Single cell view of tumor microenvironment gradients in pleural mesothelioma.

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.

Monocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs' survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.

The value of high-risk clinicopathologic features for chemotherapy in stage I non-small cell lung cancer: a propensity score-matched study.

Background: Surgical resection is the main treatment for early-stage non-small cell lung cancer (NSCLC), but recurrence remains a concern. Adjuvant chemotherapy has been shown to have survival benefits for resected stage II and III NSCLC, but debate continues regarding its use in stage I NSCLC. High-risk features, such as tumor size and stage, are considered in deciding whether to administer adjuvant chemotherapy. Methods: The data of 666,689 patients diagnosed with lung cancer from 2004 to 2016 were collected from the Surveillance, Epidemiology, and End Results database. Ultimately, 26,160 patients diagnosed with stage I NSCLC were included in the study based on a screening procedure. Results: After matching, 4,285 patients were identified, of whom 1,440 (33.6%) received chemotherapy. High-risk clinicopathologic features, including a high histologic grade, visceral pleural invasion (VPI), the examination of an insufficient number of lymph nodes (LNs), and limited resection, were independent risk factors for a poor prognosis. Chemotherapy significantly improved lung cancer-specific survival (LCSS) and overall survival (OS) in stage I patients with VPI [LCSS: hazard ratio (HR): 0.839, 95% confidence interval (CI): 0.706-0.998, P=0.047; OS: HR: 0.711, 95% CI: 0.612-0.826, P<0.001], regardless of whether or not the patient had fewer than 11 LNs (LCSS: HR: 0.809, 95% CI: 0.664-0.986, P=0.04; OS: HR: 0.677, 95% CI: 0.570-0.803, P<0.001). Chemotherapy was only observed to improve OS for stage IB patients with a high histologic grade when combined with either or both of the following high-risk factors: the presence of VPI and fewer than 11 LNs examined. Conclusions: The presence of VPI was the dominant predictor and the examination of an insufficient number of LNs was the secondary indicator, and a high histologic grade was a potential indicator of the need to administer chemotherapy in the treatment of stage I NSCLC.

Longitudinal quality of life after sublobar resection and stereotactic body radiation therapy for early-stage non-small cell lung cancer.

BACKGROUND: Many patients with early-stage lung cancer are not candidates for lobectomy because of various factors, with treatment options including sublobar resection or stereotactic body radiation therapy (SBRT). Limited information exists regarding patient-centered outcomes after these treatments. METHODS: Subjects with stage I-IIA non-small cell lung cancer (NSCLC) at high risk for lobectomy who underwent treatment with sublobar resection or SBRT were recruited from five medical centers. Quality of life (QOL) was compared with the Short Form 8 (SF-8) for physical and mental health and Functional Assessment of Cancer Therapy-Lung (FACT-L) surveys at baseline (pretreatment) and 7 days, 30 days, 6 months, and 12 months after treatment. Propensity score methods were used to control for confounders. RESULTS: Of 337 subjects enrolled before treatment, 63% received SBRT. Among patients undergoing resection, 89% underwent minimally invasive video-assisted thoracic surgery or robot-assisted resection. Adjusted analyses showed that SBRT-treated patients had both higher physical health SF-8 scores (difference in differences [DID], 6.42; p = .0008) and FACT-L scores (DID, 2.47; p = .004) at 7 days posttreatment. Mental health SF-8 scores were not different at 7 days (p = .06). There were no significant differences in QOL at other time points, and all QOL scores returned to baseline by 12 months for both groups. CONCLUSIONS: SBRT is associated with better QOL immediately posttreatment compared with sublobar resection. However, both treatment groups reported similar QOL at later time points, with a return to baseline QOL. These findings suggest that sublobar resection and SBRT have a similar impact on the QOL of patients with early-stage lung cancer deemed ineligible for lobectomy.

Change in quality of life of stage IA non-small cell lung cancer after surgery or radiation therapy.

