Giacomo Zaccherini

Background and Aims: The accuracy of Baveno criteria for avoiding endoscopy in patients with hepatocellular carcinoma (HCC) is uncertain, and systematic upper gastrointestinal endoscopy (UGE) may not be necessary. We evaluated Baveno VI criteria performance in this population and developed an alternative non-invasive rule to exclude esophagogastric varices of any grade, rather than high-risk varices (HRV). Methods: Patients with BCLC 0-C HCC and compensated advanced chronic liver disease (cACLD) from the Italian Liver Cancer (ITA.LI.CA) database, with available liver stiffness measurement (LSM), UGE, and blood tests within 6 months of diagnosis, were included. Independent predictors of varices identified by logistic regression were combined through grid search to derive a rule-out strategy (SAPHE-R), validated by bootstrap resampling and in an independent cohort (Vienna). Results: The derivation cohort comprised 598 patients (age, 69 years; male sex, 75.3%; viral etiology, 69.3%; BCLC 0/A, 77.9%; ALBI 1, 54.2%; varices, 33.4%; HRV, 11.2%). Baveno VI criteria missed 8.5% of varices and 6.0% of HRV, sparing 31.1% of UGE. Independent predictors of varices were incorporated into SAPHE-R (LSM≤16 kPa, platelet count ≥160×10 ⁹ /L, ALBI grade 1), which missed 4.0% of varices (HRV 3.0%, spared UGE 17.6%). In the validation cohort (n=149), SAPHE-R missed 4.8% of varices (HRV 3.1%, spared UGE 14.8%). Results remained consistent in sensitivity analyses. In an exploratory analysis, no HVPG-defined CSPH was observed among SAPHE-R rule-out patients (0/22). Conclusions: Baveno VI criteria showed suboptimal performance in patients with HCC and cACLD, whereas SAPHE-R provided a reliable non-invasive strategy to rule out varices, facilitating variceal risk assessment in patients with HCC.

Background & Aims: YAQ001 is a novel, non‐absorbable, gut‐restricted, multiporous, carbon bead adsorbent. Pre‐clinical studies and a clinical trial suggested its therapeutic potential and safety in patients with cirrhosis. This substudy aimed to explore the effects of YAQ001 on the gut microbiome and their exploratory association with biomarkers of gut permeability and systemic inflammation. Methods: Twenty‐eight‐patients with cirrhosis were randomized (double‐blind) to receive YAQ001 (4 g once daily) or placebo. Gut microbiome and biomarkers of inflammation and gut permeability were assessed at baseline, after 4 and 12 weeks. Changes in biomarkers and relationship with microbiome composition and gene profiling were assessed. The effect of YAQ001 on Klebsiella pneumoniae biofilms was assessed in vitro. Results: Overall alpha and beta diversity remained unaltered. YAQ001 increased the abundance of bacteria associated with improved gut health such as Adlercreutzia equolifaciens , a bacterium commonly depleted in liver disease, and decreased the abundance of bacteria associated with infections and poor outcomes such as Klebsiella pneumonia , and Streptococcus mutans . YAQ001 impacted positively on virulence factors such as siderophores, fimbriae structures, and lipopolysaccharides that are associated with inflammation and invasion. Antibiotic resistance genes decreased significantly in the YAQ001 group. These changes were associated with a reduction in markers of gut permeability and systemic inflammation. YAQ001 prevented K. pneumoniae biofilms in vitro. Conclusion: YAQ001 was associated with favourable compositional shifts and trends towards reduced virulence‐related gene signatures in the gut microbiome, alongside trends towards improved inflammatory biomarkers. The in vitro anti‐biofilm effect of YAQ001 warrants further mechanistic investigation. The findings position YAQ001 as a potential microbiome therapeutic.

Background and Aims: The benefit of long‐term albumin (LTA) in improving survival and reducing complications in patients with cirrhosis and ascites is not consistently observed across studies, possibly reflecting differences in patient populations and treatment regimens. This study aimed to determine whether baseline serum albumin (SA) levels can predict which patients are most likely to benefit from LTA therapy. Methods: A post hoc analysis of the ANSWER trial was performed in 431 patients randomized to receive standard medical treatment (SMT) alone or SMT plus human albumin (SMT + HA). The interaction between baseline SA and LTA was investigated using competing‐risk survival analysis. The primary endpoint was 18‐month survival. Secondary endpoints included the incidence of cirrhosis‐related complications and hospitalizations. Results: A significant treatment‐by‐albumin non‐linear interaction was found ( p = 0.010), indicating heterogeneity of treatment effect across baseline SA levels with the upper bound of the region of statistically demonstrable benefit occurring at approximately 3.2 g/dL (sHR 0.53, 95% CI 0.28–0.99). In patients with SA ≤ 3.2 g/dL, 18‐month survival was significantly higher in the SMT + HA group compared with SMT alone (HR 0.47, 95% CI 0.29–0.77; p = 0.0021). No significant survival difference could be demonstrated in patients with SA > 3.2 g/dL (HR 1.04, 95% CI 0.41–2.63; p = 0.93). Regardless of baseline SA levels, LTA was associated with improved ascites control and reduced rates of complications and hospitalizations. Conclusions: LTA provides survival and morbidity benefits in patients with mild‐to‐moderate hypoalbuminemia, whereas in patients with normal SA levels, its benefit appears mainly limited to morbidity reduction. Baseline SA may therefore help in prioritizing LTA therapy when resources are constrained.

