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Abstract Neoadjuvant immunochemotherapy (nICT) has dramatically changed the treatment landscape of operable esophageal squamous cell carcinoma (ESCC), but factors influencing tumor response to nICT are not well understood. Here, using single-cell RNA sequencing paired with T cell receptor sequencing, we profile tissues from ESCC patients accepting nICT treatment and characterize the tumor microenvironment context. CXCL13+CD8+ Tex cells, a subset of exhausted CD8+ T cells, are revealed to highly infiltrate in pre-treatment tumors and show prominent progenitor exhaustion phenotype in post-treatment samples from responders. We validate CXCL13+CD8+ Tex cells as a predictor of improved response to nICT and reveal CXCL13 to potentiate anti-PD-1 efficacy in vivo. Post-treatment tumors from non-responders are enriched for CXCL13+CD8+ Tex cells with notably remarkable exhaustion phenotype and TNFRSF4+CD4+ Tregs with activated immunosuppressive function and a significant clone expansion. Several critical markers for therapeutic resistance are also identified, including LRRC15+ fibroblasts and SPP1+ macrophages, which may recruit Tregs to form an immunosuppressive landscape. Overall, our findings unravel immune features of distinct therapeutic response to nICT treatment, providing a rationale for optimizing individualized neoadjuvant strategy in ESCC.

Abstract Background In China, real‐world data on surgical challenges and postoperative complications after neoadjuvant immunotherapy of lung cancer are limited. Methods Patients were retrospectively enrolled from January 2018 to January 2023, and their clinical and pathological characters were subsequently analyzed. Surgical difficulty was categorized into a binary classification according to surgical duration: challenging or routine. Postoperative complications were graded using Clavien–Dindo grades. Logistic regression was used to identify risk factors affecting the duration of surgery and postoperative complications greater than Clavien–Dindo grade 2. Results In total, 261 patients were included. Of these, stage III patients accounted for 62.5% (163/261) at initial diagnosis, with 25.3% (66/261) at stage IIIB. Central‐type non‐small‐cell lung cancer accounted for 61.7% (161/261). One hundred and forty patients underwent video‐assisted thoracoscopic surgery and lobectomy accounted for 53.3% (139/261) of patients. Surgical time over average duration was defined as challenging surgeries, accounting for 43.7%. The postoperative complications rate of 261 patients was only 22.2%. Smoking history (odds ratio [OR] = 9.96, 95% [CI] 1.15–86.01, p = 0.03), chemoimmunotherapy (OR = 2.89, 95% CI 1.22–6.86, p = 0.02), and conversion to open surgery (OR = 11.3, 95% CI 1.38–92.9, p = 0.02) were identified as independent risk factors for challenging surgeries, while pneumonectomy (OR = 0.36, 95% CI 0.15–0.86, p= 0.02) was a protective factor. Meanwhile, pneumonectomy (OR = 7.51, 95% CI 2.40–23.51, p

Abstract Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher’s exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher’s exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

Abstract Introduction The 8th edition lung cancer staging system was the first to describe the detailed diagnosis and staging of multiple primary lung cancers (MPLC). However, the characteristics and prognosis of MPLC categorized according to the new system have not been evaluated. Method We retrospectively analyzed data from surgically treated MPLC patients in a single center from 2011 to 2013 and explored the characteristics and outcomes of different MPLC disease patterns. Results In total, 202 surgically treated MPLC patients were identified and classified into different groups according to disease categories and diagnostic time (multifocal ground glass/lepidic (GG/L) nodules: n = 139, second primary lung cancer (SPLC): n = 63, simultaneous MPLC (sMPLC): n = 171, and metachronous MPLC (mMPLC): n = 31). There were significant differences in clinical characteristics between SPLC and GG/L nodule patients and simultaneous and metachronous MPLC patients. The overall 1-, 3-, and 5-year lung cancer-specific survival rates of MPLC were 97.98%, 90.18%, and 82.81%, respectively. Five-year survival was better in patients with multiple GG/L nodules than in those with SPLC (87.94% vs. 71.29%, P

Background Neoadjuvant anti-programmed cell death protein-1 (PD-1) therapy exhibits potential in treating resectable non-small cell lung cancer (NSCLC). Previously, we have reported the 3-year clinical outcomes of this trial, implying the effectiveness and feasibility of neoadjuvant sintilimab monotherapy. However, the long-term prognosis of patients receiving neoadjuvant mono-immunotherapy has yet to be elucidated.Methods For patients with stage IA-IIIB NSCLC, two doses of sintilimab (200 mg) were administered intravenously in the neoadjuvant setting. The 5-year event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) were assessed in these updated results. The predictive role of specific biomarkers in neoadjuvant immunotherapy was also explored.Results With a median follow-up of 61.0 months, 5-year DFS and OS rates of patients who underwent R0 resection were 65.7% and 80.4%, respectively. The 5-year DFS and OS rates of patients with positive programmed death-ligand 1 (PD-L1) expression were 71.9% and 90.9%, respectively. The presence of PD-L1 positivity (tumor proportion score ≥1%) showed a tendency toward the promising prognosis (OS, HR, 0.143; 95% CI: 0.027 to 0.743), especially for those who did not achieve pathological complete response (pCR). In addition, tumor mutation burden was positively correlated with a favorable prognosis. A total of 10 recurrences and 5 subsequent deaths were identified within the 5-year follow-up, with lung metastasis being the predominant.Conclusions These updated analyses were the first to unveil the 5-year survival benefits of neoadjuvant sintilimab monotherapy, implying the potential value of PD-1 inhibitors in neoadjuvant therapy.

Abstract Background Radiomics is increasingly utilized to distinguish pulmonary nodules between lung adenocarcinoma (LUAD) and tuberculosis (TB). However, it remains unclear whether different segmentation criteria, such as the inclusion or exclusion of the cavity region within nodules, affect the results. Methods A total of 525 patients from two medical centers were retrospectively enrolled. The radiomics features were extracted according to two regions of interest (ROI) segmentation criteria. Multiple logistic regression models were trained to predict the pathology: (1) The clinical model relied on clinical‐radiological semantic features; (2) The radiomics models (radiomics+ and radiomics−) utilized radiomics features from different ROIs (including or excluding cavities); (3) the composite models (composite+ and composite−) incorporated both above. Results In the testing set, the radiomics+/− models and the composite+/− models still possessed efficient prediction performance (AUC ≥ 0.94), while the AUC of the clinical model was 0.881. In the validation set, the AUC of the clinical model was only 0.717, while that of the radiomics+/− models and the composite+/− models ranged from 0.801 to 0.825. The prediction performance of all the radiomics+/− and composite+/− models were significantly superior to that of the clinical model (p 0.05). Conclusions The present study established a machine learning‐based radiomics strategy for differentiating LUAD from TB lesions. The ROI segmentation including or excluding the cavity region may exert no significant effect on the predictive ability.

