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Background: Lung adenocarcinoma (LUAD) with lymph node (LN) metastasis is linked to poor prognosis, yet the underlying mechanisms remain largely undefined. This study aimed to elucidate the immunogenomic landscape associated with LN metastasis in LUAD., Methods: We employed broad-panel next-generation sequencing (NGS) on a cohort of 257 surgically treated LUAD patients to delineate the molecular landscape of primary tumors and identify actionable driver-gene alterations. Additionally, we used multiplex immunohistochemistry (mIHC) on a propensity score-matched cohort, which enabled us to profile the immune microenvironment of primary tumors in detail while preserving cellular metaclusters, interactions, and neighborhood functional units. By integrating data from NGS and mIHC, we successfully identified spatial immunogenomic patterns and developed a predictive model for LN metastasis, which was subsequently validated independently., Results: Our analysis revealed distinct immunogenomic alteration patterns associated with LN metastasis stages. Specifically, we observed increased mutation frequencies in genes such as PIK3CG and ATM in LN metastatic primary tumors. Moreover, LN positive primary tumors exhibited a higher presence of macrophage and regulatory T cell metaclusters, along with their enriched neighborhood units (p < 0.05), compared to LN negative tumors. Furthermore, we developed a novel predictive model for LN metastasis likelihood, designed to inform non-surgical treatment strategies, optimize personalized therapy plans, and potentially improve outcomes for patients who are ineligible for surgery., Conclusions: This study offers a comprehensive analysis of the genetic and immune profiles in LUAD primary tumors with LN metastasis, identifying key immunogenomic patterns linked to metastatic progression. The predictive model derived from these insights marks a substantial advancement in personalized treatment, underscoring its potential to improve patient management., (© 2024. The Author(s).)

The remarkable success of mRNA-based coronavirus 2019 (COVID-19) vaccines has propelled the advancement of nanomedicine, specifically in the realm of RNA technology and nanomaterial delivery systems. Notably, significant strides have been made in the development of RNA-based in vivo chimeric antigen receptor (CAR) therapy. In comparison to the conventional ex vivo CAR therapy, in vivo CAR therapy offers several benefits including simplified preparation, reduced costs, broad applicability and decreased potential for carcinogenic effects. This review summarises the RNA-based CAR constructs in in vivo CAR therapy, discusses the current applications of in vivo delivery vectors and outlines the immune cells edited with CAR molecules. We aim for the conveyed messages to contribute towards the advancement of in vivo CAR application., (© 2024 John Wiley & Sons Ltd.)

Background: In order to address the low compliance and dissatisfied specificity of low-dose computed tomography (LDCT), efficient and non-invasive approaches are needed to complement its limitations for lung cancer screening and management. The ASCEND-LUNG study is a prospective two-stage case-control study designed to evaluate the performance of a liquid biopsy-based comprehensive lung cancer screening and post-screening pulmonary nodules management system., Methods: We aimed to develop a comprehensive lung cancer system called Peking University Lung Cancer Screening and Management System (PKU-LCSMS) which comprises a lung cancer screening model to identify specific populations requiring LDCT and an artificial intelligence-aided (AI-aided) pulmonary nodules diagnostic model to classify pulmonary nodules following LDCT. A dataset of 465 participants (216 cancer, 47 benign, 202 non-cancer control) were used for the two models' development phase. For the lung cancer screening model development, cancer participants were randomly split at a ratio of 1:1 into the train and validation cohorts, and then non-cancer controls were age-matched to the cancer cases in a 1:1 ratio. Similarly, for the AI-aided pulmonary nodules model, cancer and benign participants were also randomly divided at a ratio of 2:1 into the train and validation cohorts. Subsequently, during the model validation phase, sensitivity and specificity were validated using an independent validation cohort consisting of 291 participants (140 cancer, 25 benign, 126 non-cancer control). Prospectively collected blood samples were analyzed for multi-omics including cell-free DNA (cfDNA) methylation, mutation, and serum protein. Computerized tomography (CT) images data was also obtained. Paired tissue samples were additionally analyzed for DNA methylation, DNA mutation, and messenger RNA (mRNA) expression to further explore the potential biological mechanisms. This study is registered with ClinicalTrials.gov, NCT04817046., Findings: Baseline blood samples were evaluated for the whole screening and diagnostic process. The cfDNA methylation-based lung cancer screening model exhibited the highest area under the curve (AUC) of 0.910 (95% CI, 0.869-0.950), followed by the protein model (0.891 [95% CI, 0.845-0.938]) and lastly the mutation model (0.577 [95% CI, 0.482-0.672]). Further, the final screening model, which incorporated cfDNA methylation and protein features, achieved an AUC of 0.963 (95% CI, 0.942-0.984). In the independent validation cohort, the multi-omics screening model showed a sensitivity of 99.2% (95% CI, 0.957-1.000) at a specificity of 56.3% (95% CI, 0.472-0.652). For the AI-aided pulmonary nodules diagnostic model, which incorporated cfDNA methylation and CT images features, it yielded a sensitivity of 81.1% (95% CI, 0.732-0.875), a specificity of 76.0% (95% CI, 0.549-0.906) in the independent validation cohort. Furthermore, four differentially methylated regions (DMRs) were shared in the lung cancer screening model and the AI-aided pulmonary nodules diagnostic model., Interpretation: We developed and validated a liquid biopsy-based comprehensive lung cancer screening and management system called PKU-LCSMS which combined a blood multi-omics based lung cancer screening model incorporating cfDNA methylation and protein features and an AI-aided pulmonary nodules diagnostic model integrating CT images and cfDNA methylation features in sequence to streamline the entire process of lung cancer screening and post-screening pulmonary nodules management. It might provide a promising applicable solution for lung cancer screening and management., Funding: This work was supported by Science, Science, Technology & Innovation Project of Xiongan New Area, Beijing Natural Science Foundation, CAMS Innovation Fund for Medical Sciences (CIFMS), Clinical Medicine Plus X-Young Scholars Project of Peking University, the Fundamental Research Funds for the Central Universities, Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Peking University People's Hospital Research and Development Funds, National Key Research and Development Program of China, and the fundamental research funds for the central universities., Competing Interests: Yezhen Shi, Xiaoran Sun, Bo Yang, Peng Cui, Chengcheng Li, Fang Liu, Yuxia Liu, Guoqiang Wang, Jing Zhao, Yuzi Zhang, and Shangli Cai are employees of Burning Rock Biotech., (© 2024 Published by Elsevier Ltd.)

Abstract: This expert consensus reviews current literature and provides clinical practice guidelines for the diagnosis and treatment of multiple ground glass nodule-like lung cancer. The main contents of this review include the following: ① follow-up strategies, ② differential diagnosis, ③ diagnosis and staging, ④ treatment methods, and ⑤ post-treatment follow-up., (Copyright © 2024 Copyright: © 2024 Journal of Cancer Research and Therapeutics.)

Currently, conventional immunotherapies for the treatment of non-small cell lung cancer (NSCLC) have low response rates and benefit only a minority of patients, particularly those with advanced disease, so novel therapeutic strategies are urgent deeded. Therapeutic cancer vaccines, a form of active immunotherapy, harness potential to activate the adaptive immune system against tumor cells via antigen cross-presentation. Cancer vaccines can establish enduring immune memory and guard against recurrences. Vaccine-induced tumor cell death prompts antigen epitope spreading, activating functional T cells and thereby sustaining a cancer-immunity cycle. The success of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rendered cancer vaccines a promising avenue, especially when combined with immunotherapy or chemoradiotherapy for NSCLC. This review delves into the intricate antitumor immune mechanisms underlying therapeutic cancer vaccines, enumerates the tumor antigen spectrum of NSCLC, discusses different cancer vaccines progress and summarizes relevant clinical trials. Additionally, we analyze the combination strategies, current limitations, and future prospects of cancer vaccines in NSCLC treatment, aiming to offer fresh insights for their clinical application in managing NSCLC. Overall, cancer vaccines offer promising potential for NSCLC treatment, particularly combining with chemoradiotherapy or immunotherapy could further improve survival in advanced patients. Exploring inhaled vaccines or prophylactic vaccines represents a crucial research avenue., (© 2024 UICC.)