Background and Aims: Long‐term albumin (LTA) is effective for treating ascites in decompensated cirrhosis. This study aims to analyse the clinical courses of patients receiving LTA and provide a 3 month stratification to personalise management integrating LTA with other options. Methods: Patients receiving LTA included in the multicentre, retrospective, observational Real‐ ANSWER study were stratified into three categories according to the response of ascites after 3 months of treatment: ‘responders’ (grade 0–1 ascites), ‘partial responders’ (at least grade 2 ascites not receiving therapeutic paracentesis) and ‘non‐responders’ (at least grade 2 ascites receiving therapeutic paracentesis). Clinical trajectories and outcomes of the different categories were compared. Results: Of the 252 patients included (median Child‐Pugh 9, MELDNa 18), 36% were responders, 29% partial responders and 35% non‐responders. Responders differed significantly from the other groups, with higher cumulative incidence of LTA discontinuation for clinical improvement (33%) and transplantation (26%), a lower 18 month mortality (13%) and minimal use of TIPS . Partial and non‐responders showed similar trajectories with high mortality (35% and 42%) and low incidence of transplantation (12% and 11%). TIPS was performed predominantly among non‐responders (15%). Both groups had a few patients (12% and 8%) able to stop LTA for clinical improvement frequently related to an effective etiologic treatment. Conclusions: Using a 3 month stratification according to the ascites response of LTA , patients can be grouped into three categories with different clinical courses and outcomes. This may help to stratify prognosis and inform clinical discussions on the management of ascites by integrating LTA with other available options.

Background and aims: YAQ001 is a novel, highly engineered, non-absorbable, gut-restricted, multiporous, carbon bead adsorbent. Pre-clinical studies and a clinical trial confirmed its therapeutic potential and safety in patients with cirrhosis. The aims of this sub study were to evaluate the effect of YAQ001 on the gut microbiome and its association with biomarkers of gut permeability and systemic inflammation. Methods: In total, 28-patients with cirrhosis were randomized (double-blind) to receive YAQ001 (4g once daily) or Placebo. Gut microbiome and biomarkers of inflammation and gut permeability were assessed at baseline, after 4 and 12-weeks. Changes in biomarkers and relationship with microbiome composition and gene profiling were assessed. The effect of YAQ001 on Klebsiella pneumoniae bacterial biofilms was also assessed using an in vitro gut epithelial model. Results: Alpha and beta diversity at different time points were unaltered. YAQ001 increased the abundance of bacteria associated with improved gut health such as Adlercreutzia equolifaciens (pKlebsiella pneumonia and Streptococcus mutans (pKlebsiella pneumoniae biofilms in vitro . Conclusions: The results show that YAQ001 impacts positively on the composition of the microbiome, significantly reduces its virulence, antibiotic resistance genes and biofilm formation, which is associated with modulation of gut permeability and systemic inflammation. Impact and implications: YAQ001 exerts its therapeutic effect by favorably modulating the gut ecosystem in cirrhosis. It selectively increases beneficial gut bacteria while suppressing pathogenic taxa linked to adverse outcomes. Beyond composition, YAQ001 reduces microbial virulence by limiting the production of invasive toxins and lowers the abundance of antibiotic-resistance genes. In vitro models also demonstrated its efficacy in inhibiting biofilm formation by key pathogens. In summary, this multifaceted modulation of the microbiome led to tangible clinical improvements, notably enhanced gut barrier function and reduced systemic inflammation. The data support further development of YAQ001 as a novel microbiome therapeutic. Highlights: In patients with cirrhosis, YAQ001 specifically enhanced beneficial gut bacteria while suppressing pathogenic bacteria linked to adverse clinical outcomes. YAQ001 significantly reduced the genetic expression of critical virulence factors, including siderophores, fimbriae, and lipopolysaccharides, thereby diminishing the potential for microbial invasion and inflammation. YAQ001 administration led to a significant decrease in the abundance of antibiotic resistance genes within the gut microbiome, potentially restoring therapeutic efficacy of antibiotics. In vitro studies demonstrated that YAQ001 effectively prevents the formation of Klebsiella pneumoniae biofilms, a key mechanism of bacterial persistence and chronic infection. The beneficial microbial shifts were directly associated with clinically relevant improvements in biomarkers of gut permeability and systemic inflammation.