Summary: Background: In recent years, a growing number of patients with multiple primary lung cancer (MPLC) are being diagnosed, and a subset of these patients is found to have a large number of lesions at the time of diagnosis, which are referred to as ‘super MPLC’. Methods: Here, we perform whole exome sequencing (WES) and immunohistochemistry (IHC) analysis of PD-L1 and CD8 on 212 tumor samples from 42 patients with super MPLC. Findings: We report the genomic alteration landscape of super MPLC. EGFR, RBM10 and TP53 mutation and TERT amplification are important molecular events in the evolution of super MPLC. We propose the conception of early intrapulmonary metastasis, which exhibits different clinical features from conventional metastasis. The IHC analyses of PD-L1 and CD8 reveal a less inflamed microenvironment of super MPLC than that of traditional non-small cell lung cancer (NSCLC). We identify the potentially susceptible germline mutations for super MPLC. Interpretation: Our study depicts the genomic characteristics and immune landscape, providing insights into the pathogenesis and possible therapeutic guidance of super MPLC. Funding: A full list of funding bodies that supported this study can be found in the Acknowledgements section.

Abstract Multimodal epigenetic characterization of cell-free DNA (cfDNA) could improve the performance of blood-based early cancer detection. However, integrative profiling of cfDNA methylome and fragmentome has been technologically challenging. Here, we adapt an enzyme-mediated methylation sequencing method for comprehensive analysis of genome-wide cfDNA methylation, fragmentation, and copy number alteration (CNA) characteristics for enhanced cancer detection. We apply this method to plasma samples of 497 healthy controls and 780 patients of seven cancer types and develop an ensemble classifier by incorporating methylation, fragmentation, and CNA features. In the test cohort, our approach achieves an area under the curve value of 0.966 for overall cancer detection. Detection sensitivity for early-stage patients achieves 73% at 99% specificity. Finally, we demonstrate the feasibility to accurately localize the origin of cancer signals with combined methylation and fragmentation profiling of tissue-specific accessible chromatin regions. Overall, this proof-of-concept study provides a technical platform to utilize multimodal cfDNA features for improved cancer detection.

Introduction: Oesophageal cancer is a prevalent and deadly cancer around the world. Objectives: We aimed to present a comprehensive analysis of the global geographic patterns and temporal trends in the mortality and incidence of oesophageal cancer. Methods: The mortality and incidence data of oesophageal cancer in 2020 were obtained from the GLOBOCAN database. Based on World Health Organization (WHO) mortality database and the Cancer Incidence in Five Continents (CI5), we also retrieved the mortality and incidence age-standardized rates (ASRs) of oesophageal cancer. The average annual percentage changes (AAPCs) of mortality and incidence were calculated using the joinpoint regression analysis. Results: Globally, 0.54 million deaths and 0.6 million new cases were identified in 2020. In the majority of countries of South America and Asia, the mortality and incidence trends have substantially decreased, but trends in European countries have varied. The prevalence in European nations varied, but the incidence in most other continents decreased dramatically. In terms of mortality, the global average rate was 5.6 per 100000, ranging from 16.7 (Malawi) to 0.28 (Belize). European countries varied in mortality, such as Norway (AAPC, male: 0.68; female: 0.89) and Ireland (AAPC, male: −0.96; female: −1.52). Most non-European countries saw large decreases in mortality, such as Singapore (AAPC, male: −4.78; female: −6.89). The elderly had more noticeable trends in mortality and incidence in most countries. Conclusions: We have identified different trends in mortality and incidence among European countries, whereas declining trends were identified in most non-European countries. However, increasing trends were identified in specific subgroups of some countries, such as men in Thailand. For populations with rising mortality and incidence trends, more preventative efforts are required.

Abstract Background Locoregional recurrence is of high risk and is associated with a poor prognosis in terms of OS for non‐small cell lung cancer (NSCLC). Local control is essential for radical cure of NSCLC. Previous studies have investigated the clinicopathological risk factors for locoregional recurrence, but the genomic biomarkers associated with locoregional recurrence have been inadequately studied. Methods A total of 118 patients who underwent tumor resection with mutation‐detected tumor specimens were included. Tumor samples at surgery and pretreatment/postoperative blood samples were collected for mutational profiling. Results Among 48 patients with disease recurrence, 46% developed locoregional recurrence (LR) and 75% developed distant metastasis (DM). The 3‐year actuarial risk of LR and DM was 25% and 43%, respectively. The first sites of failure were locoregional only (29%), locoregional and distant (10%), and distant only (61%). Patients with LR showed significantly higher ctDNA level than those with only DM at the time of initial recurrence. On multivariate analysis of baseline risk factors, the presence of allele frequency heterogeneity and baseline ctDNA shedding were found to be independently associated with a higher risk of LR. Patients with disruptive TP53 mutations had significantly lower LR‐free survival as compared to patients with wild‐type TP53 or nondisruptive mutations. EGFR mutations showed a favorable prognostic value for LR and is not induced by EGFR tyrosine kinase inhibitor therapy. Both disruptive TP53 mutation and EGFR mutation remained the significant prognostic factor after adjustment for histological type, pathologic nodal stage and adjuvant therapy. Conclusions Nearly half of disease recurrences after surgery for NSCC involved locoregional sites. We identified genomic biomarkers from baseline tumor and ctDNA samples which showed promising prognostic value for LR only. This can help identify patients who had a higher risk of locoregional recurrence regardless of the risk of distant metastasis.

Background: Whether minimally invasive esophagectomy (MIE) is superior to open esophagectomy (OE) in the treatment of esophageal squamous cell carcinoma (ESCC) is still uncertain. Therefore, this multicenter prospective study aimed to compare MIE with OE in postoperative parameters and long-term survival. Methods: All hospitalized patients with cT1b-3N0–1M0 thoracic ESCC treated by MIE or OE were enrolled from 19 selected centers from April 1, 2015 to December 31, 2018. The propensity score matching (PSM) was performed to minimize the selection bias. The basic clinicopathological characteristics and 3-year overall survival (OS) as well as disease-free survival (DFS) of two groups were compared by R version 3.6.2. Results: MIE were performed in 1,387 patients and OE in 335 patients. 335 cases in each group were finally matched by PSM, and no significant differences in the essential demographic characteristics were observed between the MIE and OE groups after PSM. Compared with OE, MIE had significantly less intraoperative bleeding, less total drainage volume, shorter postoperative hospital stay, and harvested significantly more lymph nodes (LNs) (all P < 0.001). There were no significant differences in the major postoperative complications and death rates between MIE and OE. The 3-year OS and DFS were 77.0% and 68.1% in the MIE group versus 69.3% and 60.9% in the OE group (OS: P = 0.03; DFS: P = 0.09), and the rates were 75.1% and 66.5% in the MIE group versus 66.9% and 58.6% in the OE group for stage cII patients (OS: P = 0.04, DFS: P = 0.09), respectively. Conclusions: Compared with OE, MIE is a safe and effective treatment approach with similar mortality and morbidity. It has the advantages in harvesting more LNs, improving postoperative recovery and survival of stage cII ESCC patients.

Abstract Background A Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC). Methods Sixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m2 IV, day 1/8) and cisplatin (75 mg/m2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety. Results A total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1–84.0% vs. 42.4–78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1–60.9% vs. 13.5–47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature. Conclusions The neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates. Trial registration Registration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma. Registration number: NCT04460066.

