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Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We identified tumor microenvironmental features previously described to associate with therapy response. We identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response., Competing Interests: E.M.V.: Advisory/Consulting: Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Serinus Bio, TracerDx Research support: Novartis, BMS, Sanofi, NextPoint Equity: Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics, Serinus Bio, Syapse, TracerDx Travel reimbursement: None Patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag Editorial Boards: Science Advances A.J.A. has consulted for Anji Pharmaceuticals, Affini-T Therapeutics, Arrakis Therapeutics, AstraZeneca, Boehringer Ingelheim, Kestrel Therapeutics, Merck & Co., Inc., Mirati Therapeutics, Nimbus Therapeutics, Oncorus, Inc., Plexium, Quanta Therapeutics, Revolution Medicines, Reactive Biosciences, Riva Therapeutics, Servier Pharmaceuticals, Syros Pharmaceuticals, T-knife Therapeutics, Third Rock Ventures, and Ventus Therapeutics. A.J.A. holds equity in Riva Therapeutics and Kestrel Therapeutics. A.J.A. has research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Deerfield, Inc., Eli Lilly, Mirati Therapeutics, Nimbus Therapeutics, Novartis, Novo Ventures, Revolution Medicines, and Syros Pharmaceuticals.

Objective: To evaluate race- and sex-based disparities in lung cancer screening eligibility under the 2013 US Preventive Services Task Force, 2021 US Preventive Services Task Force, and National Comprehensive Cancer Network lung cancer screening guidelines., Methods: Participants in the Southern Community Cohort Study with a smoking history diagnosed with lung cancer from 2002 to 2021 were identified for analysis. Differences in age at lung cancer diagnosis and smoking characteristics were evaluated among 4 groups: Black men, Black women, White men, and White women., Results: A total of 2011 patients with lung cancer met study inclusion criteria, of whom 968 (48.1%) were women and 1248 (62.1%) were Black. Under the 2013 guideline, Black men with lung cancer were significantly less likely to be eligible for screening when compared with White men with lung cancer (37.7% vs 62.4%; P < .001), and Black women with lung cancer were significantly less likely to be eligible for screening when compared with White women with lung cancer (27.8% vs 56.7%; P < .001). Under the 2021 guideline, 62.6% of Black and 73.8% of White men (P < .001) with lung cancer would have been eligible for screening, resulting in an 11.2 percentage point difference in screening eligibility between Black and White men. Under the 2021 guideline, 50.3% of Black and 74.9% of White (P < .001) women with lung cancer would have been eligible for screening; notably, there remained a 24.6 percentage point difference in screening eligibility between Black and White women. In multivariable-adjusted analysis, under the 2021 USPSTF guideline, Black men with lung cancer had 46% lower odds of being eligible for screening compared with White men with lung cancer (multivariable-adjusted odds ratio [aOR], 0.54; 95% CI, 0.39-0.76; P < .001) and Black women with lung cancer had 66% lower odds of being eligible for screening compared with White women with lung cancer (aOR, 0.34; 95% CI, 0.25-0.46; P < .001). The National Comprehensive Cancer Network guideline increased the proportion of patients with lung cancer eligible for screening in each group., Conclusions: In this analysis of patients with lung cancer in the Southern Community Cohort Study, there remained a large gap in lung cancer screening eligibility between Black and White men and women under the 2021 US Preventive Services Task Force guideline. Only 50% of Black women and 63% of Black men diagnosed with lung cancer would have qualified for screening., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Despite the growing relevance of immunotherapy for non-small cell lung cancer (NSCLC), there is limited consensus on the optimal treatment strategy for locally advanced NSCLC. This study evaluated the overall survival of patients with stage III-N2 NSCLC undergoing induction chemoimmunotherapy with surgery (CT/IO+Surgery) and definitive concurrent chemoradiation followed by immunotherapy (cCRT+IO)., Methods: Patients with cT1-3, N2, M0 NSCLC in the National Cancer Database (2013 to 2019) were included and stratified by treatment regimen: CT/IO+Surgery or cCRT+IO. Overall survival was evaluated using Kaplan-Meier analysis, Cox proportional hazards modeling, and propensity score matching on 10 prognostic variables., Results: Of the 3382 patients who met the study eligibility criteria, 3289 (97.3%) received cCRT+IO and 93 (2.8%) received CT/IO+Surgery. The 3-year overall survival of the entire cohort was 58.2% (95% CI, 56.2% to 60.1%). Multivariable-adjusted Cox proportional hazards modeling demonstrated better survival after CT/IO+Surgery than after cCRT+IO (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.32 to 0.84; P = .007). In a 3:1 variable ratio propensity score-matched analysis of 223 patients who received cCRT+IO and 76 patients who received CT/IO+Surgery, 3-year overall survival was 63.2% (95% CI, 55.9% to 70.2%) after cCRT+IO and 77.2% (95% CI, 64.6% to 85.7%) after CT/IO+Surgery (P = .029)., Conclusions: In this national analysis, multimodal treatment including immunotherapy was associated with a 3-year overall survival rate of 58.2% for all patients with stage III-N2 NSCLC and 77.2% for patients who underwent chemoimmunotherapy followed by surgery. These results should be considered hypothesis-generating and demonstrate the importance of developing a randomized trial to evaluate the role of surgery versus chemoradiation for locally advanced NSCLC in the modern immunotherapy era., Competing Interests: Conflict of Interest Statement L.M. has received consulting fees from AstraZeneca, Genentech, Ontarget Laboratories, and Ethicon. The other authors have no conflicts of interest to report. