Lung adenocarcinoma promotion by air pollutants.

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 development1. Here we propose that environmental particulate matter measuring ≤2.5 µm (PM2.5), 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 PM2.5 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-1ß. 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  PM2.5 air pollutants  and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

The current therapeutic cancer vaccines landscape in non-small cell lung cancer.

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.

Systemic inflammation influences the prognosis of patients with radically resected non-small cell lung cancer and correlates with the immunosuppressive microenvironment.

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.

Individualized dynamic methylation-based analysis of cell-free DNA in postoperative monitoring of lung cancer.

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 .

Near-infrared fluorescence imaging of thoracic duct in minimally invasive esophagectomy.

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.

Potential clinical utility of liquid biopsy in early-stage non-small cell lung cancer.

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.

Artificial intelligence: opportunities in lung cancer.

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.

Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity.

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).

Monitoring of circulating tumor DNA and its aberrant methylation in the surveillance of surgical lung Cancer patients: protocol for a prospective observational study.

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).

Signaling protein signature predicts clinical outcome of non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression. Many of these proteins have been reported to be correlated with clinical outcomes of NSCLC. However, none of them could provide adequate accuracy of prognosis prediction in clinical application. METHODS: A total of 384 resected NSCLC specimens from two hospitals in Beijing (BJ) and Chongqing (CQ) were collected. Using immunohistochemistry (IHC) staining on stored formalin-fixed paraffin-embedded (FFPE) surgical samples, we examined the expression levels of 75 critical proteins on BJ samples. Random forest algorithm (RFA) and support vector machines (SVM) computation were applied to identify protein signatures on 2/3 randomly assigned BJ samples. The identified signatures were tested on the remaining BJ samples, and were further validated with CQ independent cohort. RESULTS: A 6-protein signature for adenocarcinoma (ADC) and a 5-protein signature for squamous cell carcinoma (SCC) were identified from training sets and tested in testing sets. In independent validation with CQ cohort, patients can also be divided into high- and low-risk groups with significantly different median overall survivals by Kaplan-Meier analysis, both in ADC (31 months vs. 87 months, HR 2.81; P <  0.001) and SCC patients (27 months vs. not reached, HR 9.97; P <  0.001). Cox regression analysis showed that both signatures are independent prognostic indicators and outperformed TNM staging (ADC: adjusted HR 3.07 vs. 2.43, SCC: adjusted HR 7.84 vs. 2.24). Particularly, we found that only the ADC patients in high-risk group significantly benefited from adjuvant chemotherapy (P = 0.018). CONCLUSIONS: Both ADC and SCC protein signatures could effectively stratify the prognosis of NSCLC patients, and may support patient selection for adjuvant chemotherapy.

The Video-Assisted Thoracic Surgery for Mediastinal Bronchogenic Cysts: A Single-Center Experience.

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.

[Clinical features and treatment outcome of multiple primary lung cancer patients with different imaging performance].

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.

Risk factors of recurrence for resected T1aN0M0 invasive lung adenocarcinoma: a clinicopathologic study of 177 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.

Development of new techniques and clinical applications of liquid biopsy in lung cancer management.

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.

Efficacy of neoadjuvant chemo-immunotherapy in non-small cell lung cancer: a real-world, multicenter, retrospective study.

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.

Development and validation of an integrated system for lung cancer screening and post-screening pulmonary nodules management: a proof-of-concept study (ASCEND-LUNG).

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.

Current and emerging applications of liquid biopsy in pan-cancer.

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.

The Prognostic Value of TTF-1/NKX2-1 in Lung Squamous Cell Carcinoma.

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.