Abstract Objectives This study aims to characterize the specific organ metastatic rates in lung adenocarcinoma (LUAD) patients and identify the prognosis‐associated factors. Methods Using the Surveillance, Epidemiology and End Results database, 40 117 patients diagnosed with positive histology as the only primary LUAD were included. We stratified patients by diagnosed year, age, sex, race/ethnicity, marital status, insurance, location, TNM stage, organ‐specific metastases, surgery, chemotherapy, and radiation therapy. We performed multivariable logistic and Cox regression to identify the factors associated with the presence of specific organ metastases and prognosis predictors. Results For the 40 117 LUAD patients, 43.69%, 26.25%, 19.66%, 10.60%, and 17.89% had specific organ, bone, brain, liver, and lung metastases, respectively. The average survival in patients with organ metastases was 12.19 months, compared to 36.40 months in patients without metastases. In different kinds of metastatic organ cohorts, the longest average survival was 12.60 months in the lung metastases cohort, and the shortest was 8.43 months in liver metastases cohort. In total, 571 patients with metastases received surgery, which was significantly associated with decreased mortality (hazard ratio 1.82, 95% confidence interval 1.65–2.01, p

Abstract Introduction With the advancements in early diagnosis, more and more patients with multiple primary lung cancer (MPLC) have been identified. However, the progression of MPLC involves complex changes in cell composition and metabolic function, which remains largely controversial. Objective Our study aims to comprehensively reveal the cellular characteristics and inter‐cellular connections of MPLC. Methods We performed scRNA‐seq from 23 samples of six MPLC patients, combined with bulk whole‐exome sequencing. We performed trajectory analysis to investigate the transition of different cell types during the development of MPLC. Results A total of 1 67 397 cells were sequenced derived from tumour and adjacent tissues of MPLC patients, and tumour, normal, immune and stromal cells were identified. Two states of epithelial cells were identified, which were associated with immune response and cell death, respectively. Furthermore, both CD8+ naïve and memory T cells participated in the differentiation of CD8+ T cells. The terminal states of CD8+ T cells were exhausted T cells and cytotoxic T cells, which positively regulated cell death and were implicated in the regulation of cytokine production, respectively. Two main subpopulations of B cells with distinct functions were identified, which participate in the regulation of the immune response and antigen presentation, respectively. In addition, we found a specific type of endothelial cells that were abundant in tumour samples, with an increasing trend from normal to tumour samples. Conclusions Our study showed the comprehensive landscape of different cells of MPLC, which might reveal the key cellular mechanisms and, therefore, may provide new insights into the early diagnosis and treatment of MPLC.

Neoadjuvant immunotherapy has brought new hope for patients with non-small cell lung cancer (NSCLC). However, limited by the lack of clinically feasible markers, it is still difficult to select NSCLC patients who respond well and to predict patients’ clinical outcomes before the treatment. Before the treatment, we isolated plasma extracellular vesicles (EVs) from three cohorts (discovery, training and validation) of 78 NSCLC patients treated with neoadjuvant immunotherapy. To identify differentially-expressed EV long RNAs (exLRs), we employed RNA-seq in the discovery cohort. And we subsequently used qRT-PCR to establish and validate the predictive signature in the other two cohorts. We have identified 8 candidate exLRs from 27 top-ranked exLRs differentially expressed between responders and non-responders, and tested their expression with qRT-PCR in the training cohort. We finally identified H3C2 (P = 0.029), MALAT1 (P = 0.043) and RPS3 (P = 0.0086) significantly expressed in responders for establishing the predictive signature. Integrated with PD-L1 expression, our signature performed well in predicting immunotherapeutic responses in the training (AUC=0.892) and validation cohorts (AUC=0.747). Furthermore, our signature was proven to be a predictor for favorable prognosis of patients treated with neoadjuvant immunotherapy, which demonstrates the feasibility of our signature in clinical practices (P = 0.048). Our results demonstrate that the exLR-based signature could accurately predict responses to neoadjuvant immunotherapy and prognosis in NSCLC patients.

Purpose: The aim of present study was to investigate the efficiency of 18F-FDG uptake in predicting major pathological response (MPR) in resectable non-small cell lung cancer (NSCLC) patients with neoadjuvant immunotherapy. Methods: A total of 104 patients with stage I-IIIB NSCLC were retrospectively derived from National Cancer Center of China, of which 36 cases received immune checkpoint inhibitors (ICIs) monotherapy (I-M) and 68 cases with ICI combination therapy (I-C). 18F-FDG PET-CT scans were performed at baseline and after neoadjuvant therapy (NAT). Receiver‐operating characteristic (ROC) curve analyses were conducted and area under ROC curve (AUC) was calculated for biomarkers including maximum standardized uptake value (SUVmax), inflammatory biomarkers, tumor mutation burden (TMB), PD-L1 tumor proportion score (TPS) and iRECIST. Results: Fifty-four resected NSCLC tumors achieved MPR (51.9%, 54/104). In both neoadjuvant I-M and I-C cohorts, post-NAT SUVmax and the percentage changes of SUVmax (ΔSUVmax%) were significantly lower in the patients with MPR versus non-MPR (p < 0.01), and were also negatively correlated with the degree of pathological regression (p < 0.01). The AUC of ΔSUVmax% for predicting MPR was respectively 1.00 (95% CI: 1.00–1.00) in neoadjuvant I-M cohort and 0.94 (95% CI: 0.86–1.00) in I-C cohort. Baseline SUVmax had a statistical prediction value for MPR only in I-M cohort, with an AUC up to 0.76 at the threshold of 17.0. ΔSUVmax% showed an obvious advantage in MPR prediction over inflammatory biomarkers, TMB, PD-L1 TPS and iRECIST. Conclusion: 18F-FDG uptake can predict MPR in NSCLC patients with neoadjuvant immunotherapy.

Abstract Background The most common form of treatment for non-metastatic lung cancer is surgery-based combination therapy, which may also include adjuvant radiotherapy or chemotherapy. Second primary malignancies (SPMs) are uncommon but significant radiation side effects in patients with resectable lung cancer, and SPMs have not been adequately investigated. Our study aims to assess the correlations of radiotherapy with the development of SPMs in patients with resectable lung cancer. Methods We screened for any primary malignancy that occurred more than five years after the diagnosis of resectable lung cancer. Based on the large cohort of the Surveillance, Epidemiology and End Results database, radiotherapy-correlated risks were estimated using the Poisson regression analysis and the cumulative incidence of SPMs was calculated using Fine-Gray competing risk regression analysis. Results Among the 62,435 patients with non-metastatic lung cancer undergoing surgery, a total of 11,341 (18.16%) patients have received radiotherapy. Our findings indicated that radiotherapy was substantially related to a high risk of main second solid malignancies (RR = 1.21; 95%CI, 1.08 to 1.35) and a negligible risk of main second hematologic malignancies (RR = 1.08; 95%CI, 0.84 to 1.37). With the greatest number of patients, the risk of acquiring a second primary gastrointestinal cancer was the highest overall (RR = 1.77; 95 percent CI, 1.44 to 2.15). The cumulative incidence and standardized incidence ratios of SPMs revealed similar findings. Furthermore, the young and the elderly may be more vulnerable, and the highest risk of acquiring most SPMs was seen more than ten years after lung cancer diagnosis. Additionally, more attention should be paid to the second primary gastrointestinal cancer in young individuals with resectable lung cancer. Conclusion After receiving radiotherapy, an increased risk of developing second primary solid and gastrointestinal cancers was observed for patients with resectable lung cancer. The prevention of SPMs associated with radiotherapy requires further attention.