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Recent prospective trials have demonstrated the noninferiority of segmentectomy to lobectomy in the surgical management of early non-small cell lung cancer (NSCLC). It remains unknown, however, whether segmentectomy is sufficient for treating small tumors with visceral pleural invasion (VPI), a known indicator of aggressive disease biology and poor prognosis in NSCLC., Methods: Patients in the National Cancer Database (2010-2020) with cT1a-bN0M0 NSCLC and VPI and additional high-risk features who underwent segmentectomy or lobectomy were identified for analysis. Only patients with no comorbidities were included in this analysis to reduce selection bias. Overall survival of patients who underwent segmentectomy vs lobectomy was evaluated using multivariable-adjusted Cox proportional hazards and propensity score- matched analyses. Short-term and pathologic outcomes were also evaluated., Results: Of the 2568 patients with cT1a-bN0M0 NSCLC and VPI included in our overall cohort, 178 (7%) underwent segmentectomy and 2390 (93%) underwent lobectomy. No significant differences were found in the 5-year overall survival between patients undergoing segmentectomy vs lobectomy in multivariable-adjusted and propensity score-matched analyses (adjusted hazard ratio, 0.91 [95% CI, 0.55-1.51], P = .72; 86% [95% CI, 75%-92%] vs 76% [95% CI, 65%-84%], P = .15, respectively). There were also no differences in surgical margin positivity, 30-day readmission, and 30- and 90-day mortality between patients undergoing either surgical approach., Conclusions: In this national analysis, no differences were found in survival or in short-term outcomes between patients undergoing segmentectomy vs lobectomy for early-stage NSCLC with VPI. Our findings suggest that if VPI is detected after segmentectomy for cT1a-bN0M0 tumors, completion lobectomy is unlikely to confer an additional survival advantage., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: This study sought to evaluate the long-term survival and causes of death after surgery among patients with pathologic stage IA non-small cell lung cancer (NSCLC) in the National Lung Screening Trial (NLST)., Methods: Patients who underwent surgery and who had a diagnosis of pathologic stage IA NSCLC in the NLST were identified for analysis. The 5- and 10-year overall survival and lung cancer-specific survival, stratified by operation type, were evaluated. Among patients who underwent lobectomy, the causes of death and the cumulative incidence of lung cancer death were assessed., Results: A total of 380 patients (n = 329, 86.6% lobectomy; n = 20, 5.3% segmentectomy; n = 31, 8.1% wedge resection) met inclusion criteria. Median follow-up time from the date of surgery was 7.8 years (interquartile range, 4.8-10.7 years). The 10-year overall survival rate was 58.3% (95% CI, 52.4%-63.8%) for lobectomy, 59.9% (95% CI, 33.2%-78.8%) for segmentectomy, and 45.2% (95% CI, 20.8%-66.9%) for wedge resection. The 10-year lung cancer-specific survival rate was 74.3% (95% CI, 68.6%-79.1%) for lobectomy, 81.3% (95% CI, 51.3%-93.8%) for segmentectomy, and 84.8% (95% CI, 64.0%-94.1%) for wedge resection. Lung cancer was the leading cause of death, accounting for 55.8% of deaths after lobectomy. The 10-year cumulative incidence of lung cancer death after lobectomy was 22.5% (95% CI, 18.3%-27.1%)., Conclusions: The 10-year overall survival rate after lobectomy among patients with pathologic stage IA NSCLC in the NLST was 58%. Lung cancer was the leading cause of death, accounting for more than 55% of deaths., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to evaluate the overall survival of patients with ≤8 mm non-small cell lung cancer (NSCLC) who undergo wedge resection versus stereotactic body radiation therapy (SBRT). Kaplan-Meier analysis, multivariable Cox proportional hazards modeling, and propensity score-matched analysis were performed to evaluate the overall survival of patients with ≤8 mm NSCLC in the National Cancer Database (NCDB) from 2004 to 2017 who underwent wedge resection versus patients who underwent SBRT. The above-mentioned matched analyses were repeated for patients with no comorbidities. Patients who were coded in the NCDB as having undergone radiation because surgery was contraindicated due to patient risk factors (e.g., comorbid conditions, advance age, etc.) and those with a history of prior malignancy were excluded from analysis. Of the 1505 patients who had NSCLC ≤8 mm during the study period, 1339 (89%) patients underwent wedge resection, and 166 (11%) patients underwent SBRT. In the unadjusted analysis, multivariable Cox modeling and propensity score-matched analysis, wedge resection was associated with improved survival when compared to SBRT. These results were consistent in a sensitivity analysis limited to patients with no comorbidities.