Background: Few studies have examined the differential impact of stereotactic body radiotherapy (SBRT) and surgery for early-stage non-small cell lung cancer (NSCLC) on quality of life (QoL) during the first post-treatment year. Methods: A prospective cohort of stage IA NSCLC patients undergoing surgery or SBRT at Mount Sinai Health System had QoL measured before treatment, and 2, 6, and 12 months post-treatment using: 12-item Short Form Health Survey version 2 (SF-12v2) [physical component summary (PCS) and mental component summary (MCS)], Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS), and the Patient Health Questionnaire-4 (PHQ-4) measuring depression and anxiety. Locally weighted scatterplot smoothing (LOWESS) was fitted to identify the best interval knot for the change in the QoL trends post-treatment, adjusted piecewise linear mixed effects model was developed to estimate differences in baseline, 2- and 12-month scores, and rates of change. Results: In total, 503 (88.6%) patients received surgery and 65 (11.4%) SBRT. LOWESS plots suggested QoL changed at 2 months post-surgery. Worsening in PCS was observed for both surgery and SBRT within 2 months after treatment but was only significant for surgical patients (-2.11, P<0.001). Two months later, improvements were observed for surgical but not SBRT patients (0.63 vs. -0.30, P<0.001). Surgical patients had significantly better PCS (P<0.001) and FACT-LCS (P<0.001) scores 1-year post-treatment compared to baseline, but not SBRT patients. Both surgical and SBRT patients reported significantly less anxiety 1-year post-treatment compared to baseline (P<0.001 and P=0.03). Decrease in depression from baseline to 1-year post-treatment was only significant for surgical patients (P<0.001). Conclusions: Post-treatment, surgical patients exhibited improvements in physical health and reductions in lung cancer symptoms following initial deterioration within the first two months; in contrast, SBRT patients showed persistent decline in these areas throughout the year. Nonetheless, improved mental health was noted across both patient categories post-treatment. Targeted interventions and continuous monitoring are recommended during the initial 2 months post-surgery and throughout the year post-SBRT to alleviate physical and mental distress in patients.

Outcomes in Incidentally Versus Screening Detected Stage I Lung Cancer Surgery Patients.

INTRODUCTION: Although the importance of lung cancer screening for early diagnosis is established, because of poor enrollment, incidental findings still play a role in diagnosis of patients who qualify. Nevertheless, analysis of this incidental cohort is lacking. We present a retrospective analysis comparing patients with thoracic surgery with incidental versus screening detected stage I lung cancer. METHODS: Thoracic surgery cases at Mount Sinai Hospital from March, 1, 2012, to June, 30, 2022, were queried for patients eligible for lung cancer screening and a stage I diagnosis. The basis of lung nodule detection (incidental versus screening detected) was identified. We compared demographic variables, comorbidities, tumor staging, procedure details, and postoperative outcomes between the cohorts. RESULTS: Of the patients eligible for screening with lung cancer resection and stage I diagnosis at Mount Sinai, 153 were identified incidentally and 67 through screening. The patients in the incidental cohort were older (p = 0.005), more likely to have quit smoking (p = 0.04), and had a greater number of comorbidities (p = 0.0002). There was no statistically significant difference between the groups with regard to pack-year smoking history, lung cancer histological type, location or size of tumor, and surgical approach, length of surgery or stay, number of postoperative outcomes, and survival. CONCLUSIONS: In stage I lung cancers, no significant differences were identified between incidentally and screening detected lung nodules with regard to tumor characteristics, surgical approach, and postoperative outcomes. Imaging conducted for other reasons should be considered as a valid and important diagnostic tool, similar to traditional low-dose computed tomography, in patients who qualify for screening.

Prospective Cohort Study to Compare Long-Term Lung Cancer-Specific and All-Cause Survival of Clinical Early Stage (T1a-b; ≤20 mm) NSCLC Treated by Stereotactic Body Radiation Therapy and Surgery.