Abstract Small-cell lung cancer (SCLC) is the most aggressive and lethal subtype of lung cancer, for which, better understandings of its biology are urgently needed. Single-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment (TME) and investigate their roles in tumorigenic processes. Here, we performed high-precision single-cell transcriptomic analysis of ~5000 individual cells from primary tumors (PTs) and matched normal adjacent tissues (NATs) from 11 SCLC patients, including one patient with both PT and relapsed tumor (RT). The comparison revealed an immunosuppressive landscape of human SCLC. Malignant cells in SCLC tumors exhibited diverse states mainly related to the cell cycle, immune, and hypoxic properties. Our data also revealed the intratumor heterogeneity (ITH) of key transcription factors (TFs) in SCLC and related gene expression patterns and functions. The non-neuroendocrine (non-NE) tumors were correlated with increased inflammatory gene signatures and immune cell infiltrates in SCLC, which contributed to better responses to immune checkpoint inhibitors. These findings indicate a significant heterogeneity of human SCLC, and intensive crosstalk between cancer cells and the TME at single-cell resolution, and thus, set the stage for a better understanding of the biology of SCLC as well as for developing new therapeutics for SCLC.

Esophageal squamous cell carcinoma (ESCC) is invasive cancer and the complex mechanisms underlying carcinogenesis remain unclear. Extracellular vesicles (EVs), secreted by most cell types, serve as a critical factor in tumorigenesis via intercellular communications. Our study aims to investigate the cellular origin of EVs in ESCC, and unveil the unknown molecular and cellular mechanisms underlying cell-cell communications. Six ESCC patients were enrolled and single-cell RNA sequencing (scRNA-seq) analyses were conducted to screen different cell subpopulations. The genetic origin of EVs was tracked using the supernatant from different cellular extracts. Nanoparticle tracking analysis (NTA), western blot analysis, and transmission electron microscopy (TEM) were performed for validation. Using scRNA-seq analysis, eleven cell subpopulations were identified in ESCC. Differences in gene expression in EVs between malignant and non-malignant esophageal tissues were found. Our findings demonstrated that epithelial cells releasing EVs were the most prevalent in malignant tissues, while endothelial cells and fibroblasts releasing EVs were predominant in non-malignant tissues. Furthermore, the high levels of gene expression in EVs released from these cells were correlated significantly with a worse prognosis. Our findings revealed the genetic origin of EVs in malignant and non-malignant esophageal tissues and provided a comprehensive overview of the associated cell-cell interactions in ESCC.

Abstract Background Except for B7-CD28 family members, more novel immune checkpoints are being discovered. They are closely associated with tumor immune microenvironment and regulate the function of many immune cells. Various cancer therapeutic studies targeting these novel immune checkpoints are currently in full swing. However, studies concerning novel immune checkpoints phenotypes and clinical significance in lung adenocarcinoma (LUAD) are still limited. Methods We enrolled 1883 LUAD cases from nine different cohorts. The samples from The Cancer Genome Atlas (TCGA) were used as a training set, whereas seven microarray data cohorts and an independent cohort with 102 qPCR data were used for validation. The immune profiles and potential mechanism of the system were also explored. Results After univariate Cox proportional hazards regression and stepwise multivariable Cox analysis, a novel immune checkpoints-based system (LTA, CD160, and CD40LG) were identified from the training set, which significantly stratified patients into high- and low-risk groups with different survivals. Furthermore, this system has been well validated in different clinical subgroups and multiple validation cohorts. It also acted as an independent prognostic factor for patients with LAUD in different cohorts. Further exploration suggested that high-risk patients exhibited distinctive immune cells infiltration and suffered an immunosuppressive state. Additionally, this system is closely linked to various classical immunotherapy biomarkers. Conclusion we constructed a novel immune checkpoints-based system for LUAD, which predicts prognosis and immunotherapeutic implications. We believe that these findings will not only aid in clinical management but will also shed some light on screening appropriate patients for immunotherapy.

Abstract Background Recent studies indicated that T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) and cluster of differentiation 47 (CD47) have emerged as new potential immunotherapy targets. However, the roles of TIGIT and CD47 in lung squamous cell carcinoma (LUSC) have not been fully illustrated. Methods The specimens and clinicopathological information from 190 LUSC patients who underwent surgeries in our center were retrospectively collected. Immunohistochemical staining for TIGIT and CD47 was conducted. Transcriptional and clinical data of 479 LUSC were downloaded from The Cancer Genome Atlas (TCGA). Results In the TCGA LUSC cohort, 142 (29.6%) cases were TIGIT/CD47 dual high expression at RNA level. The expression levels of TIGIT and CD47 were significantly correlated (p

Abstract Early detection can benefit cancer patients with more effective treatments and better prognosis, but existing early screening tests are limited, especially for multi-cancer detection. This study investigated the most prevalent and lethal cancer types, including primary liver cancer (PLC), colorectal adenocarcinoma (CRC), and lung adenocarcinoma (LUAD). Leveraging the emerging cell-free DNA (cfDNA) fragmentomics, we developed a robust machine learning model for multi-cancer early detection. 1,214 participants, including 381 PLC, 298 CRC, 292 LUAD patients, and 243 healthy volunteers, were enrolled. The majority of patients (N = 971) were at early stages (stage 0, N = 34; stage I, N = 799). The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio while maintaining the ratio for the major histology subtypes. An ensemble stacked machine learning approach was developed using multiple plasma cfDNA fragmentomic features. The model was trained solely in the training cohort and then evaluated in the test cohort. Our model showed an Area Under the Curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals. At 95.0% specificity, the sensitivity of detecting all cancer reached 95.5%, while 100%, 94.6%, and 90.4% for PLC, CRC, and LUAD, individually. The cancer origin model demonstrated an overall 93.1% accuracy for predicting cancer origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Our model sensitivity is consistently high for early-stage and small-size tumors. Furthermore, its detection and origin classification power remained superior when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). In conclusion, we have incorporated plasma cfDNA fragmentomics into the ensemble stacked model and established an ultrasensitive assay for multi-cancer early detection, shedding light on developing cancer early screening in clinical practice.

ObjectivesThis study aimed to evaluate the prognostic significance of the eighth edition TNM stage criteria in patients with combined small-cell lung cancer (C-SCLC) on a population level.MethodsUsing the Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with C-SCLC (histology code 8245) between the years 2004 and 2015 were identified. We performed a Kaplan–Meier analysis and used the multivariable cox regression proportional hazards model to obtain prognostic overall survival estimates for each group of patients.ResultsA total of 477 patients diagnosed with C-SCLC were identified. The T, N, M, TNM, and combined TNM stage status of the eighth edition were all significant prognostic factors for patients’ overall survivals, with the best discrimination identified in the combined stages. Surgery was also found to be a prognostic factor (HR =1.95, 95%CI =1.49-2.56, p

Abstract Anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy has dramatically changed the therapeutic landscape of inoperable non-small cell lung cancer (NSCLC), and has been included in first-line treatments. Sintilimab is a domestic anti-PD-1 monoclonal antibody in China that has received approvals from the National Medical Products Administration to treat classical Hodgkin’s lymphoma, hepatocellular carcinoma, and squamous and non-squamous NSCLC. In a prospective clinical study we led, neoadjuvant sintilimab has led to major and complete pathologic responses, which are recommended as surrogate endpoints for neoadjuvant immunotherapy; however, its effect remains inconclusive in pulmonary ground glass nodules. Meanwhile, combination plans seem more likely to be satisfying therapeutic options. Specifically, sintilimab plus platinum-based chemotherapy plans conferred better anti-tumor efficacy and clinical benefits compared to chemotherapy alone, which led to their approval in China and the acceptance of a biological license application in the US. Besides, the combination with other plans, such as docetaxel, cytokine-induced killer cell immunotherapy, radiation therapy, and anlotinib have also shown promising anti-tumor efficacy, with acceptable toxicities, and are therefore worth further exploration. In addition, several clinical trials on NSCLC at our center are ongoing. In general, sintilimab and its combinatorial plans were effective and well tolerated, but the treatment requires appropriate timing; pathologic responses can be surrogate endpoints for neoadjuvant immunotherapy, while more effective biomarkers are warranted. This study provides an overview of sintilimab-based clinical trials on NSCLC, and may support further investigation of sintilimab in future clinical trials.

