Causal association between immune cells and lung cancer risk: a two-sample bidirectional Mendelian randomization analysis.

Background: Previous studies have highlighted the crucial role of immune cells in lung cancer development; however, the direct link between immunophenotypes and lung cancer remains underexplored. Methods: We applied two-sample Mendelian randomization (MR) analysis, using genetic variants as instruments to determine the causal influence of exposures on outcomes. This method, unlike traditional randomized controlled trials (RCTs), leverages genetic variants inherited randomly at conception, thus reducing confounding and preventing reverse causation. Our analysis involved three genome-wide association studies to assess the causal impact of 731 immune cell signatures on lung cancer using genetic instrumental variables (IVs). We initially used the standard inverse variance weighted (IVW) method and further validated our findings with three supplementary MR techniques (MR-Egger, weighted median, and MR-PRESSO) to ensure robustness. We also conducted MR-Egger intercept and Cochran's Q tests to assess heterogeneity and pleiotropy. Additionally, reverse MR analysis was performed to explore potential causality between lung cancer subtypes and identified immunophenotypes, using R software for all statistical calculations. Results: Our MR analysis identified 106 immune signatures significantly associated with lung cancer. Notably, we found five suggestive associations across all sensitivity tests (P<0.05): CD25 on IgD- CD24- cells in small cell lung carcinoma (ORIVW =0.885; 95% CI: 0.798-0.983; P IVW =0.022); CD27 on IgD+ CD24+ cells in lung squamous cell carcinoma (ORIVW =1.054; 95% CI: 1.010-1.100; P IVW =0.015); CCR2 on monocyte cells in lung squamous cell carcinoma (ORIVW =0.941; 95% CI: 0.898-0.987; P IVW =0.012); CD123 on CD62L+ plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) as well as on plasmacytoid dendritic cells (ORIVW =0.958; 95% CI: 0.924-0.992; P IVW =0.017) in lung squamous cell carcinoma. Conclusion: This study establishes a significant genomic link between immune cells and lung cancer, providing a robust basis for future clinical research aimed at lung cancer management.

Pembrolizumab for the better treatment of EGFR-mutant T790M-negative advanced lung adenocarcinoma patients than dual treatment of pemetrexed plus platinum after tyrosine kinase inhibitor treatment failure.

BACKGROUND: The treatment of lung cancer patients, especially those with epidermal growth factor receptor (EGFR)-mutant T790M-negative adenocarcinoma, after first- or second-line tyrosine kinase inhibitor (TKI) treatment failure is challenging due to the poor prognosis and limited effectiveness of platinum two-drug chemotherapy or chemotherapy plus anti-angiogenesis therapy. It is well-known that pembrolizumab monotherapy exhibits low toxicity and long-term survival, but it is unknown in these patients. METHODS: From September 2018 to March 2021, 460 patients in Jiangmen Central Hospital were included and 82 patients with disease progression in lung adenocarcinoma who remained T790M-negative on the second biopsy were screened. Two groups were divided according to treatment status, and simple random sampling was performed to obtain 32 cases respectively. The safety of the patients was subsequently evaluated by telephone follow-up. RESULTS: The objective response rate (ORR) and disease control rate (DCR) in the pembrolizumab group were 15.63% and 53.13%. In the chemotherapy group, the ORR was 8.33% and the DCR was 25% (P<0.05). In the pembrolizumab group, the progression-free survival (PFS) [14.65 months, 95% confidence interval (CI): 13.03 to 16.28] was significantly higher than that of the control group (9.54 months, 95% CI: 8.43 to 10.65) (P<0.05). In the univariate analysis, programmed cell death protein 1 ligand (PD-L1) expression, smoking status, gender, and whether first-line chemotherapy was associated with survival. In the multivariate analysis, gender [P=0.001; hazard ratio (HR) 10.98, 95% CI: 2.49-46.67], first-line chemotherapy (P=0.037; HR 4.5, 95% CI: 1.1-4.81), and PD-L1 expression (P=0.039; HR 0.16, 95% CI: 0.04-0.68) were correlated with patient survival. Grade 3 or grade 4 treatment-related adverse events were not found in the pembrolizumab group, while 2 cases of grade 3 or 4 treatment-related adverse events occurred in the control group. CONCLUSIONS: In advanced lung adenocarcinoma patients with EGFR-mutant T790M-negative after TKI treatment, pembrolizumab had a higher ORR and PFS. Pembrolizumab in women with first-line chemotherapy and PD-L1 ≥25% of those patients may have a good response and a low rate of adverse reactions. A multicenter, prospective, evidence-based study of pembrolizumab salvage therapy in those patients is warranted for posterior line treatment.

