ABSTRACTBackgroundPlasma protein has gained prominence in the non‐invasive predicting of lung cancer. We utilised Zeolite Zotero NaY‐based plasma proteomics to investigate its potential for multiple event predicting, including lung cancer diagnosis (task #1), lymph node metastasis detection (task #2) and tumour‒node‒metastasis (TNM) staging (task #3).MethodsA total of 4703 plasma proteins were quantified from 241 participants based on a prospective cohort of 2757 participants. An additional 46 participants from external prospective cohort of 735 participants were used for validation. Feature selection was performed using differential expressed protein analysis, area under curve (AUC) evaluation and least absolute shrinkage and selection operator (LASSO) regression. Random forest was used for multitask model construction based on the key proteins. Feature importance was interpreted using Shapley additive explanations (SHAP) algorithm.ResultsFor task #1, 10 proteins panel showed an AUC of .87 (.77‒.97) in the external validation. After integrating clinical factors, a significant increase diagnostic accuracy was observed with AUC of .91 (.85‒.98). For task #2, nine proteins panel achieved an AUC of .88 (.80‒.96), integration model showed an increase diagnostic accuracy with AUC of .90 (.85‒.97). For task #3, 10 proteins panel showed an AUC of .88 (.74‒.96) for stage I, .92 (.84‒.97) for stage II, .88 (.76‒.96) for stage III and .99 (.98‒.99) for stage IV in the integration model.ConclusionsThis study comprehensively profiled the NaY‐based plasma proteome biomarker, laying the foundation for a high‐performance blood test for predicting multiple events in lung cancer.Key points Our study developed an innovative nanomaterial, Zeolite NaY, which addressed the masking effect and improved the depth of the proteome. The performance of NaY‐based plasma proteomics as a preclinical diagnostic tool was validated through both internal and external cohort. Furthermore, we explored the different patterns of plasma protein changes during the progression of lung cancer and used the explanations method to elucidate the roles of proteins in the multitask predictive model.

Background:Studying the relationship between strenuous sports or other exercises (SSOE) and lung cancer risk remains underexplored. Traditional observational studies face challenges like confounders and inverse causation. However, Mendelian randomization (MR) provides a promising approach in epidemiology and genetics, using genetic variants as instrumental variables to investigate causal relationships. By leveraging MR, we have scrutinized the causal link between SSOE and lung cancer development. Methods:Twelve single-nucleotide polymorphisms (SNPs) associated with SSOE, as identified in previously published genome-wide association studies, were utilized as instrumental variables in our investigation. Summary genetic data at the individual level were obtained from relevant studies and cancer consortia. The study encompassed a total of 11,348 cases and 15,861 controls. The statistical technique of inverse variance-weighting (IVW), commonly employed in meta-analyses and MR studies, was employed to assess the causal relationship between SSOE and lung cancer risk. Results:The MR risk analysis indicated a causal relationship between SSOE and the incidence of lung cancer, with evidence of a reduced risk for overall lung cancer [odds ratio (OR) =0.129; 95% confidence interval (CI): 0.021-0.779; P=0.03], lung adenocarcinoma (OR =0.161; 95% CI: 0.012-2.102; P=0.16) and squamous cell lung cancer (OR =0.045; 95% CI: 0.003-0.677; P=0.03). The combined OR for lung cancer from SSOE (controlling for waist circumference and smoking status) was 0.054 (95% CI: 0.010-0.302, P<0.001). Conclusions:Our MR analysis findings indicate a potential correlation between SSOE and a protective effect against lung cancer development. Further investigation is imperative to uncover the precise mechanistic link between them.

Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) protein significantly improve survival in patients with advanced non-small-cell lung cancer (NSCLC), but its impact on early-stage ground-glass opacity (GGO) lesions remains unclear. This is a single-arm, phase II trial (NCT04026841) using Simon’s optimal two-stage design, of which 4 doses of sintilimab (200 mg per 3 weeks) were administrated in 36 enrolled multiple primary lung cancer (MPLC) patients with persistent high-risk (Lung-RADS category 4 or had progressed within 6 months) GGOs. The primary endpoint was objective response rate (ORR). T/B/NK-cell subpopulations, TCR-seq, cytokines, exosomal RNA, and multiplexed immunohistochemistry (mIHC) were monitored and compared between responders and non-responders. Finally, two intent-to-treat (ITT) lesions (pure-GGO or GGO-predominant) showed responses (ORR: 5.6%, 2/36), and no patients had progressive disease (PD). No grade 3–5 TRAEs occurred. The total response rate considering two ITT lesions and three non-intent-to-treat (NITT) lesions (pure-solid or solid-predominant) was 13.9% (5/36). The proportion of CD8+ T cells, the ratio of CD8+/CD4+, and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time. Correspondingly, the mIHC analysis showed more CD8+ T cells infiltrated in responders. Besides, responders’ cytokine concentrations of EGF and CTLA-4 increased during treatment. The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders. Collectively, PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns. Such effects were associated with specific T-cell re-distribution, EGF/CTLA-4 cytokine compensation, and regulation of metabolism pathways.

Background:Malignant esophageal stent esophagorespiratory fistula (ERF) is an abnormal communication between esophagus and airway among advanced tumor patients with indwelling esophageal stent, which is devastating and life-threatening. This study aims to provide a new feasible treatment scheme for malignant esophageal stent ERF and report its potential advantage compared with double stenting, which was recommended by European Society of Gastrointestinal Endoscopy Guideline.Methods:We retrospectively analyzed the medical data of malignant esophageal stent ERF patients between January 2018 to May 2023 at the First Affiliated Hospital of Guangzhou Medical University and divided them into two groups. Group 1 consisted of patients treated with rigid bronchoscopy to remove the esophageal stent and implant Y silicone trachea stent, while group 2 consisted of patients treated with additional airway stenting without removing the esophageal stent. Demographic parameters, disease diagnoses and treatment, radiological findings before and after the intervention, and complications caused by the stents were obtained and analyzed with chi-squared, Mann-Whitney U, independent-samples t-tests, Kaplan-Meier methods, and log-rank test.Results:Ten patients (seven patients in group 1 and three in group 2) were included. No procedure complications occurred in both groups. The mean Karnofsky Performance Score after the procedure significantly improved compared to the pre-procedure (57.14 vs. 77.14, P=0.001) in group 1, while decreased in group 2 (50 vs. 40, P=0.026). The control of pneumonia in group 1 patients is better than that in group 2. There was significant improvement in the degree of dysphagia after the procedure (3.86 vs. 2.43, P=0.002) in group 1, while no improvement was found in group 2 (4.00 vs. 3.33, P=0.423). The mean survival of group 1 was significantly longer group 2 (381.00 vs. 80.33 days, P<0.001, log-rank test). No patient needed stent repositioning due to migration in both groups. Cause of death in the group 1 included disease progression, novel coronavirus pneumonia, massive hemoptysis, and respiratory insufficiency, while group 2 included severe pneumonia and disease progression. No death was directly attributed to the procedure in both groups.Conclusions:Removing the esophageal stent and implanting Y silicone trachea stent through a rigid bronchoscopy is a safe and feasible treatment for malignant esophageal stent ERF. This procedure can effectively seal the fistula, prevent from recurrent aspiration pneumonia, improve the quality of life, and prolong the survival time.

