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We investigated whether curcumin, a chemopreventive agent, inhibited chenodeoxycholate (CD)- or phorbol ester (PMA)-mediated induction of cyclooxygenase-2 (COX-2) in several gastrointestinal cell lines (SK-GT-4, SCC450, IEC-18 and HCA-7). Treatment with curcumin suppressed CD- and PMA-mediated induction of COX-2 protein and synthesis of prostaglandin E2. Curcumin also suppressed the induction of COX-2 mRNA by CD and PMA. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with CD or PMA and these effects were inhibited by curcumin. Treatment with CD or PMA increased binding of AP-1 to DNA. This effect was also blocked by curcumin. In addition to the above effects on gene expression, we found that curcumin directly inhibited the activity of COX-2. These data provide new insights into the anticancer properties of curcumin. [ABSTRACT FROM PUBLISHER]

TCF1 high progenitor CD8 + T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2 KO CD8 + T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2- 13 C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8 + T cells toward a TCF1 high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8 + T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Circulating tumor cells (CTCs) captured from the bloodstream of patients with solid tumors have the potential to accelerate precision oncology by providing insight into tumor biology, disease progression and response to treatment. However, their potential is hampered by the lack of standardized CTC enrichment platforms across tumor types. EpCAM-based CTC enrichment, the most commonly used platform, is limited by EpCAM downregulation during metastasis and the low EpCAM expression in certain tumor types, including the highly prevalent and lethal NSCLC. In this study we demonstrate that Transferrin Receptor (TfR) is a selective, efficient biomarker for CTC identification and capture in patients with prostate, pancreatic and NSCLC. TfR identifies significantly higher CTC counts than EpCAM, and TfR + -CTC enumeration correlates with disease progression in metastatic prostate and pancreatic cancers, and overall survival and osimetrinib-resistance in non-small cell lung cancer (NSCLC). Profiling of TfR + -CTCs provides a snapshot of the molecular landscape of each respective tumor type and identifies potential mechanisms underlying treatment response to EGFR TKi and immune checkpoint inhibitors in NSCLC., One Sentence Summary: Transferrin Receptor identifies circulating tumor cells in solid tumors.

In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGE SNV uses deep learning and a ctDNA-specific feature space to increase SNV signal-to-noise enrichment in WGS by ~300× compared to previous WGS error suppression. MRD-EDGE CNV also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1 Gb to 200 Mb, vastly expanding its applicability within solid tumors. We harness the improved performance to identify MRD following surgery in multiple cancer types, track changes in TF in response to neoadjuvant immunotherapy in lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal-to-noise enrichment in MRD-EDGE SNV enables plasma-only (non-tumor-informed) disease monitoring in advanced melanoma and lung cancer, yielding clinically informative TF monitoring for patients on immune-checkpoint inhibition., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Sublobar resection for early-stage non-small cell lung cancer has been an emerging topic of great interest to thoracic surgeons. However, data regarding the efficacy and safety of sublobar resection vs lobectomy was lacking until now. Recently, 3 published randomized controlled trials (Cancer and Leukemia Group B [CALGB]140503/Alliance, Japan Clinical Oncology Group [JCOG]0802 and Das Deutsche Register Klinischer Studien [DRKS]00004897) confirmed the noninferiority of sublobar resection for early-stage non-small cell lung cancer in carefully selected populations. This review aims to summarize and compare these 3 landmark trials and inform surgeons of new best practices., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Anastomotic leak after esophagectomy carries important short- and long-term sequelae. The authors conducted a systematic review and meta-analysis to determine its association with surgical volume., Materials and Methods: A systematic literature review was performed to identify all studies reporting on anastomotic leak after esophagectomy. Studies with less than 100 cases were excluded. The primary outcome was postesophagectomy anastomotic leak, while secondary outcomes were operative mortality overall and after anastomotic leak. Pooled event rates (PER) were calculated, and the association with annual esophagectomy volume by center was investigated., Results: Of the 3932 retrieved articles, 472 were included ( n =177 566 patients). The PER of anastomotic leak was 8.91% [95% CI=8.32; 9.53%]. The PER of early mortality overall and after an anastomotic leak was 2.49% [95% CI=2.27; 2.74] and 11.39% [95% CI=9.66; 13.39], respectively. Centers with less than 37 annual esophagectomies had a higher leak rate compared to those with greater than or equal to 37 annual esophagectomies (9.58% vs. 8.34%; P =0.040). On meta-regression, surgical volume was inversely associated with the PER of esophageal leak and of early mortality., Conclusions: The frequency of anastomotic leaks after esophagectomy, perioperative, and leak associated mortality are inversely associated with esophagectomy volume., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

