Trending Topics in Gastroenterology | GastroAGI

Fibrolamellar Carcinoma: Hepatology | March 2026

Introduction Fibrolamellar carcinoma (FLC) is a rare and biologically distinct primary liver cancer that predominantly affects adolescents and young adults without cirrhosis or other chronic liver disease. Unlike conventional hepatocellular carcinoma, FLC usually presents with normal or minimally elevated alpha-fetoprotein and often behaves aggressively despite occurring in otherwise healthy livers. A major advance in the field was the discovery of the DNAJB1::PRKACA fusion, which is now recognized as the central molecular driver in nearly all classical cases and has fundamentally changed the diagnostic and therapeutic framework of this disease. Because FLC responds poorly to treatments borrowed from conventional HCC or hepatoblastoma, this guideline is important in establishing a disease-specific approach to diagnosis, surgery, locoregional therapy, systemic treatment, and supportive care. Key Takeaways FLC should no longer be viewed as a subtype of conventional hepatocellular carcinoma, because it is a biologically separate disease with a different molecular driver, clinical pattern, and treatment response. The diagnosis of FLC requires three essential components: a primary liver tumor, characteristic histology, and molecular confirmation of DNAJB1::PRKACA fusion or, in very rare cases, PRKAR1A loss. Histology alone is not sufficient for diagnosis, because some conventional HCCs, especially scirrhous tumors, can mimic fibrolamellar morphology. Core needle biopsy is preferred over fine needle aspiration because preservation of fibrotic architecture is important for accurate diagnosis. The DNAJB1::PRKACA fusion is the defining molecular hallmark of classical FLC and should be actively tested for using targeted RNA-based assays, RT-PCR, or FISH. FLC usually affects adolescents and young adults with noncirrhotic livers and normal or minimally elevated AFP, and this clinical profile strongly supports the diagnosis. A large liver mass with a central scar on imaging is suggestive of FLC, but this finding is not specific and should never be used alone to make the diagnosis. FLC has a striking tendency to spread to regional lymph nodes, peritoneum, and lungs, making nodal assessment much more important than in conventional HCC. Baseline ancillary work-up should include broad NGS testing, HER2 immunohistochemistry, and serum ammonia measurement, because these may influence therapeutic planning and supportive care. Hyperammonemia and hyperammonemic encephalopathy are clinically important complications in FLC and may occur independently of liver failure. Surgery remains the cornerstone of treatment because FLC is only modestly responsive to systemic therapy and many patients tolerate aggressive liver surgery due to preserved underlying liver function. Patients with apparently classic and easily resectable FLC may occasionally proceed directly to surgery without preoperative biopsy when imaging and clinical context are highly convincing. Routine regional lymph node sampling or lymphadenectomy is strongly recommended even when imaging does not clearly show nodal disease, because occult nodal spread is common. Repeat surgery for recurrence, including metastasectomy and staged resection, can meaningfully prolong survival and is an accepted strategy in selected patients. Debulking surgery may still be worthwhile in advanced disease, including selected patients with lymph node, peritoneal, lung, brain, or bone metastases, especially when disease biology is indolent. Liver transplantation should be considered in patients with unresectable disease confined to the liver, even when the tumor does not fit traditional Milan criteria. Locoregional therapies such as Y-90 radioembolization, TACE, and SBRT are recommended both for palliation and as bridges to definitive surgery or control of unresectable disease. For advanced unresectable disease, the guideline supports GEMOX, GEMOX plus lenvatinib, or ipilimumab plus nivolumab as the most favored first-line systemic options based on available evidence and expert consensus. Clinical trial participation should be offered whenever possible because no universal standard systemic regimen exists and several promising fusion-directed or immunotherapy-based strategies are under active investigation. FLC care must include psychosocial, palliative, and multidisciplinary support, because this disease affects adolescents and young adults during a highly vulnerable stage of life and often imposes major emotional, social, fertility, and financial burdens. Conclusion This guideline is highly important because it formally establishes FLC as a unique liver cancer that requires its own diagnostic criteria and treatment strategy. The most practice-changing message is that molecular confirmation of the DNAJB1::PRKACA fusion, aggressive surgery with nodal assessment, and thoughtful use of systemic and locoregional therapies should define modern management. At present, surgery remains central, but the future of FLC care is clearly moving toward fusion-directed immunotherapy, biologically informed clinical trials, and more personalized multimodality treatment.

