Third-generation EGFR tyrosine kinase inhibitors (TKIs) have improved outcomes in EGFR-mutant non-small cell lung cancer (NSCLC), but resistance occurs, especially in patients with Brain metastases (BMs). Antiangiogenic therapy may enhance CNS drug delivery and EGFR-TKI efficacy​. We evaluated the efficacy of high-dose furmonertinib plus bevacizumab in patients with BMs after third-generation EGFR-TKI failure. We conducted a single-center retrospective study in EGFR-mutant NSCLC patients with BMs (leptomeningeal and/or parenchymal) who had progressed after ≥1 third-generation EGFR-TKI. Patients received furmonertinib 160 mg daily plus bevacizumab 7.5 mg/kg every 3 weeks until progression or unacceptable toxicity. Primary endpoints were intracranial and overall progression-free survival (iPFS, PFS); secondary endpoints were intracranial and systemic objective response rates (iORR, ORR) and safety. Among the 78 enrolled patients (median follow-up: 11.8 months), median iPFS and PFS were 7.2 months (95 % CI: 5.6-10.5) and 5.85 months (95 % CI: 4.6-7.4), respectively. The iORR was 37.1 %, and ORR was 28.6 %. OS data remain immature at the time of analysis. In patients with both parenchymal and leptomeningeal metastases (n = 47), median iPFS was 7.63 months (95 % CI: 5.0-10.8), and median PFS was 5.7 months (95 % CI: 4.5-10.0); iORR and ORR were 40.5 % and 34.2 %, respectively. In the parenchymal-only subgroup (n = 31), median iPFS and PFS were 7.20 months (95 % CI: 5.5-NR) and 6.4 months (95 % CI: 4.4-11.3), iORR and ORR were 32 % and 20 %. In multivariate analysis, EGFR exon 19 deletion was independently associated with prolonged iPFS (HR = 0.32, P = 0.011) and PFS (HR = 0.47, P = 0.047). CNS radiotherapy administered during treatment also emerged as an independent prognostic factor for both iPFS (HR = 0.34, P = 0.022) and PFS (HR = 0.40, P = 0.018). In this retrospective study, high-dose furmonertinib combined with bevacizumab demonstrated favorable intracranial and systemic activity with an acceptable safety profile in EGFR-mutant NSCLC patients with CNS metastases after resistance to third-generation EGFR-TKIs. These findings provide preliminary evidence supporting the potential clinical benefit of this chemotherapy-sparing strategy. Importantly, these findings warrant further validation in biomarker-stratified prospective trials to guide patient selection and optimize treatment outcomes.

Background: Sleep deprivation (SD) is a common health problem that causes molecular, immune and neurological changes. The aim of this study was to identify key genes by analyzing gene expression changes induced by prolonged sleep deprivation and to explore their potential relationship with immune regulation and neurobehavioral disorders. Methods: Microarray data of sleep deprivation at different time points were obtained by obtaining them from the Gene Expression Omnibus (GEO) database. Differential expression analysis was performed on SD samples and control samples at different time points using the Limma package in R to screen for significantly differentially expressed genes (DEGs). The functions of DEGs and the biological pathways involved were explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. In addition, genes that were significantly differentially expressed at all time points were screened as key genes for SD by overlap analysis. Finally, immune scores and immune cell scores were calculated using ESTIMATE, CIBERSORT and single-sample gene set enrichment analysis (ssGSEA). The relationships between key genes and immune scores and immune-related pathways were explored by Spearman correlation analysis. Results: At each time point from t01 to t12, we identified 367, 438, 615, 311, 444, 939, 629, 526, 200, 760 and 1026 DEGs between SD and control samples, respectively. Notably, six genes (USP32P1, TREML1, PF4V1, GPR146, DEFA1B, and CLEC1B) were identified as the DEGs between the two types of samples across all time points. Among these, CLEC1B, GPR146, PF4V1, and TREML1 were significantly upregulated in SD samples, while DEFA1B and USP32P1 were significantly downregulated. These key genes are involved in critical biological processes, including DNA repair, KRAS signaling, and the PI3K-AKT signaling pathway. Furthermore, PF4V1, GPR146, TREML1, and CLEC1B exhibited a significant negative correlation with immune scores and were closely associated with various immune regulatory pathways, such as antigen processing and presentation, B cell receptor signaling, and T cell receptor signaling pathways. Conclusion: In summary, this study systematically investigated the dynamic changes in gene expression induced by SD and their underlying molecular mechanisms, identifying six key genes. These findings provide a crucial molecular foundation for the early diagnosis and personalized treatment of SD-related diseases. conclusion: In this study, 6 key genes were identified for neurobehavioral disorders caused by SD at different time periods, and 4 of the 6 key genes were identified as overexpressed immunomodulators. The 6 key genes we identified may be biomarkers of SD or therapeutic targets for SD-related diseases.

Current evidence suggests that low-grade intracranial dural arteriovenous fistulas (DAVFs) generally follow a benign clinical course. However, due to differences in study populations and institutional expertise, recommendations regarding the treatment of low grade DAVFs remain inconsistent. Some studies advocate for intervention, while others do not. In addition, limited research exists on whether achieving complete obliteration is necessary in the management of low-grade DAVFs. We retrospectively reviewed patients with low-grade DAVFs from the Dural Arteriovenous Fistula Research and Management in China (DREAM-INI) database. Patients with low-grade DAVFs were included and classified into intervention or observation cohorts, as well as into complete or partial occlusion groups, cavernous sinus and non-cavernous sinus groups, among others. Further subgroup analyses and propensity score matching were also performed. The primary comparison focused on their clinical outcomes. A total of 327 patients with low-grade DAVFs were identified. The mean age was 52.0 ± 13.2 years, and 55.4% were female. Among the 304 patients (93.0%) who received treatment, 99.3% underwent primarily endovascular embolization. We found no significant differences in clinical outcomes between the treatment and observation cohorts at the last follow-up, even after propensity score matching. However, among patients in the treatment group, complete obliteration and cavernous sinus DAVF were associated with significantly greater symptomatic improvement compared to partial obliteration and non-cavernous sinus DAVF. Progression to high grade DAVF was documented in 0.7% of DAVFs. Among treated patients, complete fistula obliteration and cavernous sinus DAVF are associated with better symptomatic improvement compared to partial embolization and non-cavernous sinus DAVF.