Lung cancer is an exceedingly malignant tumor reported as having the highest morbidity and mortality of any cancer worldwide, thus posing a great threat to global health. Despite the growing demand for precision medicine, current methods for early clinical detection, treatment and prognosis monitoring in lung cancer are hampered by certain bottlenecks. Studies have found that during the formation and development of a tumor, molecular substances carrying tumor-related genetic information can be released into body fluids. Liquid biopsy (LB), a method for detecting these tumor-related markers in body fluids, maybe a way to make progress in these bottlenecks. In recent years, LB technology has undergone rapid advancements. Therefore, this review will provide information on technical updates to LB and its potential clinical applications, evaluate its effectiveness for specific applications, discuss the existing limitations of LB, and present a look forward to possible future clinical applications. Specifically, this paper will introduce technical updates from the prospectives of engineering breakthroughs in the detection of membrane-based LB biomarkers and other improvements in sequencing technology. Additionally, it will summarize the latest applications of liquid biopsy for the early detection, diagnosis, treatment, and prognosis of lung cancer. We will present the interconnectedness of clinical and laboratory issues and the interplay of technology and application in LB today., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

Background: Resectable non-small cell lung cancer (NSCLC) patients have a high risk of recurrence. Multiple randomized controlled trials (RCTs) have shown that neoadjuvant chemo-immunotherapy brings new hope for these patients. The study aims to evaluate the safety, surgery-related outcomes and oncological outcomes for neoadjuvant chemo-immunotherapy in real-world setting with a large sample size and long-term follow-up., Methods: Patients with clinical stage IB-IIIB NSCLC who received neoadjuvant chemo-immunotherapy at two Chinese institutions were included in this retrospective cohort study. Surgical and oncological outcomes of the enrolled NSCLC patients were collected and analyzed., Results: There were 158 patients identified, of which 124 (78.5%) were at stage IIIA-IIIB and the remaining 34 (21.5%) were at stage IB-IIB. Forty-one patients (25.9%) received two cycles of neoadjuvant treatment, 80 (50.6%) had three cycles, and 37 (23.4%) had four cycles. Twenty-four patients (15.2%) experienced grade 3 or worse immune-related adverse events. The median interval time between the last neoadjuvant therapy and surgery was 37 [interquartile range (IQR), 31-43] days. Fifty-eight out of 96 (60.4%) central NSCLC patients who were expected to undergo complex surgery had the scope or the difficulty of operation reduced. Ninety-five (60.1%) patients achieved major pathologic response (MPR), including 62 (39.2%) patients with pathologic complete response (pCR). Multivariate regression analysis showed that no clinical factor other than programmed death-ligand 1 (PD-L1) expression was predictive of the pathological response. The median follow-up time from diagnosis was 27.1 months. MPR and pCR were significantly associated with improved progression-free survival (PFS) and overall survival (OS). Neither stage nor PD-L1 expression was significantly associated with long-term survival., Conclusions: The neoadjuvant chemo-immunotherapy is a feasible strategy for NSCLC with a favorable rate of pCR/MPR, modified resection and 2-year survival. No clinical factor other than PD-L1 expression was predictive of the pathological response. pCR/MPR may be effective surrogate endpoint for survival in NSCLC patients who received neoadjuvant chemo-immunotherapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-17/coif). The authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Background: Prognosis is crucial for personalized treatment and surveillance suggestion of the resected non-small-cell lung cancer (NSCLC) patients in stage I-III. Although the tumor-node-metastasis (TNM) staging system is a powerful predictor, it is not perfect enough to accurately distinguish all the patients, especially within the same TNM stage. In this study, we developed an intelligent prognosis evaluation system (IPES) using pre-therapy CT images to assist the traditional TNM staging system for more accurate prognosis prediction of resected NSCLC patients., Methods: 20,333 CT images of 6371 patients from June 12, 2009 to March 24, 2022 in West China Hospital of Sichuan University, Mianzhu People's Hospital, Peking University People's Hospital, Chengdu Shangjin Nanfu Hospital and Guangan Peoples' Hospital were included in this retrospective study. We developed the IPES based on self-supervised pre-training and multi-task learning, which aimed to predict an overall survival (OS) risk for each patient. We further evaluated the prognostic accuracy of the IPES and its ability to stratify NSCLC patients with the same TNM stage and with the same EGFR genotype., Findings: The IPES was able to predict OS risk for stage I-III resected NSCLC patients in the training set (C-index 0.806; 95% CI: 0.744-0.846), internal validation set (0.783; 95% CI: 0.744-0.825) and external validation set (0.817; 95% CI: 0.786-0.849). In addition, IPES performed well in early-stage (stage I) and EGFR genotype prediction. Furthermore, by adopting IPES-based survival score (IPES-score), resected NSCLC patients in the same stage or with the same EGFR genotype could be divided into low- and high-risk subgroups with good and poor prognosis, respectively (p < 0.05 for all)., Interpretation: The IPES provided a non-invasive way to obtain prognosis-related information from patients. The identification of IPES for resected NSCLC patients with low and high prognostic risk in the same TNM stage or with the same EGFR genotype suggests that IPES have potential to offer more personalized treatment and surveillance suggestion for NSCLC patients., Funding: This study was funded by the National Natural Science Foundation of China (grant 62272055, 92259303, 92059203), New Cornerstone Science Foundation through the XPLORER PRIZE, Young Elite Scientists Sponsorship Program by CAST (2021QNRC001), Clinical Medicine Plus X - Young Scholars Project, Peking University, the Fundamental Research Funds for the Central Universities (K.C.), Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Chinese Academy of Medical Sciences (2021RU002), BUPT Excellent Ph.D. Students Foundation (CX2022104)., Competing Interests: The authors have declared no conflicts of interest., (© 2023 The Author(s).)

We report a personalized tumor-informed technology, Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50 patient-specific variants to detect molecular residual disease (MRD) with a limit of detection of 0.004%. PROPHET and state-of-the-art fixed-panel assays were applied to 760 plasma samples from 181 prospectively enrolled early stage non-small cell lung cancer patients. PROPHET shows higher sensitivity of 45% at baseline with circulating tumor DNA (ctDNA). It outperforms fixed-panel assays in prognostic analysis and demonstrates a median lead-time of 299 days to radiologically confirmed recurrence. Personalized non-canonical variants account for 98.2% with prognostic effects similar to canonical variants. The proposed tumor-node-metastasis-blood (TNMB) classification surpasses TNM staging for prognostic prediction at the decision point of adjuvant treatment. PROPHET shows potential to evaluate the effect of adjuvant therapy and serve as an arbiter of the equivocal radiological diagnosis. These findings highlight the potential advantages of personalized cancer techniques in MRD detection., Competing Interests: Declaration of interests Z.Z., C.W., X.L., D.P., F.Q., S.W., X.Z., and S.C. are employment and stock/stock option ownership in Burning Rock Biotech. The remaining authors declare no potential conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The impact of host condition on prognosis of non-small cell lung cancer (NSCLC) and the interaction between host and NSCLC remain unclear. This study investigated the association between systemic inflammation and prognosis and characteristics of radically resected NSCLC. This study consisted of a cohort study and an exploratory study of institutional prospective databases. All participants underwent video-assisted thoracoscopic lobectomy as the primary treatment. Systemic inflammation was assessed before surgery using the advanced lung cancer inflammation index and the systemic inflammation response index. Next-generation sequencing and multiplex immunofluorescence analysis were conducted to delineate tumor characteristics. In the cohort study including 1507 participants, high inflammation was associated with poor disease-free survival and overall survival before and after propensity score matching and in multivariable analysis. Systemic inflammation showed good prognostic value for stage IA-IB NSCLC, and the prognostic value diminished with upstaging of NSCLC. In the exploratory study including 217 adenocarcinomas, tumor microenvironment of high inflammation group showed a greater abundance of PDL1+ tumor cells and immune cells, which were independent from driver gene mutations and clinicopathological characteristics. Spatial analysis demonstrated a higher frequency of immune-suppressed cellular neighborhood, increased avoidance between immune cells and PDL1- tumor cells and compromised immune killing and presentation in tumor microenvironment of high inflammation group. Systemic inflammation showed limited association with genomic mutations. Systemic inflammation may influence the prognosis of NSCLC at both the systematic level and the local immune response. The correlation between high inflammation and immunosuppressive microenvironment indicates a novel thread for anticancer treatment., (© 2023 UICC.)

