody-drug conjugate (ADC) to specifically deliver TPL to epidermal growth factor receptor (EGFR)-overexpressing non-small cell lung cancer (NSCLC) and others. The ADC (Cet-TPL) is made by conjugation of TPL to lysine residues of cetuximab (Cet), a clinically available anti-EGFR monoclonal antibody. Studies of antitumor efficacy demonstrated that Cet-TPL drastically suppressed in vitro proliferation and in vivo growth of these EGFR-overexpressing cancers, including NSCLC A549 and H1299 cells and two patient-derived xenografts, and head and neck squamous carcinoma UM-SCC6 cell, while it did not inhibit the proliferation and growth of NSCLC H520 that rarely expresses EGFR. Furthermore, immunofluorescence analysis revealed that Cet-TPL was effectively internalized and transported into lysosomes of EGFR-overexpressing cells. Cet-TPL effectively led to degradation of RNA polymerase II (Pol II) and demethylation of histone H3 lysines, and significantly induced apoptosis in these EGFR-overexpressing cancers. Compared with TPL, Cet, or their combination, Cet-TPL displayed higher target-specific cytotoxicity against EGFR-expressing cancers and much lower in vivo toxicity. In addition, Cet-TPL efficiently suppressed the activated EGFR pathway in UM-SCC6 cancer cells. Taken together, Cet-TPL represents a potent targeting therapeutic agent against EGFR-overexpressing NSCLC and others.

Incorporating lung cancer screening education into tobacco cessation group counseling.

INTRODUCTION: Lung cancer screening (LCS) with low-dose computed tomography (LDCT) reduces lung cancer mortality, yet few people who are eligible for LCS get screened. In the present study, we studied the feasibility of tobacco cessation counselors to inform about LCS during tobacco cessation group counseling. METHODS: Four tobacco cessation counselors at two different facilities offering group tobacco cessation counseling were trained to administer an educational intervention about LCS. The intervention was administered to 25 participants during May 2019 who completed surveys that assessed how much the information provided helped with understanding various aspects of lung cancer screening including benefits, risks, eligibility criteria, and insurance coverage. The intervention also provided information on how to learn more about LCS and assessed the acceptability of the information. RESULTS: The median score for understanding of all components of the intervention was 5 ('completely understand'). Most participants (92%) felt that the information provided about LCS was the right amount. Most participants (72%) were aged 55-80 years, the age range for LCS eligibility. Four participants (16%) reported undergoing LCS in the past. When we reanalyzed the subset of participants who reported no prior LCS, the results of surveys were similar. CONCLUSIONS: Our findings suggest that it is feasible to train tobacco cessation counselors to educate smokers, attending group tobacco cessation counseling classes, also about LCS. The education provided in this study was both understood and well received by the large majority of smokers surveyed. Further study is needed to understand the effect of LCS education on utilization of LDCT among smokers enrolled in tobacco cessation counseling.

G9a regulates tumorigenicity and stemness through genome-wide DNA methylation reprogramming in non-small cell lung cancer.

BACKGROUND: Eukaryotic histone methyltransferases 2 (EHMT2 or G9A) has been regarded as a potential target for non-small cell lung cancer (NSCLC) therapy. This study investigated the regulatory roles of G9A in tumorigenesis and stemness in NSCLC. We isolated and enriched tumor-initiating cells (TIC) from surgically resected NSCLC tissues by FACS and sphere formation assays. We then knocked down G9A using shRNA and carried out genome-wide 850K methylation array and RNA sequencing analyses. We carried out in vivo tumorigenecity asssay using mice xenografts and examined G9A interactions with its novel target using chromatin Immunoprecipitation (ChIP). RESULTS: We identified 67 genes hypomethylated and 143 genes upregulated following G9A knockdown of which 43 genes were both hypomethylated and upregulated. We selected six genes (CDYL2, DPP4, SP5, FOXP1, STAMBPL1, and ROBO1) for validation. In addition, G9A expression was higher in TICs and targeting G9a by shRNA knockdown or by selective inhibitor UNC0642 significantly inhibited the expression of cancer stem cell markers and sphere forming capacity, in vitro proliferation, and in vivo growth. Further, transient overexpression of FOXP1, a protein may promote normal stem cell differentiation, in TICs resulted in downregulation of stem cell markers and sphere forming capacity and cell proliferation in vitro indicating that the genes we identified are directly regulated by G9A through aberrant DNA methylation and subsequent expression. Similarly, ChIP assay has shown that G9a interacts with its target genes through H3K9me2 and downregulation of H3K9me2 following G9a knockdown disrupts its interaction with its target genes. CONCLUSIONS: These data suggest that G9A is involved in lung cancer stemness through epigenetic mechanisms of maintaining DNA methylation of multiple lung cancer stem cell genes and their expression. Further, targeting G9A or its downstream genes could be a novel therapeutic approach in treating NSCLC patients.

Causes of Death and Hospitalization in Long-term Lung Cancer Survivors: A Population-based Appraisal.

INTRODUCTION: Lung cancer survivorship is emerging as an important topic owing to improved survival, but information about health issues among survivors of lung cancer is still lacking. This study used a population dataset to assess causes of death (COD) and hospitalization among long-term (5-year) survivors of lung cancer. MATERIALS AND METHODS: Using linked data from the California Cancer Registry and Office of Statewide Health Planning and Development, all patients with lung cancer diagnosed from 2000 to 2012 were identified. COD and principal admission diagnoses were categorized for all survivors beginning 5 years after diagnosis. Annual proportional distribution of diagnoses and COD were calculated over time. RESULTS: Among 102,768 patients with lung cancer, 12,048 (11.7%) survived at least 5 years after diagnosis. Lung cancer was the most common reason for admission in the first 5 years after diagnosis. In the sixth year after diagnosis, 3662 (41.8%) of 8755 long-term survivors had at least 1 hospitalization, which declined to 804 (10.4%) of 7718 in year 10. Among long-term survivors, pulmonary disease (18.3%) became the most common reason for admission, followed by cardiovascular and gastrointestinal disease. However, 48.7% of 4728 deaths occurring among long-term survivors were still owing to lung cancer. The next most common COD were cardiovascular disease, pulmonary disease, and secondary neoplasm. CONCLUSIONS: Hospitalizations among long-term survivors of lung cancer are common and occur most often owing to cardiovascular, pulmonary, and gastrointestinal diseases. Lung cancer remains the dominant COD even after 5-year survival. Active control of chronic cardiopulmonary disease and cancer surveillance should be priorities when providing patient-centered, comprehensive survivorship care.