In early-stage non-small cell lung cancer, the combination of neoadjuvant anti-PD-L1 and subablative stereotactic body radiation therapy (SBRT) is associated with higher rates of major pathologic response compared to anti-PD-L1 alone. Here, we identify a 140-gene set, enriched in genes characteristic of highly proliferating cells, associated with response to the dual therapy. Analysis of on-treatment transcriptome data indicate roles for T and B cells in response. The 140-gene set is associated with disease-free survival when applied to the combined trial arms. This 140-gene set identifies a subclass of tumors in all 7 of The Cancer Genome Atlas tumor types examined. Worse survival is associated with the 140-gene signature in 5 of these tumor types. Collectively, our data support that this 140-gene set, discovered in association with response to combined anti-PD-L1 and SBRT, identifies a clinically aggressive subclass of solid tumors that may be more likely to respond to immunotherapies., Competing Interests: Declaration of interests N.K.A. has equity in Angiocrine Bioscience, TMRW, and View Point Medical. O.E. is supported by Janssen, J&J, AstraZeneca, Volastra, and Eli Lilly research grants. He is a scientific advisor and equity holder in Freenome, Owkin, Volastra Therapeutics, and One Three Biotech, and a paid scientific advisor to Champions Oncology. T.E.M. receives research funding from Janssen. Cornell University has filed a patent application on the work described in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but patients with other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than BRCA1/2 is mutation to the TP53 gene. In 2D breast cancer cell lines, mutant p53 (mtp53) proteins tightly associate with replicating DNA and Poly (ADP-ribose) polymerase (PARP) protein. Combination drug treatment with the alkylating agent temozolomide and the PARPi talazoparib kills mtp53 expressing 2D grown breast cancer cell lines. We evaluated the sensitivity to the combination of temozolomide plus PARPi talazoparib treatment to breast and lung cancer patient-derived tumor organoids (PDTOs). The combination of the two drugs was synergistic for a cytotoxic response in PDTOs with mtp53 but not for PDTOs with wtp53. The combination of talazoparib and temozolomide induced more DNA double-strand breaks in mtp53 expressing organoids than in wild-type p53 expressing organoids as shown by increased γ-H2AX protein expression. Moreover, breast cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We previously reported the results of a randomized phase II trial (NCT02904954) in patients with early-stage non-small cell lung cancer (NSCLC) who were treated with either two preoperative cycles of the anti-PD-L1 antibody durvalumab alone or combined with immunomodulatory doses of stereotactic radiation (DRT). The trial met its primary endpoint of major pathological response, which was significantly higher following DRT with no new safety signals. Here, we report on the prespecified secondary endpoint of disease-free survival (DFS) regardless of treatment assignment and the prespecified exploratory analysis of DFS in each arm of the trial. DFS at 2 and 3 years across patients in both arms of the trial were 73% (95% CI: 62.1-84.5) and 65% (95% CI: 52.5-76.9) respectively. For the exploratory endpoint of DFS in each arm of the trial, three-year DFS was 63% (95% CI: 46.0-80.4) in the durvalumab monotherapy arm compared to 67% (95% CI: 49.6-83.4) in the dual therapy arm. In addition, we report post hoc exploratory analysis of progression-free survival as well as molecular correlates of response and recurrence through high-plex immunophenotyping of sequentially collected peripheral blood and gene expression profiles from resected tumors in both treatment arms. Together, our results contribute to the evolving landscape of neoadjuvant treatment regimens for NSCLC and identify easily measurable potential biomarkers of response and recurrence., (© 2023. The Author(s).)

Background: Lung cancer remains the major cause of cancer-related deaths worldwide. Early stages of lung cancer are characterized by long asymptomatic periods that are ineffectively identified with the current screening programs. This deficiency represents a lost opportunity to improve the overall survival of patients. Serum biomarkers are among the most effective strategies for cancer screening and follow up., Methods: Using bead-based multiplexing assays we screened plasma and tumours of the KrasG12D/+; Lkb1f/f (KL) mouse model of lung cancer for cytokines that could be used as biomarkers. We identified tissue inhibitor of metalloproteinase 1 (TIMP1) as an early biomarker and validated this finding in the plasma of lung cancer patients. We used immunohistochemistry (IHC), previously published single-cell RNA-seq and bulk RNA-seq data to assess the source and expression of TIMP1in the tumour. The prognostic value of TIMP1 was assessed using publicly available human proteomic and transcriptomic databases., Results: We found that TIMP1 is a tumour-secreted protein with high sensitivity and specificity for aggressive cancer, even at early stages in mice. We showed that TIMP1 levels in the tumour and serum correlate with tumour burden and worse survival in mice. We validated this finding using clinical samples from our institution and publicly available human proteomic and transcriptomic databases. These data support the finding that high tumour expression of TIMP1 correlates with an unfavorable prognosis in lung cancer patients., Conclusion: TIMP1 is a suitable biomarker for lung cancer detection., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Programmed death-ligand 1 (PD-L1) is a transmembrane ligand for the programmed cell death protein 1 (PD-1), a receptor that inhibits T-cell activity. The PD-L1/PD-1 immune checkpoint axis has been successfully targeted to enhance antitumor immune responses. Tethering PD-L1 to the membrane spatially restricts its ability to inhibit immune responses, and it provides for the acute and reversible modulation of PD-L1 plasma membrane density by regulation of its trafficking. PD-L1 has functions that are independent of its role as a ligand for PD-1, and control of PD-L1 residence in different intracellular compartments might contribute to the regulation of those activities. Thus, control of PD-L1 trafficking is emerging as a key feature of its biology. Herein, we focus on current understating of PD-L1 trafficking and review current attempts to therapeutically target this process in cancer cells to enhance antitumor immunity., (©2023 The Authors; Published by the American Association for Cancer Research.)

Rationale: Remodeling and loss of distal conducting airways, including preterminal and terminal bronchioles (pre-TBs/TBs), underlie progressive airflow limitation in chronic obstructive pulmonary disease (COPD). The cellular basis of these structural changes remains unknown. Objectives: To identify biological changes in pre-TBs/TBs in COPD at single-cell resolution and determine their cellular origin. Methods: We established a novel method of distal airway dissection and performed single-cell transcriptomic profiling of 111,412 cells isolated from different airway regions of 12 healthy lung donors and pre-TBs of 5 patients with COPD. Imaging CyTOF and immunofluorescence analysis of pre-TBs/TBs from 24 healthy lung donors and 11 subjects with COPD were performed to characterize cellular phenotypes at a tissue level. Region-specific differentiation of basal cells isolated from proximal and distal airways was studied using an air-liquid interface model. Measurements and Main Results: The atlas of cellular heterogeneity along the proximal-distal axis of the human lung was assembled and identified region-specific cellular states, including SCGB3A2 + SFTPB + terminal airway-enriched secretory cells (TASCs) unique to distal airways. TASCs were lost in COPD pre-TBs/TBs, paralleled by loss of region-specific endothelial capillary cells, increased frequency of CD8 + T cells normally enriched in proximal airways, and augmented IFN-γ signaling. Basal cells residing in pre-TBs/TBs were identified as a cellular origin of TASCs. Regeneration of TASCs by these progenitors was suppressed by IFN-γ. Conclusions: Altered maintenance of the unique cellular organization of pre-TBs/TBs, including loss of the region-specific epithelial differentiation in these bronchioles, represents the cellular manifestation and likely the cellular basis of distal airway remodeling in COPD.

