Background: A number of studies have reported an association between the occurrence of immune-related adverse events (irAEs) and clinical efficacy in patients undergoing treatment with immune checkpoint inhibitors (ICIs), but the results remain controversial. Methods: Under the guidance of a predefined protocol and Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, this meta-analysis included cohort studies investigating the association of irAEs and efficacy of ICIs in patients with cancer. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Subgroup analyses involving the cancer type, class of ICIs, combination therapy, sample size, model, landmark analysis, and approach used to extract the data were performed. Specific analyses of the type and grade of irAEs were also performed. Results: This meta-analysis included 30 studies including 4971 individuals. Patients with cancer who developed irAEs experienced both an OS benefit and a PFS benefit from ICI therapy compared to patients who did not develop irAEs (OS: hazard ratio (HR), 0.54, 95% confidence interval (CI), 0.45–0.65; p < 0.001; PFS: HR, 0.52, 95% CI, 0.44–0.61, p < 0.001). Subgroup analyses of the study quality characteristics and cancer types recapitulated these findings. Specific analyses of endocrine irAEs (OS: HR, 0.52, 95% CI, 0.44–0.62, p < 0.001), dermatological irAEs (OS: HR, 0.45, 95% CI, 0.35–0.59, p < 0.001), and low-grade irAEs (OS: HR, 0.57, 95% CI, 0.43–0.75; p < 0.001) yielded similar results. The association between irAE development and a favorable benefit on survival was significant in patients with cancer who were undergoing treatment with programmed cell death-1 inhibitors (OS: HR, 0.51, 95% CI, 0.42–0.62; p < 0.001), but not cytotoxic T-lymphocyte antigen-4 inhibitors (OS: HR, 0.89, 95% CI, 0.49–1.61; p = 0.706). Additionally, the association was significant in patients with cancer who were treated with ICIs as a monotherapy (OS: HR, 0.53, 95% CI, 0.43–0.65; p < 0.001), but not as a combination therapy (OS: HR, 0.62, 95% CI, 0.36–1.05; p = 0.073). Conclusions: The occurrence of irAEs was significantly associated with a better ICI efficacy in patients with cancer, particularly endocrine, dermatological, and low-grade irAEs. Further large-scale prospective studies are warranted to validate our findings. Systematic review registration: PROSPERO CRD42019129310.

Introduction: Little evidence exists on the safety and efficacy of the rechallenge of immune checkpoint inhibitors (ICIs) after immune-related adverse events (irAEs) in patients with cancer.Methods: We searched PubMed, Web of Science, Embase, and Cochrane for articles on ICI rechallenge after irAEs for systemic review and meta-analysis. The outcomes included the incidence and associated factors for safety and objective response rate (ORR) and disease control rate (DCR) for efficacy.Results: A total of 789 ICI rechallenge cases from 18 cohort studies, 5 case series studies, and 54 case reports were included. The pooled incidence of all-grade and high-grade irAEs after rechallenge in patients with cancer was 34.2% and 11.7%, respectively. Compared with initial ICI treatment, rechallenge showed a higher incidence for all-grade irAEs (OR, 3.81; 95% CI, 2.15–6.74; p < 0.0001), but similar incidence for high-grade irAEs (p > 0.05). Types of initial irAEs (pneumonitis and global irAEs) and cancer (non-small cell lung cancer and multiple cancer) recapitulated these findings. Gastrointestinal irAEs and time interval between initial irAEs and ICI rechallenge were associated with higher recurrence of high-grade irAEs (p < 0.05), whereas initial anti-PD-1/PD-L1 antibodies were associated with a lower recurrence (p < 0.05). Anti-PD-1/PD-L1 antibodies rechallenge was associated with a lower all-grade irAE recurrence (p < 0.05). The pooled ORR and DCR after rechallenge were 43.1% and 71.9%, respectively, showing no significant difference compared with initial ICI treatment (p > 0.05).Conclusions: ICI rechallenge after irAEs showed lower safety and similar efficacy outcomes compared with initial ICI treatment.Systematic Review Registration: PROSPERO, identifier CRD42020191405.

