Trending Topics in Gastroenterology | GastroAGI

Sintilimab–Lenvatinib Enables Conversion Surgery in Advanced HCC : Signal Transduct Target Ther | May 2026

Introduction Most patients with Hepatocellular Carcinoma present with advanced unresectable disease, limiting curative-intent treatment opportunities. Although systemic therapy remains the standard for advanced-stage HCC, modern immunotherapy-based combinations have raised the possibility of “conversion therapy,” where effective tumor regression permits subsequent surgical resection. The SILENSES phase II expansion trial evaluated whether combined PD-1 inhibition with sintilimab and multikinase inhibition with lenvatinib could convert initially unresectable HCC into surgically treatable disease. Problem Statement Advanced HCC with macrovascular invasion or extrahepatic disease has historically carried poor long-term survival, with systemic therapy rarely leading to durable remission. Whether modern immunotherapy-targeted therapy combinations can reliably create a surgical window and improve long-term survival remains uncertain. Summary This prospective single-arm phase II trial enrolled 120 treatment-naïve patients with radiologically confirmed unresectable HCC, the majority of whom had very advanced disease features including BCLC stage C disease, macrovascular invasion and extrahepatic metastases. Patients received sintilimab plus lenvatinib, with multidisciplinary reassessment of resectability every 6–8 weeks. Successful conversion was achieved in 56% of patients, and 60 individuals ultimately underwent curative-intent hepatectomy. Most surgical candidates achieved resectability within approximately 3 months of systemic therapy initiation. Radiologic responses were substantial, with objective response rates approaching 58% by mRECIST and 46% by RECIST v1.1. Importantly, pathological tumor regression was also profound among resected patients. Pathological complete response occurred in 35% of surgical patients, while an additional 42% achieved pathological partial response, supporting the ability of combined immunotherapy and targeted therapy to induce major biological tumor regression beyond radiographic shrinkage alone. Long-term survival outcomes were particularly notable. Across the entire cohort, median overall survival reached 36 months. However, patients who successfully underwent surgery demonstrated markedly superior outcomes, with estimated 5-year overall survival approaching 74%, compared with poor survival among nonsurgical patients. Landmark analyses designed to reduce immortal time bias continued to demonstrate major survival advantages associated with sequential surgery following successful conversion therapy. Recurrence-free survival after curative-intent resection reached a median of 40 months, although recurrence remained common, occurring in nearly half of resected patients. Depth of pathological response emerged as a major prognostic determinant for both recurrence-free and overall survival. Treatment-related toxicity was frequent but generally manageable. Nearly all patients experienced adverse events, while grade 3–5 toxicities occurred in approximately one-third of cases. Serious immune-related and hemorrhagic complications were uncommon but clinically important, including several treatment-related deaths. Surgical morbidity was acceptable despite the complexity of operations following systemic conversion therapy. Overall, the SILENSES study provides important proof-of-concept evidence that effective immunotherapy-targeted therapy combinations can create meaningful surgical opportunities in selected patients with advanced unresectable HCC. The findings support routine multidisciplinary reassessment of resectability during systemic therapy and reinforce the evolving paradigm of biology-guided conversion surgery in advanced liver cancer. However, randomized multicenter validation studies remain necessary before widespread adoption of this strategy.

Real-World STRIDE Validates Survival Benefit in Advanced HCC : JHEP Report | Mar 2026