Objectives: The aim of this study was to explore the potential value of extended nodal-dissection following neoadjuvant chemoradiation (CRT), by analyzing data from the National Cancer Database (NCDB)., Background: A CROSS-trial post-hoc analysis showed that the number of dissected lymph nodes was associated with improved survival in patients undergoing upfront surgery but not in those treated with neoadjuvant CRT., Methods: The NCDB was queried (2004-2014) for patients who underwent esophagectomy following induction CRT. Predictors of overall survival (OS) were assessed. The optimal number of dissected LNs associated with highest survival benefit was determined by multiple regression analyses and receiveroperating characteristic curve analysis. The whole cohort was divided into 2 groups based on the predefined cutoff number. The two groups were propensity-matched (PMs)., Results: Esophagectomy following induction-CRT was performed in 14,503 patients. The number of resected nodes was associated with improved OS in the multivariable analysis (hazard ratio for every 10 nodes: 0.95 (95% confidence interval: 0.93-0.98). The cutoff number of resected LNs that was associated with the highest survival benefit was 20 nodes. In the PM groups, patients in the "≥20 LNs" group had a 14% relative-increase in OS ( P = 0.002), despite having more advanced pathological stages (stage II-IV: 76% vs 72%, P < 0.001), and higher number of positive nodes (0-2 vs 0-1, P < 0.001)., Conclusions: The total number of resected nodes is a significant determinant of improved survival following induction CRT in patients with either node negative or node positive disease. In the matched groups, patients with higher number of resected lymph nodes had higher OS rate, despite having more advanced pathological disease and higher number of resected positive lymph nodes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: PD-L1, a transmembrane ligand for immune checkpoint receptor PD1, has been successfully targeted to activate an anti-tumor immune response in a variety of solid tumors, including non-small cell lung cancer (NSCLC). Despite the success of targeting PD-L1, only about 20% of patients achieve a durable response. The reasons for the heterogeneity in response are not understood, although some molecular subtypes (e.g., mutant EGF receptor tumors) are generally poor responders. Although PD-L1 is best characterized as a transmembrane PD1 ligand, the emerging view is that PD-L1 has functions independent of activating PD1 signaling. It is not known whether these cell-intrinsic functions of PD-L1 are shared among non-transformed and transformed cells, if they vary among cancer molecular subtypes, or if they are impacted by anti-PD-L1 therapy., Methods: Here we use quantitative microscopy techniques and APEX2 proximity mapping to describe the behavior of PD-L1 and to identify PD-L1's proximal proteome in human lung epithelial cells., Results: Our data reveal growth factor control of PD-L1 recycling as a mechanism for acute and reversible regulation of PD-L1 density on the plasma membrane. In addition, we describe novel PD-L1 biology restricted to mutant EGFR cells. Anti-PD-L1 antibody treatment of mutant EGFR cells perturbs cell intrinsic PD-L1 functions, leading to reduced cell migration, increased half-life of EGFR and increased extracellular vesicle biogenesis, whereas anti-PD-L1 antibody does not induce these changes in wild type EGFR cells., Conclusions: Growth factor acute regulation of PD-L1 trafficking, by contributing to the control of plasma membrane density, might contribute to the regulation of PD-L1's immune checkpoint activity, whereas the specific effects of anti-PD-L1 on mutant EGFR cells might contribute to the poor anti-PD-L1 response of mutant EGFR tumors. Video Abstract., (© 2023. The Author(s).)

IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC. This protective effect is accompanied by alterations in intratumoral immune cell subsets eliciting durable adaptive anti-cancer immunity. Mechanistically, cancer cell-intrinsic IRE1α activation sustains mPGES-1 expression, enabling production of the immunosuppressive lipid mediator prostaglandin E 2 . Accordingly, restoring mPGES-1 expression in IRE1α KO cancer cells rescues normal tumor progression. We have developed an IRE1α gene signature that predicts immune cell infiltration and overall survival in human NSCLC. Our study unveils an immunoregulatory role for cancer cell-intrinsic IRE1α activation and suggests that targeting this pathway may help enhance anti-tumor immunity in NSCLC., (© 2023. The Author(s).)

Introduction: The pathogenesis of thymic epithelial tumors remains largely unknown. We previously identified GTF2I L424H as the most frequently recurrent mutation in thymic epithelial tumors. Nevertheless, the precise role of this mutation in tumorigenesis of thymic epithelial cells is unclear., Methods: To investigate the role of GTF2I L424H mutation in thymic epithelial cells in vivo, we generated and characterized a mouse model in which the Gtf2i L424H mutation was conditionally knocked-in in the Foxn1+ thymic epithelial cells. Digital spatial profiling was performed on thymomas and normal thymic tissues with GeoMx-mouse whole transcriptome atlas. Immunohistochemistry staining was performed using both mouse tissues and human thymic epithelial tumors., Results: We observed that the Gtf2i mutation impairs development of the thymic medulla and maturation of medullary thymic epithelial cells in young mice and causes tumor formation in the thymus of aged mice. Cell cycle-related pathways, such as E2F targets and MYC targets, are enriched in the tumor epithelial cells. Results of gene set variation assay analysis revealed that gene signatures of cortical thymic epithelial cells and thymic epithelial progenitor cells are also enriched in the thymomas of the knock-in mice, which mirrors the human counterparts in The Cancer Genome Atlas database. Immunohistochemistry results revealed similar expression pattern of epithelial cell markers between mouse and human thymomas., Conclusions: We have developed and characterized a novel thymoma mouse model. This study improves knowledge of the molecular drivers in thymic epithelial cells and provides a tool for further study of the biology of thymic epithelial tumors and for development of novel therapies., (Copyright © 2022 International Association for the Study of Lung Cancer. All rights reserved.)