Abstract Several clinical trials have shown the safety and effectiveness of PD-1/PD-L1 inhibitors in neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC). However, 18–83% patients can benefit from it. In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden, copy number alteration (CNA, including copy number gain and loss) burden with the pathologic response to neoadjuvant PD-1 blockade and investigate the changes in the tumor immune microenvironment (TIME) during neoadjuvant immunotherapy in NSCLC. Pre-immunotherapy treatment tumor samples from twenty-nine NSCLC patients who received neoadjuvant immunotherapy with sintilimab, an anti-PD-1 drug, were subjected to targeted DNA sequencing and PD-L1 immunochemistry staining. The pathological response was positively correlated with tumor proportion score (TPS) of PD-L1 and negatively correlated with copy number gain (CNgain) burden. Of note, the combination of CNgain burden and TPS can better stratify major pathological response (MPR) patients than did CNgain or TPS alone. Whereas, TMB showed a limited correlation with pathological regression. Additionally, PD-1 blockade led to an increase in CD8+PD-1−T cells which was clinically relevant to MPR as evaluated by multiplex immunofluorescence. A significant reduction in CD19+ cells was observed in the Non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC. Together, our study provides new data for the correlation of PD-L1 expression and genomic factors with drug response in neoadjuvant immunotherapy settings in NSCLC. The changes of TIME may provide novel insight into the immune responses to neoadjuvant anti-PD-1 therapy.

Abstract Background The function of spindle apparatus coiled-coil protein 1 (SPDL1) as a cancer-promoting gene has been reported in a number of studies. However, the pan-cancer analysis of SPDL1 is still lacking. Here, we performed this pan-cancer analysis to evaluate the expression and prognostic value of SPDL1 and gain insights into the association between SPDL1 and immune infiltration. Methods In this study, based on the datasets of The cancer genome atlas (TCGA), Gene expression omnibus (GEO), The Genotype-Tissue Expression (GTEx) and Clinical Proteomic Tumor Analysis Consortium (CPTAC), we used R4.1.0 software and the online tools, including TIMER2.0, GEPIA2, cBioPortal, Modbase, UALCAN, MEXPRESS, STRING, Ensembl, NCBI, HPA, Oncomine, PhosphoNET and the Kaplan-Meier plotter, to explore the potential oncogenic roles of SPDL1. The expression of SPDL1 was also further verified by immunohistochemistry (IHC) in lung adenocarcinoma (LUAD) tissues. Results SPDL1 was overexpressed in most tumors compared with adjacent normal tissues, and SPDL1 expression was significantly correlated with the prognosis in most tumor types. The main type of genetic mutation of SPDL1 was missense mutation and the frequency of R318Q/W mutation was highest (4/119). The expression of SPDL1 was closely associated with genomic instability. The SPDL1 phosphorylation levels in S555 was enhanced in ovarian cancer. The SPDL1 expression was positively correlated with the immune infiltration of CD8+ T-cells and cancer-associated fibroblasts (CAFs) in most of the tumor types. Nuclear division, organelle fission and chromosome segregation were involved in the functional mechanisms of SPDL1. Conclusions These findings suggested that SPDL1 might serve as a biomarker for poor prognosis and immune infiltration in cancers, shedding new light on therapeutics of cancers.

In recent decades, multiple primary lung cancer (MPLC) has been increasingly prevalent in clinical practice. However, many details about MPLC have not been completely settled, such as understanding the driving force, clinical management, pathological mechanisms, and genomic architectures of this disease. From the perspective of diagnosis and treatment, distinguishing MPLC from lung cancer intrapulmonary metastasis (IPM) has been a clinical hotpot for years. Besides, compared to patients with single lung lesion, the treatment for MPLC patients is more individualized, and non-operative therapies, such as ablation and stereotactic ablative radiotherapy (SABR), are prevailing. The emergence of next-generation sequencing has fueled a wave of research about the molecular features of MPLC and advanced the NCCN guidelines. In this review, we generalized the latest updates on MPLC from definition, etiology and epidemiology, clinical management, and genomic updates. We summarized the different perspectives and aimed to offer novel insights into the management of MPLC.

Abstract Background Patients with small-cell lung cancer (SCLC) are burdened by limited treatment options and the disease’s dismal prognosis. Long non-coding RNAs (lncRNAs) are essential regulators of genetic alteration and are actively involved in tumor immunity. However, few studies have examined interactions between immune genes and lncRNAs in SCLC. Methods Immune-related lncRNA (irlncRNA) expression profiles and their clinical significance were explored. We enrolled 227 patients with SCLC, including 79 cases from GSE65002 and 148 cases from a validation cohort with corresponding qPCR data. The least absolute shrinkage and selection operator (LASSO) model was applied to identify prognostic irlncRNAs for an irlncRNA-based SCLC signature. We additionally investigated the potential mechanisms and immune landscape of the signature using bioinformatics methods. Results An irlncRNA signature including 8 irlncRNAs (ENOX1-AS1, AC005162, LINC00092, RPL34-AS1, AC104135, AC015971, AC126544, AP001189) was established for patients with SCLC in the training cohort. Low-risk patients were more likely to benefit from chemotherapy and achieve a favorable prognosis. The signature was also well-validated in the validation cohort and various clinical subgroups. Compared to other clinical parameters, the irlncRNA signature exhibited superior predictive performance for chemotherapy response and prognosis. The signature was as an independent prognostic factor in the training and validation cohorts. Interestingly, low-risk patients showed an activated immune phenotype. Conclusion We constructed the first irlncRNA-based signature for chemotherapy efficacy and outcome prediction. The irlncRNA signature is a reliable and robust prognostic classifier that could be useful for clinical management and determination of potential chemotherapy benefit for patients with SCLC.

ObjectivesWith low-dose computed tomography(CT) lung cancer screening, many studies with an increasing number of patients with ground-glass opacity (GGO) are published. Hence, the present study aimed to analyze the published studies on GGO using bibliometric analysis. The findings could provide a basis for future research in GGO and for understanding past advances and trends in the field.MethodsPublished studies on GGO were obtained from the Web of Science Core Collection. A bibliometric analysis was conducted using the R package and VOSviewer for countries, institutions, journals, authors, keywords, and articles relevant to GGO. In addition, a bibliometric map was created to visualize the relationship.ResultsThe number of publications on GGO has been increasing since 2011. China is ranked as the most prolific country; however, Japan has the highest number of citations for its published articles. Seoul National University and Professor Jin Mo Goo from Korea had the highest publications. Most top 10 journals specialized in the field of lung diseases. Radiology is a comprehensive journal with the greatest number of citations and highest H-index than other journals. Using bibliometric analysis, research topics on “prognosis and diagnosis,” “artificial intelligence,” “treatment,” “preoperative positioning and minimally invasive surgery,” and “pathology of GGO” were identified. Artificial intelligence diagnosis and minimally invasive treatment may be the future of GGO. In addition, most top 10 literatures in this field were guidelines for lung cancer and pulmonary nodules.ConclusionsThe publication volume of GGO has increased rapidly. The top three countries with the highest number of published articles were China, Japan, and the United States. Japan had the most significant number of citations for published articles. Most key journals specialized in the field of lung diseases. Artificial intelligence diagnosis and minimally invasive treatment may be the future of GGO.

ctDNA has been shown to identify minimal residual disease (MRD) and is thus dynamically monitored in different types of tumours. Here, the authors show that serial longitudinal ctDNA analysis can be used as a tool to detect MRD, inform the use of adjuvant therapy, and predict recurrence risk in lung cancer.