Cancer morbidity and mortality are growing rapidly worldwide and it is urgent to develop a convenient and effective method that can identify cancer patients at an early stage and predict treatment outcomes. As a minimally invasive and reproducible tool, liquid biopsy (LB) offers the opportunity to detect, analyze and monitor cancer in any body fluids including blood, complementing the limitations of tissue biopsy. In liquid biopsy, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are the two most common biomarkers, displaying great potential in the clinical application of pan-cancer. In this review, we expound the samples, targets, and newest techniques in liquid biopsy and summarize current clinical applications in several specific cancers. Besides, we put forward a bright prospect for further exploring the emerging application of liquid biopsy in the field of pan-cancer precision medicine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Neoadjuvant chemoimmunotherapy has shown a good therapeutic effect on non-small cell lung cancer (NSCLC), which also opens up the possibility of applying organ preservation strategies. This study investigated the feasibility of modified surgery after potent neoadjuvant chemoimmunotherapy in central type NSCLC., Methods: In this multicenter retrospective cohort study, patients with central type NSCLC who received 2-4 cycles of neoadjuvant chemoimmunotherapy between January 2019 and June 2022 at Air Force Medical University Tangdu Hospital and Peking University People's Hospital were eligible. Patients were divided into modified and nonmodified groups according to the extent of surgery, after which, the safety and long-term prognosis of surgery were investigated., Results: A total of 84 patients were enrolled. Of 36 (42.9%) patients who underwent modified surgery, 21 patients underwent lobectomy, 12 patients underwent lobectomy with bronchoplasty, 2 patients underwent sleeve lobectomy, and 1 patient underwent bilobectomy. The modification rate for the initially estimated pneumonectomy, sleeve lobectomy, and bilobectomy was 48.6, 44.8, and 30%, respectively. Grades II-V postoperative complications were found in 5 (13.9%) patients in the modified group and 17 (35.4%) patients in the nonmodified group (relative risk, 0.393; 95% CI, 0.016-0.963; P =0.026). No significant difference was observed regarding the surgical approach, operative duration, blood loss, or R0 resection rate. The 2-year local recurrence rate was 3.7% (95% CI, 0.004-0.175) and 5.2% (95% CI, 0.012-0.168) in the modified group and nonmodified group, respectively. The 1-year PFS rate of modified and nonmodified groups was 97.1% (95% CI, 83.7-99.8) and 86.9% (95% CI, 73.4-94.4), respectively, while 2-year PFS were 89.8% (95% CI, 74.1-96.9) and 71.8% (95% CI, 56.7-83.4), respectively., Conclusion: Applying organ preservation strategies, that is, undergoing modified surgery after neoadjuvant chemoimmunotherapy, is feasible for selected central type NSCLC patients with favorable safety and long-term survival., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The feasibility of DNA methylation-based assays in detecting minimal residual disease (MRD) and postoperative monitoring remains unestablished. We aim to investigate the dynamic characteristics of cancer-related methylation signals and the feasibility of methylation-based MRD detection in surgical lung cancer patients., Methods: Matched tumor, tumor-adjacent tissues, and longitudinal blood samples from a cohort (MEDAL) were analyzed by ultra-deep targeted sequencing and bisulfite sequencing. A tumor-informed methylation-based MRD (timMRD) was employed to evaluate the methylation status of each blood sample. Survival analysis was performed in the MEDAL cohort (n = 195) and validated in an independent cohort (DYNAMIC, n = 36)., Results: Tumor-informed methylation status enabled an accurate recurrence risk assessment better than the tumor-naïve methylation approach. Baseline timMRD-scores were positively correlated with tumor burden, invasiveness, and the existence and abundance of somatic mutations. Patients with higher timMRD-scores at postoperative time-points demonstrated significantly shorter disease-free survival in the MEDAL cohort (HR: 3.08, 95% CI: 1.48-6.42; P = 0.002) and the independent DYNAMIC cohort (HR: 2.80, 95% CI: 0.96-8.20; P = 0.041). Multivariable regression analysis identified postoperative timMRD-score as an independent prognostic factor for lung cancer. Compared to tumor-informed somatic mutation status, timMRD-scores yielded better performance in identifying the relapsed patients during postoperative follow-up, including subgroups with lower tumor burden like stage I, and was more accurate among relapsed patients with baseline ctDNA-negative status. Comparing to the average lead time of ctDNA mutation, timMRD-score yielded a negative predictive value of 97.2% at 120 days prior to relapse., Conclusions: The dynamic methylation-based analysis of peripheral blood provides a promising strategy for postoperative cancer surveillance., Trial Registration: This study (MEDAL, MEthylation based Dynamic Analysis for Lung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826). https://clinicaltrials.gov/ct2/show/NCT03634826 ., (© 2023. The Author(s).)

Background: TTF-1/NKX2-1 is a lineage-specific transcription factor that is expressed in the thyroid gland, lung, and forehead. It functions as a key component in regulating lung morphogenesis and differentiation. It is mainly expressed in lung adenocarcinoma, while its prognostic value in non-small-cell lung cancer remains controversial. This study evaluates the prognostic value of TTF-1 in different cellular locations in lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC)., Materials and Methods: The expression of TTF-1 was analyzed by immunohistochemistry in 492 patients (ADC 340 and SCC 152) who had undergone surgery between June 2004 and June 2012. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method., Results: Positive TTF-1 expression was 68.2% in ADC (located in the nucleus) and 29.6% in SCC (cytoplasm staining). The presence of TTF-1 was associated with better OS in SCC and ADC ( P =0.000 and P =0.003, respectively). In SCC, an increased level of TTF-1 was associated with a longer disease-free survival (DFS). Positive TTF-1 expression was an independent favorable prognostic factor in SCC ( P =0.020, HR: 2.789, 95%CI: 1.172-6.637) and ADC ( P =0.025, HR: 1.680, 95%CI: 1.069-2.641)., Conclusions: TTF-1 was largely located in the nucleus of ADC, while it always accumulated in the cytoplasm of SCC. The higher level of TTF-1 in the different subcellular locations of ADC and SCC was an independent, favorable prognostic factor, respectively. Increased TTF-1 in the cytoplasm of SCC was associated with a longer OS and DFS., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Liquid biopsy is a promising non-invasive alternative for cancer screening and minimal residual disease (MRD) detection, although there are some concerns regarding its clinical applications. We aimed to develop an accurate detection platform based on liquid biopsy for both cancer screening and MRD detection in patients with lung cancer (LC), which is also applicable to clinical use., Methods: We applied a modified whole-genome sequencing (WGS) -based High-performance Infrastructure For MultIomics (HIFI) method for LC screening and postoperative MRD detection by combining the hyper-co-methylated read approach and the circulating single-molecule amplification and resequencing technology (cSMART2.0)., Findings: For early screening of LC, the LC score model was constructed using the support vector machine, which showed sensitivity (51.8%) at high specificity (96.3%) and achieved an AUC of 0.912 in the validation set prospectively enrolled from multiple centers. The screening model achieved detection efficiency with an AUC of 0.906 in patients with lung adenocarcinoma and outperformed other clinical models in solid nodule cohort. When applied the HIFI model to real social population, a negative predictive value (NPV) of 99.92% was achieved in Chinese population. Additionally, the MRD detection rate improved significantly by combining results from WGS and cSMART2.0, with sensitivity of 73.7% at specificity of 97.3%., Interpretation: In conclusion, the HIFI method is promising for diagnosis and postoperative monitoring of LC., Funding: This study was supported by CAMS Innovation Fund for Medical Sciences, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Beijing Natural Science Foundation and Peking University People's Hospital., Competing Interests: Declaration of interests Wendy Wu, Wenjie Liu, Hao Yang, Airong Yang, and Xueying Zhang are the employee of Berry Oncology Corporation. Two patents are planning to implement on China National Intellectual Property Administration and we declare no relevant interest conflict exists against this article. The other authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development 1 . Here we propose that environmental particulate matter measuring ≤2.5 μm (PM 2.5 ), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM 2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for  PM 2.5 air pollutants  and provide impetus for public health policy initiatives to address air pollution to reduce disease burden., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In the era of histopathology-based diagnosis, the discrimination between multiple lung cancers (MLCs) poses significant uncertainties and has thus become a clinical dilemma. However, recent significant advances and increased application of molecular technologies in clonal relatedness assessment have led to more precision in distinguishing between multiple primary lung cancers (MPLCs) and intrapulmonary metastasis (IPMs). This review summarizes recent advances in the molecular identification of MLCs and compares various methods based on somatic mutations, chromosome alterations, microRNAs, and tumor microenvironment markers. The paper also discusses current challenges at the forefront of genomics-based discrimination, including the selection of detection technology, application of next-generation sequencing, and intratumoral heterogeneity (ITH). In summary, this paper highlights an entrance into the primary stage of molecule-based diagnostics., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2023. Published by Elsevier B.V.)

