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Introduction Major pathologic response (MPR), defined as residual viable tumor of less than or equal to 10%, currently serves as a surrogate end point for survival for patients with resectable NSCLC after neoadjuvant chemotherapy. However, the significance of pathologic response in lymph nodes harboring metastatic tumors in such patients remains uncertain. Therefore, we studied the effect of neoadjuvant chemotherapy on resected positive lymph nodes and determined if the degree of pathologic response in the lymph nodes alone (LN-MPR) or in combination with that of the primary tumor (PT-MPR) was able to predict the outcome. Methods A total of 75 patients with NSCLC who underwent neoadjuvant chemotherapy and completed surgical resection were included in this study. Tissue specimens were retrospectively evaluated by two pathologists blinded to the patients' treatments and outcomes. Specimens were reviewed for the degree of pathologic response in the primary tumor and in any involved lymph nodes. The prognostic performance of LN-MPR alone or in combination with PT-MPR with respect to overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression model. Results LN-MPR was significantly predictive of long-term OS after neoadjuvant chemotherapy. A combination of PT-MPR with LN-MPR was significantly associated with outcome and allowed stratification of patients into three prognostic groups (p = 0.001). Conclusions LN-MPR in isolation is a reliable predictor of OS in patients with NSCLC receiving neoadjuvant chemotherapy. A combination of LN-MPR with PT-MPR seems to correlate well with the outcome and can be used to predict prognosis in this patient population.

Objectives Although colorectal cancer bowel segment location has been shown to independently predict the outcomes in early stage disease, it has not been previously studied in the setting of pulmonary metastases. We sought to determine whether colorectal cancer location affects survival after pulmonary metastasectomy. Methods Patients who had undergone pulmonary metastasectomy for colorectal cancer at a single institution from 2011 to 2018 were reviewed. Univariable and multivariable Cox regression analyses were performed to identify predictors of overall survival and disease-free survival. The Kaplan-Meier survival method was used to determine differences between groups. Results A total of 194 patients were evaluated. The median follow-up, survival time, and 5-year survival rate were 36.8 months, 75.8 months, and 57%, respectively, and 122 patients (63%) had experienced disease recurrence at any location. On univariable analysis, age, primary tumor location, pulmonary nodule size, ≥3 pulmonary nodules, and intrathoracic nodal disease were associated with overall survival. On multivariable analysis, patients with left-sided tumors experienced a survival benefit (hazard ratio, 0.31; P = .036). Kaplan-Meier analysis revealed a median survival time of 90 months (95% confidence interval, 82 months to not reached) compared with 55 months (95% confidence interval, 49 months to not reached) for patients with left-sided and rectal tumors, respectively, after metastasectomy (P = .078). Location was not associated with disease-free survival on Cox multivariable regression. Conclusions We found that left-sided colorectal cancer is associated with prolonged survival after pulmonary metastasectomy. Future investigations are required to determine the validity of such findings, including the effect of location in the prognostication for patients who are candidates for pulmonary metastasectomy.

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand–receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. Significance: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception. This article is highlighted in the In This Issue feature, p. 2355

Introduction Immune infiltration in lung adenocarcinomas (LUADs) has been associated with response to immune checkpoint inhibitors. Clinical features underlying differential responses of patients with LUADs to immunotherapy are not well understood. Here, we analyzed the association between LUAD immune infiltration and clinicopathologic variables. Materials and Methods Intratumoral CD3, CD8, and CD68 cell densities (tumor-associated immune cells [TAICs]) were immunohistochemically assessed in 146 surgically resected LUADs. LUADs were classified into 2 groups, low and high TAICs, based on the median values of cell densities for CD3, CD8, and CD68. Somatic mutation burden and driver gene mutation status were analyzed in a subset of the cases (n = 92). We statistically analyzed the association between the TAIC groups and various clinicopathologic and molecular variables by using the χ2/Fisher and Wilcoxon sum tests and multivariable logistic regression models. Results Patient gender, tumor size, and STK11 mutations were significantly associated with TAIC levels in LUAD. Female patients exhibited significantly elevated TAIC levels (P = .005) compared with male patients. Tumor size was inversely associated with TAIC levels (P = .012). STK11 mutated tumors were associated with lower TAICs (P = .008). Higher TAICs were consistently observed in female patients with LUADs after adjusting for stage, tumor size, and age. Multivariable regression models confirmed female gender as an independent variable associated with TAIC levels in LUAD (P = .0141). Conclusion Immune infiltration in LUADs was significantly higher in female patients, warranting further exploration into the association between this clinical variable and immunotherapeutic response in LUAD.

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC. The evolution of immune landscape in lung adenocarcinoma (ADC) is largely unknown. Here the authors use a cohort of resected invasive lung ADC and its precursors and show a gradual increase of immunosuppression and decrease of anti-tumor response associated with specific genomic and epigenetic features.

Introduction Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood. Methods We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response. Results EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth. Conclusions Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.

BACKGROUND: For patients with bilateral pulmonary metastases, staged resections have historically been the preferred surgical intervention. During the spring of 2020, the COVID-19 pandemic made patient travel to the hospital challenging and necessitated reduction in operative volume so that resources could be conserved. We report our experience with synchronous bilateral metastasectomies for the treatment of disease in both lungs. METHODS: Patients with bilateral pulmonary metastases who underwent simultaneous bilateral resections were compared with a cohort of patients who underwent staged resections. We used nearest-neighbor propensity score (1:1) matching to adjust for confounders. Perioperative outcomes were compared between groups using paired statistical analysis techniques. RESULTS: Between 1998 and 2020, 36 patients underwent bilateral simultaneous metastasectomies. We matched 31 pairs of patients. The length of stay was significantly shorter in patients undergoing simultaneous resection (median 3 vs. 8 days, p < .001) and operative time was shorter (156 vs. 235.5 min, p < .001) when compared to the sum of both procedures in the staged group. The groups did not significantly differ with regard to postoperative complications. CONCLUSION: In a carefully selected patient population, simultaneous bilateral metastasectomy is a safe option. A single procedure confers benefits for both the patient as well as the hospital resource system.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC. Neoadjuvant treatment with nivolumab plus ipilimumab is well tolerated and demonstrates clinical efficacy in patients with early stage lung cancer.

Most patients undergoing esophagectomy will experience intermittent reflux of gastric and biliary content into the remnant esophagus postoperatively. The incidence of new or recurrent intestinal metaplasia following chemoradiation and surgery has not been well-described. Furthermore, post-resection guidelines do not exist regarding surveillance for metaplasia in the esophageal remnant. Patients undergoing Ivor Lewis esophagectomy after concurrent chemoradiation for a diagnosis of esophageal adenocarcinoma from 2006 to 2018 were identified. Pathology records were reviewed for the presence of intestinal metaplasia on pretreatment biopsies, surgical specimen, or post-resection biopsies. In total, 619 patients met inclusion criteria, including 267 (43%) who had intestinal metaplasia noted either prior to or at the time of esophagectomy. The median duration of metaplastic disease prior to resection was 4.4 months. During a median follow-up time of 28 months (interquartile range, 12–60), intestinal metaplasia was noted in the remnant esophagus in 12 (2%) patients, 7 of whom had a prior history of metaplasia. Local recurrence of adenocarcinoma was also uncommon, and occurred in 37/577 (6%) of patients with complete resections, with similar event rates among those with and without a prior history of metaplasia (14/249 [6%] vs. 23/328 [7%], p = 0.614). Our findings suggest that despite several factors predisposing to mucosal damage following esophagectomy, occurrence of new intestinal metaplasia after trimodality therapy in our patient population appears to be rare, even among patient with a previous history of this pathologic finding, which may have significant implications for surveillance and cost-savings after resection.