INTRODUCTION: We aimed to compare outcomes of patients with first primary clinical T1a-bN0M0 NSCLC treated with surgery or stereotactic body radiation therapy (SBRT). METHODS: We identified patients with first primary clinical T1a-bN0M0 NSCLCs on last pretreatment computed tomography treated by surgery or SBRT in the following two prospective cohorts: International Early Lung Cancer Action Program (I-ELCAP) and Initiative for Early Lung Cancer Research on Treatment (IELCART). Lung cancer-specific survival and all-cause survival after diagnosis were compared using Kaplan-Meier analysis. Propensity score matching was used to balance baseline demographics and comorbidities and analyzed using Cox proportional hazards regression. RESULTS: Of 1115 patients with NSCLC, 1003 had surgery and 112 had SBRT; 525 in I-ELCAP in 1992 to 2021 and 590 in IELCART in 2016 to 2021. Median follow-up was 57.6 months. Ten-year lung cancer-specific survival was not significantly different: 90% (95% confidence interval: 87%-92%) for surgery versus 88% (95% confidence interval: 77%-99%) for SBRT, p = 0.55. Cox regression revealed no significant difference in lung cancer-specific survival for the combined cohorts (p = 0.48) or separately for I-ELCAP (p = 1.00) and IELCART (p = 1.00). Although 10-year all-cause survival was significantly different (75% versus 45%, p < 0.0001), after propensity score matching, all-cause survival using Cox regression was no longer different for the combined cohorts (p = 0.74) or separately for I-ELCAP (p = 1.00) and IELCART (p = 0.62). CONCLUSIONS: This first prospectively collected cohort analysis of long-term survival of small, early NSCLCs revealed that lung cancer-specific survival was high for both treatments and not significantly different (p = 0.48) and that all-cause survival after propensity matching was not significantly different (p = 0.74). This supports SBRT as an alternative treatment option for small, early NSCLCs which is especially important with their increasing frequency owing to low-dose computed tomography screening. Furthermore, treatment decisions are influenced by many different factors and should be personalized on the basis of the unique circumstances of each patient.

A 20-year Follow-up of the International Early Lung Cancer Action Program (I-ELCAP).

Background The low-dose CT (≤3 mGy) screening report of 1000 Early Lung Cancer Action Program (ELCAP) participants in 1999 led to the International ELCAP (I-ELCAP) collaboration, which enrolled 31 567 participants in annual low-dose CT screening between 1992 and 2005. In 2006, I-ELCAP investigators reported the 10-year lung cancer-specific survival of 80% for 484 participants diagnosed with a first primary lung cancer through annual screening, with a high frequency of clinical stage I lung cancer (85%). Purpose To update the cure rate by determining the 20-year lung cancer-specific survival of participants diagnosed with first primary lung cancer through annual low-dose CT screening in the expanded I-ELCAP cohort. Materials and Methods For participants enrolled in the HIPAA-compliant prospective I-ELCAP cohort between 1992 and 2022 and observed until December 30, 2022, Kaplan-Meier survival analysis was used to determine the 10- and 20-year lung cancer-specific survival of participants diagnosed with first primary lung cancer through annual low-dose CT screening. Eligible participants were aged at least 40 years and had current or former cigarette use or had never smoked but had been exposed to secondhand tobacco smoke. Results Among 89 404 I-ELCAP participants, 1257 (1.4%) were diagnosed with a first primary lung cancer (684 male, 573 female; median age, 66 years; IQR, 61-72), with a median smoking history of 43.0 pack-years (IQR, 29.0-60.0). Median follow-up duration was 105 months (IQR, 41-182). The frequency of clinical stage I at pretreatment CT was 81% (1017 of 1257). The 10-year lung cancer-specific survival of 1257 participants was 81% (95% CI: 79, 84) and the 20-year lung cancer-specific survival was 81% (95% CI: 78, 83), and it was 95% (95% CI: 91, 98) for 181 participants with pathologic T1aN0M0 lung cancer. Conclusion The 10-year lung cancer-specific survival of 80% reported in 2006 for I-ELCAP participants enrolled in annual low-dose CT screening and diagnosed with a first primary lung cancer has persisted, as shown by the updated 20-year lung cancer-specific survival for the expanded I-ELCAP cohort. © RSNA, 2023 See also the editorials by Grenier and by Sequist and Olazagasti in this issue.

A narrative review of anastomotic leak in the Ivor Lewis esophagectomy: expected, accepted, but preventable.

Background and Objective: Anastomotic leak (AL) remains a common and highly morbid complication after Ivor Lewis Esophagectomy. Leak is associated with increased morbidity, mortality, strictures and even cancer recurrence. Unfortunately, despite advances in surgical technique and perioperative care, the reported frequency of AL has remained largely unchanged. Methods: A PubMed search for all English-language articles that discuss Ivor Lewis esophagectomy, AL, risk factors, and outcomes was conducted from 1901 to 2023 prioritizing research from randomized trials that evaluated outcomes from patients undergoing esophagectomy. Key Content and Findings: This narrative review will discuss the prevailing literature on AL, risk factors and outcomes with a focus on its relationship to the Ivor Lewis esophagectomy (ILE). In particular, we emphasize that the gastric conduit, as commonly created for most esophagectomy procedures, is inherently vulnerable to ischemia. We will show trends in the literature that have contributed to the high rate of postoperative complications, with a focus on the AL. In addition, we propose that the traditional Ivor Lewis procedure itself is a risk factor for AL. We review a surgical alternative that increases blood supply of the conduit, and is associated with reduced leak, no strictures, and improved surgical outcomes. Conclusions: Multiple factors contribute to AL after esophagectomy; including several current surgical practices. We believe that some of them, especially the commonly accepted approach to the gastric conduit, can be modified to optimize tissue perfusion. With further investigation, we may reduce the incidence of short and long-term anastomotic complications and improve surgical outcomes.