Abstract Background Small cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy—with or without immune checkpoint inhibitors (anti-PDs)—is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N 6-methyladenosine (m6A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m6A modification in SCLC remains poorly understood. Methods We systematically explored the molecular features and clinical significance of m6A regulators in SCLC. We then constructed an m6A regulator-based prognostic signature (m6A score) based on our examination of 256 cases with limited-stage SCLC (LS-SCLC) from three different cohorts—including an independent cohort that contained 150 cases with qPCR data. We additionally evaluated the relationships between the m6A score and adjuvant chemotherapy (ACT) benefits and the patients’ responses to anti-PD-1 treatment. Immunohistochemical (IHC) staining and the HALO digital pathological platform were used to calculate CD8+ T cell density. Results We observed abnormal somatic mutations and expressions of m6A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m6A score was generated from the significant regulators to classify patients into high- and low-score groups. In the training cohort, patients with high scores had shorter overall survival (HR, 5.19; 2.75–9.77; P < 0.001). The prognostic accuracy of the m6A score was well validated in two independent cohorts (HR 4.6, P = 0.006 and HR 3.07, P < 0.001). Time-dependent ROC and C-index analyses found the m6A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m6A score to be an independent prognostic indicator. Additionally, patients with low scores received a greater survival benefit from ACT, exhibited more CD8+ T cell infiltration, and were more responsive to cancer immunotherapy. Conclusions Our results, for the first time, affirm the significance of m6A regulators in LS-SCLC. Our multicentre analysis found that the m6A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.

Summary: Background: RNA modifications, including adenosine-to-inosine RNA editing, alternative polyadenylation, m1A and m6A, play a significant role in tumorigenesis and tumor immunity. However, the functions of RNA modification enzymes (writers) in immunotherapy and tumor microenvironment (TME) remain unknown. Methods: Nonnegative matrix factorization clustering was applied to identify RNA modification clusters in lung adenocarcinoma, one of the most prevalent subtypes of non-small cell lung cancer (NSCLC). CIBERSORT and ESTIMATE algorithms were performed to depict TME characteristics. Additionally, a scoring system called Writer-Score was established to quantify RNA modification patterns and subsequently predict clinical outcomes. We subsequently used RNA sequencing, targeted DNA sequencing and multiplex immunofluorescence to further evaluate the efficacy of Writer-Score in NSCLC patients receiving neoadjuvant immunotherapy. Findings: We identified three distinct RNA modification clusters and two DEGclusters, which were shown to be strongly associated with a variety of TME features and biological processes. Additionally, the Writer-Score served as an important factor in post-transcriptional events and immunotherapy. The Writer-Score was capable of properly predicting the prognosis of NSCLC patients receiving neoadjuvant PD-1 inhibitor therapy. Interpretation: Our work systematically analyzed four types of RNA modifications and constructed a scoring system to guide neoadjuvant immunotherapy in NSCLC, which highlighted the writers’ roles in post-transcriptional events, TME and neoadjuvant immunotherapy. Funding: A full list of funding bodies that supported this study can be found in the Acknowledgements section.

Summary: Background: The tumor microenvironment (TME) serves as an important factor in tumorigenesis and metastasis. Although distinct cell subsets can be identified via single-cell RNA sequencing (scRNA-seq), the spatial composition of cells within the TME is difficult to characterise. Methods: Tissue samples were collected from three patients with esophageal squamous cell carcinoma (ESCC), and scRNA-seq was performed to identify distinct cell subsets. In addition, a microarray-based spatial transcriptomics (ST) method was used to characterise the spatial landscape of expression data via an array of spots. Using multimodal intersection analysis (MIA) to integrate scRNA-seq and ST, the exact cellular components of the tumor and stromal regions were annotated. Findings: The subpopulations of seven stromal cells were identified within the TME of ESCC, and the architecture of scRNA-seq-determined subsets was mapped in cancer and stromal regions. The distribution of various stromal cells and their subpopulations was heterogeneous. Compared with immune cells, non-immune stromal cells were significantly enriched in the TME. Most subsets of epithelial cells were enriched in the cancer regions, whereas inflammatory cancer-associated fibroblasts were correlated with the stromal regions. Furthermore, TME features were different between metastatic and non-metastatic samples and between the primary and metastatic sites of the metastatic sample. Interpretation: This study revealed the spatial landscape of various cell subsets within the TME and the potential cross-talk among diverse cells, which provides novel insights into cancer intervention. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

PVR/TIGIT and PD-L1/PD-1 axes play essential roles in tumor immune evasion and could be potential targets for combined immunotherapy. We aimed to evaluate the expression status of the above-mentioned immune markers in lung squamous cell carcinoma (LUSC), and investigate their survival impact and relevance with the immune microenvironment and clinicopathological features. We retrospectively collected specimens from 190 LUSC patients, who underwent pulmonary surgeries, and we performed immunohistochemistry assays of PVR, TIGIT, PD-L1, PD-1 and CD8. In our cohort, the positive rate of PVR was 85.8%, which was much higher than the positive rate of PD-L1 at 26.8%. A total of 32 (16.8%) patients demonstrated co-expression of PVR/PD-L1. High TIGIT density was correlated with positive PD-L1 expression, high PD-1 density, and high CD8 density (PD-L1, P=0.033; PD-1, P

Abstract Backgroud Recent studies have indicated that programmed cell death‐ligand 1 (PD‐L1) and cluster of differentiation 47 (CD47) play an essential role in tumor immune evasion and may serve as potential targets for combined immunotherapy. The aim of our study was to evaluate the PD‐L1/CD47 expression status in lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD), and explore its survival impact and relevance with the immune microenvironment. Methods The specimens from 190 LUSC and 240 LUAD patients who underwent intent‐to‐treat surgeries were retrospectively collected for immunohistochemistry assays of PD‐L1, CD47, cluster of differentiation 8 (CD8), and cluster of differentiation 68 (CD68). Results A total of 96 (22.3%) and 296 (68.8%) cases were positive for PD‐L1 and CD47 expression, respectively, and 80 (18.6%) of them demonstrated the co‐expression of PD‐L1/CD47. The rate of PD‐L1/CD47 co‐expression was 23.7% in LUSC, significantly higher than the 14.6% in LUAD (p = 0.018). The median overall survival (OS) for all patients was 55.9 months (range 2.0–146.0 months). The univariate analysis showed that patients with positive CD47 expression (LUSC p = 0.003, LUAD p = 0.036) and PD‐L1/CD47 co‐expression (LUSC p = 0.023, LUAD p = 0.004) exhibited significantly worse prognosis. The multivariate analysis demonstrated that PD‐L1/CD47 co‐expression was an independent prognostic factor for OS (LUSC hazard ratio [HR] 1.922, 95% CI 1.245–2.969, p = 0.003; LUAD HR 1.549, 95% CI 1.015–2.364, p = 0.043). PD‐L1/CD47 co‐expression was associated with high CD8‐positive T‐lymphocyte density in LUSC (p = 0.004) and LUAD (p = 0.043), and with high CD68‐positive macrophage density in LUSC (p = 0.026). Conclusions PD‐L1/CD47 co‐expression was an independent prognostic factor for LUSC and LUAD patients and may serve as a potential predictive biomarker for combined dual‐targeting immunotherapy.