Introduction CD73 is a membrane-bound enzyme crucial in adenosine generation. The adenosinergic pathway plays a critical role in immunosuppression and in anti-tumor effects of immune checkpoint inhibitors (ICI). Here, we interrogated CD73 expression in a richly annotated cohort of human lung adenocarcinoma (LUAD) and its association with clinicopathological, immune, and molecular features to better understand the role of this immune marker in LUAD pathobiology. Materials and methods Protein expression of CD73 was evaluated by immunohistochemistry in 106 archived LUADs from patients that underwent surgical treatment without neoadjuvant therapy. Total CD73 (T +) was calculated as the average of luminal (L +) and basolateral (BL +) percentage membrane expression scores for each LUAD and was used to classify tumors into three groups based on the extent of T CD73 expression (high, low, and negative). Results CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and LUAD. In LUAD, BL CD73 expression was associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Stratification of LUADs based on T CD73 extent also revealed that tumors with high expression of this enzyme overall exhibited significantly elevated immune infiltration and PD-L1 protein expression. Immune profiling demonstrated that T-cell inflammation and adenosine signatures were significantly higher in CD73-expressing lung adenocarcinomas relative to those lacking CD73. Conclusion Our study suggests that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early stage lung adenocarcinoma. Our findings warrant further studies to explore the role of CD73 in immunotherapeutic response of LUAD.

The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas., It is known that invasive lung adenocarcinomas evolve from pre-cancerous dysplastic lesions. In this study, the authors show that evolution of pre-cancerous lesions is accompanied by DNA methylation alterations, and that global hypomethylation correlates with immune infiltration, mutational burden and copy number alterations.

The advent of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment of patients with locally advanced unresectable and metastatic non-small cell lung cancer (NSCLC). Now, ICIs are undergoing evaluation as neoadjuvant therapy in patients with early-stage, resectable NSCLC using candidate surrogate endpoints of clinical efficacy, i.e., major pathologic response (MPR, ≤10% viable tumor cells in resected tumors). The initial results from early, small-scale trials are encouraging; however, they also reveal that a substantial number of patients with operable disease may not benefit from neoadjuvant ICIs. Consequently, much investigative effort is currently directed toward identifying mechanisms of resistance to ICI therapy in resectable NSCLC. There is also an urgent need for biomarkers that could be used to guide the clinical decision-making process and maximize the clinical benefit of ICIs in patients with early-stage, resectable NSCLC. Here, we summarize the initial results from the trials of neoadjuvant ICIs in patients with early-stage and locally advanced operable NSCLC and review the findings of studies investigating emerging biomarkers associated with those trials.

Introduction The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade. Methods Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73). Results NCT was associated with increased infiltration of cytotoxic CD8+ T cells and CD20+ B cells. Moreover, NCT was associated with increases in CD8+CD103+ and CD4+CD103+PD-1+TIM3− tissue resident memory T cells. Gene expression profiling supported memory function of CD8+ and CD4+ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery. Conclusions Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8+ and CD4+ memory helper T cells.

BACKGROUND: Mutations in the serine-threonine kinase LKB1/STK11 have been implicated in mediating resistance to checkpoint blockade among patients with advanced lung adenocarcinoma. We sought to examine the associations between clinicopathologic characteristics, tumor LKB1 expression, features of the immune microenvironment, and postoperative prognosis among patients with early-stage lung adenocarcinoma undergoing surgical therapy. METHODS: Formalin-fixed, paraffin-embedded specimens of patients undergoing resection of stage I-III, chemotherapy-naïve adenocarcinomas (1997–2008) were analyzed using tissue microarray sectioning. Sublobar resections were excluded. Intratumoral LKB1/STK11 expression was quantified as H-score. In a subset, tumor associated immune cell populations were quantified using whole tumor sections in peritumoral and intratumoral compartments. RESULTS: 104 patients met inclusion criteria. LKB1/STK11 expression (median H-score 102.9) was higher in women (median 123.3) than men (100.0, p=0.004) and in never-smokers (median 145.0) than former/current smokers (100.0, p=0.002). LKB1/STK11 expression was positively correlated with intratumoral infiltration of CD3(+) (r=0.351, P=0.005), CD4(+) (r=0.436, P

Programmed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC.PD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed.PD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (1%, 1%-49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival.PD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.

Purpose: Nintedanib enhances the activity of chemotherapy in metastatic non–small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint. Patients and Methods: Eligible patients had stage IB (≥4 cm)–IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m2), docetaxel (75 mg/m2) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%. Results: Twenty-one patients (stages I/II/III, N = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%–32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%–54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%–93%) and 91% (95% CI, 79%–100%), respectively. Most frequent treatment-related grade 3–4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3+ and cytotoxic CD3+CD8+ T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm2, P = 0.048; 142.3 vs. 35.6 cells/mm2, P = 0.018). Conclusions: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies. See related commentary by Blakely and McCoach, p. 3499

Introduction We have suggested that major pathologic response (MPR) could serve as a surrogate endpoint for survival and provide rapid means of comparing different neoadjuvant treatment regimens. Here, we confirm that MPR is predictive of long-term overall survival (OS) in patients with non–small-cell lung cancer (NSCLC) who underwent neoadjuvant chemotherapy and surgical resection, to assess agreement on MPR between 2 observers, and to determine the minimum number of slides needed to obtain an accurate determination of MPR. Patients and Methods We identified 151 patients with NSCLC who had been treated with neoadjuvant chemotherapy followed by complete surgical resection from 2008 to 2012. Tissue specimens were retrospectively evaluated by 2 pathologists who had been blinded to patients’ treatment and outcome. We assessed the relationships between MPR and OS, the levels of agreement between the pathologists, and determined the number of slides needed to obtain an accurate determination of MPR. Results Our results reveal that MPR examined by either observer 1 (experienced) or by observer 2 (trained) was significantly predictive of long-term OS after neoadjuvant chemotherapy. MPR was associated with long-term OS in patients with NSCLC undergoing neoadjuvant chemotherapy on multivariable analysis (hazard ratio 2.68; P = .01). The levels of agreement between 2 pathologists were high after direct in-person training by one pathologist or the other (R2 = 0.994). Our data suggest that at least 3 slides should be read to accurately determine MPR. Conclusions MPR is significantly predictive of long-term OS in neoadjuvant chemotherapy–treated patients with NSCLC. MPR may serve as a surrogate endpoint for evaluating novel chemotherapies and immunotherapy response in biomarker-driven translational clinical trials.

Introduction The standard of care for stage IIIA (N2) non–small-cell lung cancer (NSCLC) includes concurrent definitive chemoradiation (dCRT) followed by durvalumab, thus challenging the role of surgery in resectable patients. We assessed locoregional disease control and survival in patients with surgically resected and unresected stage IIIA (N2) NSCLC disease. Patients and Methods We conducted a retrospective analysis from prospectively collected databases at MD Anderson Cancer Center. Patients undergoing neoadjuvant chemotherapy and surgery or dCRT for clinical stage IIIA (N2) disease (2004-2014) were evaluated. Primary outcomes included locoregional disease control, disease-free survival (DFS), and overall survival (OS). Kaplan-Meier outcome analyses were performed. Results Of the 159 resected patients, the majority had lobectomy (82.4%), followed by pneumonectomy (11.9%) and sublobar resection (5.7%). The 30- and 90-day mortality rates were 0.6% and 1.3%, respectively. At median follow-up of 52.8 months, recurrence was 55.3%, with 44.0% having distant and 15.1% locoregional recurrence. At 5 years, OS was 50.8% and DFS was 33.1% Median OS was 61.2 months. A total of 366 patients underwent dCRT, with intensity-modulated radiation in 64.5%, proton therapy in 26.0%, and 3-dimensional conformal radiotherapy in 9.6%. The mean dose was 68.1 Gy. At median follow-up of 20.8 months, recurrence was 53.6%, with distant and locoregional recurrence of 40.7% and 30.3%, respectively. At 5 years, OS was 29.2% and DFS was 20.5%. Median OS was 27.5 months. Conclusion Stage IIIA (N2) NSCLC continues to be a heterogeneous disease, and patients with surgically resected and unresected disease represent different risk populations. Ongoing immunotherapy trials may further redefine treatment algorithms in this complex patient population.

