Angelo Armandi

Prognostic assessment in hepatocellular carcinoma (HCC) primarily relies on clinical staging integrating tumour burden, liver function, and performance status; circulating cytokines may capture complementary tumour‐host biology. To assess whether cytokines measured at diagnosis were associated with overall survival (OS) and improved prognostic stratification beyond AFP and BCLC, we retrospectively analysed 656 consecutive adults with HCC (median age 67 [IQR 59–75] years; 516 men, 78.7%). Viral liver disease predominated ( n = 432, 65.9%). BCLC stage was 0/A/B/C in 101 (15.4%)/301 (45.9%)/151 (23.0%)/103 (15.7%); BCLC D was excluded. Serum GM‐CSF, IFN‐γ, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, and TNF‐α were measured at diagnosis using Bio‐Plex 200 bead‐based multiplex immunoassay (Luminex xMAP technology). The primary endpoint was OS. Overall, IL‐6 and IL‐8 levels increased across BCLC stages and were the only cytokines significantly associated with OS (IL‐6: HR = 1.12, p < 0.001; IL‐8: HR = 1.14, p < 0.001). Using previously published cut‐offs, IL‐6 > 4.28 pg/mL (aHR = 2.01, p < 0.001) and IL‐8 > 17.60 pg/mL (aHR = 1.35, p = 0.033) were significantly associated with OS independently from age, sex, AFP > 400 ng/mL, BCLC stage, and HCC treatment. The combination of IL‐6/IL‐8 was able to stratify patients into low‐risk (neither cytokine elevated; n = 358), intermediate‐risk (one elevated; n = 155), and high‐risk (both elevated; n = 143) groups, with median OS of 53.0, 28.7, and 20.5 months, respectively (log‐rank p < 0.001). The C‐index was 0.619 for IL‐6/IL‐8, 0.588 for AFP, 0.674 for BCLC, and 0.717 for the combined BCLC + AFP + IL‐6/IL‐8 model, which significantly improved model fit over BCLC + AFP alone ( p < 0.001). Time‐dependent AUCs for the combined model were 0.787, 0.755, 0.763, and 0.768 at 12, 24, 36, and 60 months, respectively. In conclusion, circulating IL‐6 and IL‐8 measured at HCC diagnosis define a simple inflammatory prognostic model independently associated with OS. When combined with BCLC and AFP, the IL‐6/IL‐8 score improves baseline prognostic discrimination and shows acceptable internal calibration.

INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease, and liver biopsy remains the gold standard for diagnosis. However, a subset of patients diagnosed with MASLD by imaging paradoxically exhibit steatosis grade S0 on liver biopsy, posing a diagnostic challenge. This study investigated the outcomes and causes of steatosis 0. METHODS: Steatosis 0 was defined as imaging-detected MASLD with a biopsy-defined steatosis grade S0. We used global cohorts to evaluate outcomes, histologic progression by paired biopsies, and possible causes. The cause analysis included MRI-proton density fat fraction (MRI-PDFF) for fat distribution, pathologist consistency testing, and comparison of serial biopsy sections. RESULTS: In a follow-up cohort of 3,273 biopsy individuals from 16 centers, 123 (3.8%) exhibited steatosis 0. Of these, 29.3% of them had advanced fibrosis (burnt-out MASLD) and demonstrated a risk of liver-related events, whereas those without advanced fibrosis had no such events. In the paired-biopsy cohort of 1,865 patients, 74 (4.0%) individuals initially showed steatosis grade S0; among them, 93.2% retained no or mild steatosis on follow-up biopsy. MRI-PDFF assessments in 42 MASLD patients revealed heterogeneous hepatic fat distribution, with some segments showing steatosis grade S0 despite elevated average liver fat. Interpathologist variability and discrepancies across consecutive biopsy sections contributed to misclassification of steatosis grade. DISCUSSION: Steatosis 0 represents a potential diagnostic gray zone in MASLD. It may be caused by burnt-out MASLD, uneven liver fat distribution, or variability in pathological assessment. Understanding the causes and implications of steatosis 0 is critical for diagnosis and management.