Introduction Durvalumab plus Tremelimumab (STRIDE regimen) has emerged as a first-line immunotherapy option for unresectable Hepatocellular Carcinoma following the pivotal HIMALAYA trial. However, real-world evidence regarding efficacy, safety and applicability in patients outside strict clinical trial eligibility criteria has remained limited. Problem Statement Patients encountered in routine hepatology and oncology practice frequently have impaired liver function, portal vein invasion, prior systemic therapy exposure or poor performance status, all of which were underrepresented in the HIMALAYA trial. Whether STRIDE maintains clinical effectiveness and tolerability in these higher-risk populations remains uncertain, particularly given the central impact of hepatic decompensation on survival outcomes in advanced HCC. Summary The international multicentre DT-real study evaluated real-world outcomes of durvalumab with or without tremelimumab in 233 patients with unresectable or advanced HCC treated across 35 centres. Approximately half of the cohort fulfilled key HIMALAYA eligibility criteria (HIMALAYA-IN), whereas the remaining patients (HIMALAYA-OUT) had more advanced liver dysfunction, poorer performance status, Vp4 portal invasion or prior systemic therapy exposure. Median overall survival in the entire cohort reached 20.4 months, confirming meaningful reproducibility of STRIDE efficacy outside clinical trials. Importantly, HIMALAYA-IN patients achieved a median survival of 23 months, substantially outperforming HIMALAYA-OUT patients, who demonstrated a median survival of 12.2 months. Disease control emerged as a major determinant of durable survival benefit, with long-term survival substantially improved among patients achieving complete response, partial response or stable disease. Macrovascular invasion and hepatic decompensation independently predicted mortality, reinforcing the dual prognostic importance of tumour burden and preservation of liver function during immunotherapy. Notably, hepatic decompensation occurred in approximately 10% of patients within one year, emphasizing that cirrhosis progression remains a critical competing risk even during effective oncologic therapy. The study also suggested that STRIDE may retain efficacy in selected patients with Vp4 portal invasion, potentially offering an important therapeutic alternative in patients unsuitable for anti-angiogenic combinations because of bleeding risk. Safety outcomes were acceptable and comparable to clinical trial experience, with grade 3–4 treatment-related adverse events occurring in 16% of patients. Skin toxicity and immune-mediated diarrhoea/colitis were the most frequent adverse events. Overall, this study validates the effectiveness of dual checkpoint inhibition in routine HCC practice while highlighting the importance of patient selection, liver function preservation and careful monitoring for hepatic decompensation during therapy.

FAP CAR-T Therapy Emerges as a Novel Antifibrotic Strategy in Liver Disease : JHEP Report | May 2026

Introduction Chimeric antigen receptor T-cell therapy has revolutionized hematologic oncology and is increasingly being explored beyond cancer. In chronic liver disease, progressive fibrosis driven by activated hepatic stellate cells (HSCs) remains a central pathogenic mechanism leading to cirrhosis and hepatocellular carcinoma (HCC). Effective therapies capable of selectively targeting pathogenic fibrogenic cells are urgently needed. Problem Statement Current antifibrotic therapies remain limited and largely ineffective in advanced fibrosis or cirrhosis. Because hepatic stellate cells are heterogeneous and also contribute to normal hepatic homeostasis, nonspecific depletion strategies may produce harmful consequences. Selective targeting of activated fibrogenic HSC populations has therefore emerged as a major therapeutic challenge. Summary This editorial highlights a major translational advance demonstrating the therapeutic potential of fibroblast activation protein (FAP)-targeted CAR-T cells in liver fibrosis and hepatocellular carcinoma. Activated HSCs were shown to highly express FAP, whereas quiescent HSCs and most normal tissues demonstrated minimal expression, making FAP an attractive selective target for cellular immunotherapy. In multiple murine fibrosis models—including toxic, cholestatic, metabolic and alcohol-associated liver injury—single-dose anti-FAP CAR-T therapy markedly reduced fibrosis severity, collagen deposition, α-smooth muscle actin expression and fibrogenic gene programs. The antifibrotic effects exceeded those observed with pharmacologic FAP inhibition, emphasizing the potency of immune-mediated cellular depletion. Mechanistic analyses using single-cell and transcriptomic approaches demonstrated reduction of activated HSC populations, suppression of extracellular matrix pathways and enhanced hepatic infiltration of activated T cells and NK cells. Macrophage subsets with phagocytic signatures contributed to clearance of apoptotic activated HSCs, indicating coordinated immune remodeling within the fibrotic liver microenvironment. Importantly, anti-FAP CAR-T cells retained efficacy even in advanced cirrhotic models, suggesting that engineered T cells can successfully penetrate dense fibrotic tissue. The approach also demonstrated antitumor activity in experimental HCC, reducing tumour burden, AFP levels, epithelial–mesenchymal transition and cancer stemness signatures while promoting cytotoxic immune activation. The article further discusses broader implications of stromal-targeted immunotherapy, particularly in desmoplastic malignancies such as pancreatic, colorectal and breast cancer, where FAP-expressing fibroblasts contribute to immune exclusion and tumor progression. Collectively, these findings position FAP CAR-T therapy as a highly promising platform strategy capable of simultaneously remodeling fibrosis, restoring immune surveillance and potentially preventing fibrosis-associated carcinogenesis.