Background and objectives It is unclear if a specific strategy for simultaneous treatment of primary thymic neoplasms and pleural metastases confers benefit for Masaoka stage IVA disease. We reviewed our experience with thymic neoplasms with concurrent pleural metastases to identify factors influencing outcomes. Methods Records of patients who presented with stage IVA thymic neoplasms from 2000 to 2018 were assessed. Multivariate Cox proportional hazards analyses were completed to determine predictors of progression-free and overall survival. Results Forty-eight patients were identified, including 34 (71%) who underwent surgery. Median overall and progression-free survival were 123 and 21 months, respectively. The extent of resection varied, and was most commonly thymectomy plus partial pleurectomy (22, 65%). Median progression-free survival for patients who underwent surgical resection versus those who had not was 24 versus 12 months (P = .018). Following surgical resection, mediastinal recurrence was uncommon (2, 6%, vs 7, 50% nonoperatively). Five-year survival rates in these groups were suggestive of possible benefit to surgery (87% vs 68%). Conclusions Thymic neoplasms with pleural dissemination represents a treatment challenge. As part of a multidisciplinary approach, surgery appears to be associated with more favorable long-term results, although selection bias may account for some of the survival differences observed.

Background The improvement in the management of lung cancer have the potential to improve survival in patients undergoing resection for early-stage (stage I and II) non-small cell lung cancer (NSCLC), but few studies have evaluated time trends and identified predictors of overall survival (OS). Methods We identified surgically resected early-stage NSCLC between 1998 and 2016. The 3-year OS (1998-2014) and 5-year OS (1998-2012) rates were calculated for each year. Joinpoint regression was used to calculate annual percentage changes (APC) and to test time trends in OS. Multivariable Cox regression was used to identify predictors of OS. Results There was a significant upward trend in the 3-year (1998, 56%; 2014, 83%; APC = 1.8) and 5-year (1998, 47%; 2012, 76%; APC = 3.1) OS. Older age; male sex; history of diabetes, coronary artery disease, and chronic obstructive pulmonary disease; high ASA score; smoking pack-years; high-grade tumor; pneumonectomy; thoracotomy; neoadjuvant therapy; nodal disease; and positive tumor margin were predictors of poor OS. Conclusion The upward time trend in OS suggests that improved staging, patient selection, and management have conferred a survival benefit in early-stage NSCLC patients. The prediction model of OS could be used to refine selection criteria for resection and improve survival outcomes.

BACKGROUND: We previously reported that post-discharge nursing telephone assessments identified a frequent number of patient complaints. Our aim was to determine if telephone assessments can identify patients at risk for emergency room (ER) visits or hospital readmissions. METHODS: A single-institution, retrospective review was performed on all patients undergoing pulmonary resection over a 12-month period. Standardized nursing telephone calls were conducted and records were reviewed to determine postoperative issues. ER visits and readmissions within 30 and 90 days were recorded. RESULTS: In total, 521 patients underwent pulmonary resection and 245 (47%) were reached for telephone assessment. ER visits within 30/90 days were 8.1% (n=42) and 12.1% (n=63). Readmissions within 30/90 days were 3.1% (n=16) and 6% (n=31). For those reached by telephone assessment, patients with major issue demonstrated increased 30-day ER visits: 22.6% (n=7) vs. 8.0% (n=17), P=0.019. For all patients, those with 90-day ER visit and/or readmission were more likely to have pulmonary complications during initial admission (43.8% vs. 21.2%, P

Background Opioids represent the mainstay for treating postsurgical pain but can cause significant morbidity in addition to dependency. The aim of the study was to determine the incidence of persistent opioid use after lung surgery. Methods Patients who underwent lung resection from 2008 to 2013 for non-small cell lung cancer were identified in the Surveillance, Epidemiology and End Results-Medicare database. Patients were categorized as being chronic, intermittent, or naive preoperative opioid users using information obtained from part D records. Persistent opioid use was defined as having a filled opioid prescription between 3 and 6 months after lung resection. Results A total of 6948 patients were identified, among whom 3946 (56.8%) were opioid naive, 2017 (29.0%) were intermittent opioid users, and 985 (14.2%) were chronic opioid users preoperatively. Persistent opioid use (3-6 months) after lung resection was high (31%), even among opioid-naive patients (17%). Among those who were previously opioid naive, independent predictors of persistent opioid use were receipt of adjuvant radiation or chemotherapy, less than 70 years of age, Charlson comorbidity score of 1 or 2, and residence in zip codes associated with lower education. Conversely, patients who underwent minimally invasive surgery were less likely to have persistent opioid use. Those with persistent opioid use after surgery did not show any trend toward returning to preoperative opioid utilization for at least the first postoperative year. Conclusions Opioid dependence after lung resection in the population over 65 years of age is high but was significantly lower among those who received minimally invasive surgery, in addition to other factors.

Background Adenocarcinoma of the gastroesophageal junction (AEG) poses a management challenge, as preoperative prediction of occult mediastinal nodal metastasis is difficult. We sought to identify factors predictive of mediastinal involvement among patients undergoing trimodality therapy. Methods Patients undergoing trimodality therapy for Siewert II and III AEG at a single institution between 2000 and 2015 were identified. Mediastinal involvement was defined as pathologic nodal involvement after neoadjuvant chemoradiation (ypN+) in mediastinal stations or mediastinal recurrence 2 years or less after resection. Maximal χ2 analysis and Youden's J index were used to identify the pretreatment proximal tumor extent that best discriminated mediastinal involvement. Results In all, 204 patients (151 [74%] AEG II, 53 [26%] AEG III) were included, of whom 47 (23%) had clinical evidence of thoracic nodal disease. Thirty-one of the 204 patients (15%) met criteria for mediastinal involvement (24 of 31 ypN+, 10 of 31 mediastinal recurrence). Patients with mediastinal involvement had greater proximal tumor extent (median 2 cm [interquartile range, 1.0 to 3.0 cm] vs 1.4 cm [interquartile range, 0.7 to 3.0 cm], P = .030), were more frequently Siewert II lesions (27 of 31 [87.1%] vs 124 of 173 [71.7%], P = .071), and were more often observed to have clinical thoracic nodal metastasis (cN) evidence (13 of 31 [42%] vs 34 of 173 [20%], P = .007) than patients who did not. On multivariable analysis of patients with intrathoracic cN0, esophageal extent of 1.5 cm or greater was independently predictive of mediastinal involvement (odds ratio 5.46, P = .011), whereas Siewert classification was not (Siewert II odds ratio 3.48, P = .116). Conclusions Pretreatment proximal tumor extent, rather than Siewert classification, is an independent predictor of mediastinal involvement among AEG II/III patients without clinical evidence of mediastinal metastasis and should be considered during treatment planning.