Background: Routine mutation profiling for resected lung cancers is not widespread despite an increasing array of targeted therapies. We report the incidence of epidermal growth factor receptor mutations (EGFRmu+) in resected lung adenocarcinomas and their outcomes at a large North American cancer center to characterize this population now eligible for targeted adjuvant therapy., Methods: Among 1036 pulmonary resections performed between 2015 and 2019, 647 patients (62%) had adenocarcinomas that underwent molecular profiling by next-generation sequencing. Clinical and pathologic characteristics, along with survival, were analyzed., Results: EGFRmu+ were identified in 238 patients (37%). Patients with EGFRmu+ were more likely to be Asian than those with EGFR wild-type (79/238 [33%] vs 37/409 [9%], respectively; P < .001) and more likely to be never-smokers (115/238 [48%] vs 73/409 [18%], P < .001). However, most patients with EGFRmu+ in our cohort were White (45%) and had a history of smoking (52%). A statistically nonsignificant trend was observed toward improved 3-year overall survival for pathologic stage IB to III cancers with EGFRmu+ (91% vs 77%, P = .09). Patients with pathologic stage IB lung cancers with EGFRmu+ had a 97% rate of 3-year disease-free survival, with only 1 recurrence in the first 3 years of follow-up. EGFR mutation subtype was not associated with survival differences., Conclusions: Although Asians and never-smokers comprised a disproportionately large group of patients with lung adenocarcinomas with EGFRmu+, most EGFR mutations within our cohort were found in patients who were White or with a smoking history, supporting a routine rather than selective approach to mutation profiling. Patients with surgically resected stage IA and IB lung adenocarcinomas enjoy excellent survival regardless of their mutational status., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Pulmonary resections following neoadjuvant therapy (NT) can be technically demanding. There is a paucity of data regarding the use of minimally invasive surgery (MIS) approaches in that setting on the National level. In this study, we explored the trends of using MIS approaches following NT and its associated outcomes. Methods: The study included all adult patients with non-small cell lung cancer who underwent pulmonary resection following NT between 2010 and 2016. Propensity score (PS) matching (MIS versus open) was performed and the perioperative outcomes were compared. Results: The study included 11,287 patients who underwent pulomonary resection after NT. The percentage of patients undergoing MIS lung resection and the number of hospitals performing one or more MIS increased from 19% and 166 (2010) to 41% and 305 (2016), respectively. When compared with thoracotomy, MIS lung resections were more frequently performed in academic centers in patients with higher income ( P  < .001). In PS matched groups, the use of MIS was associated with shorter hospital length of stay (5 days versus 6 days; P  < .001), compared with open approach. However, there were no differences between the two groups in readmission rate ( P  = .513), or 30-/90-day mortality ( P  = .145/.685). In multivariable regression analysis, MIS approach was not associated with worse long-term, all-cause, survival (confidence interval: 0.91-1.09). Conclusion: The use of MIS approaches after NT increased significantly over the study period and was associated with perioperative outcomes and long-term survival comparable to those noted with the open approach.

Background: The influence of SARS-CoV-2 on surgery for non-small cell lung cancer needs to be understood to inform clinical decision making during and after the COVID-19 pandemic., Objective: This study reports on the 90-day rate of infection as well as the morbidity and mortality of lung surgery for cancer in a tertiary care hospital located in a pandemic epicenter., Methods: We conducted a retrospective review of a prospective database to identify consecutive patients who underwent lung cancer resection before (January 1, 2020-March 10, 2020, group 1; 57 patients) and during the COVID-19 pandemic (March 11, 2020-June 10, 2020, group 2; 41 patients). The primary end point was the occurrence of SARS-CoV-2 infection during the first 90-days after surgery. The secondary outcome measure was 90-day perioperative morbidity and mortality., Results: Patient characteristics were not significantly different between the groups. Ninety-day COVID-19 infection rates was 7.3% (3 out of 41) for patients undergoing an operation during the pandemic and 3.5% (2 out of 57) in patients operated on immediately before the pandemic. All patients tested positive 10 to 62 days after the index surgical procedure following hospital discharge. Four COVID-19-positive patients were symptomatic and 4 out of 5 patients required hospitalization, were men, previous or current smokers with hyperlipidemia, and underwent a sublobar resection. Univariate analysis did not identify any differences in postoperative complications before or during the COVID-19 pandemic. Ninety-day mortality was 5% (2 out of 41) for lung cancer surgery performed during the pandemic, with all deaths occurring due to COVID-19, compared with 0% (0 out of 57) mortality in patients who underwent an operation before the pandemic., Conclusions: During the COVID-19 pandemic, COVID-19 infections occurred in 7.3% of patients who underwent surgery for non-small cell lung cancer. In this series all infections occurred after hospital discharge. Our results suggest that COVID-19 infections occurring within 90 days of surgery portend a 40% mortality, warranting close postoperative surveillance., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Sublobar resection is frequently offered to patients with small, peripheral lung cancers, despite the lack of outcome data from ongoing randomized clinical trials. Sublobar resection may be a particularly attractive surgical strategy for screen-detected lung cancers, which have been suggested to be less biologically aggressive than cancers detected by other means. Using prospective data collected from patients undergoing surgery in the National Lung Screening Trial, we sought to determine whether extent of resection affected survival for patients with screen-detected lung cancer., Methods: The National Lung Screening Trial database was queried for patients who underwent surgical resection for confirmed lung cancer. Propensity score matching analysis (lobectomy vs sublobar resection) was done (nearest neighbor, 1:1, matching with no replacement, caliper 0.2). Demographics, clinicopathologic and perioperative outcomes, and long-term survival were compared in the entire cohort and in the propensity-matched groups. Multivariable logistic regression analysis was done to identify factors associated with increased postoperative morbidity or mortality., Results: We identified 1029 patients who underwent resection for lung cancer in the National Lung Screening Trial, including 821 patients (80%) who had lobectomy and 166 patients (16%) who had sublobar resection, predominantly wedge resection (n = 114, 69% of sublobar resection). Patients who underwent sublobar resection were more likely to be female (53% vs 41%, P = .004) and had smaller tumors (1.5 cm vs 2 cm, P < .001). The sublobar resection group had fewer postoperative complications (22% vs 32%, P = .010) and fewer cardiac complications (4% vs 9%, P = .033). For stage I patients undergoing sublobar resection, there was no difference in 5-year overall survival (77% for both groups, P = .89) or cancer-specific survival (83% for both groups, P = .96) compared with patients undergoing lobectomy. On multivariable logistic regression analysis, sublobar resection was the only factor associated with lower postoperative morbidity/mortality (odds ratio, 0.63; 95% confidence interval, 0.40-0.98). To compare surgical strategies in balanced patient populations, we propensity matched 127 patients from each group undergoing sublobar resection and lobectomy. There were no differences in demographics or clinical and tumor characteristics among matched groups. There was again no difference in 5-year overall survival (71% vs 65%, P = .40) or cancer-specific survival (75% vs 73%, P = .89) for patients undergoing lobectomy and sublobar resection, respectively., Conclusions: For patients with screen-detected lung cancer, sublobar resection confers survival similar to lobectomy. By decreasing perioperative complications and potentially preserving lung function, sublobar resection may provide distinct advantages in a screened patient cohort., (Copyright © 2021. Published by Elsevier Inc.)