Chylothorax is a serious complication after esophagectomy and there are unmet needs for new intraoperative navigation tools to reduce its incidence. The aim of this study is to explore the feasibility and effectiveness of near-infrared fluorescence imaging (NIR-FI) with indocyanine green (ICG) to identify thoracic ducts (TDs) and chyle leakage during video-assisted thoracoscopic esophagectomy. We recruited 41 patients who underwent thoraco-laparoscopic minimally invasive esophagectomy (MIE) for esophageal cancer in this prospective, open-label, single-arm clinical trial. ICG was injected into the right inguinal region before operations, after which TD anatomy and potential chyle leakage were checked under the near-infrared fluorescence intraoperatively. In 38 of 41 patients (92.7%) using NIR-FI, TDs were visible in high contrast. The mean signal-to-background ratio (SBR) value of all fluorescent TDs was 3.05 ± 1.56. Fluorescence imaging of TDs could be detected 0.5 hours after ICG injection and last up to 3 hours with an acceptable SBR value. The optimal observation time window is from about 1 to 2 hours after ICG injection. Under the guidance of real-time NIR-FI, three patients were found to have chylous leakage and the selective TD ligations were performed intraoperatively. No patient had postoperative chylothorax. NIR-FI with ICG can provide highly sensitive and real-time assessment of TDs as well as determine the source of chyle leakage, which might help reduce TD injury and direct selective TD ligation. It could be a promising navigation tool to reduce the incidence of chylothorax after minimally invasive esophagectomy., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Liquid biopsy has been widely researched for early diagnosis, prognostication and disease monitoring in lung cancer, but there is a need to investigate its clinical utility for early-stage non-small cell lung cancer (NSCLC)., Methods: We performed a meta-analysis and systematic review to evaluate diagnostic and prognostic values of liquid biopsy for early-stage NSCLC, regarding the common biomarkers, circulating tumor cells, circulating tumor DNA (ctDNA), methylation signatures, and microRNAs. Cochrane Library, PubMed, EMBASE databases, ClinicalTrials.gov, and reference lists were searched for eligible studies since inception to 17 May 2022. Sensitivity, specificity and area under the curve (AUC) were assessed for diagnostic values. Hazard ratio (HR) with a 95% confidence interval (CI) was extracted from the recurrence-free survival (RFS) and overall survival (OS) plots for prognostic analysis. Also, potential predictive values and treatment response evaluation were further investigated., Results: In this meta-analysis, there were 34 studies eligible for diagnostic assessment and 21 for prognostic analysis. The estimated diagnostic values of biomarkers for early-stage NSCLC with AUCs ranged from 0.84 to 0.87. The factors TNM stage I, T1 stage, N0 stage, adenocarcinoma, young age, and nonsmoking contributed to a lower tumor burden, with a median cell-free DNA concentration of 8.64 ng/ml. For prognostic analysis, the presence of molecular residual disease (MRD) detection was a strong predictor of disease relapse (RFS, HR, 4.95; 95% CI, 3.06-8.02; p < 0.001) and inferior OS (HR, 3.93; 95% CI, 1.97-7.83; p < 0.001), with average lead time of 179 ± 74 days between molecular recurrence and radiographic progression. Predictive values analysis showed adjuvant therapy significantly benefited the RFS of MRD + patients (HR, 0.27; p < 0.001), while an opposite tendency was detected for MRD - patients (HR, 1.51; p = 0.19). For treatment response evaluation, a strong correlation between pathological response and ctDNA clearance was detected, and both were associated with longer survival after neoadjuvant therapy., Conclusions: In conclusion, our study indicated liquid biopsy could reliably facilitate more precision and effective management of early-stage NSCLC. Improvement of liquid biopsy techniques and detection approaches and platforms is still needed, and higher-quality trials are required to provide more rigorous evidence prior to their routine clinical application., (© 2022. The Author(s).)

Stage I non-small cell lung cancer (NSCLC) presents diverse outcomes. To identify molecular features leading to tumor recurrence in early-stage NSCLC, we perform multiregional whole-exome sequencing (WES), RNA sequencing, and plasma-targeted circulating tumor DNA (ctDNA) detection analysis between recurrent and recurrent-free stage I NSCLC patients (CHN-P cohort) who had undergone R0 resection with a median 5-year follow-up time. Integrated analysis indicates that the multidimensional clinical and genomic model can stratify the prognosis of stage I NSCLC in both CHN-P and EUR-T cohorts and correlates with positive pre-surgical deep next generation sequencing (NGS) ctDNA detection. Increased genomic instability related to DNA interstrand crosslinks and double-strand break repair processes is significantly associated with early tumor relapse. This study reveals important molecular insights into stage I NSCLC and may inform clinical postoperative treatment and follow-up strategies., Competing Interests: Declaration of interests M.J.-H. is a Cancer Research UK Fellow and has received funding from CRUK, National Institute for Health Research, Rosetrees Trust, UKI NETs, and NIHR University College London Hospitals Biomedical Research Center. M.J.-H. is a member of the Scientific Advisory Board and Steering Committee for Achilles Therapeutics. A.Y., K.L., R.W., J.B., L.W., H.L., Y.S., and S.W. are employees of Berry Oncology Corporation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest. Professor Xiao Li and Jun Wang are members of Chronic Diseases and Translational Medicine editorial board and is not involved in the peer review process of this article.

Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 10%-50% of patients experience relapse after radical surgery, which may be attributed to the persistence of minimal/molecular residual disease (MRD). Circulating tumor DNA (ctDNA), a common liquid biopsy approach, has been demonstrated to have significant clinical merit. In this study, we review the evidence supporting the use of ctDNA for MRD detection and discuss the potential clinical applications of postoperative MRD detection, including monitoring recurrence, guiding adjuvant treatment, and driving clinical trials in lung cancer. We will also discuss the problems that prevent the routine application of ctDNA MRD detection. Multi-analyte methods and identification of specific genetic and molecular alterations, especially methylation, are effective detection strategies and show considerable prospects for future development. Interventional prospective studies based on ctDNA detection are needed to determine whether the application of postoperative MRD detection can improve the clinical outcomes of lung cancer patients, and the accuracy, sensitivity, specificity, and robustness of different detection methods still require optimization and refinement., Competing Interests: 8The authors declare no conflict of interest., (© 2022 The Authors. Chronic Diseases and Translational Medicine published by John Wiley & Sons Ltd on behalf of Chinese Medical Association.)

