Background: Prognostic assessment of hepatocellular carcinoma (HCC) remains suboptimal within the Barcelona Clinic Liver Cancer (BCLC), which lacks parameters reflecting tumor biology. Among serum biomarkers, alpha-fetoprotein (AFP), protein induced by vitamin-K absence-II (PIVKA-II), and glypican-3 (GPC-3) have shown potential as tumor biology indicators. We evaluated their independent prognostic value in a multicenter retrospective-study.Methods: We measured baseline serum AFP, PIVKA-II, and GPC-3 in 605 consecutive patients newly diagnosed with HCC at two tertiary Italian centers (2010–2024). We analyzed them as continuous and categorical variables (>20 ng/mL, >200 mAU/mL and >150 pg/mL respectively). BCLC-D patients were excluded from analysis. The primary endpoint was overall survival (OS). Survival analyses were performed using Kaplan–Meier and Cox proportional hazards models adjusted for BCLC stage, ALBI grade, and ascites.Results: Median OS was 29.0 months, declining from 47.9 months (BCLC-0) to 10.7 months (BCLC-C; p<0.001). In univariate analysis, presence of ascites, higher ALBI grade, portal hypertension, and all three biomarkers above cut-off were significantly associated with shorter OS (all p<0.001). Biomarker levels increased stepwise across BCLC stages (Figure-1). In multivariate analysis (table-1), PIVKA-II >200 mAU/mL emerged as the strongest independent prognostic factor (HR 1.56, 95% CI 1.24–1.95, p<0.001), while GPC-3 showed a borderline association (HR 1.27, p=0.058); AFP lost independent significance.Conclusions: PIVKA-II outperformed AFP and GPC-3 as an independent biomarker of poor prognosis, reflecting intrinsic tumor aggressiveness beyond anatomical staging and liver function. These data prompt future prospective studies integrating PIVKA-II and potentially GPC-3 into BCLC-based prognostic algorithms to enhance risk stratification and support a precision personalized approach for HCC management.

BACKGROUND:Digital single-operator cholangiopancreatoscopy (DSOC) is an important adjunct to endoscopic retrograde cholangiopancreatography (ERCP) for the diagnosis and treatment of complex biliary and pancreatic diseases. However, data regarding its safety and efficacy in elderly patients remain limited. AIM:To evaluate the safety and efficacy of DSOC in patients aged 75 years compared with a younger population. METHODS:We retrospectively analyzed consecutive patients who underwent ERCP with DSOC at a tertiary referral center between January 2017 and July 2025. Patients were stratified according to age (≥75 vs. <75 years). The primary outcome was procedure-related adverse events, defined according to American Society for Gastrointestinal Endoscopy criteria. Secondary outcomes included technical and clinical success rates and factors associated with complications. RESULTS:A total of 136 patients underwent 170 DSOC procedures. Elderly patients had more comorbidities and higher American Society of Anesthesiologists scores compared with younger patients. Overall adverse event rates were comparable between elderly and younger patients (8 vs. 13%; P = 0.44), while technical and clinical success rates were high in both groups. Multivariate analysis showed that age was not independently associated with adverse events. CONCLUSION:In this retrospective single-center study, DSOC was feasible in selected elderly patients, with complication rates and procedural outcomes comparable to those of younger individuals. The lack of formal frailty assessment and procedural burden metrics limits generalizability to frail or unselected elderly populations. In this retrospective single-center study, DSOC was feasible in selected elderly patients, with complication rates and procedural outcomes comparable to those of younger individuals. The lack of formal frailty assessment and procedural burden metrics limits generalizability to frail or unselected elderly populations.