To investigate changes in the tumor microenvironment (TME) during lung cancer progression, we interrogate tumors from two chest computed tomography (CT)-defined groups. Pure non-solid (pNS) CT density nodules contain preinvasive/minimally invasive cancers, and solid density nodules contain invasive cancers. Profiling data reveal a dynamic interaction between the tumor and its TME throughout progression. Alterations in genes regulating the extracellular matrix and genes regulating fibroblasts are central at the preinvasive state. T cell-mediated immune suppression is initiated in preinvasive nodules and sustained with rising intensity through progression to invasive tumors. Reduced T cell infiltration of the cancer cell nests is more frequently associated with preinvasive cancers, possibly until tumor evolution leads to a durable, viable invasive phenotype accompanied by more varied and robust immune suppression. Upregulation of immune checkpoints occurs only in the invasive nodules. Throughout progression, an effector immune response is present but is effectively thwarted by the immune-suppressive elements., Competing Interests: Declaration of interests N.K.A. has equity in Angiocrine Bioscience, TMRW, and View Point Medical. O.E. is supported by Janssen, J&J, Astra-Zeneca, Volastra, and Eli Lilly research grants. He is a scientific advisor and an equity holder in Freenome, Owkin, Volastra Therapeutics, and One Three Biotech and a paid scientific advisor to Champions Oncology. T.E.M. receives research funding from Janssen and from Pfizer, Inc. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Here we focus on the molecular characterization of clinically significant histological subtypes of early-stage lung adenocarcinoma (esLUAD), which is the most common histological subtype of lung cancer. Within lung adenocarcinoma, histology is heterogeneous and associated with tumor invasion and diverse clinical outcomes. We present a gene signature distinguishing invasive and non-invasive tumors among esLUAD. Using the gene signatures, we estimate an Invasiveness Score that is strongly associated with survival of esLUAD patients in multiple independent cohorts and with the invasiveness phenotype in lung cancer cell lines. Regulatory network analysis identifies aurora kinase as one of master regulators of the gene signature and the perturbation of aurora kinases in vitro and in a murine model of invasive lung adenocarcinoma reduces tumor invasion. Our study reveals aurora kinases as a therapeutic target for treatment of early-stage invasive lung adenocarcinoma., (© 2022. The Author(s).)

Background: Characterization of circulating tumor DNA (ctDNA) has been integrated into clinical practice. Although labs have standardized validation procedures to develop single locus tests, the efficacy of on-site plasma-based next-generation sequencing (NGS) assays still needs to be proved., Materials and Methods: In this retrospective study, we profiled DNA from matched tissue and plasma samples from 75 patients with cancer. We applied an NGS test that detects clinically relevant alterations in 33 genes and microsatellite instability (MSI) to analyze plasma cell-free DNA (cfDNA)., Results: The concordance between alterations detected in both tissue and plasma samples was higher in patients with metastatic disease. The NGS test detected 77% of sequence alterations, amplifications, and fusions that were found in metastatic samples compared with 45% of those alterations found in the primary tumor samples (p = .00005). There was 87% agreement on MSI status between the NGS test and tumor tissue results. In three patients, MSI-high ctDNA correlated with response to immunotherapy. In addition, the NGS test revealed an FGFR2 amplification that was not detected in tumor tissue from a patient with metastatic gastric cancer, emphasizing the importance of profiling plasma samples in patients with advanced cancer., Conclusion: Our validation experience of a plasma-based NGS assay advances current knowledge about translating cfDNA testing into clinical practice and supports the application of plasma assays in the management of oncology patients with metastatic disease. With an in-house method that minimizes the need for invasive procedures, on-site cfDNA testing supplements tissue biopsy to guide precision therapy and is entitled to become a routine practice., Implications for Practice: This study proposes a solution for decentralized liquid biopsy testing based on validation of a next-generation sequencing (NGS) test that detects four classes of genomic alterations in blood: sequence mutations (single nucleotide substitutions or insertions and deletions), fusions, amplifications, and microsatellite instability (MSI). Although there are reference labs that perform single-site comprehensive liquid biopsy testing, the targeted assay this study validated can be established locally in any lab with capacity to offer clinical molecular pathology assays. To the authors' knowledge, this is the first report that validates evaluating an on-site plasma-based NGS test that detects the MSI status along with common sequence alterations encountered in solid tumors., (© 2021 AlphaMed Press.)

Radiation therapy (RT) in combination with immune checkpoint inhibitor (ICI) represents a promising regimen for non-small cell lung cancer (NSCLC), however, the underlying mechanisms are poorly characterized. We identified a specific dose of RT that conferred tumor regression and improved survival in NSCLC models when combined with ICI. The immune-modulating functions of RT was ascribed to activated lung-resident Scgb1a1+ club cells. Importantly, mice with club cell-specific knockout of synaptosome-associated protein 23 failed to benefit from the combination treatment, indicating a pivotal role of club cell secretome. We identified 8 club cells secretory proteins, which inhibited immunosuppressive myeloid cells, reduced pro-tumor inflammation, and enhanced anti-tumor immunity. Notably, CC10, a member of club cell secretome was increased in plasma of NSCLC patients responding to the combination therapy. By revealing an immune-regulatory role of club cells, our studies have the potential to guide future clinical trials of ICI in NSCLC., Competing Interests: Competing financial interests: The authors declare no competing financial interests. The authors declare no potential conflicts of interest