Surgical markup in lung cancer resection, 2015-2020.

Objective: The objective of this study was to assess procedure markup (charge-to-cost ratio) across lung resection procedures and examine variability by geographic region. Methods: Provider-level data for common lung resection operations was obtained from the 2015 to 2020 Medicare Provider Utilization and Payment Data datasets using Healthcare Common Procedure Coding System codes. Procedures studied included wedge resection; video-assisted thoracoscopic surgery; and open lobectomy, segmentectomy, and mediastinal and regional lymphadenectomy. Procedure markup ratio and coefficient of variation (CoV) was assessed and compared across procedure, region, and provider. The CoV, a measure of dispersion defined as the ratio of the SD to the mean, was likewise compared across procedure and region. Results: Median markup ratio across all procedures was 3.56 (interquartile range, 2.87-4.59) with right skew (mean, 4.13). Median markup ratio was 3.59 for lymphadenectomy (CoV, 0.51), 3.13 for open lobectomy (CoV, 0.45), 3.55 for video-assisted thoracoscopic surgery lobectomy (CoV, 0.59), 3.77 for segmentectomy (CoV, 0.74), and 3.80 for wedge resection (CoV, 0.67). Increased beneficiaries, services, and Healthcare Common Procedure Coding System score (total) were associated with a decreased markup ratio (P < .0001). Markup ratio was highest in the Northeast at 4.14 (interquartile range, 3.09-5.56) and lowest in the South (Markup ratio 3.26; interquartile range, 2.68-4.02). Conclusions: We observe geographic variation in surgical billing for thoracic surgery.

Unequal racial distribution of immunotherapy for late-stage non-small cell lung cancer.

Immunotherapy has increased survival for non-small cell lung cancer (NSCLC), especially for those diagnosed with late-stage disease. However, it is not known if its use is equally distributed across races. We assessed immunotherapy use in 21 098 pathologically confirmed stage IV NSCLC patients according to race in the Surveillance Epidemiology, and End Results-Medicare linked dataset. Multivariable models were conducted to evaluate the independent association of receipt of immunotherapy with race and overall survival according to race. Black patients had statistically significantly lower odds of receiving immunotherapy (adjusted odds ratio = 0.60, 95% confidence interval = 0.44 to 0.80); receipt of immunotherapy was lower in Asian and Hispanic patients but not statistically significant. When immunotherapy was received, survival was similar across races. Immunotherapy for NSCLC is not used equally among races, underscoring the racial disparities that exist in access to the newest cancer treatment. Efforts should be directed toward expanding access to novel, efficacious treatments for advanced stage lung cancer.

Effect of stage shift and immunotherapy treatment on lung cancer survival outcomes.

OBJECTIVES: Non-small-cell lung cancer mortality has declined at a faster rate than incidence due to multiple factors, including changes in smoking behaviour, early detection which shifts diagnosis, and novel therapies. Limited resources require that we quantify the contribution of early detection versus novel therapies in improving lung cancer survival outcomes. METHODS: Non-small-cell lung cancer patients from the Surveillance, Epidemiology, and End Results-Medicare data were queried and divided into: (i) stage IV diagnosed in 2015 (n = 3774) and (ii) stage I-III diagnosed in 2010-2012 (n = 15 817). Multivariable Cox-proportional hazards models were performed to assess the independent association of immunotherapy or diagnosis at stage I/II versus III with survival. RESULTS: Patients treated with immunotherapy had significantly better survival than those who did not (HRadj: 0.49, 95% confidence interval: 0.43-0.56), as did those diagnosed at stage I/II versus stage III (HRadj: 0.36, 95% confidence interval: 0.35-0.37). Patients on immunotherapy had a 10.7-month longer survival than those who were not. Stage I/II patients had an average survival benefit of 34 months, compared to stage III. If 25%% of stage IV patients not on immunotherapy received it, there would be a gain of 22 292 person-years survival per 100 000 diagnoses. A switch of only 25% from stage III to stage I/II would correspond to 70 833 person-years survival per 100 000 diagnoses. CONCLUSIONS: In this cohort study, earlier stage at diagnosis contributed to life expectancy by almost 3 years, while gains from immunotherapy would contribute ½ year of survival. Given the relative affordability of early detection, risk reduction through increased screening should be optimized.