Background:Neoadjuvant immunotherapy is effective in treating resectable non-small cell lung cancer (NSCLC) but shows different responses in lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Current studies are limited in size, necessitating further research to clarify these differences. This study aims to investigate whether there is a difference between the efficacy of neoadjuvant immune checkpoint inhibitors (ICIs) on lung SCC vs. ADC. Methods:Studies provided data of pathological or radiological response of ADC and SCC receiving neoadjuvant ICIs published before August 1, 2023, were retrieved. Pathological response included major pathological response (MPR), complete pathological response (cPR) and the sum of major pathological response and complete pathological response (McPR). Radiological response includes complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), disease control rate (DCR). The protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO CRD42022328240). Results:A total of 22 studies with 430 patients were included. Pathological response and radiological response were used to evaluate the efficacy of neoadjuvant immunotherapy on ADC and SCC. No significant difference was found in pathological response (MPR: P=0.15; cPR: P=0.61), while SCC had significantly higher ORR (P=0.02), lower SD (P<0.04) and PD (P=0.04) than ADC after neoadjuvant ICIs. Both SCC and ADC achieved significantly higher PR (P<0.01), ORR (P<0.01), and lower SD (P<0.01) when treated with chemo-immunotherapy compared to ICI monotherapy. Chemo-immunotherapy significantly improved the McPR in ADC (P<0.05). Toripalimab showed a higher ORR for both SCC and ADC (P<0.05) without a clear advantage in pathological remission across the ICIs. Pembrolizumab had significantly higher McPR (P<0.05) for treating SCC patients compare to ADC patients. Conclusions:In conclusion, our findings indicate that SCC patients exhibited higher ORR and lower SD and PD than those with ADC. No significant differences in pathological responses were seen between SCC and ADC, across ICI monotherapy or chemo-immunotherapy. Chemo-immunotherapy notably improved McPR in ADC. Toripalimab showed higher ORR in both cancers without distinct pathological remission advantage. Pembrolizumab, however, demonstrated superior McPR in SCC, indicating a preference in treating SCC.

[18F]-FDG PET/CT and brain MRI are common approaches to detect metastasis in patients of lung cancer. Current guidelines for the use of PET/CT and MRI in clinical T1-category lung cancer lack risk-based stratification and require optimization. This study stratified patients based on metastatic risk in terms of the lesions' size and morphological characteristics. The detection rate of metastasis was measured in different sizes and morphological characteristics (solid and sub-solid) of tumors. To confirm the cut-off value for discriminating metastasis and overall survival (OS) prediction, the receiver operating characteristic (ROC) analysis was performed based on PET/CT metabolic parameters (SUVmax/SUVmean/SULpeak/MTV/TLG), followed by Kaplan–Meier analysis for survival in post-operation patients with and without PET/CT plus MRI. 2,298 patients were included. No metastasis was observed in patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm. The cut-off of PET/CT metabolic parameters on discriminating metastasis were 1.09 (SUVmax), 0.26 (SUVmean), 0.31 (SULpeak), 0.55 (MTV), and 0.81 (TLG), respectively. Patients undergoing PET/CT plus MRI exhibited longer OS compared to those who did not receive it in solid nodules ≥ 8.0 mm sub-solid nodules ≥ 10.0 mm (HR, 0.44; p < 0.001); in solid nodules ≥ 8.0 mm (HR, 0.12; p<0.001) and in sub-solid nodules ≥ 10.0 mm (HR; 0.61; p=0.075), respectively. Compared to patients with metabolic parameters lower than cut-off values, patients with higher metabolic parameters displayed shorter OS: SUVmax (HR, 12.94; p < 0.001), SUVmean (HR, 11.33; p <0.001), SULpeak (HR, 9.65; p < 0.001), MTV (HR, 9.16; p = 0.031), and TLG (HR, 12.06; p < 0.001). The necessity of PET/CT and MRI should be cautiously evaluated in patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm, however, these examinations remained essential and beneficial for patients with solid nodules ≥ 8.0 mm and sub-solid nodules ≥ 10.0 mm.

Background::Light at night (LAN) has become a concern in interdisciplinary research in recent years. This global interdisciplinary study aimed to explore the exposure-lag-response association between LAN exposure and lung cancer incidence.Methods::LAN data were obtained from the Defense Meteorological Satellite Program’s Operational Linescan System. Data of lung cancer incidence, socio-demographic index, and smoking prevalence of populations in 201 countries/territories from 1992 to 2018 were collected from the Global Burden of Disease Study. Spearman correlation tests and population-weighted linear regression analysis were used to evaluate the correlation between LAN exposure and lung cancer incidence. A distributed lag nonlinear model (DLNM) was used to assess the exposure-lag effects of LAN exposure on lung cancer incidence.Results::The Spearman correlation coefficients were 0.286-0.355 and the population-weighted linear regression correlation coefficients were 0.361-0.527. After adjustment for socio-demographic index and smoking prevalence, the Spearman correlation coefficients were 0.264-0.357 and the population-weighted linear regression correlation coefficients were 0.346-0.497. In the DLNM, the maximum relative risk was 1.04 (1.02-1.06) at LAN exposure of 8.6 with a 2.6-year lag time. After adjustment for socio-demographic index and smoking prevalence, the maximum relative risk was 1.05 (1.02-1.07) at LAN exposure of 8.6 with a 2.4-year lag time.Conclusion::High LAN exposure was associated with increased lung cancer incidence, and this effect had a specific lag period. Compared with traditional individual-level studies, this group-level study provides a novel paradigm of effective, efficient, and scalable screening for risk factors.