Introduction: Over the years, multiple models have been developed for the evaluation of pulmonary nodules (PNs). This study aimed to comprehensively investigate clinical models for estimating the malignancy probability in patients with PNs., Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for studies reporting mathematical models for PN evaluation until March 2020. Eligible models were summarized, and network meta-analysis was performed on externally validated models (PROSPERO database CRD42020154731). The cut-off value of 40% was used to separate patients into high prevalence (HP) and low prevalence (LP), and a subgroup analysis was performed., Results: A total of 23 original models were proposed in 42 included articles. Age and nodule size were most often used in the models, whereas results of positron emission tomography-computed tomography were used when collected. The Mayo model was validated in 28 studies. The area under the curve values of four most often used models (PKU, Brock, Mayo, VA) were 0.830, 0.785, 0.743, and 0.750, respectively. High-prevalence group (HP) models had better results in HP patients with a pooled sensitivity and specificity of 0.83 (95% confidence interval [CI]: 0.78-0.88) and 0.71 (95% CI: 0.71-0.79), whereas LP models only achieved pooled sensitivity and specificity of 0.70 (95% CI: 0.60-0.79) and 0.70 (95% CI: 0.62-0.77). For LP patients, the pooled sensitivity and specificity decreased from 0.68 (95% CI: 0.57-0.78) and 0.93 (95% CI: 0.87-0.97) to 0.57 (95% CI: 0.21-0.88) and 0.82 (95% CI: 0.65-0.92) when the model changed from LP to HP models. Compared with the clinical models, artificial intelligence-based models have promising preliminary results., Conclusions: Mathematical models can facilitate the evaluation of lung nodules. Nevertheless, suitable model should be used on appropriate cohorts to achieve an accurate result., (© 2022 The Authors.)

Purpose of Review: In this article, we focus on the role of artificial intelligence in the management of lung cancer. We summarized commonly used algorithms, current applications and challenges of artificial intelligence in lung cancer., Recent Findings: Feature engineering for tabular data and computer vision for image data are commonly used algorithms in lung cancer research. Furthermore, the use of artificial intelligence in lung cancer has extended to the entire clinical pathway including screening, diagnosis and treatment. Lung cancer screening mainly focuses on two aspects: identifying high-risk populations and the automatic detection of lung nodules. Artificial intelligence diagnosis of lung cancer covers imaging diagnosis, pathological diagnosis and genetic diagnosis. The artificial intelligence clinical decision-support system is the main application of artificial intelligence in lung cancer treatment. Currently, the challenges of artificial intelligence applications in lung cancer mainly focus on the interpretability of artificial intelligence models and limited annotated datasets; and recent advances in explainable machine learning, transfer learning and federated learning might solve these problems., Summary: Artificial intelligence shows great potential in many aspects of the management of lung cancer, especially in screening and diagnosis. Future studies on interpretability and privacy are needed for further application of artificial intelligence in lung cancer., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. Objectives: To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. Methods: We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. Measurements and Main Results: GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Conclusions: Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).

Objective: This study aims to compare the clinical and pathological characteristics between patients undergoing surgery for extremely multiple ground-glass nodules (GGNs) and those for single GGN., Methods: We defined extremely multiple GGNs as follows: (i) number of GGNs ≥3, (ii) GGN diameter between 3 and 30 mm, and (iii) no less than three nodules that were surgically removed and pathologically diagnosed. Patients with extremely multiple GGNs and single GGNs who underwent surgery at the same time were retrospectively analyzed. The patients were divided into three groups according to the number of nodules: exceedingly multiple nodules (EMN) group (>10), highly multiple nodules (HMN) group (three to 10), and single nodule (SN) group. The clinical and pathological characteristics, surgical methods and prognosis were analyzed., Results: Ninety-nine patients with single nodules and 102 patients with extremely multiple nodules were enrolled. Among the patients with extremely multiple nodules, 43 (42.2%) had >10 nodules. There were no significant differences in demographic characteristics, such as age, sex, and smoking history, between the groups, but there were differences in tumor characteristics. All patients with >10 nodules showed bilateral pulmonary nodules and presented with both pure and mixed GGNs. The single GGNs were smaller in diameter, and the proportion of mixed GGNs and pathologically invasive adenocarcinoma was lower than that of the primary nodules in the exceedingly multiple GGNs group ( p < 0.05). However, the proportion of both mixed GGNs and malignant nodules decreased significantly with the increasing number of total lesions. During postoperative follow-up, one patient in the highly multiple nodules group had a local recurrence, and 16 (15.7%) patients in the extremely multiple GGNs group and 10 (9.8%) patients in the single GGN group had enlarged unresected GGNs or additional GGNs., Conclusions: Our study revealed the clinical and pathologic characteristics, surgical methods, and prognosis of patients with extremely multiple GGNs and compared them with those of patients with a single GGN. Although the primary nodules in extremely multiple GGNs may have higher malignancy than those in the single nodule group, the proportion of both mGGNs and malignant nodules decreased significantly with the increasing number of lesions, and the prognosis of patients with extremely multiple GGNs was satisfied., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Wu, Shen, Nie, Zhang, Wei, Wang, Yang and Chen.)

Background: We evaluated the long-term prognosis of synchronous multiple primary lung cancer (SMPLC) patients after surgical treatment and explored prognostic factors for overall survival (OS)., Materials and Methods: A systematic review and meta-analysis was performed regarding the surgical prognosis of SMPLC. A literature search was performed using online databases. All studies were rigorously categorized following the 8th edition of the tumor, node, metastasis classification (TNM) staging rules for multiple lung cancers: SMPLC and multifocal ground-glass/lepidic (GG/L) lung cancers. Five-year OS after surgery was pooled, and hazard ratios (HRs) for prognostic factors were synthesized. Specific subgroup analysis and sensitivity analysis were conducted (PROSPERO registration CRD42019142420)., Results: An analysis of 26 studies including 1788 patients was performed. The pooled 5-year OS was 45% (95% confidence interval [CI], 37-53) of true SMPLC patients and 62% (95% CI, 57-67) of patients with pathologic stage I disease, which was different from the 5-year OS of 93% (95% CI, 85-100) of patients with multifocal GG/L lung cancers. Poor prognostic factors for SMPLC were lymph node metastasis (HR = 2.36; 95% CI, 1.75-3.20; P < .001) and pneumonectomy (HR = 2.96; 95% CI, 1.36-6.45; P = .006], whereas histology (HR = 1.11; 95% CI, 0.82-1.50; P = .508), laterality (HR = 1.16; 95% CI, 0.93-1.44, P = .190), sublobar resection (HR = 1.29; 95% CI, 0.90-1.84; P = .159), and adjuvant therapy (HR = 1.07; 95% CI, 0.64-1.80; P = .791) were not found to influence the outcome., Conclusion: The long-term prognosis of SMPLC patients after surgery is acceptable, especially in patients with early-stage disease. Sublobar resection can be applied, although pneumonectomy should be avoided. Advanced criteria are needed to diagnose SMPLC and distinguish it from multifocal GG/L lung cancer to perform accurate surgical evaluation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The study aimed to compare the long-term oncological efficacy and perioperative outcomes of patients with locally advanced non-small-cell lung cancers who underwent minimally invasive surgery (MIS) or thoracotomy., Methods: Cochrane Library, PubMed and EMBASE databases, ClinicalTrials.gov and reference lists were searched for relevant studies. Two reviewers independently assessed the quality of the studies. Recurrence-free survival (RFS) and overall survival (OS) and perioperative outcomes were synthesized. Random-effects models were used to summarize hazard ratios (HRs), relative risks and standardized mean differences (SMDs) with 95% confidence intervals (CIs)., Results: Twenty-three retrospective cohort studies were reviewed with a total of 3281 patients, of whom 1376 (41.9%) received MIS and 1905 (58.1%) received thoracotomy. Meta-analysis showed no significant differences in both RFS (HR, 1.02; 95% CI, 0.89-1.17; P = 0.78) and OS (HR, 0.91; 95% CI, 0.80-1.03; P = 0.15) between MIS versus thoracotomy approaches. Similar results were observed in propensity score matched studies (RFS, HR, 0.94; 95% CI, 0.73-1.20; P = 0.62; OS, HR, 0.96; 95% CI, 0.72-1.30; P = 0.81). No significant difference was found in lymph node clearance and margin positivity. As for perioperative outcomes, MIS was associated with a significant reduction in postoperative complications (relative risk, 0.83; P = 0.01), intraoperative blood loss (standardized mean difference, -0.68; P = 0.007), chest tube drainage (standardized mean difference, -0.38; P = 0.03) and length of hospital stay (standardized mean difference, -0.79; P = 0.002) when compared with thoracotomy., Conclusions: The use of MIS for resectable stage II and III non-small-cell lung cancers is an eligible alternative to conventional thoracotomy without compromising the long-term survival and short-term outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: Nodule evaluation is challenging and critical to diagnose multiple pulmonary nodules (MPNs). We aimed to develop and validate a machine learning-based model to estimate the malignant probability of MPNs to guide decision-making., Experimental Design: A boosted ensemble algorithm (XGBoost) was used to predict malignancy using the clinicoradiologic variables of 1,739 nodules from 520 patients with MPNs at a Chinese center. The model (PKU-M model) was trained using 10-fold cross-validation in which hyperparameters were selected and fine-tuned. The model was validated and compared with solitary pulmonary nodule (SPN) models, clinicians, and a computer-aided diagnosis (CADx) system in an independent transnational cohort and a prospective multicentric cohort., Results: The PKU-M model showed excellent discrimination [area under the curve; AUC (95% confidence interval (95% CI)), 0.909 (0.854-0.946)] and calibration (Brier score, 0.122) in the development cohort. External validation (583 nodules) revealed that the AUC of the PKU-M model was 0.890 (0.859-0.916), higher than those of the Brock model [0.806 (0.771-0.838)], PKU model [0.780 (0.743-0.817)], Mayo model [0.739 (0.697-0.776)], and VA model [0.682 (0.640-0.722)]. Prospective comparison (200 nodules) showed that the AUC of the PKU-M model [0.871 (0.815-0.915)] was higher than that of surgeons [0.790 (0.711-0.852), 0.741 (0.662-0.804), and 0.727 (0.650-0.788)], radiologist [0.748 (0.671-0.814)], and the CADx system [0.757 (0.682-0.818)]. Furthermore, the model outperformed the clinicians with an increase of 14.3% in sensitivity and 7.8% in specificity., Conclusions: After its development using machine learning algorithms, validation using transnational multicentric cohorts, and prospective comparison with clinicians and the CADx system, this novel prediction model for MPNs presented solid performance as a convenient reference to help decision-making., (©2021 American Association for Cancer Research.)