Objective Trimodality therapy may prolong survival for patients with resectable malignant pleural mesothelioma. However, many patients are unable to complete therapy. We sought to identify risk factors for failing to complete adjuvant intensity-modulated radiation therapy after cytoreduction for malignant pleural mesothelioma. Methods We performed a single-institution review of those who received an extrapleural pneumonectomy or pleurectomy/decortication for malignant pleural mesothelioma from 2004 to 2017. Multivariable logistic regression was used to assess preoperative or intraoperative risk factors associated with failing to complete adjuvant intensity-modulated radiation therapy. Results A total of 160 patients were identified, among whom 94 (59%) received an extrapleural pneumonectomy and 66 (41%) received a pleurectomy/decortication. Adjuvant intensity-modulated radiation therapy was completed among 105 patients (66%). Reasons for failing to complete adjuvant intensity-modulated radiation therapy included mortality (19), dose constraints (21), postoperative morbidity or delayed recovery (11), and refused or unknown status (4). On multivariable analysis, American Society of Anesthesiologists 3+ classification (P = .002) and smoking history (P = .022) were associated with failure to complete adjuvant intensity-modulated radiation therapy, whereas forced expiratory volume in 1 second 70% or less of predicted and pStage 4 (T4) were significant on univariable analysis only. Other factors, including extrapleural pneumonectomy or pleurectomy/decortication, margin status, age, and histology, were not associated with receiving adjuvant intensity-modulated radiation therapy. Conclusions Many patients are unable to complete adjuvant intensity-modulated radiation therapy after cytoreduction. Failure to complete adjuvant intensity-modulated radiation therapy was associated with worse preoperative comorbidity, but not the type of surgery or margin status.

This article is a joint effort arising from a task force formed at a National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting, held at the NIH in March 2017. Malignant pleural mesothelioma remains one of the most virulent and recalcitrant malignancies, still considered incurable, and in desperate need of clinical trials in order to make progress for our patients. Although not standard of care, there is compelling evidence that a select subgroup of mesothelioma patients benefit from a surgery-based multimodal approach. As it is not possible to achieve a microscopically complete resection with mesothelioma, there appears to be no role for surgery alone. Thus, it is anticipated that significant strides in the surgery-based treatment of this cancer will require trials that determine which complementary treatments best augment the cytoreductive efficacy of surgery. Although lung-sacrificing surgery for mesothelioma is fairly standardized, approaches to lung-sparing surgery are highly variable and lung sparing surgery is emerging internationally as the dominant extirpative procedure for this cancer. It is not currently possible to rigorously assess the contribution of the adjuvant treatments combined with surgery because of the variability in procedures used to debulk this cancer, the extreme variability of the cancer itself, the variability in patient selection, the variability in treatment of the inevitable recurrence, and even the variability in follow up schedules. This article is an effort to address these problems by suggesting a more uniform approach to the surgical procedure and also proposing a series of data collection forms that could be adopted immediately, with any eye toward collecting the information that will be necessary to facilitate patient selection and determine which aspects of mesothelioma surgery can and should be standardized - with the goal being extension of life while maintaining quality of life as an equal priority. Furthermore, a completely original contribution in this manuscript is the proposal of a grading system that takes the information from the surgical procedure data forms and generates a completeness of resection score. This is the initial effort to establish a common denominator for mesothelioma surgery that will allow for more accurate comparison between surgical series and better assessment of the impact of the treatments combined with surgery.

Although specialty outreach clinics have been associated with improved outcomes and access to care, their role for patients with non-small cell lung cancer (NSCLC) has not been described. We sought to characterize perceptions of the utility of a specialty outreach clinic among patients with suspected NSCLC.Surveys were administered to patients who were suspected to have NSCLC and were seen at an outreach thoracic surgery clinic (2016 to 2017). The clinic was located approximately 20 miles from the academic cancer center.Sixty-nine patients completed surveys. The median distance traveled to the clinic was 43.5 miles (interquartile range: 5.0 to 111.3 miles). Among patients traveling 50 miles or more, the overwhelming majority (27 of 32 patients, 84.4%) cited physician expertise as the primary benefit of treatment at the clinic. Moreover, compared with patients living in closer proximity, they were more willing to travel 100 miles or more to have surgery (71.0% versus 26.7%, p = 0.001) or to consult with a surgeon (71.0% versus 25.8%, p0.001). Patients for whom it was very important to receive care close to home (33 of 68 patients, 48.5%) were less willing to travel 100 miles or more for consultation (surgeon: 33.3% versus 65.6%, p = 0.011; medical oncologist: 33.3% versus 65.6%, p = 0.011; radiation oncologist: 33.3% versus 64.5%, p = 0.015) and for treatment (surgery: 33.3% versus 65.6%, p = 0.011; chemotherapy: 36.7% versus 60.7%, p = 0.067; radiotherapy: 33.3% versus 64.3%, p = 0.018).Many patients value receiving oncologic care close to home and are sensitive to distance required to travel for care. Thoracic surgical outreach clinics may provide a benefit for patients with lung cancer in the settings of initial consultation, preoperative care, and postoperative care.

The incidence of persistent opioid use after lung surgery is high. Although adverse effects by opioids have been well described, it is unknown whether persistent opioid use is associated with worse survival. Patients who received a lobectomy for stage I NSCLC from 2007 to 2013 were identified from the Surveillance, Epidemiology and End Results-Medicare database. Opioid use was ascertained through records of prescriptions filled through part D. Patients were matched 2:1 according to their likelihood of persistent opioid use, which was defined as any opioid prescription filled 3 to 6 months after surgery. Two thousand eight hundred eighty-four patients were identified. The incidence of persistent opioid use 3 to 6 months after surgery was 27.0%. After matching, persistent opioid use was associated with worse overall survival (P < 0.001) and cancer-specific survival (P < 0.001). Those who used the lowest quartile of opioids, which was often manifested as a single opioid prescription, showed similar overall survival as no opioid use (HR 1.27, 95% confidence interval [CI] 0.93-1.72). However, the second and third quartiles of opioid use were associated with decreased overall survival (HR 1.53, 95% CI 1.14-2.03 and HR 1.39, 95% CI 1.04-1.86, respectively) that was nonetheless less severe than the highest quartile of opioid use (HR 2.50, 95% CI 1.95-3.21). Age, sex, marital status, comorbidity, tumor size, tumor grade, and radiation were also associated with worse overall survival, with chemotherapy use and video-assisted thoracoscopic surgery being associated with improved overall survival. Persistent opioid use 3 to 6 months after lobectomy is independently associated with worse overall survival and worse cancer-specific survival.

Background: Multimodality therapy may prolong survival among resectable malignant pleural mesothelioma (MPM). However, the role of adjuvant radiation remains controversial. We explored a large nationwide database to determine whether adjuvant radiation is associated with improved survival. Methods: The National Cancer Database (NCDB) was queried to identify patients with MPM who received cancer-directed surgery between 2004–2013. Adjuvant radiation included intensity modulated radiation therapy or conformal 3D radiation. Propensity matching was performed with a 150-day landmark to address survivorship bias. Cox regression was used with an interaction term between pathologic stage and radiation. Results: A total of 2,846 patients were identified as having undergone cancer-directed surgery for MPM; among whom 213 (7%) received adjuvant radiation. Adjuvant radiation was associated with improved survival among those who were stage I–II (P=0.024), but not stage III or IV (P=0.890 and P=0.183, respectively). After propensity matching, adjuvant radiation was associated with improved survival for those who were stage I–II [hazard ratio (HR) 0.52, P=0.035], whereas no similar effect was observed for those who were stage III or IV (P=0.190 and P=0.562, respectively). Multivariable regression revealed that sarcomatoid histology (HR 1.80, P=0.018) and stage IV disease (HR 1.65, P=0.033) were also associated with worse survival. Conclusions: Adjuvant radiation was associated with improved survival among those with pathologic stage I–II MPM. No survival advantage was observed for those with pathologic stage III or stage IV MPM, however. Our results justify the need for further prospective trials to investigate the utility of adjuvant radiotherapy among those with MPM.