PURPOSE:Despite achieving sustained virologic response (SVR) after treatment with direct-acting antivirals (DAAs), patients with hepatitis C virus (HCV)-related cirrhosis remain at risk of hepatocellular carcinoma (HCC) development. Glypican-3 (GPC-3) is a heparan sulfate proteoglycan with oncogenic role in HCC. This study aimed to assess the diagnostic and prognostic value of serum GPC-3 in patients with HCV-related cirrhosis who achieved SVR following DAA therapy. METHODS:We conducted a retrospective, observational study including 832 patients with HCV-related cirrhosis treated with DAAs between 2014 and 2024. Patients were divided into two cohorts: cohort A (n = 551) without HCC at enrolment and cohort B (n = 281) with established HCC. Serum GPC-3 was measured using a commercially available enzyme immunoassay (CanAg Glypican-3 EIA, Fujirebio Diagnostics AB, Gothenburg, Sweden). RESULTS:We analyzed 832 single serum samples: collected at SVR12 in Cohort A and at HCC diagnosis in Cohort B. GPC-3 levels were significantly higher in patients with HCC compared to those without (95, 50-185 pg/mL vs. 48, 29-79 pg/mL; p < 0.001), with moderate diagnostic accuracy (AUC = 0.711). During follow-up (37, 20-51 months), GPC-3 levels did not predict the development of de novo HCC in cohort A. However, in cohort B, GPC-3 > 150 pg/mL was independently associated with reduced survival (adjusted HR = 1.68, 95% CI 1.03-2.67, p = 0.036). CONCLUSIONS:While GPC-3 may be of limited utility for predicting HCC occurrence in patients cured of HCV, it could represent a valuable prognostic factor able to predict survival of patients with established HCC.

The incidence of metabolic dysfunction–associated steatohepatitis (MASH) – related hepatocellular carcinoma (HCC) is markedly increased in recent years, paralleling the global rise in obesity, type 2 diabetes, and metabolic syndrome. This form of HCC exhibits a distinct metabolic profile characterized by enhanced glycolysis and pentose phosphate pathway (PPP) activity. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, plays a pivotal role in maintaining NADPH production, redox homeostasis, lipid metabolism, and tumour growth, thus emerging as a key determinant of metabolic adaptation and therapy resistance in MASH-related HCC. This study aims is to investigate the role of G6PD in metabolic reprogramming, immune modulation, and tumor progression in MASH-associated HCC, and to evaluate its potential as a therapeutic target.We analyzed liver specimens from MASH patients and MASH-associated HCC and integrated these data with public TCGA-LIHC datasets. In vitro studies were performed using Huh7 cells with G6PD overexpression. Experimental approaches included enzymatic activity and metabolic profiling, cell proliferation and spheroid formation assays, gene expression analysis of lipid metabolism pathways, oxidative stress and redox measurements, macrophage polarization assays, and pharmacological inhibition using G6PD-targeting compounds.Analysis of public datasets, including TCGA-LIHC, revealed that elevated G6PD expression is associated with advanced BCLC stage and poor prognosis. Further examination of paraffin-embedded liver specimens from MASH patients showed a progressive increase in G6PD levels across fibrosis stages (F0–F4), with highest expression in MASH-associated HCC versus both late-stage fibrosis (F3–F4) and HCC of viral or alcoholic aetiology.Overexpression of G6PD in Huh7 cells leads to increased enzymatic activity, resulting in altered cellular metabolism and the promotion of multiple pro-tumorigenic processes. These include (i) enhanced cell proliferation and spheroid growth, (ii) upregulation of lipid metabolism genes (FASN, PPARγ, CD36, and SREBP1c) with consequent increases in fatty acid synthesis and storage, (iii) reduced oxidative stress through NADPH production and Nrf2 activation, and (iv) polarization of macrophages toward an immunosuppressive M2-like phenotype (TGF-β, CD206, CCL22, IL-10), thereby fostering a permissive tumour microenvironment.Finally, AB109 and AB196 drugs, developed from the commercial G6PDi scaffold, produced more potent and selective inhibition of G6PD-overexpressing cells, resulting in dose-dependent anti-proliferative effect, further supporting G6PD as a promising therapeutic target.These findings outline G6PD as a pivotal regulator of metabolic reprogramming, immune evasion, and tumor progression in MASH-associated HCC, highlighting its dual potential as a prognostic biomarker and a strategic target for novel metabolism-focused therapeutic interventions.