Propranolol Adds No Benefit to Band Ligation in HCC-Related Variceal Bleeding | Gut

Introduction Secondary prevention of oesophageal variceal bleeding traditionally relies on combination therapy with non-selective beta-blockers and endoscopic band ligation in patients with cirrhosis. However, patients with hepatocellular carcinoma (HCC) represent a distinct high-risk population with advanced portal hypertension, impaired liver reserve and competing oncologic mortality, raising uncertainty about whether standard variceal prophylaxis strategies provide similar benefit in this setting. Problem Statement Although propranolol combined with endoscopic band ligation is widely accepted for secondary prophylaxis of variceal bleeding in cirrhosis, evidence specifically supporting this approach in patients with HCC has been limited. The balance between efficacy, tolerability and survival benefit in patients with advanced liver cancer and portal hypertension remains unclear. Summary This randomized trial demonstrates that adding propranolol to endoscopic band ligation does not improve outcomes in patients with HCC undergoing secondary prevention of oesophageal variceal bleeding. Rates of early re bleeding, cumulative recurrent bleeding and overall survival were similar between patients treated with combination therapy and those receiving band ligation alone. Importantly, the study population largely consisted of patients with advanced disease and impaired hepatic reserve, reflecting a clinically relevant real-world HCC cohort. Large varices emerged as the primary predictor of recurrent bleeding, emphasizing the dominant role of portal hypertensive severity rather than beta-blocker therapy in determining outcomes. These findings challenge the routine extrapolation of cirrhosis-based secondary prophylaxis strategies to patients with HCC and suggest that the additional use of propranolol may not provide meaningful clinical benefit in this population. The study supports a more individualized approach to variceal management in HCC, particularly in patients with advanced tumor burden and decompensated liver disease.