Objective: The study objective was to identify whether the results of JCOG0802 could be generalized to US clinical settings., Methods: Patients diagnosed with clinical stage IA (≤2 cm) non-small cell lung cancer who underwent segmentectomy versus lobectomy (2004-2017) in the National Cancer Database were identified. Overall survival of patients in the National Cancer Database was assessed using propensity score-matched analysis. A separate analysis of the Surveillance Epidemiology End Results database was conducted to evaluate treatment patterns of second primary lung cancers among patients who underwent segmentectomy versus lobectomy for a first primary lung cancer., Results: Of the 23,286 patients in the National Cancer Database meeting inclusion criteria, 1397 (6.0%) underwent segmentectomy and 21,889 (94.0%) underwent lobectomy. In a propensity score-matched analysis of all patients in the study cohort, there were no significant differences in overall survival between patients undergoing segmentectomy versus lobectomy (5-year overall survival: 79.9% [95% CI, 76.7%-82.0%] vs 81.8% [95% CI, 78.7%-84.4%], log-rank: P = .72). In subgroup analyses by tumor grade and histologic subtype, segmentectomy was associated with similar overall survival compared with lobectomy in all subgroups evaluated. In a propensity score-matched analysis of patients in the Surveillance Epidemiology End Results database, there were no significant differences in treatment patterns of second primary lung cancers between patients who underwent segmentectomy and patients who underwent lobectomy for their first primary lung cancer., Conclusions: In this national analysis of US patients diagnosed with stage IA (≤2 cm) non-small cell lung cancer, there were no significant differences in overall survival between segmentectomy and lobectomy in the overall cohort or in subgroup analyses by tumor grade or histologic subtype., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Primary clear cell adenocarcinoma of the lung (CCAL) is a rare form of lung cancer with poorly understood clinical features. We sought to investigate the clinicopathological characteristics and independent prognostic factors of primary CCAL., Methods: Overall survival (OS) of patients with CCAL in the National Cancer Database (NCDB) from 2004 to 2017 was compared to lung adenocarcinoma using Kaplan-Meier analysis, multivariable Cox proportional hazards modeling, and propensity score matching. Independent prognostic indicators for patients with CCAL were determined using multivariable Cox proportional hazards analysis., Results: A total of 1,396 CCAL and 462,360 lung adenocarcinoma patients were included in our analysis. When compared to patients diagnosed with lung adenocarcinoma, those diagnosed with CCAL were more likely to be younger, white, reside farther from a hospital, have higher Charlson/Deyo comorbidity condition (CDCC) scores, have private insurance, have T1, N0, M0 status. In unadjusted analysis, patients with CCAL had better survival than those with lung adenocarcinoma, although no significant differences in survival were found between the two groups with multivariable Cox proportional hazards and propensity score-matched analyses., Conclusions: In this national analysis, we found that the clinicopathological characteristics of CCAL are distinct from those of lung adenocarcinoma, but CCAL is not itself an independent predictor of survival after multivariable adjustment or propensity score-matched analysis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-76/coif). CJY serves as an unpaid editorial board member of Journal of Thoracic Disease from February 2023 to January 2025. The other authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Background: The objective of this study is to evaluate the trends of and outcomes associated with the use of minimally invasive lobectomy for stage I and II non-small cell lung cancer (NSCLC) in the United States., Methods: The use of and outcomes associated with open and minimally invasive lobectomy for clinical stage I and stage II NSCLC from 2010 to 2017 in the National Cancer Database were assessed by multivariable logistic regression and propensity score matching., Results: From 2010 to 2017, use of minimally invasive lobectomies increased for stage I NSCLC (multivariable-adjusted odds ratio [aOR] 4.52; 95% CI, 3.95-5.18; P < .001) and stage II NSCLC (aOR 4.38; 95% CI, 3.38-5.68; P < .001). In 2015, for the first time, more lobectomies for stage I NSCLC were performed by minimally invasive techniques (52.2%, n = 5647) than by thoracotomy (47.8%, n = 5164); and in 2017, more lobectomies for stage