IntroductionGenetic variants involved in lipid and glucose metabolism have been implicated in liver disease progression and hepatocellular carcinoma (HCC) development in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, their prognostic role in patients with established HCC remains unclear. We aimed to investigate the association between MASLD-related genetic variants and overall survival (OS) in patients with MASLD-related HCC.MethodsWe retrospectively evaluated 258 patients with MASLD-related HCC (median age: 73, 49–79 years; male sex: 86.8%); most patients had a diagnosis of early tumor (BCLC 0/A: n = 162; 62.8%). PNPLA3 rs738409, TM6SF2 rs58542926, MBOAT7 rs641738, GCKR rs780094, and HSD17B13 rs72613567 variants were genotyped. An independent cohort of viral-related HCC (n = 384) was analysed for exploratory comparison. Overall survival (OS) was evaluated using Kaplan-Meier analysis and multivariable Cox regression.ResultsAmong the investigated gene variants, only the MBOAT7 rs641738 TT genotype was associated with reduced OS in patients with MASLD-related HCC compared to CC/CT carriers (19.8 vs. 32.2 months; p = 0.006). At multivariable analysis, MBOAT7 rs641738 TT genotype retained a nominal association with poorer OS after adjustment for age, sex, tumor burden, and metabolic cofactors (aHR = 1.61, 95% CI 1.05–2.46; p = 0.028). Conversely, OS did not differ according to MBOAT7 rs641738 genotype in the exploratory viral-related HCC comparison cohort (p = 0.449).ConclusionsMBOAT7 rs641738 genotype was associated with poorer OS in patients with MASLD-related HCC. This finding was not observed in an exploratory viral-related HCC comparison cohort, but between-cohort differences limit etiological interpretation. These results should be considered hypothesis-generating and require external validation.

Text 64 yo man has a clinical history of cirrhosis. An abdominal US follow-up and a subsequent CT scan diagnosed cholelithiasis, two big pancreatic cysts, and thickening of the colon wall, with multiple mesenteric lymphnodes. A colonoscopy and biopsies revealed a signet-ring cell colon carcinoma(CCR). Laparoscopic cholecystectomy, segmental colon resection, and removal of multiple mesenteric lymph nodes were performed and adjuvant CH was started. To study the pancreatic cysts, a pEUS with FNA and Micro-forceps was performed. Histopathology confirmed the presence of mucus with signet-ring adenocarcinoma cells inside the body cyst, and amorphous and biliary material, along with numerous histiocytes inside the tail cyst. With all these findings, a diagnosis of pancreatic tail pseudocyst and a rare case of pancreatic body metastasis of signet-ring cell CCR was established. [1]

We aimed to evaluate the prognostic impact of baseline clinical features and treatment procedure, including liver function measured with albumin–bilirubin (ALBI) formula and dosing methods in HCC patients treated with SIRT. The study includes 82 consecutive patients with liver-dominant HCC treated with SIRT (90Y glass microspheres, TheraSphereTM) between October 2014 and September 2023. Twenty-five patients were treated with standard dosimetry, while for remaining patients, multi-compartment dosimetry was performed using Simplicit90YTM software. Impact of baseline patient's characteristics including presence of portal vein thrombosis (PVT), Child–Pugh score (CP), ALBI score, bilirubin levels, tumor size and prior locoregional liver-directed or systemic treatments was assessed through multivariable Cox proportional hazard model. Median follow-up after treatment was 40.0 months (15.2–67.9). At univariable analysis, ALBI score and bilirubin levels were found to be independent prognostic factors for survival after SIRT (p = 0.001, respectively); furthermore, at Cox proportional hazards analysis, HR for death of ALBI 2 versus ALBI 1 was 10.54 (95