Malignant pleural mesothelioma characteristics and outcomes: A SEER-Medicare analysis.

BACKGROUND: Pleural mesothelioma is rare cancer linked to asbestos exposure. Previous research has indicated that female individuals have better survival than male individuals, but this has never been examined in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. MATERIALS AND METHODS: Malignant pleural mesothelioma cases diagnosed from 1992 to 2015 were queried from the linked SEER-Medicare database. Multivariable logistic regression was used to assess the clinical and demographic factors associated with sex. A multivariable Cox proportional hazards model and propensity matching methods were used to assess sex differences in overall survival (OS) while accounting for potential confounders. RESULTS: Among 4201 patients included in the analysis, 3340 (79.5%) were males and 861 (20.5%) females. Females were significantly older, with more epithelial histology than males were, and had significantly better OS, adjusted for confounders (adjusted hazard ratio, 0.83, 95% confidence interval: 0.76-0.90). Other variables independently associated with improved survival included younger age at diagnosis, having a spouse/domestic partner, epithelial histology, lower comorbidity score, and receipt of surgery or chemotherapy. CONCLUSIONS: The study describes sex differences in mesothelioma occurrence, treatment, and survival and is the first to examine SEER-Medicare. It provides directions for future research into potential therapeutic targets.

Antibiotic treatment and survival in non-small cell lung cancer patients receiving immunotherapy: a systematic review and meta-analysis.

Background: In patients with non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) are an effective mode of treatment. Despite their efficacy, responses to ICIs have been shown to differ based on several factors; for example, antibiotic use prior to and/or during immunotherapy has been associated with lower survival in NSCLC patients. The objective of this study is to provide an updated review of the literature and to fill in important knowledge gaps by accounting for potential confounding in the relationship between ICIs and survival. Methods: We performed a systematic review and meta-analysis on peer-reviewed studies that examined the effects of antibiotic use on overall survival (OS) and progression-free survival (PFS) in NSCLC patients treated with ICIs. We searched MEDLINE for studies published up to June 30th, 2023 that included NSCLC patients treated with anti-programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) agents, who received antibiotics before and/or during immunotherapy, and included a control group who did not receive antibiotics and had available data on the associations between antibiotics and OS and PFS. We calculated aggregated crude OS and PFS for all studies, and only for studies that reported multivariable hazard ratios (HRs). Risk of bias was assessed using a funnel plot. All results were synthesized and displayed using the metaphor statistical package in R, version 4.2.1. Results: Nineteen studies, conducted between 2017 and 2022, met the inclusion criteria, and included 2,932 patients with advanced and/or metastatic NSCLC. Compared to those who did not receive antibiotics, immunotherapy patients who did had a significantly reduced PFS (HR: 1.22, 95% CI: 1.03-1.44) and OS (HR: 1.56, 95% CI: 1.23-1.99). Adjusted HRs were even more pronounced (OS HRadj: 1.67, 95% CI: 1.23-2.27, PFS HRadj: 1.64, 95% CI: 1.16-2.32). Conclusions: NSCLC patients treated with antibiotics have significantly lowered survival compared with patients not treated with antibiotics. These results support the hypothesis that antibiotic use in conjunction with ICI among NSCLC patients lowers survival. Limitations of this analysis include the use of studies available only on a single database, limiting the literature search to NSCLC patients, which may impact the generalizability of results to other cancer patient populations, and the inability to account for and adjust the estimates for the same variables (e.g., age, sex) across all studies. Nevertheless, our findings underscore the importance of taking antibiotic use into consideration when using ICIs to treat NSCLC and suggest that confounders should be taken into account when designing future similar studies.

Purse-indigitation mechanical anastomosis vs. traditional mechanical anastomosis undergoing McKeown esophagectomy: a retrospective comparative cohort study.