Background Induction chemoradiation for resectable N2 non-small cell lung cancer (NSCLC) is used with the intent to optimize locoregional control, whereas induction chemotherapy given in systemic doses is meant to optimally target potential distant disease. However, the optimal preoperative treatment regimen is still unknown and practice patterns continue to vary widely. We compared multiinstitutional oncologic outcomes for N2 NSCLC from 4 experienced lung cancer treatment centers. Methods This collaborative retrospective study unites 4 major thoracic oncology centers. Patients with N2 NSCLC undergoing surgical resection after induction chemotherapy (CxT) or concurrent chemoradiation (CxRT) were included. Primary outcomes were overall and disease-free survival (OS and DFS). Results 822 patients were identified (CxT = 662 and CxRT = 160). There were no differences in 5-year OS (CxT 39.9% versus CxRT 42.9%, p = 0.250) nor in DFS (CxT 28.7% versus 29.8%, p = 0.207). Recurrence rates (CxT 46.8% versus CxRT 51.6%, p = 0.282) and recurrence patterns were not significantly different (Local: CxT 9.8% versus CxRT 9.7%; and Distant: CxT 30.4% versus CxRT 33.1%, p = 0.764). There was no difference in perioperative mortality. In the analyses of patients who underwent pretreatment invasive mediastinal staging (n = 555), there were still no significant differences in OS (p = 0.341) and DFS (p = 0.455) between the 2 treatment strategies. Conclusions Both treatment strategies produce equivalent and better than expected outcomes compared with historical controls for N2 NSCLC, with no differences in recurrence patterns. How these conventional therapeutic strategies will compare with those involving immunotherapy combined with surgical locoregional disease control for N2 disease remains to be determined.

Background and objectives Adoptive T-cell therapies (ACTs) using expansion of tumor-infiltrating lymphocyte (TIL) populations are of great interest for advanced malignancies, with promising response rates in trial settings. However, postoperative outcomes following pulmonary TIL harvest have not been widely documented, and surgeons may be hesitant to operate in the setting of widespread disease. Methods Patients who underwent pulmonary TIL harvest were identified, and postoperative outcomes were studied, including pulmonary, cardiovascular, infectious, and wound complications. Results 83 patients met inclusion criteria. Pulmonary TIL harvest was undertaken primarily via a thoracoscopy with a median operative blood loss and duration of 30 ml and 65 min, respectively. The median length of stay was 2 days. Postoperative events were rare, occurring in only five (6%) patients, including two discharged with a chest tube, one discharged with oxygen, one episode of urinary retention, and one blood transfusion. No reoperations occurred. The median time from TIL harvest to ACT infusion was 37 days. Conclusions Pulmonary TIL harvest is safe and feasible, without major postoperative events in our cohort. All patients were able to receive intended ACT infusion without delays. Therefore, thoracic surgeons should actively participate in ongoing ACT trials and aggressively seek to enroll patients on these protocols.

New therapy approaches in the treatment of surgically resectable non-small cell lung cancer (NSCLC) challenge the traditional handling and examination of pathology specimens. The increasingly common use of neoadjuvant therapies before surgical resection, due to advantages in novel drug administration, tolerance, and measurement of radiographic and pathologic response compared to adjuvant treatment, has the potential to alter the microscopic tumor appearance and its biology. Currently, many clinical trials use pathologic response as a surrogate endpoint of clinical efficacy, since the extent of residual viable tumor appears to correlate with outcome in patients treated with neoadjuvant chemotherapy. Consequently, pathologic assessment of the extent of residual viable tumor is of paramount importance. However, high level evidence-based guidelines on how to process and evaluate such specimens are lacking. Moreover, while pathologic response has been shown to be associated with survival after chemotherapy, its significance after immunotherapy remains to be determined. Additionally, many clinical trials do not routinely include pathologists in trial design, which may lead to non-standardized evaluation of pathologic response. Although recently, several algorithms have been proposed to address these issues, none of them represents evidence-based recommendations or is universally applied. Therefore, controversies and challenges continue to exist, raising concerns about the validity, reproducibility, and comparability of the results of many neoadjuvant clinical trials. Herein, we discuss the current difficulties in pathologic specimen evaluation following neoadjuvant therapy in NSCLC and propose potential approaches to overcome these challenges.

Background Long-term survival outcomes of trimodal therapy (TMT; chemoradiation plus surgery) and bimodal therapy (BMT; chemoradiation) have seldom been analysed. In a selective-surgery paradigm, the benefit of TMT in patients with a complete clinical response is controversial. Factors associated with survival in patients with a clinical complete response to chemoradiation were evaluated. Methods Patients with stage II–III oesophageal squamous cell carcinoma treated with TMT or BMT from 2002 to 2017 were evaluated. The BMT group consisted of patients who were otherwise eligible for surgery but underwent chemoradiation alone followed by observation. This group included patients who later had salvage oesophagectomy. Survival was evaluated and compared between TMT and BMT groups. Elastic net regularization was performed to select co-variables for Cox multivariable survival analysis in patients with a clinical complete response. Results Of 143 patients, 60 (41.9 per cent) underwent TMT and 83 (58.0 per cent) BMT. Patients who underwent TMT had longer median overall survival than those who had BMT (77 versus 33 months; P = 0.019). For patients with a clinical complete response, TMT achieved longer median overall survival than BMT (123 versus 55 months; P = 0.04). BMT had a high locoregional recurrence rate (48 versus 6 per cent; P Conclusion In patients who achieve a clinical complete response, TMT reduces locoregional recurrence but may not prolong survival. The differences in survival outcomes may be due to patient selection; therefore, a selective-surgery strategy in oesophageal squamous cell carcinoma is a reasonable approach.

Background Tumor and nodal downstaging following neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC) are important markers of therapeutic response associated with favorable prognosis. We studied the impact of four different systemic neoadjuvant therapies on tumor, nodal and overall pathological downstaging of surgically resectable I-IIIA NSCLC (AJCC 7th edition). Methods Our study cohorts consisted of NSCLC patients treated with three cycles of neoadjuvant platinum doublet chemotherapy from 2001–2012 (N=302, 84%), and patients treated on the NEOSTAR study (NCT03158129) who received neoadjuvant nivolumab (N=21,6%), nivolumab plus ipilimumab (N=16, 4%), or platinum doublet chemotherapy plus nivolumab (N=22, 6%). Clinical and pathological (yp) T and N staging were evaluated for downstaging and upstaging; differences were assessed using Fisher’s exact test. Results Following neoadjuvant platinum doublet chemotherapy, nivolumab, nivolumab plus ipilimumab and platinum doublet chemotherapy plus nivolumab, the rates of clinical-to-pathological ypT downstaging were 26% (N=79), 29% (N=6), 38% (N=6) and 59% (N=13), respectively, p =0.012 (table 1). The rates of clinical-to-pathological ypN downstaging in patients with clinical N1 or N2 disease with each therapy were 55% (N=96), 50% (N=3), 50% (N=2), and 42% (N=5) respectively, p =0.862. Overall clinical-to-pathological (ypT and/or ypN) downstaging rates were 38% (N=114), 38% (N=8), 38% (N=6), and 68% (N=15) respectively, p=0.048. The proportions of patients being overall upstaged following each therapy were 28% (N=85), 38% (N=8), 38% (N=6) and 14% (N=3), respectively, p=0.251. These results suggest superior downstaging effect and clinically meaningful lower upstaging probability of combined platinum doublet chemotherapy plus nivolumab as compared to other neoadjuvant regimens. Conclusions The combination of neoadjuvant platinum doublet chemotherapy with nivolumab achieves the most robust tumor and overall pathological downstaging and decreases the probability of upstaging at surgery. Whether the overall downstaging effect results in improved survival will be determined with longer follow-up, in conjunction with results from ongoing phase III neoadjuvant chemo-immunotherapy trials. Trial Registration NCT03158129 Ethics Approval This study was approved by the University of Texas MD Anderson Institutional Review Board with a waiver of informed consent, protocol 2020-0337.

Immunotherapy, targeted therapy, and adoptive T-cell therapy have been revolutionary advancements in cancer research. Some of these therapies have become the standard of care for lung cancer and replaced older treatment algorithms; some continue to be studied in clinical trials. This article discusses the current state of novel treatment options for non–small cell lung cancer patients with metastatic and locoregional disease, with focus on immunotherapy, targeted therapy, and adoptive T-cell therapy.