With the advancement of oncologic and endoscopic therapies, the survival of patients with pancreatic cancer is increasing, even in patients with advanced disease, meaning complications due to previous treatments are being seen more frequently. We describe the case of a 57-year-old woman with advanced pancreatic adenocarcinoma that had been diagnosed 2 years before admission who presented with jaundice requiring biliary stenting. She had developed gastric outlet obstruction 1 year after diagnosis and an initial duodenal uncovered self-expandable metal stent (USEMS) had been placed, which was then followed by placement of a second stent because of tumor ingrowth ([Fig. 1]).

Investigational use of nivolumab as first-line therapy for the treatment of hepatocellular carcinoma (HCC) yielded promising results but not enough to be introduced in guidelines. Limited data exists on its use beyond first-line.Aims: to evaluate the efficacy and safety of nivolumab as monotherapy beyond first-line in patients with HCCMethods: we analyzed data from consecutive HCC patients, ineligible for any other therapy, receiving off-label nivolumab at two referral centers in Italy and Germany between May-2016 and October-2023.Measured outcomes were overall survival (OS), progression-free survival (PFS), disease-control-rate (DCR), biological response (BR), defined as an ≥25% decrease in alpha-fetoprotein (AFP) level after 3 months of therapy, and adverse events.Results: 30 patients were enrolled (Italy n=24, Germany n=6). Patient characteristics were as follows: median age 65 (range 30-82) years, Child-Pugh A-B 80%-20%, BCLC B-C 13%-87%. One patient received nivolumab as I-line, 19 as II-line, 8 as III-line, and 2 as IV-line.Median OS was 9.1 (95%CI 6.4-14.2) months and median PFS was 3.5 (95%CI 2.8-6.4) months. At 3 months, DCR was 27% (8/30) and BR was obtained in 23% (7/30) of patients. Two patients achieving complete radiologic response.Median OS in patients with radiological disease control at 3 months was 27.7 (95%CI 4.7-41.2) months compared to 7.3 (95%CI 4.0-9.1) months in patients with disease progression (p<0.001). Median OS in patients with BR was 38.0 (95%CI 23.5-41.2) months compared to 7.8 (95%CI 3.6-12.1) months in patients without BR (p<0.001).At baseline, better performance status, presence of metastatic lymphnodes, AFP≥400 µg/L, and lower disease burden were associated with longer OS (all p<0.05).Grade 3-4 adverse events occurred in 10 patients (33%).Conclusion: nivolumab could represent a valuable option in patients without other alternatives, showing an OS greater than 6 months in 77% of patients and an acceptable safety profile. Radiological response at 3 months and BR predict a significantly longer survival.

The evaluation of biliary strictures poses a challenge due to the low sensitivity of standard diagnostic approaches, but the advent of direct single-operator cholangioscopy (DSOC) has revolutionized this paradigm. Our study aimed to assess the diagnostic performance of DSOC and DSOC-targeted biopsies, intraductal ultrasound (IDUS), and standard brush cytology in patients with indeterminate biliary strictures (IBS). We reviewed patients who underwent advanced diagnostic evaluation for IBS at our endoscopy unit from January 2018 to December 2022, all of whom had previously undergone at least one endoscopic attempt to characterize the biliary stricture. Final diagnoses were established based on surgical pathology and/or clinical and radiological follow-up spanning at least 12 months. A total of 57 patients, with a mean age of 67.2 ± 10.0 years, were included, with a mean follow-up of 18.2 ± 18.1 months. The majority of IBS were located in the distal common bile duct (45.6%), with malignancy confirmed in 35 patients (61.4%). DSOC and IDUS demonstrated significantly higher accuracies (89.5% and 82.7%, respectively) compared to standard cytology (61.5%, p < 0.05). Both DSOC visualization and IDUS exhibited optimal diagnostic yields in differentiating IBS with an acceptable safety profile.