Background:Recently, the impact of solar radiation (RAD) on diseases worldwide has garnered growing attention. However, the association between RAD and lung cancer remains largely unknow and no consensus has been reached. The aim of this study was to investigate the lag exposure-response of RAD on lung cancer and provide robust scientific evidence for updating prevention and treatment strategies of lung cancer. Methods:Data of RAD were obtained from Google Earth Engine, which was post-processed by European Centre for Medium-Range Weather Forecasts (ECMWF). Lung cancer incidence, smoking prevalence and socio-demographic index (SDI) were obtained from Global Burden of Disease (GBD). Spearman's rank correlation tests and linear regression analyses were performed to investigate the relationship between RAD and lung cancer incidence. Additionally, a distributed lag non-linear model (DLNM) was utilized to reveal the lag effects of RAD on lung cancer incidence. Results:There were 204 countries and territories and selected subnational locations with information recorded in GBD and radiation exposure was calculated in 272 countries and territories. After excluding missing and abnormal data, as well as Kashmir and Western Sahara which were two disputed districts, this study included 186 countries from 1992 to 2019. After adjusted for smoking and SDI, the Spearman's correlation coefficient ranged from -0.630 to -0.581. In the DLNM for lung cancer adjusted for smoking and SDI, the maximum relative risk (RR) was 1.013 [95% confidence interval (CI): 1.011-1.014], at RAD exposure of 12,760,000 with 5.8 lag years, while the minimum RR was 0.973 (95% CI: 0.947-0.992) at RAD exposure of 12,845,000 with 8.0 lag years. Conclusions:The global rise in lung cancer incidence has been notably associated with low exposure to RAD, whereas the defensive influence of sunlight against lung cancer demonstrated hysteresis. This study shows that properly exposure to sunlight is a possible strategy for lung cancer prevention, which provides scientific support for the formulation of future health strategies. It is also crucial in epidemiological research as it offers a novel pattern for identifying additional potential risk factors for diseases.

Background:The benefits of spontaneous ventilation (SV)-video-assisted thoracoscopic surgery (VATS) in octogenarian patients with non-small-cell lung cancer (NSCLC) have rarely been reported. This retrospective study was conducted to evaluate the safety and feasibility of SV-VATS in octogenarian patients with NSCLC. Methods:Patients with NSCLC aged >80 years who underwent SV-VATS or mechanical ventilation (MV)-VATS between 2017 and 2022 were included in this study. The baseline characteristics of the two groups were balanced by a 1:2 propensity score matching (PSM). Intraoperative and postoperative outcomes were compared. Overall survival (OS) and disease-free survival (DFS) were analyzed by Kaplan-Meier survival analysis and Cox regression. Results:A total of 251 patients were initially included, and after applying selection criteria and PSM, 22 patients were in the SV-VATS group and 44 in the MV-VATS group. Baseline characteristics were well balanced between the two groups. Compared with the MV-VATS group, the SV-VATS group had shorter post-anesthesia care unit (PACU) stay (88.8±22.3 vs. 111±38.8, P=0.01) and shorter resuscitation time (88.8±22.7 vs. 112±40.4, P=0.02). No statistically significant differences were observed in the surgical and anaesthesia times, chest tube duration, total volume of chest drainage, intraoperative blood loss, postoperative hospital stay, or complications in the PACU. The OS and DFS of patients who underwent SV-VATS were comparable to those of patients who underwent MV-VATS. Conclusions:SV-VATS appears to be a safe and feasible option for octogenarian patients with NSCLC, providing a new approach to surgical treatment. Large-scale prospective studies are required to further validate its feasibility.