Biomarkers in HCC Surveillance: Gastroenterology | May 2026

Introduction and Summary This commentary discusses the role of serum biomarkers in hepatocellular carcinoma surveillance, particularly after a randomised trial by Hirode et al. evaluated whether adding AFP, AFP-L3, and DCP to routine ultrasound improves early HCC detection. The original trial found that adding these biomarkers to biannual ultrasound did not significantly improve early-stage HCC detection compared with ultrasound alone. This challenges the routine use of biomarker panels in all high-risk patients. However, the authors of this letter argue that biomarkers should not be dismissed too quickly. They highlight important methodological issues that may influence interpretation. Problem Statement HCC surveillance is difficult because ultrasound has variable sensitivity, especially in obesity, cirrhosis, and nodular liver disease. Biomarkers may help, but their value depends on patient risk, biomarker thresholds, tumour biology, and timing of measurement. The key question is not simply whether biomarkers should be added to ultrasound for everyone, but which patients may benefit most and how biomarkers should be interpreted longitudinally. Key Points Raised by the Authors 1. Baseline HCC Risk Was Not Clearly Stratified The authors note that although both trial groups appeared balanced clinically, baseline HCC risk scores were not clearly reported. This matters because lower-risk patients, especially those without cirrhosis, may reduce the apparent benefit of biomarkers. 2. Risk-Based Surveillance May Be Better Instead of a uniform surveillance strategy, the authors suggest using validated HCC risk scores to adjust surveillance intensity, biomarker cutoffs, and cost-effectiveness. 3. AFP-L3 May Have Limited Added Value Although AFP-L3 showed relatively better individual diagnostic accuracy, the GALAD score, which includes AFP-L3, numerically performed slightly worse than the ASAP model, which excludes it. This raises the possibility that AFP-L3 may add limited independent value in some populations. 4. AFP-L3 Should Be Tested in Specific Subgroups The authors suggest evaluating AFP-L3, particularly in patients with negative ultrasound and AFP <20 ng/mL, where its incremental value would be clinically more meaningful. 5. Ultrasound False Positives Remain a Major Problem A high proportion of positive ultrasound findings did not lead to HCC diagnosis. Biomarkers may be useful not only for detecting cancer but also for helping distinguish benign ultrasound abnormalities from true malignancy. 6. More Direct Comparison Is Needed The authors request performance data for ultrasound alone within the biomarker arm, so the true incremental value of biomarkers can be better quantified. 7. Longitudinal Biomarker Trends May Be More Informative Rather than analysing biomarkers only from baseline, aligning biomarker changes to the actual date of HCC diagnosis may reveal rising trends before cancer detection. Clinical Relevance This letter provides an important caution: a negative overall trial result does not mean biomarkers have no role in HCC surveillance. Their value may be greatest in selected high-risk patients, ultrasound-negative patients, patients with poor ultrasound visualisation, or those showing rising biomarker trends over time. For clinicians, the key message is that biomarkers should not replace ultrasound, and routine addition for all patients may not be justified. However, risk-adapted and longitudinal biomarker strategies may still improve future surveillance models. Conclusion The commentary supports the trial’s important finding that routine addition of AFP, AFP-L3, and DCP to ultrasound may not significantly improve early HCC detection in a broad surveillance population. However, it argues that further subgroup analysis, risk stratification, ultrasound false-positive assessment, and longitudinal biomarker kinetics are needed. The future of HCC surveillance may not be “ultrasound versus biomarkers,” but rather personalised surveillance using risk scores, imaging quality, biomarker combinations, and dynamic trends over time.

AGA Guidelines on HCC Surveillance: Gastroenterology | May 2026

Introduction Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality in patients with cirrhosis. Despite advances in treatment, outcomes are largely determined by stage at diagnosis, making surveillance critical. Current strategies rely on ultrasound with AFP, but limitations in sensitivity and poor real-world uptake have created a need for better risk stratification and improved surveillance tools. Why This Guideline Is Required Traditional surveillance approaches are suboptimal due to: Underuse in clinical practice Limited sensitivity of ultrasound Changing epidemiology (rise of MASLD and alcohol-related liver disease) Lack of validated biomarkers and risk-based strategies This guideline focuses on improving risk stratification, surveillance efficiency, and early detection. 20 Key Takeaways for Clinicians 1. Prevention of cirrhosis is the most effective HCC strategy Treat viral hepatitis, alcohol use, and metabolic syndrome early. 2. Surveillance saves lives Early detection improves access to curative therapies and survival. 3. Standard surveillance = Ultrasound + AFP every 6 months Still the recommended global standard. 4. Semiannual surveillance is superior to annual surveillance. It detects earlier-stage tumours and improves outcomes. 5. Ultrasound has limitations Reduced sensitivity in obesity, MASLD, and advanced liver disease. 6. AFP improves sensitivity when added to ultrasound A combination is better than ultrasound alone. 7. Surveillance is underutilised Less than 25% of eligible cirrhosis patients undergo regular screening. 8. Target population = All cirrhosis patients Regardless of aetiology. 9. Select non-cirrhotic HBV patients need surveillance Based on age, ethnicity, and risk scores. 10. No routine surveillance in non-cirrhotic MASLD or HCV Unless better risk stratification tools are available. 11. Surveillance not useful in limited life expectancy Especially non-transplant candidates with advanced disease. 12. Harms of surveillance must be considered False positives, anxiety, cost, and unnecessary procedures. 13. Biomarkers like GALAD are promising but not ready Do not replace ultrasound + AFP yet. 14. Liquid biopsy is the future—but still experimental Requires validation in large prospective trials. 15. Multicancer detection panels should NOT be used Not validated for HCC surveillance populations. 16. MRI has higher sensitivity, but is not routine Cost, access, and practicality limit widespread use. 17. Abbreviated MRI is promising May become a future alternative in selected patients. 18. Risk stratification is the future of surveillance Not all cirrhosis patients have equal risk. 19. Current risk models are imperfect Limited validation and modest predictive performance. 20. HBV risk scores (PAGE-B, REAL-B) are useful Can guide surveillance decisions in non-cirrhotic HBV patients. Practical Clinical Message HCC surveillance is evolving from a uniform approach to a personalised strategy. While ultrasound + AFP remains the backbone, future progress will depend on risk-based surveillance, better biomarkers, and improved patient selection. Conclusion This guideline reinforces that current surveillance methods are effective but imperfect. The next phase in HCC care lies in precision surveillance, combining clinical risk, biomarkers, and imaging innovations to improve early detection while minimising harm.