Purpose:Malignant pleural mesothelioma (MPM) is considered an orphan disease with few treatment options. Despite multimodality therapy, the majority of MPMs recur and eventually become refractory to any systemic treatment. One potential mechanism underlying therapeutic resistance may be intratumor heterogeneity (ITH), making MPM challenging to eradicate. However, the ITH architecture of MPM and its clinical impact have not been well studied.Experimental Design:We delineated the immunogenomic ITH by multiregion whole-exome sequencing and T-cell receptor (TCR) sequencing of 69 longitudinal MPM specimens from nine patients with resectable MPM, who were treated with dasatinib.Results:The median total mutation burden before dasatinib treatment was 0.65/Mb, similar with that of post-dasatinib treatment (0.62/Mb). The median proportion of mutations shared by any given pair of two tumor regions within the same tumors was 80% prior to and 83% post-dasatinib treatment indicating a relatively homogenous genomic landscape. T-cell clonality, a parameter indicating T-cell expansion and reactivity, was significantly increased in tumors after dasatinib treatment. Furthermore, on average, 82% of T-cell clones were restricted to individual tumor regions, with merely 6% of T-cell clones shared by all regions from the same tumors indicating profound TCR heterogeneity. Interestingly, patients with higher T-cell clonality and higher portion of T cells present across all tumor regions in post-dasatinib–treated tumors had significantly longer survival.Conclusions:Despite the homogeneous genomic landscape, the TCR repertoire is extremely heterogeneous in MPM. Dasatinib may potentially induce T-cell response leading to improved survival.

BackgroundThe biological underpinnings of the prognostic and predictive significance of a relative neutrophilia in patients with non-small lung cancer (NSCLC) are undefined. We sought to comprehensively examine the relationships between circulating and intratumoral neutrophil populations and features of the immune contexture in patients undergoing NSCLC resection.MethodsPreoperative soluble cytokine and angiogenic factors; tumor multiplex immunofluorescence; RNA, whole exome, and T-cell receptor sequencing; and flow cytometry were analyzed for relationships with populations of circulating (from complete blood counts) and intratumoral neutrophils (transcriptional signatures) in a prospectively enrolled resected NSCLC cohort (n=66). In a historical cohort (n=1524), preoperative circulating neutrophil and lymphocyte counts were analyzed for associations with overall survival (OS).ResultsCirculating neutrophil populations were positively correlated with increased tumor burden, and surgical tumor resection was followed by a subsequent reduction in peripheral neutrophil counts. Expansion of the circulating neutrophil compartment was associated with increased levels of pro-granulopoietic (IL-1β, IL-17A, TNFα, IL-6) and TH2-associated (IL-5, IL-13) cytokines. Tumors with high intratumoral neutrophil burden were marked by a blunted T-cell response characterized by reduced expression of cytotoxic T-cell genes (CD8A,CD8B,GZMA,GZMB), decreased CD3+CD8+cell infiltration, and diminished expression of IFNγ-related genes. The associations between increased intratumoral neutrophil burden and reduced CD3+CD8+infiltration persisted after adjustment for tumor size, histology, mutational burden, and PD-L1 expression. In 1524 patients, elevated preoperative circulating neutrophil count was independently associated with worse OS (main effect HR 1.82, 95% CI 1.24 to 2.68, p=0.002).ConclusionsOur findings demonstrate that neutrophil expansion reflects protumorigenic and immunosuppressive processes that manifest as worse OS in patients undergoing NSCLC resection. These results justify further investigation of therapeutic strategies targeting neutrophil-associated immune evasion.

Background Adjuvant chemotherapy, postoperative radiation (PORT), and prophylactic cranial irradiation (PCI) have been individually examined in limited-stage small cell lung cancer (SCLC). There is a paucity of data on the effectiveness of each adjuvant treatment modality when used in combination after surgical resection of SCLC. Methods Data were collected from 5 cancer centers on all patients with limited-stage SCLC who underwent surgical resection between 1986 and 2019. Univariate and multivariable models were conducted to identify predictors of long-term outcomes, focusing on freedom from recurrence and survival benefit of adjuvant chemotherapy, PORT, and PCI. Results A total of 164 patients were analyzed. Multivariable Cox regression analysis did not identify any adjuvant therapies to significantly influence recurrence in this cohort. Specifically, PORT was not associated with a significant influence on locoregional recurrence and PCI was not significantly associated with intracranial outcomes. Adjuvant chemotherapy improved survival in all stage I through III disease (hazard ratio, 0.49; 95% confidence interval, 0.29-0.81; P = .005) and even in pathologically node negative patients (hazard ratio, 0.49; 95% confidence interval, 0.27-0.91; P = .024). Although PCI was found to improve survival in univariate analysis, it was not significant in a multivariable model. PORT was not found to affect survival on either univariate or multivariable analysis. Conclusions This is among the largest multi-institutional studies on surgically resected limited-stage SCLC. Our results highlight survival benefit of adjuvant chemotherapy, but did not identify a statistically significant influence from mediastinal PORT or PCI in our cohort. Larger prospective studies are needed to determine the benefit of PORT or PCI in a surgically resected limited-stage SCLC population.

Objectives The influence of surgical approach on systemic inflammatory response and the subsequent oncologic impact for non-small cell lung cancer is debated. We aimed to measure the effects of thoracic surgical approach on peripheral cytokine milieu over time. Methods Patients undergoing primary lung resection without neoadjuvant therapy (2016–2018) were evaluated. A panel of 43 cytokines, angiogenic factors, and inflammatory molecules (CAFs) were evaluated in peripheral blood preoperatively, at 24 -hs and 4-weeks postoperatively. Differences between CAFs in patients undergoing thoracotomy versus video-assisted thoracoscopic surgery (VATS) at all timepoints were assessed using Student’s t-test. Results 76 patients with available peripheral CAF panels met inclusion criteria. Thoracotomy was performed in 53 (70 %) patients while VATS was undertaken in 23 (30 %). Upon examination of known inflammatory CAFs, including IL-1β, IL-6, IL-8, IL-10, IFN-γ, and soluble (s) CD27, no differences were detected at 24 h or 4 weeks postoperatively between surgical groups. Examination of trends over time did not demonstrate any temporal derangements for these CAFs, with return to baseline levels by 4 weeks postoperatively for both groups. Evaluation of soluble (s) checkpoint molecules, including sPD-1, sPD-L1, sTIM-3, and sCTLA-4, did not reveal any differences in the immediate postoperative or long-term recovery period. Conclusions Peripheral immune profiles following pulmonary resection do not appear to differ between VATS and thoracotomy postoperatively. CAF fluctuations are transient and recover rapidly. These results, at the peripheral cytokine level, suggest that the surgical approach for lung cancer is unlikely to alter the effectiveness of novel immune-modulating systemic therapies, although more studies are needed to validate these findings.

Purpose: We aimed to assess the survival benefit of surgery for patients with stage IA–IIB small cell lung cancer (SCLC) and construct a nomogram for predicting overall survival (OS).Methods: Patients who had been diagnosed with stage IA–IIB SCLC between 2004 and 2014 and who had received active treatment were selected from the Surveillance, Epidemiology, and End Results database. The primary endpoint was OS. Cox proportional hazards models and propensity score (PS) analyses were used to compare the associations between surgery and OS. The probability of 1- and 3-year OS was predicted using a nomogram.Results: We reviewed 2,246 patients. The median OS of the surgery and non-surgery groups was 35 months and 19 months, respectively. Multivariable Cox proportional hazards models showed a survival benefit in the surgery group (hazards ratio [HR], 0.642; 95% confidence interval [CI], 0.557–0.740; P < 0.001). To balance the between-group measurable confounders, the impact of surgery on OS was assessed using PS matching. After PS matching, OS analysis still favored surgical resection. The PS-stratification, PS-weighting, and PS-adjustment models showed similar results to demonstrate a statistically significant benefit for surgery. Further, the nomogram was well calibrated and had good discriminative ability (Harrell's C-index = 0.645).Conclusion: Our analysis suggests that surgery is a viable option for patients with early-stage SCLC. Our nomogram is a viable tool for quantifying treatment trade-off assumptions and may assist clinicians in decision-making. Future work is needed to validate our results and improve our tools.