Background: In this study we aimed to assess the clinical outcomes of performing video-assisted thoracic surgery (VATS) to treat primary mediastinal cysts (PMCs) and investigate the clinical factors which increase the difficulties associated with VATS., Methods: The medical records of all consecutive PMC patients, who underwent surgical resection from April 2001 to July 2016, were reviewed and 282 patients were included. Clinical characteristics, imaging features, and surgical outcomes were analyzed. Follow-up data were successfully obtained from 230 PMC patients by telephone or outpatient clinic annually. The latest follow-up was July 2019., Results: VATS was performed in 278 patients and four patients were converted into thoracotomy. The mean operation time and intraoperative bleeding were 102.4 ± 40.9 minutes (range 25-360 minutes) and 52.4 ± 75.1 mL (range 5-600 mL), respectively. The intra- and postoperative complication rates were 2.8 and 5.7%, respectively. Seven patients with bronchogenic cysts showed severe cyst adhesion to vital mediastinal structures and thus had incomplete resection. Multivariable logistic analysis revealed that a maximal cyst diameter greater than 5 cm was significantly associated with increased risks of operation time extension (OR = 2.106; 95% CI: 1.147-3.865, P = 0.016) and intraoperative blood loss increase (OR = 4.428; 95% CI: 1.243-16.489, P = 0.022). A total of 230 patients had follow-up data. The median follow-up time was 70 months (range, 36-210 months). No local recurrence was observed., Conclusions: Surgical resection by VATS may be recommended for PMC management as a primary therapeutic strategy. Cysts with a maximum diameter greater than 5 cm or cysts adjacent to vital mediastinal structures can increase the surgical difficulties., Key Points: • Significant findings of the study A diameter >5 cm and adhesions significantly increased the risk of operation time extension together with increased blood loss. • What this study adds Cysts with a diameter >5 cm or those adjacent to vital mediastinal structures increased the potential for surgical difficulties., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: No study has investigated the precise perioperative dynamic changes in circulating tumor DNA (ctDNA) in any patients with early-stage cancer. This study (DYNAMIC) investigated perioperative dynamic changes in ctDNA and determined the appropriate detection time of ctDNA-based surveillance for surgical patients with lung cancer. Experimental Design: Consecutive patients who underwent curative-intent lung resections were enrolled prospectively (NCT02965391). Plasma samples were obtained at multiple prespecified time points including before surgery (time A), during surgery after tumor resection (time B-time D), and after surgery (time P1-time P3). Next-generation sequencing-based detection platform was performed to calculate the plasma mutation allele frequency. The primary endpoint was ctDNA half-life after radical tumor resection., Results: Thirty-six patients showed detectable mutations in time A. The plasma ctDNA concentration showed a rapid decreasing trend after radical tumor resection, with the average mutant allele fraction at times A, B, C, and D being 2.72%, 2.11%, 1.14%, and 0.17%, respectively. The median ctDNA half-life was 35.0 minutes. Patients with minimal residual disease (MRD) detection had a significant slower ctDNA half-life than those with negative MRD (103.2 minutes vs. 29.7 minutes, P = 0.001). The recurrence-free survival of patients with detectable and undetectable ctDNA concentrations at time P1 was 528 days and 543 days, respectively ( P = 0.657), whereas at time P2 was 278 days and 637 days, respectively ( P = 0.002)., Conclusions: ctDNA decays rapidly after radical tumor resection. The ctDNA detection on the third day after R0 resection can be used as the baseline value for postoperative lung cancer surveillance., (©2019 American Association for Cancer Research.)

Background: Detection of circulating tumor DNA (ctDNA) is a promising method for postoperative surveillance of lung cancer. However, relatively low positive rate in early stage patients restricts its application. Aberrant methylation of ctDNA can be detected in blood samples, and may provide a more sensitive method. This study is designed to systematically evaluate and compare the detection of aberrant methylation and mutations in ctDNA among surgical non-small cell lung cancer (NSCLC) patients, aiming to investigate the feasibility of ctDNA detection as a means of lung cancer surveillance., Methods: This is a prospective observational study. Consecutive surgical NSCLC patients will be recruited. Blood samples will be collected both before and after surgery (during the follow-up period), while matching tumor tissues and tumor-adjacent normal tissues will be collected during surgery. Quantitative analysis of aberrant methylation and mutations of ctDNA will be conducted in combination with a three-year follow-up data., Discussion: This is the first registered prospective study designed to investigate the feasibility of ctDNA methylation detection as a means of postoperative lung cancer surveillance. We will systematically evaluate and compare the quantitative detection of ctDNA mutations and ctDNA methylation in surgical NSCLC patients, combining with the follow-up information. By integrating genetic and epigenetic information of ctDNA, more effective strategies for postoperative surveillance may be defined., Trial Registration: This study (MEDAL, MEthylation based Dynamic Analysis for Lung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826; Pre-results).