A comparison of modelling the spatio-temporal pattern of disease: a case study of schistosomiasis japonica in Anhui Province, China.

The construction of spatio-temporal models can be either descriptive or dynamic. In this study we aim to evaluate the differences in model fitting between a descriptive model and a dynamic model of the transmission for intestinal schistosomiasis caused by Schistosoma japonicum in Guichi, Anhui Province, China. The parasitological data at the village level from 1991 to 2014 were obtained by cross-sectional surveys. We used the fixed rank kriging (FRK) model, a descriptive model, and the integro-differential equation (IDE) model, a dynamic model, to explore the space-time changes of schistosomiasis japonica. In both models, the average daily precipitation and the normalized difference vegetation index are significantly positively associated with schistosomiasis japonica prevalence, while the distance to water bodies, the hours of daylight and the land surface temperature at daytime were significantly negatively associated. The overall root mean square prediction error of the IDE and FRK models was 0.0035 and 0.0054, respectively, and the correlation reflected by Pearson's correlation coefficient between the predicted and observed values for the IDE model (0.71; p<0.01) was larger than that for the FRK model (0.53; p=0.02). The IDE model fits better in capturing the geographic variation of schistosomiasis japonica. Dynamic spatio-temporal models have the advantage of quantifying the process of disease transmission and may provide more accurate predictions.

Dynamic evolution of schistosomiasis distribution under different control strategies: Results from surveillance covering 1991-2014 in Guichi, China.

BACKGROUND: Since the founding of the China, the Chinese government, depending on the changing epidemiological situations over time, adopted different strategies to continue the progress towards elimination of schistosomiasis in the country. Although the changing pattern of schistosomiasis distribution in both time and space is well known and has been confirmed by numerous studies, the problem of how these patterns evolve under different control strategies is far from being understood. The purpose of this study is, therefore, to investigate the spatio-temporal change of the distribution of schistosomiasis with special reference to how these patterns evolve under different control strategies. METHODOLOGY / PRINCIPAL FINDINGS: Parasitological data at the village level were obtained through access to repeated cross-sectional surveys carried out during 1991-2014 in Guichi, a rural district along the Yangtze River in Anhui Province, China. A hierarchical dynamic spatio-temporal model was used to evaluate the evolving pattern of schistosomiasis prevalence, which accounted for mechanism of dynamics of the disease. Descriptive analysis indicates that schistosomiasis prevalence displayed fluctuating high-risk foci during implementation of the chemotherapy-based strategy (1991-2005), while it took on a homogenous pattern of decreasing magnitude in the following period when the integrated strategy was implemented (2006-2014). The dynamic model analysis showed that regularly global propagation of the disease was not present after the effect of proximity to river was taken into account but local pattern transition existed. Maps of predicted prevalence shows that relatively high prevalence (>4%) occasionally occurred before 2006 and prevalence presents a homogenous and decreasing trend over the study area afterwards. CONCLUSIONS: Proximity to river is still an important determinant for schistosomiasis infection regardless of different types of implemented prevention and control strategies. Between the transition from the chemotherapy-based strategy to the integrated one, we noticed a decreased prevalence. However, schistosomiasis would remain an endemic challenge in these study areas. Further prevention and control countermeasures are warranted.