Abstract Background Published findings suggest sex differences in lung cancer risk and a potential role for sex steroid hormones. Our aim was to perform a meta-analysis to investigate the effects of sex steroid hormone exposure specifically on the risk of lung cancer in women. Methods The PubMed, MEDLINE, Web of Science, and EMBASE databases were searched. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for female lung cancer risk associated with sex steroid hormones were calculated overall and by study design, publication year, population, and smoking status. Sensitivity analysis, publication bias, and subgroup analysis were performed. Results Forty-eight studies published between 1987 and 2019 were included in the study with a total of 31,592 female lung cancer cases and 1,416,320 subjects without lung cancer. Overall, higher levels of sex steroid hormones, both endogenous (OR: 0.92, 95% CI: 0.87–0.98) and exogenous (OR: 0.86, 95% CI: 0.80–0.93), significantly decreased the risk of female lung cancer by 10% (OR: 0.90, 95% CI: 0.86–0.95). The risk of lung cancer decreased more significantly with a higher level of sex steroid hormones in non-smoking women (OR: 0.88, 95% CI: 0.78–0.99) than in smoking women (OR: 0.98, 95% CI: 0.77–1.03), especially in Asia women (OR: 0.84, 95% CI: 0.74–0.96). Conclusions Our meta-analysis reveals an association between higher levels of sex steroid hormone exposure and the decreased risk of female lung cancer. Surveillance of sex steroid hormones might be used for identifying populations at high risk for lung cancer, especially among non-smoking women.

The epitranscriptomic regulation of adenomatous polyposis coli (APC) tumour suppressor gene in cancers is unclear. Here the authors show that N6-methyladenosine methylation writer METTL3 downregulates APC by recruiting YTHDF2 for APC mRNA degradation, and that this promotes glycolysis and tumour growth in oesophageal cancers.

Primary small cell carcinoma of the oesophagus has a poor prognosis, and has not been fully characterised molecularly. Here, the authors study the disease using multi-omics technology and find frequent RB1 disruptions and similarities to small cell lung cancer, opening potential therapeutic avenues.

Summary: Background: Early diagnosis benefits lung cancer patients with higher survival, but most patients are diagnosed after metastasis. Although cell-free DNA (cfDNA) analysis holds promise, its sensitivity for detecting early-stage lung cancer is unsatisfying. We leveraged cfDNA fragmentomics to develop a predictive model for invasive stage I lung adenocarcinoma (LUAD). Methods: 292 stage I LUAD patients from three medical centers were included together with 230 healthy controls whose plasma cfDNA samples were profiled by whole-genome sequencing (WGS). Multiple cfDNA fragmentomic motif features and machine learning models were compared in the training cohort to select the best model. Model performance was assessed in the internal and external validation cohorts and an additional dataset. Findings: A logistic regression model using the 6bp-breakpoint-motif feature was selected. It yielded 98·0% sensitivity and 94·7% specificity in the internal validation cohort [Area Under the Curve (AUC): 0·985], while 92·5% sensitivity and 90·0% specificity were achieved in the external validation cohort (AUC: 0·954). It is sensitive for early-stage (100% sensitivity for minimally invasive adenocarcinoma, MIA) and

USP13 is significantly amplified in over 20% of lung cancer patients and critical for tumor progression. However, the functional role of USP13 in small cell lung cancer (SCLC) remains largely unclear. In this study, we found that the deubiquitinase USP13 is highly expressed in SCLC tumor samples and positively associated with poor prognosis in multiple cohorts. In vitro and in vivo depletion of USP13 inhibited SCLC cancer stem cells (CSCs) properties and tumorigenesis, and this inhibitory effect was rescued by reconstituted expression of wide type (WT) USP13 but not the enzyme-inactive USP13 mutant. Mechanistically, USP13 interacts with fatty acid synthase (FASN) and enhances FASN protein stability. FASN downregulation suppresses USP13-enhanced cell renewal regulator expression, sphere formation ability, and de novo fatty acids biogenesis. Accordingly, we found FASN expression is upregulated in surgical resected SCLC specimens, positively correlated with USP13, and associated with poor prognosis of SCLC patients. More importantly, the small molecule inhibitor of FASN, TVB-2640, significantly inhibits lipogenic phenotype and attenuates self-renewal ability, chemotherapy resistance and USP13-mediated tumorigenesis in SCLC. Thus, our study highlights a critical role of the USP13-FASN-lipogenesis axis in SCLC cancer stemness maintenance and tumor growth, and reveals a potential combination therapy for SCLC patients.

Natural killer (NK) cells, the effectors of the innate immune system, have a remarkable influence on cancer prognosis and immunotherapy. In this study, a total of 1,816 samples from nine independent cohorts in public datasets were enrolled. We first conducted a comprehensive analysis of single-cell RNA-sequencing data of lung adenocarcinoma (LUAD) from the Gene Expression Omnibus (GEO) database and determined 189 NK cell marker genes. Subsequently, we developed a seven-gene prognostic signature based on NK cell marker genes in the TCGA LUAD cohort, which stratified patients into high-risk and low-risk groups. The predictive power of the signature was well verified in different clinical subgroups and GEO cohorts. With a multivariate analysis, the signature was identified as an independent prognostic factor. Low-risk patients had higher immune cell infiltration states, especially CD8+ T cells and follicular helper T cells. There existed a negative association between inflammatory activities and risk score, and the richness and diversity of the T-cell receptor (TCR) repertoire was higher in the low-risk groups. Importantly, analysis of an independent immunotherapy cohort (IMvigor210) revealed that low-risk patients had better immunotherapy responses and prognosis than high-risk patients. Collectively, our study developed a novel signature based on NK cell marker genes, which had a potent capability to predict the prognosis and immunotherapy response of LUAD patients.

Background and objective Perioperative treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancelation of surgery, additional illness, and even death, and have therefore attracted much attention. The purpose of the clinical recommendations is to form a diagnosis and treatment plan suitable for the current domestic medical situation for the immune-related adverse event (irAE). Methods This recommendation is composed of experts in thoracic surgery, oncologists, thoracic medicine and irAE related departments (gastroenterology, respirology, cardiology, infectious medicine, hematology, endocrinology, rheumatology, neurology, dermatology, emergency section) to jointly complete the formulation. Experts make full reference to the irAE guidelines, large-scale clinical research data published by thoracic surgery, and the clinical experience of domestic doctors and publicly published cases, and repeated discussions in multiple disciplines to form this recommendation for perioperative irAE. Results This clinical recommendation covers the whole process of prevention, evaluation, examination, treatment and monitoring related to irAE, so as to guide the clinical work comprehensively and effectively. Conclusion Perioperative irAE management is an important part of immune perioperative treatment of lung cancer. With the continuous development of immune perioperative treatment, more research is needed in the future to optimize the diagnosis and treatment of perioperative irAE.

