Search

Abstract This study aimed to assess the therapeutic effect of immune checkpoint inhibitors (ICIs) in patients with unresectable hepatocellular carcinoma (uHCC) and investigate the correlation between surrogate endpoints and overall survival (OS). A systematic literature search included phase I, II, and III clinical trials comparing ICIs to placebo or other therapies for uHCC treatment. Correlations between OS and surrogate endpoints were evaluated using meta-regression analyses and calculating the surrogate threshold effect (STE). The correlation analysis showed a weak association between OS and progression-free survival (PFS), with an R2 value of 0.352 (95% CI: 0.000–0.967). However, complete response (CR) exhibited a strong correlation with OS (R2 = 0.905, 95% CI: 0.728–1.000). Subgroup analyses revealed high correlations between OS and PFS, CR, stable disease (SD), and DC in phase III trials (R2: 0.827–0.922). For the ICI + IA group, significant correlations were observed between OS and SD, progressive disease (PD), and grade 3–5 immune-related adverse events (irAEs) (R2: 0.713–0.969). Analyses of the correlation between survival benefit and risk of mortality across various time points showed a strong association within the first year (R2: 0.724–0.868) but a weak association beyond one year (R2: 0.406–0.499). In ICI trials for uHCC, PFS has limited utility as a surrogate endpoint for OS, while CR exhibits a strong correlation with OS. Subgroup analyses highlight high correlations between OS and PFS, SD, and DC in phase III trials. Notably, the ICI + IA group shows significant associations between OS and SD, PD, and grade 3–5 irAEs. These findings offer valuable insights for interpreting trial outcomes and selecting appropriate endpoints in future clinical studies involving ICIs for uHCC patients.

Background: Signet ring cell carcinoma (SC) accounts for 1% of total colorectal cancer (CRC) cases and is associated with aggressive behaviors, such as lymphatic invasion and distant metastases, resulting in poor prognosis. To date, there is still a lack of consensus on the genetic etiology underpinning this cancer subtype. This study aimed to clarify the molecular associations of SC by using meta-analysis and a systematic review. Methods: PubMed, Embase, and Cochrane Library were searched for studies evaluating the KRAS, BRAF, P53 statuses, and microsatellite instability (MSI) in CRC patients with different histological subtypes, including SC. The diagnosis of SC is defined as the signet ring cells comprising ≥50 percent of the tumor mass. By dividing the studies into subgroups based on the composition of control groups, such as classic adenocarcinoma (AC; no SC components) and non-SC (including those with SC components < 50%), the relative risk (RR) of molecular alterations for SC in each study were pooled using a random-effects model. Two reviewers identified trials for inclusion, assessed quality, and extracted data independently. Results: Data from 29 studies consisting of 9366 patients were included in this analysis. SC was associated positively with MSI (RR 1.78, 95% CI 1.34 to 2.37; 95% CI 0.77 to 4.15; p = 0.0005), BRAF mutation (RR 1.99, 95% CI 1.21 to 3.26; 95%CI 0.68 to 5.82; p = 0.0146), and negatively with KRAS mutation (RR 0.48, 95% CI 0.29 to 0.78; 95% CI 0.09 to 2.49; p = 0.0062). No association was found between SC and P53 expression (RR 0.92, 95% CI 0.76 to 1.13; 95%CI 0.61 to 1.39; p = 0.3790). Moreover, it was associated negatively with P53 gene mutations (RR 0.92, 95% CI 0.77 to 1.09; 95% CI 0.46 to 1.82; p = 0.1568), and P53 protein (RR 0.93, 95% CI 0.58 to 1.49; 95% CI 0.40 to 2.17; p = 0.6885). Conclusions: The molecular etiology of SC may be associated with the BRAF and MSI pathways. Its features, such as the high frequency of BRAF mutation, could partly explain its less favorable outcomes and limited effects of traditional chemotherapy.

Abstract Objective: Results from randomized controlled trials (RCTs) and real-world study (RWS) appear to be discordant. We aimed to investigate whether data derived from RCTs and RWS evaluating long-term all-cause mortality of transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis (AS) were in agreement. Methods: RCTs or RWS comparing TAVI and SAVR, reporting longterm (≥2-year follow-up) all-cause mortality, were identified. We also carried out subgroup analyses to access the effect in different subgroups. A pre-designated data extraction form including 5 domains and 26 items was used to explore the relationship between RCTs and RWS. Mortality and effect in different subgroups were evaluated using random-effects meta-analyses. Results: Five RCTs (5421 participants, TAVI: 2759, SAVR: 2662) and 33 RWS (20839 participants; TAVI: 6585, SAVR: 14254) were identified. Pooled RCT analysis showed no difference in all-cause mortality between TAVI and SAVR (HR=0.97, 95% CI: 0.88-1.07; P=0.55). In RWS, TAVI was associated with an increased risk of allcause mortality (HR=1.46, 95% CI: 1.26-1.69; P