Background: Postoperative anastomosis-related complication rates remain high in patients undergoing McKeown esophagectomy with cervical anastomosis, and the optimal anastomotic technique remains under debate. We describe a new method of anastomosis, referred to as purse-indigitation mechanical anastomosis (PIMA) by reinforcing esophagogastric anastomosis, which can be performed after minimally invasive surgery. This study was designed to compare its feasibility, efficacy, and safety with those of traditional mechanical anastomosis (TMA). Methods: Between September 2020 and January 2022, 264 patients undergoing McKeown esophagectomy at a single center were included. Demographic data, including patient age, sex, diagnosis, neoadjuvant chemotherapy/radiation therapy in cases of malignancy, comorbidities, and operation time, anastomotic time, estimated blood loss, post­operative complications were collected. Their medical records were retrospectively reviewed, analyzed and compared between the PIMA and TMA cohorts. Results: The baseline comparability of the PIMA and TMA before the comparisons is no statistical difference. Univariable analysis revealed significantly decreased anastomotic leak rate with PIMA compared to TMA (4.10% vs. 11.59%, P=0.04). No significant difference was demonstrated in total operation time, estimated blood loss, postoperative hospital stay, or pulmonary complications between PIMA and TMA (243.94±21.98 vs. 238.70±28.45 min; 201.10±67.83 vs. 197.39±65.13 mL; 8.83±2.77 vs. 9.35±3.78 days; 8.21% vs. 11.59%; all P>0.05). The incidence of postoperative pulmonary complications (3.44% vs. 50%) was significantly associated with an increased rate of anastomotic leak [odds ratio (OR): 15.50; 95% confidence interval (CI): 4.81-43.71; P<0.01]. Conclusions: PIMA is feasible, safe to perform, and demonstrated a leak rate less than half that of TMA in this study. PIMA may represent a superior alternative to standard esophagogastric cervical anastomosis techniques. Larger sample size and long-term survival are required to fully evaluate PIMA.

Spatial Positioning and Matrix Programs of Cancer-Associated Fibroblasts Promote T-cell Exclusion in Human Lung Tumors.

It is currently accepted that cancer-associated fibroblasts (CAF) participate in T-cell exclusion from tumor nests. To unbiasedly test this, we used single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors. We identified four main CAF populations, two of which are associated with T-cell exclusion: (i) MYH11+αSMA+ CAF, which are present in early-stage tumors and form a single cell layer lining cancer aggregates, and (ii) FAP+αSMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both populations orchestrate a particular structural tissue organization through dense and aligned fiber deposition compared with T cell-permissive CAF. Yet they produce distinct matrix molecules, including collagen IV (MYH11+αSMA+ CAF) and collagen XI/XII (FAP+αSMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T-cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors. SIGNIFICANCE: The cellular and molecular programs driving T-cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T-cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to developing new strategies targeting T cell-excluding CAF. See related commentary by Sherman, p. 2501. This article is highlighted in the In This Issue feature, p. 2483.

Comparison of lung cancer aggressiveness in patients who never smoked compared to those who smoked.

OBJECTIVES: To determine whether radiographic measures of tumor aggressiveness differ by smoking status. MATERIALS AND METHODS: All patients diagnosed with non-small-cell lung cancer(NSCLC) ≤ 30 mm in maximum diameter, without clinical evidence of metastasis who had both pre-treatment PET scans and two CT scans at least 90 days apart in a prospective cohort, the Initiative for Early Lung Cancer Research on Treatment(IELCART) at Mount Sinai between 2016 and 2020 were identified. Comparison of two measures of tumor aggressiveness, positron emission tomography(PET) SUVmax and tumor volume doubling time(VDT) by smoking status was performed. RESULTS: Of 417 patients identified, 158 patients had pre-treatment PET scans and at least two CT scans available. The two measures of tumor aggressiveness, SUVmax and VDT values were significantly different between patients who had never smoked and those who smoked: patients who never smoked had lower median SUVmax[2.5(IQR: 1.1-4.8) vs. 4.2(IQR:2.1-9.2),p = 0.002] and longer median VDT[(372.6 days vs. 225.6 days,p = 0.001)] compared to those who smoked. Using multivariable analyses, when adjusting for age and sex alone, SUVmax(p = 0.004) and VDT(p = 0.0001) remained significantly different by smoking status. The final multivariable analysis, adjusted for all three co-variates(sex, age and tumor histology) showed no significant difference in SUVmax and VDT by smoking status [SUVmax(p = 0.25) and VDT(p = 0.06)]. CONCLUSION: Smoking history does not influence VDT or PET SUVmax measures of lung cancer aggressiveness.