HCC with PVTT: Liver Cancer | April 2026

Introduction Hepatocellular carcinoma with portal vein tumor thrombus represents one of the most aggressive forms of liver cancer, associated with poor prognosis and limited survival. Standard treatment relies on systemic therapy, including targeted agents and immunotherapy, but outcomes remain suboptimal. Increasingly, combining systemic therapy with locoregional approaches such as transarterial chemoembolization or hepatic arterial infusion chemotherapy is being explored to improve disease control. Problem Statement Systemic therapy alone provides limited survival benefit in HCC with PVTT, and the role of combined locoregional and systemic treatment strategies is not well established. Summary This propensity score–matched study demonstrates that combining locoregional therapy (TACE or HAIC) with systemic therapy significantly improves outcomes compared to systemic therapy alone in patients with HCC and PVTT. The combination approach nearly tripled median overall survival (15.7 vs. 5.9 months) and significantly improved progression-free survival and disease control rates. Importantly, the survival benefit was particularly pronounced in patients with advanced PVTT (Vp4) and those with poorer liver function (Child-Pugh B), suggesting that this strategy may be especially valuable in high-risk groups. Although adverse events were more frequent with combination therapy, severe toxicities were comparable between groups, indicating acceptable safety. Clinically, this study supports a shift toward multimodal therapy in advanced HCC with vascular invasion. It challenges the traditional reliance on systemic therapy alone and suggests that integrating locoregional approaches can meaningfully improve survival in selected patients.

Nutrition in MASLD: Frontline Gastroenterology | 2026

Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the leading cause of chronic liver disease worldwide and closely parallels the epidemics of obesity and type 2 diabetes. Lifestyle modification remains the first-line, evidence-based treatment, but in real practice there is often a major gap between guideline advice and what patients are actually able to follow. This review focuses on nutrition as the central modifiable factor in MASLD care, while also recognizing the importance of physical activity, sleep, culture, affordability, and food access. Problem Statement The major challenge in MASLD is not only knowing that diet matters, but translating broad recommendations into realistic, culturally sensitive, affordable, and sustainable nutrition advice for individual patients in busy clinical practice. Summary This review makes a strong case that nutrition should be at the centre of MASLD management. The main dietary message is to reduce ultra-processed foods, sugar-sweetened beverages, commercially produced fructose, saturated fats, and excess calories, while encouraging whole foods, vegetables, fruits, legumes, wholegrains, nuts, seeds, olive or rapeseed oil, and oily fish. The Mediterranean diet remains the most evidence-supported pattern because it improves liver fat and cardiometabolic health, sometimes even without significant weight loss. However, the authors rightly stress that the best diet is the one a patient can actually follow long term, so dietary advice must be personalized and culturally adapted. The review also explains the role of macronutrients and micronutrients. Fructose and saturated fat promote steatosis, while fibre, unsaturated fats, and adequate protein intake are protective. Micronutrients such as vitamin E, vitamin D, vitamin C, zinc, and polyphenols may influence liver health, although routine supplementation is not broadly recommended unless there is deficiency or a specific indication. Alcohol avoidance is emphasized, especially in more advanced disease. A particularly valuable part of this paper is its practical approach. It recognizes food insecurity, cost, and social context as real barriers. It gives adaptable Mediterranean-style advice for South and Southeast Asian, African, and lower-income populations, and even provides simple clinic checklists and sample menus. The overall message is clear: MASLD nutrition care should move from generic advice to compassionate, individualized, practical counselling that patients can sustain.