Microbial Metabolism follwoing TACE: Journal of Hepatology | April 2026

Introduction Transarterial chemoembolization (TACE) remains one of the most important treatments for unresectable hepatocellular carcinoma, but its clinical benefit is often limited by post-procedural liver injury. Traditionally, this injury has been attributed mainly to ischemia and chemotherapy-related damage to non-tumoral liver tissue. However, this explanation does not fully account for the variability in liver injury seen after TACE, suggesting that additional biological mechanisms are involved. This study explores whether disruption of the gut microbiota contributes to TACE-related liver injury. Problem Statement TACE-induced liver injury is a common complication that can compromise tolerance to repeated treatment and adversely affect long-term survival. Although direct hepatic injury is well recognized, the role of the gut–liver axis in this setting has remained poorly understood. Identifying modifiable microbial mechanisms could open a new strategy to reduce post-TACE complications and improve outcomes in HCC. Summary This study shows that TACE is associated with significant gut microbiota disturbance, and that this disturbance is not merely an epiphenomenon but a contributor to liver injury. In both rats and patients, TACE reduced the abundance of Limosilactobacillus reuteri and lowered levels of its tryptophan-derived metabolite indole-3-lactic acid (ILA). Lower levels of both were associated with more severe liver injury and poorer overall survival. Importantly, administration of live L. reuteri or ILA significantly reduced TACE-induced liver injury. Mechanistically, ILA suppressed macrophage-driven inflammation by inhibiting the HSP90–NLRP3 inflammasome pathway. This work identifies a novel microbiota-mediated mechanism of TACE toxicity and suggests that microbial or metabolite supplementation may become a practical adjunct to improve safety and prognosis in patients undergoing TACE.

BCLC Classification and AI-Based Image Quantification in HCC: Journal of Hepatology | March 2026

Introduction The Barcelona Clinic Liver Cancer (BCLC) classification has remained the cornerstone for staging, prognosis, and treatment allocation in hepatocellular carcinoma for more than two decades. Its strength lies in its simplicity and clinical applicability, integrating tumor burden, liver function, and performance status into a unified framework. However, modern imaging contains far more quantitative information than is currently utilized in BCLC. With the rapid evolution of artificial intelligence, there is now an opportunity to extract complex imaging features automatically and integrate them into clinical decision-making. This article explores how AI can complement, rather than replace, the BCLC system to enable more precise and personalized management of HCC. Summary This review highlights that while BCLC remains robust and widely validated, it underutilizes the wealth of data embedded in imaging. AI-based tools can quantify tumor volume, assess intratumoral heterogeneity, detect vascular invasion, evaluate portal hypertension through surrogate markers such as spleen volume, and even estimate body composition to reflect patient performance status. These parameters have shown strong associations with prognosis and treatment response in early studies. However, despite promising results, most AI applications remain confined to retrospective research settings due to poor reproducibility, lack of standardization, absence of prospective validation, and limited integration into clinical workflows. The article emphasizes that the key challenge is not technological capability but translational implementation. AI must be seamlessly embedded into routine workflows, supported by structured reporting, validated across diverse populations, and aligned with clinical frameworks such as BCLC. Importantly, the authors reinforce that clinical decision-making in HCC is inherently influenced by complexity, uncertainty, subjectivity, and emotion, and AI should support, not replace, this human-centered process. The future likely lies in a hybrid model where BCLC provides the clinical backbone, and AI adds quantitative refinement to improve prognostication and treatment selection.