Background We have previously demonstrated that Enhanced Recovery After Surgery protocols are associated with a reduction in pulmonary complications. As a component of enhanced recovery pathways, intercostal nerve blocks with liposomal bupivacaine are increasingly utilized, but the extent to which this element may contribute to such outcomes has not been evaluated. Methods Patients undergoing lung resection for stage I to III non-small cell lung cancer at a single institution from 2006 to 2017 were examined for major postoperative pulmonary morbidity, defined as pneumonia, acute respiratory distress syndrome, respiratory arrest, reintubation, bronchoscopy, or need for discharge with oxygen. Pharmacy records were queried for administration of liposomal bupivacaine via posterior intercostal nerve block. Patients treated with and without liposomal bupivacaine were compared in a logistic regression to determine the impact on pulmonary morbidity. Results A total of 2865 patients were identified, including 860 (30%) who were treated with liposomal bupivacaine via posterior intercostal block. Pulmonary morbidity occurred in 455 (16%). Adoption of liposomal bupivacaine analgesia occurred over several years, beginning in 2012 to full adoption by 2017. Liposomal bupivacaine management was associated with a reduction in pulmonary complications, as compared with nonuse (odds ratio, 0.63; P = .006). Additional factors associated with the occurrence of pulmonary morbidity were age, body mass index, smoking, spirometry values, and operative blood loss. Conclusions As a component of an active enhanced recovery program, liposomal bupivacaine is associated with a reduction in major pulmonary complications, and utilization should be evaluated on a hospital-by-hospital basis.

Background As strategies promoting enhanced recovery protocols and opioid minimization techniques are increasingly prioritized, use of nonsteroidal antiinflammatory drugs continues to rise. Whether this prevalent use poses increased risk for bleeding or renal dysfunction in surgical populations after extensive dissection and fluid shifts is unclear. Methods We reviewed records of patients undergoing esophagectomy for a diagnosis of esophageal adenocarcinoma at a single institution from 2006 to 2018 for ketorolac administration during the postoperative hospital admission, as well as the occurrence of postoperative events, defined as the need for blood product transfusion and/or acute kidney injury. Results We identified 1019 patients, 123 of whom experienced postoperative events (12%). Ketorolac was administered to 686 (67%). Furthermore, ketorolac use steadily increased over the study period; 36 of 72 patients received this medication in 2006 (49%), and 76 of 83 in 2018 (92%). Multivariable logistic regression failed to identify a relationship between ketorolac administration (assessed as a binary covariate) and postoperative events (P = .657). Additional examination for a dose-response relationship using the cumulative total dose from the time of surgery to discharge also did not demonstrate a relationship with postoperative events (P = .829). In an effort to evaluate a more homogeneous population, we performed a subgroup analysis using only patients treated with trimodality therapy, which showed similar findings. Conclusions Ketorolac has become a staple of multimodal postesophagectomy analgesic regimens. Importantly, this medication does not pose risk for acute kidney injury or bleeding after surgery.

Background The tumor immune microenvironment of lepidic-pattern adenocarcinoma remains poorly understood. In this study, we characterized tumor infiltrating lymphocytes (TILs) and percent PD-L1 expression among adenocarcinoma presenting as either radiographic ground glass opacities (GGOs) or solid lesions. Methods Pathologic specimens of patients with clinical stage I lung adenocarcinoma were analyzed using tissue microarray sectioning. The invasive portion of the tumor was selected for the tissue core. Lepidic growth pattern was confirmed among the GGO lesions using whole section analysis. Progression was defined as pN+ or subsequent recurrence. Results A total of 181 patients were identified, among whom 13 (7%) represented GGOs without clinical progression, 113 (62%) represented radiographic solid lesions that never progressed, and 55 (30%) represented radiographic solid lesions that ultimately did progress. CD57+ cell density, a marker for antigen-specific, oligoclonal T cells and NK cells, differed among the three cohorts, with the highest cell density observed within radiographically solid lesions without progression, and lower cell density both in the radiographic solid lesions that progressed and GGOs. Other TIL phenotypes were not statistically different between cohorts. Of substantial clinical interest, median percent PD-L1 positive cells within GGOs was 14, whereas that of radiographic solid lesions without progression was 22, and radiographic solid lesions that subsequently progressed was 27 (P=0.07). Conclusions Lepidic pattern adenocarcinoma presenting as GGOs and radiographic solid lesions show differential immune regulation. Further studies to investigate whether GGOs representing adenocarcinoma have varying susceptibility to immune checkpoint inhibitor therapy are warranted.

OBJECTIVES Major pathological response (MPR) is prognostic of outcomes for patients with non-small-cell lung cancer following neoadjuvant chemotherapy and is used as the primary end point in neoadjuvant immunotherapy trials. We studied the influence of pathological nodal disease on patterns and timing of recurrence among patients with MPR. METHODS Patients treated with neoadjuvant chemotherapy for stages I–III non-small-cell lung cancer were identified. Surgical specimens were histopathologically examined for tumour viability, categorized as ≤10% viability (MPR) or >10% (NoMPR). Overall survival and disease-free survival were evaluated with emphasis upon MPR and pathological nodal disease. RESULTS Among 307 patients, 58 (19%) had MPR within primary tumour and 42 (14%) had MPRypN0. In the MPR group, the frequency of cN0 and cN+ disease was 18 (31%) and 40 (69%); similarly, the frequency of ypN0, ypN1 and ypN2 was 72% (42/58), 16% (9/58) and 12% (7/58), respectively. When evaluating only those with MPR, recurrence rates among those with MPRypN0, MPRypN1 and MPRypN2 were 33% (14/42), 44% (4/9) and 71% (5/7) (P = 0.16). The median time-to-recurrence in MPRypN0, MPRypN1 and MPRypN2 was 40, 10 and 14 months (P = 0.006). Distant recurrences were less common among those with MPRypN0 [MPRypN0, 26% (11/42); MPRypN1, 44% (4/9); MPRypN2, 71% (5/7); P = 0.047]. Though the median disease-free survival was prolonged among those with MPR vs NoMPR (120 vs 25 months, P CONCLUSIONS MPRypN0 represents the most favourable surrogate end point following neoadjuvant chemotherapy. Patients with ypN1-2 are at the risk of early recurrence regardless of primary tumour MPR, warranting intensive surveillance and consideration for additional adjuvant therapy. We highlight that MPRypN0 is the most rigorous end point and should be considered as a surrogate end point in future neoadjuvant trials.

We present 783 surgical resections of typical and atypical carcinoid tumors of the lung identified in the pathology files of 20 different pathology departments. All cases were critically reviewed for clinical and pathological features and further correlated with clinical outcome. Long-term follow-up was obtained in all the patients and statistically analyzed to determine significance of the different parameters evaluated. Of the histopathological features analyzed, the presence of mitotic activity of 4 mitoses or more per 2mm2, necrosis, lymphatic invasion and lymph node metastasis were identified as statistically significant. Tumors measuring 3 cm or more were also identified as statistically significant and correlate with clinical outcome. Based on our analysis, we consider that the separation of low and intermediate grade neuroendocrine neoplasms of the lung needs to be readjusted in terms of mitotic count as the risk of over grading these neoplasms exceeds 10% under the current criteria. We also consider that tumor size is an important feature to be considered in the assessment of these neoplasms and together with the histological grade of the tumor offers important features that can be correlated with clinical outcome.