Response Evaluation Criteria in Solid Tumors version 1.1 is currently considered the indicator to assess the curative effect of cancer. However, radiographic measurements often fail to detect tiny lesions or changes in the tumor burden, while tumor biomarkers possess low sensitivity and stability. Circulating tumor DNA (ctDNA) is a potential noninvasive approach that can be used to make an earlier diagnosis, monitor disease progress, and determine treatment efficacy. Previous studies of non-small cell lung cancer (NSCLC) have not clearly determined the optimum time to monitor ctDNA. Hence, the appropriate time to evaluate ctDNA to determine the curative effects of treatment in advanced NSCLC compared to conventional imaging and tumor markers should be explored in order to prevent unnecessary side effects and to avoid continuing ineffective therapies. This protocol outlines a prospective clinical trial in which advanced NSCLC patients will be recruited and longitudinal changes in ctDNA levels with changes in radiographic tumor size or tumor biomarkers will be assessed. ctDNA will be quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using multigene next-generation sequencing assay. Conclusions will be drawn from data collection and analysis., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: Liquid biopsy is a promising method for the management of lung cancer, but previous studies focused mainly on patients with advanced-stage disease. As the methodology has progressed for the detection of circulating tumor DNA (ctDNA) and its aberrant methylation, researchers are gradually investigating the utility of liquid biopsy in early-stage patients. As a result, liquid biopsy has shown its potential for the application in patients with early- and locally advanced-stage non-small cell lung cancer (NSCLC). Areas covered: This review summarizes the utility of liquid biopsy in NSCLC and provide an outlook for future development. We focus on the role of ctDNA and its aberrant methylation in patients with stage IA to stageⅢA NSCLC, in the field of early detection and screening, perioperative management, and postoperative surveillance. Expert opinion: Liquid biopsy has shown the potential for clinical application of early-stage patients but has not been routinely applied yet. The utilization of liquid biopsy will be promoted by improved detection methods and data from well-designed clinical trials. With the development of precision medicine, liquid biopsy will likely play an increasingly important clinical role.

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objective: The aim of this study was to evaluate the outcomes of video-assisted thoracic surgery (VATS) for mediastinal bronchogenic cyst (MBC) excision and investigate the surgical indication for MBC., Methods: We retrospectively reviewed all consecutive MBC patients who underwent surgical excision between April 2001 and June 2016. One hundred and nineteen patients were enrolled with a median age of 45.4 years and divided into two groups: anterior mediastinum group (n = 48), and middle and posterior mediastinum group (n = 71). VATS technique was initially performed for each patient. The cyst should be resected completely as far as possible. Follow-up was completed by telephone or outpatient clinic every year. The deadline of follow-up was June 2017., Results: One hundred and eighteen patients underwent VATS, and only one patient converted to open thoracotomy. The average operative time was 103.8 ± 41.6 min (40-360 min). The average intraoperative blood loss was 56.6 ± 86.6 ml (5-600 ml). The intraoperative complication rate was 3.4%, and the incomplete excision rate was 5.9%. The multivariate logistic analysis showed that maximal diameter >5 cm was significantly associated with risk of operation time extension (OR = 3.968; 95% CI 1.179-13.355, p = 0.026) and bleeding loss increasing (OR = 12.242; 95% CI 2.420-61.933, p = 0.002). No serious postoperative complications were observed. Follow-up was performed in 102 patients, and the mean follow-up time was 45 months (12-194 months). There was no local recurrence., Conclusions: The maximal diameter >5 cm increased risk of operation time extension and bleeding loss increasing. Early surgical excision of MBC by VATS is recommended to establish histopathological diagnosis, relieve symptoms, and prevent surgery-related complications.

Competing Interests: Competing interests: None declared.