Adjuvant Immunotherapy in HCC: JGH | March 2026

Introduction Hepatocellular carcinoma remains a major global cancer burden, with high recurrence rates even after curative therapies such as resection or ablation. Historically, effective adjuvant treatments have been lacking, and surveillance has been the standard approach. With the success of immune checkpoint inhibitors in advanced HCC, there is growing interest in moving these therapies earlier into the adjuvant setting to reduce recurrence and improve survival outcomes. Problem Statement The role of immune checkpoint inhibitors as adjuvant therapy after curative treatment of HCC remains uncertain, with conflicting evidence and lack of definitive randomized trial data. Summary This meta-analysis of 18 studies involving over 3400 patients provides encouraging evidence that ICI-based adjuvant therapy significantly improves outcomes compared with surveillance alone. Recurrence-free survival was nearly halved (HR ~0.51), and overall survival also showed a meaningful improvement. Importantly, both ICI monotherapy and combination strategies with TKIs or anti-angiogenic agents demonstrated similar benefits, suggesting flexibility in therapeutic approaches. The benefit was consistent across subgroups, including patients undergoing resection or ablation, and regardless of prior treatments such as TACE. This reinforces the potential of immunotherapy to address the key challenge of post-curative recurrence. However, the evidence is largely derived from observational and region-specific studies, limiting generalizability. High-quality global randomized phase III trials with longer follow-up are urgently needed before routine adoption. Clinically, this study signals a paradigm shift—from passive surveillance to active adjuvant intervention—but caution is warranted until stronger prospective data confirm these findings.

Bridging the Gap in HCC Care: CGH | April 2026

Introduction Hepatocellular carcinoma (HCC) outcomes are critically dependent on stage at diagnosis, with early-stage disease offering opportunities for curative therapies such as resection, ablation, or transplantation. Despite advances in imaging, surveillance strategies, and treatment modalities, a substantial proportion of patients continue to be diagnosed at advanced stages. This reflects persistent gaps in cirrhosis recognition, suboptimal screening uptake, and healthcare access disparities. Understanding real-world patterns of HCC diagnosis, staging, treatment, and survival is essential to guide quality improvement in liver care. Problem Statement There is limited contemporary, system-level data evaluating how patients with HCC are diagnosed and managed across large healthcare systems. Key uncertainties remain regarding the proportion of patients diagnosed early, factors influencing treatment access, and determinants of survival—particularly in relation to screening and engagement in liver care. Summary In this Veterans Health Administration cohort (2023), only 56.7% had known cirrhosis prior to HCC diagnosis, highlighting under-recognition of at-risk patients. Early-stage diagnosis (T1/T2) occurred in ~60% but was strongly associated with prior cirrhosis recognition and screening, with 86.3% of screen-detected cases diagnosed early. Most patients (75.8%) received treatment, with Y-90 radioembolization being the most common. Survival was significantly better in patients diagnosed early, those undergoing screening, with preserved liver function, and those receiving curative therapies. This study underscores a central message for clinical practice: screening and structured liver care engagement are the most powerful modifiable factors to improve HCC outcomes, emphasizing the need for system-level interventions to close existing care gaps.