Cullin (CUL) 4A and 4B ubiquitin ligases are often highly accumulated in human malignant neoplasms and are believed to possess oncogenic properties. However, the underlying mechanisms by which CUL4A and CUL4B promote pulmonary tumorigenesis remain largely elusive. This study reports that CUL4A and CUL4B are highly expressed in patients with non-small cell lung cancer (NSCLC), and their high expression is associated with disease progression, chemotherapy resistance, and poor survival in adenocarcinomas. Depletion of CUL4A (CUL4A k/d ) or CUL4B (CUL4B k/d ) leads to cell cycle arrest at G 1 and loss of proliferation and viability of NSCLC cells in culture and in a lung cancer xenograft model, suggesting that CUL4A and 4B are oncoproteins required for tumor maintenance of certain NSCLCs. Mechanistically, increased accumulation of the cell cycle-dependent kinase inhibitor p21/Cip1/WAF1 was observed in lung cancer cells on CUL4 silencing. Knockdown of p21 rescued the G 1 arrest of CUL4A k/d or CUL4B k/d NSCLC cells, and allowed proliferation to resume. These findings reveal that p21 is the primary downstream effector of lung adenocarcinoma dependence on CUL4, highlight the notion that not all substrates respond equally to abrogation of the CUL4 ubiquitin ligase in NSCLCs, and imply that CUL4A high /CUL4B high may serve as a prognostic marker and therapeutic target for patients with NSCLC., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab., Methods: We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual., Findings: Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2-79·6]; p<0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported., Interpretation: Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial., Funding: AstraZeneca., Competing Interests: Declaration of interests NKA reports stock options from TMRW, Angiocrine Bioscience, and View Point Medical; and is on the research advisory committee for AstraZeneca. AS reports personal fees from AstraZeneca, Blueprint Medicines, Genentech, Medtronic, and Takeda. JLP reports leadership and stock options from TMRW, Angiocrine Bioscience, and View Point Medical. BMS reports personal fees from AstraZeneca, Pfizer, Flame Biosciences, Gala Therapeutics, Bristol Myers Squibb, and Ribon Therapeutics; and is on the board of directors for the Lung Cancer Research Foundation. BEL reports personal fees from AstraZeneca. KVB reports personal fees from Janssen, Eli Lilly, Takeda, Johnson and Johnson, Sanfoi, and Ariad. SCF has received grants from Bristol Myers Squibb, Varian, Merck, Eisai, Eli Lilly, Janssen, and Regeneron; and personal fees from Accuray, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Elekta, EMD Serono/Merck, GlaxoSmithKline, Janssen, MedImmune, Merck US, Regeneron, Varian, and ViewRay. PJC was partially supported by a grant from the Clinical and Translational Science Center at Weill Cornell Medical College (grant number 1-UL1-TR002384-01). All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Recent data suggest that subcutaneous adiposity represents an independent prognostic marker in cancer. We aimed to determine whether subcutaneous adiposity estimated by the subcutaneous adiposity tissue index (SATI) was associated with mortality in esophageal cancer., Methods: We conducted a retrospective analysis of a prospectively enrolled cohort from 2009 to 2015 with esophageal cancer at two major cancer centers. CT scans for initial staging were used to quantify adiposity and skeletal muscle areas. Subjects were categorized as above or below median SATI using sex-specific values. Sarcopenia was defined using previously established skeletal muscle area cutoffs. Cox proportional hazards modeling was performed to determine associations between SATI and all-cause mortality., Results: Of the original 167 patients, 78 met inclusion criteria and had CT images available. Mean age was 67 years, 81.8% had adenocarcinoma, and 58.9% had stage 3 or 4 disease. Median follow-up time was 29.5 months. Overall 5-year survival was 38.9% [95% confidence interval (CI), 26.8-50.7]. Lower body mass index, higher Charlson comorbidity score, and more advanced stage were independently associated with low SATI. Patients with low SATI had increased mortality (unadjusted HR 2.23; 95% CI, 1.20-4.12), even when adjusted for sarcopenia or for percent weight loss. In a multivariable model including age, histology, stage, and receipt of curative surgery, the association between low SATI and mortality was attenuated (adjusted HR 1.64; 95% CI, 0.81-3.34)., Conclusions: Low subcutaneous adiposity as estimated by SATI may be associated with increased mortality in esophageal cancer., Impact: Interventions to reduce loss of subcutaneous fat may improve survival in esophageal cancer., (©2020 American Association for Cancer Research.)

Objectives: Oesophagectomy following induction chemoradiation therapy (CRT) is technically challenging. To date, little data exist to describe the feasibility of a robotic approach in this setting. In this study, we assessed national trends and outcomes of robotic oesophagectomy following induction CRT compared to the traditional open approach., Methods: The National Cancer Database was queried for patients who underwent oesophagectomy following induction CRT (2010-2014). Trends of robotic utilization were assessed by a Mantel-Haenszel test of trend. Propensity matching controlled for differences in age, gender, comorbidity, stage, histology and tumour location between the robotic and open groups. Overall survival was estimated by Kaplan-Meier analysis and compared by a log-rank test., Results: Oesophagectomy following induction CRT was performed in 6958 patients. Of them, 555 patients (8%) underwent robotic surgery (5% converted to an open approach). Between 2010 and 2014, utilization of a robotic approach increased from 3% to 11% (Mantel-Haenszel, P < 0.001) and the number of hospitals performing at least 1 robotic oesophagectomy increased from 23 to 57. Compared to the traditional open approach, robotic oesophagectomy was used more frequently at academic hospitals (76% vs 60%, P < 0.001), and in patients living in metropolitan areas (85% vs 77%, P < 0.001) and those living in the Midwest (41% vs 33%, P < 0.001). In the matched groups, a robotic approach was associated with shorter median hospital stay (9 vs 10 days, P = 0.004) and dissection of more lymph nodes (median, 16 vs 12, P < 0.001). However, there were no differences in rates of positive margin resection (5% for both groups, P = 0.95), 30-day readmissions (5% vs 7%, P = 0.18), 30-day mortality (2.5% vs 4%, P = 0.79), 90-day mortality (9% vs 8.5%, P = 0.89) or 5-year overall survival (42% vs 39%, P = 0.19) between patients undergoing robotic and open surgery, respectively., Conclusions: Robotic oesophagectomy after induction CRT is feasible and associated with shorter hospitalization compared to an open approach, and does not compromise the adequacy of oncological resection, perioperative outcomes or long-term survival., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10 -5 . The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care.