II NSCLC were performed by minimally invasive techniques (54.7%, n = 1620) than by thoracotomy (45.3%, n = 1,342). From 2010 to 2017, the conversion rates from minimally invasive to open lobectomy for stage I NSCLC decreased from 19.6% (n = 466) to 7.2% (n = 521; aOR 0.32; 95% CI, 0.23-0.43; P < .001). Similarly, from 2010 to 2017, the conversion rates from minimally invasive to open lobectomy for stage II NSCLC decreased from 20% (n = 114) to 11.5% (n = 186; aOR 0.39; 95% CI, 0.21-0.72; P = .002)., Conclusions: In the United States, for stage I and stage II NSCLC from 2010 to 2017, the use of minimally invasive lobectomy significantly increased while the conversion rate significantly decreased. By 2017, the minimally invasive approach had become the predominant approach for both stage I and stage II NSCLC., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to evaluate the feasibility of minimally invasive surgery (MIS) and perioperative outcomes following neoadjuvant immunotherapy for resectable non-small cell lung cancer (NSCLC)., Methods: Patients with stage I to III NSCLC treated with immunotherapy with or without chemotherapy or chemotherapy alone prior to lobectomy were identified in the National Cancer Database (2010-2018). The percentage of operations performed minimally invasively, conversion rates, and perioperative outcomes were evaluated using propensity-score matching. Propensity-score matching was also used to compare perioperative outcomes between patients who underwent an open lobectomy and those who underwent an MIS lobectomy after neoadjuvant immunotherapy., Results: Of the 4229 patients identified, 218 (5%) received neoadjuvant immunotherapy and 4011 (95%) received neoadjuvant chemotherapy alone. There was no difference in the rate of MIS lobectomy among patients who received immunotherapy compared with those who received chemotherapy alone in propensity score-matched analysis (60.8% vs 51.6%; P = .11). There also were no significant differences in the rate of conversion from MIS to open lobectomy (14% vs 15%, P = .83; odds ratio, 1.1; 95% confidence interval, 0.51-2.24) or in nodal downstaging, margin positivity, 30-day readmission, and 30- and 90-day mortality between the 2 groups. In a subgroup analysis of only patients treated with neoadjuvant immunotherapy, there were no differences in pathologic or perioperative outcomes between patients who underwent open lobectomy and those who underwent MIS lobectomy., Conclusions: In this national analysis, neoadjuvant immunotherapy for resectable NSCLC was not associated with an increased likelihood of the need for thoracotomy, conversion from MIS to open lobectomy, or inferior perioperative outcomes., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: Anatomic lung resection remains the standard of care for early-stage non-small-cell lung cancer (NSCLC), but wedge resection may offer similar survival in older adult patients. The objective of this study was to evaluate the survival of patients aged 80 y and older undergoing wedge resection versus segmentectomy for stage IA NSCLC using a large clinical registry., Methods: Patients aged 80 y and older in the National Cancer Database who underwent wedge resection or segmentectomy for cT1a-b N0 M0 NSCLC between 2004 and 2018 were identified for an analysis. Survival was assessed using multivariable Cox proportional hazards analysis, propensity-score matching, and inverse probability weighting. A subgroup analysis of patients who underwent lymph node evaluation with their wedge resection or segmentectomy was also performed., Results: Of the 2690 patients identified, 2272 (84%) underwent wedge resection and 418 (16%) underwent segmentectomy. Wedge resection was associated with worse 5-year overall survival relative to segmentectomy in multivariable-adjusted (adjusted Hazard Ratio: 1.26, [1.06-1.51], P = 0.01) and propensity score-matched analysis (49% [95% confidence interval {CI}: 42%-55%] versus 59% [95% CI: 52%-65%], P = 0.02). Among a subgroup of 1221 wedge resection and 347 segmentectomy patients who also received intraoperative lymph node evaluation, however, there were no significant differences in 5-year survival in multivariable-adjusted (adjusted Hazard Ratio: 1.12, [0.90-1.39], P = 0.31) or propensity score-matched analysis (55% [95% CI: 48%-62%] versus 61% [95% CI: 54%-68%], P = 0.10)., Conclusions: In this national analysis, there were no significant differences in survival between older adult patients with stage IA NSCLC who underwent wedge resection versus segmentectomy when a lymph node evaluation was performed., (Copyright © 2022 Elsevier Inc. All rights reserved.)