Background/Objectives: Patients with inflammatory bowel disease (IBD) are at an increased risk of herpes zoster (HZ), particularly during immunosuppressive treatment. To assess the safety of the recombinant zoster vaccine (RZV, Shingrix^®) and describe HZ occurrence in a real-world IBD cohort, including patients receiving advanced therapies. Methods: This prospective, single-centre observational study included 114 adults with IBD who were offered RZV; 69 received at least one dose, and 45 declined or postponed vaccination. Follow-up began at the vaccine proposal. For time-to-event analyses, vaccination was modelled as a time-varying exposure beginning 14 days after a documented second dose. IBD clinical relapse was defined by worsening disease-activity indices and/or treatment escalation. Results: During a median follow-up of 17 months (IQR 9–29), 11 patient-reported HZ episodes occurred: 8/69 (11.6%) among patients who received vaccination and 3/45 (6.7%) among those who did not. The time-dependent association between complete vaccination and HZ was not statistically significant (HR 2.51; 95% CI 0.66–9.51; p = 0.18), and adjustment for advanced therapy did not materially change the estimate. Prior HZ was associated with a higher risk of a subsequent reported episode (adjusted HR 6.26; 95% CI 1.80–21.76; p = 0.004). IBD clinical relapse occurred in 4/69 (5.8%) vaccinated and 2/45 (4.4%) unvaccinated patients (p = 1.00). Among 72 patients receiving advanced therapy, HZ occurred in 4/42 vaccinated and 2/30 unvaccinated patients (p = 1.00), while IBD relapse occurred in 3/42 and 1/30, respectively (p = 0.64). No serious vaccine-related adverse events or significant pre-/post-vaccination changes in disease activity were observed. Conclusions: RZV showed a favourable short-term safety profile in patients with IBD, including those receiving advanced therapies. The small number of self-reported HZ events and the non-randomised design preclude conclusions regarding vaccine effectiveness.

Background: Current guidelines recommend a two-step approach for risk stratification of metabolic dysfunction-associated steatotic liver disease (MASLD), starting with Fibrosis-4 index (FIB-4) followed by liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE). Objective: To evaluate this approach for predicting advanced fibrosis and liver-related events (LREs) in patients with type 2 diabetes (T2D). Design: A prospective liver biopsy cohort of T2D patients with histologically confirmed MASLD from seven centres in China was used to assess diagnostic performance for advanced fibrosis. The international VCTE-Prognosis cohort, including T2D patients with MASLD who underwent VCTE at 16 centres in the USA, Europe and Asia, with longitudinal follow-up, was used to assess LREs, defined as hepatic decompensation or hepatocellular carcinoma. Results: 4781 participants were included. In the liver biopsy cohort (n=352; 22.2% with advanced fibrosis), applying LSM thresholds of 12 kPa after FIB-4 classified patients into 63.4% low-risk, 9.4% intermediate-risk and 27.3% high-risk, with a correct classification rate of 71%. In the VCTE-Prognosis cohort (n=4429; median follow-up 51.3 (IQR 27.4–70.7) months), 140 (3.2%) patients developed LREs (110 (2.5%) with hepatic decompensation and 59 (1.3%) with hepatocellular carcinoma). The two-step approach classified 72.6%, 6.8% and 20.6% of patients into low-risk, intermediate-risk and high-risk groups, with corresponding 5-year cumulative LRE incidences of 0.7%, 0.9% and 11.8%. Refining classification of intermediate FIB-4 patients using LSM 15 kPa (high-risk) reduced the intermediate-risk group to 5.6% while preserving predictive accuracy. Conclusion: The non-invasive two-step approach of FIB-4 followed by LSM effectively stratifies MASLD-related advanced fibrosis and LREs risk in T2D. Applying LSM cut-offs of 10 and 15 kPa further optimises risk stratification for future LREs.

Background and Aims: Weight control remains the cornerstone for metabolic dysfunction–associated steatotic liver disease (MASLD) management. We assessed the relationships between dynamic weight change and the risk of liver-related events (LREs) and liver stiffness changes in MASLD. Approach and Results: By enrolling adult MASLD individuals with ≥2 weight measurements from 16 tertiary referral centers, we assessed how longitude weight change, including the following categories (stable ≤5% change, weight loss >5% decrease, weight gain >5% increase) and changing status of obesity (persistent non-obesity, persistent obesity, transition from non-obesity to obesity, transition from obesity to non-obesity), were associated with LREs. Analyses were undertaken with multivariable linear regressions, Cox proportional hazards regression, and logistic regression, adjusting for age, sex, ethnicity, baseline BMI, hypertension, T2D, LSM, CAP, and SGLT-2i/GLP-1RAs usage. Analyses between weight change and liver stiffness change were also undertaken. A total of 10,014 MASLD individuals with ≥2 weight measurements were included. Over a measurement interval of 29.2 months, 123 LREs occurred during 12.4 months of follow-up after the final weight assessment. Weight gain >5% was associated with increased risk of LREs [aHR=1.84 (95% CI: 1.01–3.09), p =0.020] and liver stiffness progression [aOR=2.07 (95% CI: 1.55–2.74), p 5% exhibited liver stiffness improvement. Although those who progressed to or persisted with obesity had a higher LREs risk, obesity reversal had a comparable LREs risk [aHR=1.44 (95% CI: 0.57–3.61), p =0.435] to the persistent non-obese. Conclusions: In MASLD, weight gain is associated with increased LREs risks and liver stiffness progression. Conversely, weight loss confers benefits for liver stiffness improvement and modifies LREs risk in those who achieve obesity reversal.