BACKGROUND AND OBJECTIVES Precision medicine has altered the management of colorectal cancer (CRC). However, the concordance of mutational findings between primary CRC tumors and associated pulmonary metastases (PM) is not well-described. This study aims to determine the concordance of genomic profiles between primary CRC and PM. METHODS Patients treated for colorectal PM at a single institution from 2000 to 2017 were identified. Mutational concordance was defined as either both wild-type or both mutant alleles in lung and colorectal lesion; genes with opposing mutational profiles were reported as discordant. RESULTS Thirty-eight patients met inclusion criteria, among whom KRAS, BRAF, NRAS, MET, RET, and PIK3CA were examined for concordance. High concordance was demonstrated among all evaluated genes, ranging from 86% (KRAS) to 100% concordance (NRAS, RET, and MET). De novo KRAS mutations were detected in the PM of 4 from 35 (11%) patients, 3 of whom had previously received anti-epidermal growth factor receptor (EGFR) therapy. Evaluation of Cohen's κ statistic demonstrated moderate to perfect correlation among evaluated genes. CONCLUSIONS Because high intertumoral genomic homogeneity exists, it may be reasonable to use primary CRC mutational profiles to guide prognostication and targeted therapy for PM. However, the possibility of de novo KRAS-mutant PM should be considered, particularly among patients previously treated with anti-EGFR therapy.

To develop and validate a radiomics signature that can predict the clinical outcomes for patients with stage I non-small cell lung cancer (NSCLC).We retrospectively analyzed contrast-enhanced computed tomography images of patients from a training cohort (n = 147) treated with surgery and an independent validation cohort (n = 295) treated with stereotactic ablative radiation therapy. Twelve radiomics features with established strategies for filtering and preprocessing were extracted. The random survival forests (RSF) method was used to build models from subsets of the 12 candidate features based on their survival relevance and generate a mortality risk index for each observation in the training set. An optimal model was selected, and its ability to predict clinical outcomes was evaluated in the validation set using predicted mortality risk indexes.The optimal RSF model, consisting of 2 predictive features, kurtosis and the gray level co-occurrence matrix feature homogeneity2, allowed for significant risk stratification (log-rank P.0001) and remained an independent predictor of overall survival after adjusting for age, tumor volume and histologic type, and Karnofsky performance status (hazard ratio [HR] 1.27; P2e-16) in the training set. The resultant mortality risk indexes were significantly associated with overall survival in the validation set (log-rank P = .0173; HR 1.02, P = .0438). They were also significant for distant metastasis (log-rank P.05; HR 1.04, P = .0407) and were borderline significant for regional recurrence on univariate analysis (log-rank P.05; HR 1.04, P = .0617).Our radiomics model accurately predicted several clinical outcomes and allowed pretreatment risk stratification in stage I NSCLC, allowing the choice of treatment to be tailored to each patient's individual risk profile.

Background Previous studies have highlighted important biologic and survival-related differences among men and women with non-small cell lung cancer (NSCLC). However, differences in perioperative or short-term outcomes have not been as well characterized. In this study, we investigated differences in the perioperative period and postoperative emergency department (ED) visits among men and women after lobectomy for stage I NSCLC. Methods A retrospective review was performed of patients who underwent a lobectomy for clinical stage I NSCLC at a single institution from 2010 to 2015. Results We identified 559 patients for inclusion, including 293 women (52%) and 266 men (48%). Women were more likely to present with clinical T1 status (p = 0.005) and to undergo a minimally invasive operation (p = 0.058). To reduce confounding, 206 case-matched pairs were identified. After matching, no differences were found in length of stay (p = 0.551) or pulmonary complications (p = 0.509); however, men experienced more cardiac complications (18% versus 7%, p = 0.001). Of importance, although rates of 30- and 90-day ED visits between sexes were similar (p = 0.531, p = 0.890, respectively) and no sex-related differences were found in presenting symptom on return to the ED (p = 0.478), women were more likely to be readmitted after presenting to the ED within 30 days (p = 0.038). Conclusions Women demonstrated an increased likelihood of being admitted after presenting to the ED within 30 days after discharge, indicating important differences between men and women in the short-term period after lobectomy. Further research will be required to further understand the cause for these differences.

Background Historically, it has been assumed that indwelling urinary catheters used to prevent urinary retention in patients undergoing epidural analgesia should be left in for the duration of the epidural analgesia. Our institution initiated an early Foley removal (EFR) program in thoracic surgical oncology patients to remove indwelling catheter while the epidural analgesia was still in place, 24–72 h after surgery. The objective of this study was to evaluate the feasibility of EFR in terms of rate of re-catheterization, urinary tract infections (UTI), or the length of hospital stay (LOS). Methods We reviewed the medical records of 99 thoracic surgical oncology patients who underwent EFR with indwelling epidural analgesia from May 2012 to February 2013. The main outcome variable was re-catheterization incidence. We also compared a propensity matched subgroup of patients who had undergone surgery prior to the institution of EFR. The outcome variables for this group were the rate of UTI and LOS. Results In the EFR group (N = 99), the median duration of Foley catheterization was 40 h. Sixteen (16%) patients experienced difficulty voiding within 8 h of catheter removal, 8 required re-catheterization (8%). In the propensity-matched analysis, there was no difference in the rate of UTI between the two groups (1% in both groups). Conclusions EFR was associated with a low re-catheterization rate. Our findings support the CDC's recommendation to remove catheters early in thoracic surgical oncology patients. EFR will promote patient comfort and may play an important role in improving the postoperative care in thoracic oncology patients.

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy – characterized by some benefit but only rare durable responses – was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field. Electronic supplementary material The online version of this article (10.1186/s40425-018-0382-2) contains supplementary material, which is available to authorized users.

Enhanced recovery after surgery (ERAS) pathways aim to improve postoperative recovery through evidence-based practices, including early ambulation, multimodal opioid-sparing analgesia, and reduction of surgical stress. This study evaluated outcomes after implementation of ERAS in patients undergoing resection for pulmonary malignancy.A retrospective review compared outcomes for patients undergoing pulmonary resection for primary lung cancer. Analysis was performed between three periods: pre-ERAS (January 1, 2006, to December 31, 2011), transitional period with elements of ERAS (January 1, 2012, to August 31, 2015), and full implementation of ERAS (September 1, 2015, to December 31, 2016).We analyzed 2,886 lung resections (pre-ERAS, n = 1615; transitional, n = 929; ERAS, n = 342). For all patients, length of stay decreased in the ERAS and transitional periods compared with pre-ERAS (4 [3] versus 4 [3] versus 5 [3] days, p0.001). Pulmonary complications were decreased with ERAS compared with transitional and pre-ERAS (19.9% versus 28.2% versus 28.7%, p = 0.004). Cardiac complications decreased with ERAS (12.3% versus 13.1% versus 18.1%, p = 0.001). There was less thoracic epidural use (2.9% versus 44.5% versus 75.5%, p0.001). There were no differences in hospital readmission (p = 0.772) or mortality rates (p = 0.417). After thoracotomy, ERAS was associated with decreased length of stay, fewer intensive care unit readmissions, and decreased frequency of pneumonia, atrial arrhythmias, and need for home oxygen (all p0.05). ERAS was independently associated with decreased pulmonary (p = 0.046) and cardiac (p = 0.001) complications on logistic regression after thoracotomy but not minimally invasive operations.ERAS was associated with improved postoperative outcomes, including decreased length of stay and pulmonary and cardiac morbidity after thoracotomy, but not after minimally invasive operations. ERAS safety was demonstrated by low rates of adverse events without effect on hospital readmission or perioperative deaths.