Mutations in epidermal growth factor receptor (EGFR) play critical roles in the pathogenesis of non-small cell lung cancer (NSCLC), and they are highly associated with sensitivity to tyrosine kinase inhibitors (TKIs). While the pathogenic and pharmacological characteristics of common mutations in EGFR have been thoroughly investigated, those of uncommon mutations remain to be elucidated. Traditional approaches to study common mutations by randomized controlled trials are not feasible for uncommon mutations owing to their rarity. Therefore, by systematically reviewing laboratory and clinical studies of the G719X mutation, one of the uncommon mutations, we concluded that the G719X mutation was intermediately sensitive to TKIs, with an average response rate of 35.1% (47/134). Moreover, accordingly, we proposed a comprehensive model to investigate uncommon mutations in EGFR. The model involves both basic and clinical components, composed of structural analyses, functional alterations, cell viabilities and animal models with various types of clinical studies. In this review, we systematically reviewed studies of the G719X mutation and put forward a research model that could be generalized to explore uncommon mutations in diseases associated with gene mutations.

Background: Integrins play a crucial role in the regulation process of cell proliferation, migration, differentiation, tumor invasion and metastasis. ITGA11, ITGB4 and ITGB8 are three encoding genes of integrins family. Accumulative evidences have proved that abnormal expression of ITGA11, ITGB4 and ITGB8 are a common phenomenon in different malignances. However, their expression patterns and prognostic roles for patients with non-small cell lung cancer (NSCLC) have not been completely illustrated. Methods: We investigated the expression patterns and prognostic values of ITGA11, ITGB4 and ITGB8 in patients with NSCLC through using a series of databases and various datasets, including ONCOMINE, GEPIA, HPA, TCGA and GEO datasets. Results: We found that the expression levels of ITGA11 and ITGB4 were significantly upregulated in both LUAD and LUSC, while ITGB8 was obviously upregulated in LUSC. Additionally, higher expression level of ITGB4 revealed a worse OS in LUAD. Conclusion: Our findings suggested that ITGA11 and ITGB4 might have the potential ability to act as diagnostic biomarkers for both LUAD and LUSC, while ITGB8 might serve as diagnostic biomarker for LUSC. Furthermore, ITGB4 could serve as a potential prognostic biomarker for LUAD.

Background: Lymph node metastasis (LNM) is difficult to precisely predict before surgery in patients with early-T-stage non-small cell lung cancer (NSCLC). This study aimed to develop machine learning (ML)-based predictive models for LNM. Methods: Clinical characteristics and imaging features were retrospectively collected from 1,102 NSCLC ≤ 2 cm patients. A total of 23 variables were included to develop predictive models for LNM by multiple ML algorithms. The models were evaluated by the receiver operating characteristic (ROC) curve for predictive performance and decision curve analysis (DCA) for clinical values. A feature selection approach was used to identify optimal predictive factors. Results: The areas under the ROC curve (AUCs) of the 8 models ranged from 0.784 to 0.899. Some ML-based models performed better than models using conventional statistical methods in both ROC curves and decision curves. The random forest classifier (RFC) model with 9 variables introduced was identified as the best predictive model. The feature selection indicated the top five predictors were tumor size, imaging density, carcinoembryonic antigen (CEA), maximal standardized uptake value (SUV_max), and age. Conclusions: By incorporating clinical characteristics and radiographical features, it is feasible to develop ML-based models for the preoperative prediction of LNM in early-T-stage NSCLC, and the RFC model performed best.

Rationale: Early discovery, accurate diagnosis, and staging of lung cancer is essential for patients to receive appropriate treatment. PET/CT has become increasingly recognized as a valuable imaging modality for these patients, but there remains room for improvement in PET tracers. We aimed to evaluate the feasibility of using [⁶⁸Ga]Ga-FAPI-RGD, a dual-targeting heterodimeric PET tracer that recognizes both fibroblast activation protein (FAP) and integrin α_vβ₃ for detecting lung neoplasms, by comparing it with [¹⁸F]FDG and single-targeting tracers [⁶⁸Ga]Ga-RGD and [⁶⁸Ga]Ga-FAPI.