Background Uniportal video‐assisted thoracoscopic surgery (VATS) is being more widely used in lung cancer, yet reports on its application in pneumonectomies are limited. This study aimed to evaluate the safety and feasibility of uniportal video‐assisted thoracoscopic left pneumonectomy for lung cancer. Methods A series of 18 lung cancer patients who had received uniportal video‐assisted thoracoscopic left pneumonectomies were included in the study. Their clinical, pathological, and surgical features, as well as postoperative recovery, were analyzed. Results The majority of the patients were male and smokers and their average age was 62.0 ± 8.9 years. All had primary lung cancer, while three (16.7%) had received neoadjuvant therapy. A total of 16 (88.9%) patients had stage II–III disease, with an average tumor size of 3.6 ± 1.5 cm. The average surgery time was 137.4 ± 47.0 minutes, with a 16.7% (3/18) conversion rate. The mean blood loss was 37.5 ± 59.4 mL and no patients needed blood transfusion during, or after, surgery. There was no perioperative death and the overall complication rate was 22.2% (4/18). Two (11.1%) patients needed to stay in the intensive care unit after surgery, and the average length of hospital stay after surgery was 6.3 ± 1.1 days (range 4–7 days). Conclusions Uniportal video‐assisted thoracoscopic left pneumonectomy is a safe and feasible procedure for selected lung cancer patients. The use of uniportal VATS in right pneumonectomies and the effect of uniportal video‐assisted thoracoscopic pneumonectomy on the survival of patients merits further study. Patients receiving uniportal VATS pneumonectomies had standard surgical results and recovery. Uniportal VATS pneumonectomy is safe for properly selected lung cancer patients. Key points Significant findings of the study: • Patients receiving uniportal VATS left pneumonectomies had standard surgical results and recovery. What this study adds: • Uniportal VATS left pneumonectomy is safe for properly selected lung cancer patients.

There is no cost-effective, accurate, and non-invasive method for the detection of esophageal squamous cell carcinoma (ESCC) in clinical practice. We aimed to investigate the diagnostic potential of tumor-educated platelets in ESCC. In this study, seventy-one ESCC patients and eighty healthy individuals were enrolled and divided into a training cohort (23 patients and 27 healthy individuals) and a validation cohort (48 patients and 53 healthy individuals). Next-generation RNA sequencing was performed on platelets isolated from peripheral blood of all participants, and a support vector machine/leave-one-out cross validation (SVM/LOOCV) approach was used for binary classification. A diagnostic signature composed of ARID1A, GTF2H2, and PRKRIR discriminated ESCC patients from healthy individuals with 91.3% sensitivity and 85.2% specificity in the training cohort and 87.5% sensitivity and 81.1% specificity in the validation cohort. The AUC was 0.924 (95% CI, 0.845–0.956) and 0.893 (95% CI, 0.821–0.966), respectively, in the training cohort and validation cohort. This 3-gene platelet RNA signature could effectively discriminate ESCC from healthy control. Our data highlighted the potential of tumor-educated platelets for the noninvasive diagnosis of ESCC. Moreover, we found that keratin and collagen protein families and ECM-related pathways might be involved in tumor progression and metastasis of ESCC, which might provide insights to understand ESCC pathobiology and advance novel therapeutics.

Although emerging patient-derived samples and cellular-based evidence support the relationship between WDR74 (WD Repeat Domain 74) and carcinogenesis in multiple cancers, no systematic pan-cancer analysis is available. Our preliminary research demonstrated that WDR74 is over-expressed in lung squamous cell carcinoma (LUSC) and related with worse survival. We thus investigated the potential oncogenic roles of WDR74 across 33 tumors based on the database of TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus). WDR74 is highly expressed in most cancers and correlated with poor prognosis in several cancers (all p < 0.05). Mutation analysis demonstrated that WDR74 is frequently mutated in promoter regions of lung cancer. Moreover, we found that CD8+ T-cells and the fibroblast infiltration level increased in WDR74 over-expressed cancer cells. The GO (Gene Ontology) enrichment analysis of the WDR74 pathway revealed its participation in cellular biogenesis of the RNA metabolism and its critical role in cancer initiation and progression through the tumor cell energy metabolism. Our first pan-cancer study inferred a relatively comprehensive understanding of the oncogenic roles of WDR74 across various cancers.

Summary: Background: We comprehensively analyzed the global burdens and trends in incidence and mortality of tracheal, bronchus, and lung (TBL) cancer among subgroups of distinctive ages and genders. Methods: We retrieved incidence and mortality rates of lung cancer in 2020 from the GLOBOCAN database among 185 countries. The incidence and mortality age-standardized rates (ASRs) were mostly obtained from Cancer Incidence in Five Continents and World Health Organization mortality database, respectively. The joinpoint regression analysis has been conducted to evaluate the average annual percentage change of incidence and mortality in recent years. Findings: Trends in the incidence and mortality were decreasing among men in most countries, whereas the trends were increasing among women in some regions. As for mortality, most countries had a decreasing trend in mortality among males, but increasing trends were observed in more than half of countries among females. Furthermore, the majority of countries showed a significant decrease in incidence among males (AAPCs, -0·34 to -6·53), whereas most countries had a significant increase among females (AAPCs, 9·39 to 0·6), especially in European countries. In addition, a more drastic decrease was identified in the trends of the incidence among young people. 33 countries had a drastic decrease among males, especially in countries in Europe (AAPCs, -0·93 to -11·71). And 15 countries showed a significant decrease in incidence among young women (AAPCs, -0·94 to -9·35). Interpretation: Decreasing incidence and mortality trends were identified in TBL cancer, particularly among all-age men and women younger than 50 years old. But some other groups of individuals showed an opposite trend, such as women in European countries. More preventive interventions are required for the specific populations. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer with poor prognosis. Here the authors performed multi-omics analysis of human samples to investigate the mutational landscape of PSC and show three subgroups of PSC with distinct biology, prognosis and potential therapeutic strategies.

Abstract Background Currently, adjuvant therapy is not recommended for patients with thoracic esophageal squamous cell cancer (TESCC) after radical surgery, and a proportion of these patients go on to develop locoregional recurrence (LRR) within 2 years. Besides, there is no evidence for salvage chemoradiation therapy (CRT) in patients with residual tumor after esophagectomy (R1/R2 resection). In addition, factors like different failure patterns and relationship with normal organs influence the decision for salvage strategy. Here, we aimed to design a modularized salvage CRT strategy for patients without a chance of salvage surgery according to different failure patterns (including R1/R2 resection), and further evaluated its efficacy and safety. Methods Our study was designed as a one arm, multicenter, prospective clinical trial. All enrolled patients were stratified in a stepwise manner based on the nature of surgery (R0 or R1/2), recurrent lesion diameter, involved regions, and time-to-recurrence, and were further assigned to undergo either elective nodal irradiation or involved field irradiation. Then, radiation technique and dose prescription were modified according to the distance from the recurrent lesion to the thoracic stomach or intestine. Ultimately, four treatment plans were established. Discussion This prospective study provided high-level evidence for clinical salvage management in patients with TESCC who developed LRR after radical surgery or those who underwent R1/R2 resection. Trial registration Prospectively Registered. ClinicalTrials.gov NCT03731442 , Registered November 6, 2018.