Background: Esophageal cancer is one of the leading causes of cancer death worldwide. A deeper understanding of the trends in annual incidence, mortality, and disability-adjusted life-years (DALYs) of esophageal cancer is critical for management and prevention. In this study, we report on the disease burden of esophageal cancer in 204 countries and territories between 1990 and 2019 by age, sex, and Methods: Data on incidence, mortality, and DALYs were extracted from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. The estimated numbers and age-standardized rates for esophageal cancer in 2019 are presented in this paper, as well as trends from 1990 to 2019. All estimates are presented as counts and age-standardized rates per 100,000 population, with 95% uncertainty intervals (UIs) for each estimate. Results: In 2019, nearly 535,000 (95% UI: 467,000-595,000) new cases of esophageal cancer occurred globally. Esophageal cancer was responsible for more than 498,000 (95% UI: 438,000-551,000) deaths and 11.7 million (95% UI: 10.4-12.9) DALYs. Worldwide age-standardized rates of esophageal cancer, including incidence, deaths, and DALYs, have declined since 1990. However, the trends differ across countries and territories. Notably, there was a nonlinear but generally inverse correlation between age-standardized DALY rates and SDI. Higher age-standardized incidence and death rates were observed in males compared to females, and both increased with age. Regarding risk factors, smoking, alcohol use, and high body-mass index were 3 predominant contributors to esophageal cancer DALYs in 2019 for both sexes worldwide. Conclusions: This study found a global reduction in the esophageal cancer burden, but substantial heterogeneity remains across regions and countries. Hence, the identification of high-risk groups and the exploration of specific local strategies and primary prevention efforts are required.

Background:Respiratory cancer is the leading cause of cancer-related deaths worldwide, but its statistics vary between the East and West. This study aimed to estimate the burdens of tracheal, bronchus, and lung (TBL) cancer and larynx cancer and their attributable risks from 1990 to 2019 in Asia, and at regional and national levels. Methods:This research evaluated the incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) for respiratory tract cancers using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 database. Age-standardized rates were calculated for TBL cancer from 1990 to 2019, adjusted for smoking and socio-demographic index (SDI). Deaths from TBL cancer and larynx cancer attributable to each risk factor were estimated for 33 Asian countries. Results:The age-standardized incidence and death rates for TBL cancer in Asia declined from 2010 to 2019, while the incidence rate of larynx cancer increased. Smoking was the leading specific risk factor for deaths from both TBL and larynx cancers. The burden of TBL cancer in Asian countries was influenced by SDI and smoking, particularly among males in Central Asia. Deaths, DALYs, and incidences of larynx cancer in East Asia had not changed significantly over the past 30 years, but showed slight downward trends in males and both sexes combined, and an upward trend in females in recent years. Conclusions:The past decade saw increases in numbers of incident cases and deaths from TBL cancer and larynx cancer in Asia. SDI and smoking were the main factors influencing the disease burden of TBL cancer in Asian countries. This study highlights the need for tailored cancer control programs to address the burden of respiratory tract cancers in different Asian countries.

A comprehensive appraisal of published meta-analyses incorporating Mendelian randomization studies was performed to map the different risk factors and assess the causality for lung cancer. Systematic reviews and meta-analyses of observational and interventional studies were reviewed based on PubMed, Embase, Web of Science, and Cochrane Library. Mendelian randomization analyses were conducted to validate the causal associations of those various exposures with lung cancer using summary statistics from 10 genome-wide association studies (GWAS) consortia and other GWAS databases in MR-Base platform. In the review of meta-analyses, 105 risk factors associated with lung cancer were identified from 93 articles. It was found that 72 risk factors were nominally significant (P < 0.05) associated with lung cancer. Mendelian randomization analyses were performed to analyze 36 exposures based on 551 SNPs and 4,944,052 individuals, finding that 3 exposures had a consistent risk/protective effect on lung cancer with the results of the meta-analysis. In Mendelian randomization anaylses, smoking (OR 1.44, 95