Background: Stapling across lung parenchyma may lead to tissue granulation, which could be confused radiographically with recurrence. We sought to define the time course and radiographic characteristics of such thickening and to determine their association with recurrence., Methods: Patients who underwent limited resection for non-small cell lung cancer were included. Surveillance computed tomography scans were reviewed to characterize the morphology and size of staple line granulation tissue. Radiological and clinical findings were analyzed and univariate predictors of recurrence were examined., Results: We characterized 78 patients for tissue granulation a total of 314 times in serial scans. On initial postoperative scans, 3.8% (n = 3) of staple lines showed no thickening and 17.9% (n = 14) showed thickening less than 2 mm, whereas 78.2% (n = 61) showed thickening 2 mm or greater. Of the 75 staple lines with thickening, soft tissue was characterized as linear in 32.0% (n = 24), focal along the pleura, hilum, or parenchyma in 24.0% (n = 18), and nodular in 44.0% (n = 33). Subsequent scans revealed that 25.3% of these areas (n = 19) did not change in shape or size over time, 58.7% (n = 44) showed regressive changes, and 16.0% (n = 12) showed progressive changes, the thickening of which in all 12 of these patients showed an increase in the largest dimension by 2 mm or greater. Among the 78 patients, 7.7% (n = 6) had biopsy-proven recurrence along the staple line. An increase in the largest dimension by 2 mm or greater (83.3% versus 9.7%; P = .001) and radiologic concern for malignancy (66.7% versus 11.1%; P = .001) predicted staple line recurrence., Conclusions: Staple line thickening is a frequent occurrence after pulmonary limited resection, but rarely indicative of recurrence. The characteristics and initial size of granulation tissue do not predict recurrence. Increases in tissue 2 mm or greater at the staple line over time predict local recurrence, which typically occurs after a prolonged time interval., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Metastases are responsible for the majority of breast cancer-associated deaths. The contribution of epithelial-to-mesenchymal transition (EMT) in the establishment of metastases is still controversial. To obtain in vivo evidence of EMT in metastasis, we established an EMT lineage tracing (Tri-PyMT) model, in which tumor cells undergoing EMT would irreversibly switch their fluorescent marker from RFP + to GFP + due to mesenchymal-specific Cre expression. Surprisingly, we found that lung metastases were predominantly derived from the epithelial compartment of breast tumors. However, concerns were raised on the fidelity and sensitivity of RFP-to-GFP switch of this model in reporting EMT of metastatic tumor cells. Here, we evaluated Tri-PyMT cells at the single-cell level using single-cell RNA-sequencing and found that the Tri-PyMT cells exhibited a spectrum of EMT phenotypes, with EMT-related genes concomitantly expressed with the activation of GFP. The fluorescent color switch in these cells precisely marked an unequivocal change in EMT status, defining the pre-EMT and post-EMT compartments within the tumor. Consistently, the pre-EMT cells played dominant roles in metastasis, while the post-EMT cells were supportive in promoting tumor invasion and angiogenesis. Importantly, the post-EMT (GFP + ) cells in the Tri-PyMT model were not permanently committed to the mesenchymal phenotype; they were still capable of reverting to the epithelial phenotype and giving rise to secondary tumors, suggesting their persistent EMT plasticity. Our study addressed major concerns with the Tri-PyMT EMT lineage tracing model, which provides us with a powerful tool to investigate the dynamic EMT process in tumor biology. SIGNIFICANCE: These findings confirm the fidelity and sensitivity of the EMT lineage tracing (Tri-PyMT) model and highlight the differential contributions of pre- and post-EMT tumor cells in breast cancer metastasis. See related commentary by Bunz, p. 153 ., (©2019 American Association for Cancer Research.)

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP + exosomes. Moreover, uptake of CEMIP + exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.