Introduction: Circulating tumour DNA (ctDNA) has potential applications in cancer management. Most previous studies about ctDNA focused on advanced stage cancer patients. We have completed a clinical prospective study (NCT02645318) and showed the feasibility and clinical application of ctDNA detection in early stage non-small cell lung cancer (NSCLC) patients. The aim of this study is to investigate the elimination rate of ctDNA level after surgery. This is the first prospective study to evaluate the perioperative dynamic changes of ctDNA in surgical lung cancer patients., Methods and Analysis: This is a prospective observational study to determine the elimination rate of circulating tumour DNA after surgery. Consecutive patients with suspected lung cancer who undergo curative-intent lung resection will be enrolled. 10 mL blood samples are taken by intravenous puncture. Plasma samples are obtained before surgery (time A) and at a series of scheduled time-points (2 min to 72 hours, time B to F) after tumour resection. DNA is prepared from 4 mL of purified plasma. A multiplex assay based on circulating single-molecule amplification and resequencing technology (cSMART) is used to simultaneously detect and quantitate hot spot EGFR, KRAS, BRAF, ERBB2, PIK3CA, TP53, ALK, RET and MET plasma DNA variants. Positive plasma mutations are validated in tumour tissue and normal lung tissue by targeted sequencing., Ethics and Dissemination: Ethical approval has been obtained from the Peking University People's Hospital Medical Ethics Committee (2016PHB156-01). Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals., Trial Registration Number: NCT02965391; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Multiple primary lung cancers are detected with increasing frequency, but the ideal strategy for diagnosis and treatment remains disputable. This study evaluated both clinical characteristics and genetic alterations to investigate the appropriate strategy for patients with multiple primary lung cancer., Methods: A total of 96 patients in our practice were diagnosed with multiple primary lung cancer over 7 years by clinical-pathologic criteria. According to consolidation/tumor ratio, they were classified into 3 groups: group A (multiple ground-glass opacity-dominant nodules, consolidation/tumor ratio ≤0.5), group B (1 solid-dominant nodule, consolidation/tumor ratio >0.5 with other ground-glass opacity-dominant nodules), and group C (2 solid-dominant nodules). A series of somatic genetic mutations and fusions were analyzed in a portion of the patients., Results: There were 24, 35, and 37 patients in groups A, B, and C, respectively. During follow-up, 23 patients had recurrence. The 5-year recurrence-free survival was 100% in patients with multiple ground-glass opacity, 68% in those with 1 solid lesion, and 51.4% in those with 2 solid tumors (P = .001). Eighteen patients died of lung cancer. The 5-year overall survival was 100% in group A, 80.5% in group B, and 59.9% in group C (P = .002). A total of 77 driver mutations were detected in 61 of the 82 lesions. A high rate of discordance of genetic alterations (89.7%) was found between cancers within individual patients. Two patients in group C had concordant driver mutations between the 2 lesions, and both of them harbored tumor recurrence., Conclusions: A high discordance of driver mutations between tumors in individual patients and a favorable prognosis were identified in patients with multiple primary lung cancers diagnosed by clinical-pathologic criteria, which support different strategies from those with metastatic disease., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Thymic cysts are rare benign developmental anomalies and there is no consensus management for thymic cysts. The aim of this study was to disclose the efficacy of perioperative diagnosis for thymic cysts by chest computerized tomography (CT) and to elucidate the surgical procedure by video-assisted thoracic surgery (VATS) in the management of thymic cysts., Methods: We retrospectively reviewed 108 consecutive thymic cyst patients who underwent VATS at our institution between April 2001 and August 2015. All patients received chest CT preoperatively and underwent VATS treatment. Clinical characteristics, imaging features and surgical exploration were taken into consideration to determine the surgical extent., Results: Multivariate logistic regression analysis showed that a diameter ≤3 cm [risk ratio (RR) =4.525; 95% confidence interval (CI), 1.027-20.000; P=0.046] and an unenhanced CT value >20 Hounsfield unit (Hu) (RR =7.043; 95% CI, 1.750-28.345; P=0.006) were independent factors of incorrect diagnosis of chest CT. Three different surgical procedures were performed, which included thymectomy (n=49), cyst resection and partial thymectomy (n=46), and extended thymectomy (n=13). No serious postoperative complications were observed. The median follow-up-time was 60.6 months (range, 12.0-168.0 months) with no late complications or recurrences., Conclusions: A diameter ≤3 cm and an unenhanced CT value >20 Hu were independent factors of incorrect diagnosis of chest CT. VATS is a reliable approach for the surgical resection of thymic cysts. We think that local resection is adequate for simple thymic cysts. However, thymectomy is necessary when there is suspicion of a thymoma or multilocular thymic cyst, and radical thymectomy is advisable for patients with autoimmune diseases., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Purpose: The International Association for the Study of Lung Cancer has proposed a revision of the Tumor, Node, Metastasis (TNM) classification for lung cancer. The purpose of this study is to evaluate the prognostic value of the eighth edition of the TNM staging system in surgically treated patients with non-small-cell lung cancer., Methods: Data from 2043 consecutive patients with non-small-cell lung cancer who underwent surgical treatment in our single center between January 2006 and September 2015 were collected and analyzed retrospectively. Cox proportional hazard models were used to assess the prognostic significance of the T and N descriptors., Results: The reversed overall survival curves of stage IIA and stage IIB in the seventh edition were corrected in the eighth edition. Better prognostic value in predicting overall survival, including a higher log rank test of trend χ 2 statistic (433.6 vs. 414.2), a smaller Akaike Information Criterion value (4759.6 vs. 4768.2), a higher Harrell C-index (0.776 vs. 0.769), and a lower integrated Brier score (0.092 vs. 0.093), was observed for the eighth edition relative to the seventh edition. Recurrence-free survival analysis of subsets of patients stratified by T and N descriptors showed a stepwise deterioration. Significant differences were found between patients of subdivided stage IA (IAI vs. IA2; P = .003 and IA2 vs. IA3; P = .004)., Conclusion: The eighth edition of the TNM staging system for lung cancer has prognostic value superior to that of the seventh edition. It was able to predict recurrence-free survival well., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Noninvasive liquid biopsies of circulating tumor DNA (ctDNA) can be used to assess non-small cell lung cancer (NSCLC), but previous work focused on patients with advanced-stage cancer. Thus, we evaluated the feasibility and their potential clinical application of circulating tumor DNA approached for surgical patients with NSCLC., Method: Consecutive patients with suspected lung cancer who underwent curative-intent lung resection were enrolled prospectively in this study. Targeted DNA sequencing with a next-generation sequencing platform was used to identify a series of somatic mutations in matched tumor tissue DNA (tDNA) and plasma ctDNA samples. Plasma was collected before, during, and after surgery. Concordance was defined as matched tDNA and ctDNA with the same identified mutations or with no mutations., Results: In the enrolled 76 patients with lung cancer who were included, 31 had concordant mutations and 21 had no mutation in both ctDNA and tDNA, yielding an overall concordance of 68.4%. ctDNA samples obtained before and during surgery had the same mutations with a low variance in mutation frequency (1.2%) that was reduced to an average of 0.28% after surgery (P < .001). More patients were positive as assayed by ctDNA (48; 63.2%) than with serum tumor protein markers (36; 49.3%). The area under the curve was greater in ctDNA (0.887, 95% confidence interval [CI], 0.788-0.986) than for the 2 prediction models (0.803, 95% CI, 0.647-0.959; 0.69, 95% CI, 0.512-0.869) for estimating malignancy of solitary pulmonary nodules., Conclusion: ctDNA mutation analysis for stage I-III surgical patients with NSCLC is feasible. More studies are needed to investigate its clinical application., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: We evaluated whether video-assisted thoracoscopic lobectomy for locally advanced non-small cell lung cancer could be performed safely and with acceptable long-term outcomes by our improved technique and compared with standard thoracotomy lobectomy in a well-balanced population., Methods: Patients with clinical stage II and III A non-small cell lung cancers who received lobectomy were reviewed. Video-assisted thoracoscopic lobectomies were all performed with Wang's technique by the surgeons who had overcome the learning curve and achieved proficiency. By using propensity-matched analysis, perioperative outcomes and long-term survival were compared., Results: Matching based on propensity scores produced 120 patients in each group. Conversion rate to thoracotomy was 11.7%. After thoracoscopic lobectomy, hospital length of stay was shorter compared with thoracotomy (9.2 vs 12 days; P = .014) despite similar rates of postoperative complications (30/125 [25%] vs 34/125 [28.3%]; P = .56). Disease-free survival (49.1% vs 42.2%; P = .40) and overall survival (55.0% vs 57.1%; P = .73) at 5 years were similar between groups. Although advanced pathologic stage (hazard ratio [HR], 2.018; 95% confidence interval [CI], 1.330-3.062) and no postoperative chemotherapy (HR, 1.880; 95% CI, 1.236-2.858) were independently associated with increased hazard of death in multivariable Cox regression at each time point in follow-up, thoracoscopic lobectomy was not (HR, 1.075; 95% CI, 0.714-1.620; P = .73)., Conclusions: With continued experience and optimized technique, video-assisted thoracoscopic lobectomy can be performed in the majority of cases without compromising perioperative outcomes and oncologic efficacy., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze the clinical characteristics and follow up record of patients with synchronous multiple lung cancers (SMLC)., Methods: The medical records of 1 868 lung cancer patients who underwent surgical treatments From January 2007 to December 2014 were reviewed, in which 103 patients were diagnosed SMLC by Martini and American College of Chest Physicians modified guideline. The average age was 60.5 years, including 34 male and 69 female patients. According to consolidation/tumor ratio (CTR) on thin-section computed tomography, 103 cases were classified into three groups: group A (multiple ground-glass opacities, CTR ≤ 50%), group B (with one solid dominant nodules, CTR > 50%), group C (with two solid dominant nodules). The surgical procedure was determined according to CT findings and respiratory function. The Kaplan-Meier method was used to analyze the duration of recurrence-free survival (RFS) and over-all survival (OS), and differences were assessed using the Log-rank test. Multivariate analysis using the Cox proportional hazards models was used to assess the potential independent effects on RFS or OS., Results: There were 38 patients in group A (36.9%), 40 patients in group B (38.8%) and 25 patients (24.3%) in group C. More female (73.7% vs. 48.0%, χ² = 4.291, P = 0.038), less smoker (21.1% vs. 44.0%, 2 = 3.770, P = 0.052), younger (56.2 years old vs. 65.9 years old, t = -4.172, P = 0.000) and less tumor size (1.24 cm vs. 2.31 cm, t = -4.573, P = 0.000) patients in group A than in group C. The 3, 5-year RFS were 80.3% and 64.9% for all patients, respectively. The 3, 5-year OS were 87.3% and 68.6% for all patients, respectively. The 3, 5-year RFS were 100% and 100% in group A, 77.7% and 51.8% in group B, 59.6% and 44.7% in group C (P = 0.029). No significance were found in OS between the three groups (P = 0.214). Multivariate Cox analysis demonstrated that size of dominant nodule larger than 2 cm (HR = 4.475, 95% CI: 1.138 to 17.604, P = 0.032) is associated with poor prognosis, whereas postoperative chemotherapy did not affect RFS., Conclusions: Multifocal ground-glass opacities and multiple solid lung cancers are different in nature. RFS of patients with SMLC is strongly affected tumor size. Surgical resection is effective and should be performed specifically to patients.

Background: This study aimed at identifying risk factors of recurrence for completely resected pathologic T1aN0M0 lung adenocarcinomas., Methods: We reviewed the records of 177 T1aN0M0 invasive adenocarcinoma patients, and re-classified achieved surgical specimens according to the new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification. Impact on recurrence-free survival (RFS) for age, gender, smoking history, lymphovascular invasion (LVI) and new classification was analyzed by log-rank test and Cox regression. Two existing prognostic grouping schemes of new classification were compared, and subsequently, the correlation of high-grade group in the better prognostic grouping model with clinical data was investigated statistically., Results: The 5-year recurrence-free rate was 83.7%. The LVI and new adenocarcinoma classification were significantly associated with 5-year RFS (P = 0.012; P = 0.022, respectively). The designation of papillary predominant subtype in the low-grade group, along with lepidic- and acinar predominant subtype had more prognostic significance than the model of combining papillary-, solid- and micropapillary predominant subtypes as the high-grade group (P = 0.005 versus P = 0.181). This high-grade group has increased risk of recurrence in a multivariate Cox regression (adjusted HR 2.815, 95% CI: 1.239 to 6.397, P = 0.013), and is associated significantly more with male gender (adjusted OR 2.214, 95% CI: 1.050 to 4.668, P = 0.037), and, with borderline significance, the presence of LVI (adjusted OR 2.091, 95% CI: 0.938 to 4.662, P = 0.071)., Conclusions: Our results showed that the solid- and micropapillary predominant subtype of IASLC/ATS/ERS classification remains the only risk factor for post-operative recurrence of T1aN0M0 adenocarcinomas, suggesting that they can be indicators of aggressive tumor behaviors.