Objectives: Sublobar resection (SLR) is an alternative to lobectomy for non-small-cell lung cancer (NSCLC). Outcomes following SLR for tumours >2 cm are not well described. We sought to determine the utilization of SLR for stage I tumours >2-5 cm in size and to determine predictors of outcome., Methods: We utilized the Surveillance, Epidemiology and End Results Program (SEER)-Medicare database to identify NSCLC patients with primary lung cancer ≥66 years old with stage I cancers >2-5 cm in size. We evaluated overall survival and cancer-specific survival among cohorts undergoing lobectomy versus SLR. Propensity score matching was performed. We compared patient characteristics and survival between groups., Results: For the study time period (2007-2012), among patients with tumours >2 cm and ≤5 cm (n = 4582), 3890 lobectomies (85%) and 692 SLR (15%) were performed. Patients undergoing SLR were older, had smaller tumours and more comorbidities. Patients undergoing lobectomy were much more likely to have any lymph nodes removed (95.6% vs 65.6%, P < 0.001) and to have >10 nodes removed (29.6% vs 7.5%, P < 0.001). All-cause mortality [hazard ratio (HR) 1.65, confidence interval (CI) 1.48-1.85] and cancer-specific (HR 1.63, CI 1.29-2.06) mortality were higher following SLR. At 3 years, overall survival (60.9%, CI 57.0-64.6% vs 54.4%, CI 50.4-58.2%) and cancer-specific survival (87.3%, CI 83.5-90.3% vs 76.5%, CI 71.0-81.1%) favoured lobectomy over SLR. In propensity-matched groups, both all-cause (HR 1.27, CI 1.10-1.47) and cancer-specific (HR 1.54, CI 1.11-2.16) mortality rates were higher with SLR., Conclusions: In pathologically staged patients, SLR appears inferior to lobectomy for stage I NSCLC 2-5 cm in size. SLR is associated with less extensive lymphadenectomy and with worse survival than lobectomy in this cohort of patients. However, the 76.5% 3-year cancer-specific survival in patients undergoing SLR may exceed that of other localized treatment options for NSCLC. As such, SLR may be an appropriate option for high-risk patients with carefully staged 2-5 cm N0 tumours., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Despite the recent increased rate of adoption of robotic approaches for the resection of thymic tumours, their use is still limited to large-volume academic centres. To date, a large-scale analysis of the robotic approach has not been performed. We assessed the recent trends and outcomes of robotic thymectomies in the United States compared to those of open and video-assisted thoracoscopic surgical (VATS) approaches., Methods: The National Cancer Database was queried for patients who underwent resection for thymic tumours (2010-2014). Predictors of using the robotic approach were estimated by logistic regression analysis. Propensity matching analysis (robotic versus open and robotic versus VATS) was done (1:1-caliper 0.05), controlling for age, gender, comorbidity index, induction treatment, tumour size and tumour extension., Results: A total of 2558 thymectomies were performed (robotic = 300, VATS = 280, open = 1978). The use of a robotic approach increased from 6% (2010) to 14% (2014). The number of hospitals performing at least 1 robotic thymectomy increased from 22 (2010) to 52 (2014). Independent predictors influencing the choice of a robotic approach included an academic research/integrated cancer programme [odds ratio (OR) 1.66, confidence interval (CI) 1.22-2.27], later year of diagnosis (2014; OR 2.23, CI 1.31-3.80) and a patient's race (Asian) (OR 1.68, CI 1.05-2.69). A robotic approach was less likely to be utilized in midwestern hospitals (OR 0.65, CI 0.42-0.99), in larger tumours (cm) (OR 0.85, CI 0.80-0.90), with invasion of adjacent organs (OR 0.55, CI 0.37-0.82), thymic carcinoma (OR 0.62, CI 0.40-0.97) and following induction chemotherapy (OR 0.22, CI 0.08-0.61). In a propensity-matched analysis, there were no differences in the incidence of positive margins, nodal dissection, 30-day readmission rates and 30-/90-day mortality rates between the groups. However, a robotic approach was associated with fewer conversions compared to VATS, with a trend towards a shorter length of stay compared to an open approach. There were no differences in the 5-year overall survival rate between the matched groups (robotic 93% vs VATS 94%; P = 0.571; robotic 91% vs open 80%; P = 0.094)., Conclusions: Over a 4-year study period, there was a significant increase in robotic utilization for thymectomies and an increase in the number of hospitals performing the procedure. In a matched analysis, a robotic approach was comparable to a VATS or an open approach. Current trends demonstrate increased robotic utilization for small thymomas with excellent perioperative results., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Minimum volume standards for thoracic surgical procedures have been advocated to improve outcomes. However, such standards are controversial within the thoracic surgery literature, and the methodology to determine cut points between high- and low-volume hospitals has been criticized. Furthermore, while multiple studies have examined hospital volume and its relationship with outcomes, there have been very few attempts to study this issue from the perspective of the individual thoracic surgeon. The aim of this study was to determine if surgeon volume is associated with differences in outcomes using a large state-wide database., Methods: The study utilized the New York State Department of Health Statewide Planning and Research Cooperative (SPARCS) data for analysis. Patients who underwent major lung resections including sublobar resection, lobectomy and pneumonectomy from 1995 to 2014 were included and were categorized into 3 subgroups based on the extent of resection. Patient characteristics included age, gender, race, insurance and comorbidities. Surgeon information was obtained by using a unique identifier. Average annual surgical volumes of sublobar resection, lobectomy and pneumonectomy were calculated separately and grouped into 3 categories based on the tertiles. Demographic data and comorbidities were compared between the various volume groups to analyse the resulting complications. Primary outcomes were in-hospital mortality and 30-day readmission., Results: There were a total of 99 576 major lung resections performed between 1995 and 2014 in the SPARCS database. Among these, the majority were wedge or segmental resections (n = 54 953, 55.2%) followed by lobectomy (n = 40 421, 40.6%) and pneumonectomy (n = 4202, 4.2%). In-hospital mortality was significantly greater for low-volume surgeons compared to high-volume surgeons for all resection groups. Additionally, low-volume surgeons had higher 30-day readmission rates for patients undergoing lobectomy and pneumonectomy. However, low-volume surgeons as a group were more likely to operate on black patients and patients with Medicaid, and black race was an independent predictor of mortality across all resection groups. The vast majority of surgeons performing lobectomy (89.5%) were in the low-volume group., Conclusions: Low-volume surgeons had higher rates of in-hospital mortality compared to their high-volume counterparts. However, the vast majority of surgeons performing lobectomy (89.5%) were in the low-volume group, and low-volume surgeons operated on higher percentages of black patients. These findings suggest that minimal volume standards would significantly impact the current delivery of thoracic surgery in the US., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: The benefit of adjuvant treatment for esophageal cancer patients with positive lymph nodes after induction therapy and esophagectomy is uncertain. This in-depth multicenter study assessed the benefit of adjuvant therapy in this population., Methods: A retrospective cohort study from 9 institutions included patients who received neoadjuvant treatment, underwent esophagectomy from 2000 to 2014, and had positive lymph nodes on pathology. Factors associated with administration of adjuvant therapy were assessed using multilevel random-intercept modeling to account for institutional variation in practice. Kaplan-Meier analyses were performed based on adjuvant treatment status. Variables associated with survival were identified using Cox proportional hazards modeling., Results: The study analyzed 1082 patients with node-positive cancer after induction therapy and esophagectomy: 209 (19.3%) received adjuvant therapy and 873 (80.7%) did not. Administration of adjuvant treatment varied significantly from 3.2% to 50.0% between sites (P < .001). Accounting for institution effect, factors associated with administration of adjuvant therapy included clinically positive and negative prognostic characteristics: younger age, higher pathologic stage, pathologic grade, no neoadjuvant radiotherapy nonsmoking status, and absence of postoperative infection. Kaplan-Meier analysis showed patients receiving adjuvant therapy had a longer median survival of 2.6 years vs 2.3 years (P = .02). Cox modeling identified adjuvant treatment as independently associated with improved survival, with a 24% reduction in mortality (hazard ratio, 0.76; P = .005)., Conclusions: Adjuvant therapy was associated with improved overall survival. Therefore, consideration should be given to administration of adjuvant therapy to esophageal cancer patients who have persistent node-positive disease after induction therapy and esophagectomy and are able to tolerate additional treatment., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states 1-6 . Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.