Hypothermic Oxygenated Machine Perfusion Reduces HCC Recurrence After LT: JHEP March 2026

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation occurs in 15–20% of patients and remains a major determinant of post-transplant survival. This international matched cohort study evaluated whether hypothermic oxygenated machine perfusion (HOPE) of donor livers could influence oncologic outcomes after transplantation. The study included 599 HCC recipients from the multicenter HOPE-REAL cohort (2012–2022) who received grafts preserved using HOPE-based perfusion strategies. Outcomes were compared using propensity matching with both non-HCC recipients and external controls receiving conventional non-perfused grafts. The overall HCC recurrence rate was low (6.9%) in the HOPE-treated cohort. One-, three-, and five-year overall survival rates were 92%, 86%, and 81%, while recurrence-free survival reached 78% at 5 years. Importantly, 5-year survival was significantly higher in HOPE-treated HCC recipients compared with matched recipients of non-perfused grafts (84% vs 74%). Survival was also comparable to transplant outcomes in non-HCC recipients. These findings suggest that HOPE may reduce ischemia-reperfusion injury and graft inflammation, potentially lowering tumor recurrence risk after transplantation. If validated in randomized trials, machine perfusion could become an important strategy to improve oncologic outcomes in liver transplantation for HCC.

Biomarkers + USG and HCC Detection: Gastroenterology | March 2026

Introduction: The Biomarkers Used for HCC Surveillance Ultrasound (US) is the backbone of hepatocellular carcinoma (HCC) surveillance, but its sensitivity for early-stage HCC is imperfect. Blood-based biomarkers are attractive adjuncts because they are easy to repeat and potentially detect tumors missed by US. The commonly studied serum biomarkers include: AFP (alpha-fetoprotein): classic HCC marker, but limited specificity in active liver inflammation. AFP-L3: lectin-reactive AFP fraction, thought to reflect more malignant AFP isoforms. DCP (des-gamma-carboxy prothrombin/PIVKA-II): associated with HCC biology and vascular invasion in some cohorts. This trial tested whether combining these biomarkers with US improves early-stage detection. Summary In this randomized controlled trial, 1208 high-risk adults (cirrhosis or high-risk HBV) were assigned to biannual surveillance with US alone or US plus serum biomarkers (AFP, AFP-L3, DCP). Biomarker thresholds triggering diagnostic imaging were AFP >100 ng/mL, AFP-L3 >10%, or DCP >2 ng/mL. Over follow-up, 35 HCCs occurred in the US-only arm and 27 in the combined arm, with no difference in early-stage HCC detection between strategies (HR 0.81; P=.45). Late-stage cancers were similar in both groups. Within the biomarker arm, AFP-L3 alone performed similarly to using all three biomarkers combined. Overall, adding AFP/AFP-L3/DCP to ultrasound did not improve early HCC detection in this study, and the trial was not powered to prove benefit for biomarkers beyond US ± AFP.

AFP Thresholds for HCC Screening: Gastroenterology | March 2026

Introduction Alpha-fetoprotein (AFP) remains the most widely used biomarker in hepatocellular carcinoma (HCC) surveillance. Although AFP alone is insufficient for screening, its combination with ultrasound improves early HCC detection. However, the optimal AFP cutoff remains debated, particularly as the epidemiology of liver disease shifts from viral hepatitis toward metabolic and alcohol-related etiologies. Summary The traditional AFP threshold of 20 ng/mL should be lowered to 10 ng/mL for triggering diagnostic imaging in HCC surveillance. Using large datasets from the US Veterans Affairs (VA) system and the Organ Procurement and Transplantation Network (OPTN), found that lowering the AFP threshold improved sensitivity for HCC detection by 7–10%, with only a modest ~3% reduction in specificity. However, this increase in sensitivity also resulted in a 3–4% rise in false-positive results, leading to substantially more CT or MRI scans. In the VA cohort, lowering the threshold would have generated over 1000 additional imaging studies annually, with only a small proportion of HCC cases detected earlier. Current guidelines recommend evaluating rising AFP levels, not just a single threshold value, which was not assessed in the analysis. Additionally, the OPTN dataset is biased toward early-stage HCC patients already undergoing treatment before transplant listing. Most importantly, the study did not demonstrate improved patient-centred outcomes such as earlier curative therapy or reduced mortality. While lowering AFP thresholds may modestly increase detection rates, the authors caution that evidence is insufficient to justify immediate guideline changes. Future screening strategies may rely increasingly on multimarker panels (e.g., GALAD, HES) or emerging molecular biomarkers to improve early detection while minimising unnecessary testing.

Ancestry-Linked Genomic Signatures in HCC and cHCC–CCA - ESMO Open, Feb. 2026

This landmark genomic analysis presents one of the largest real-world datasets of hepatocellular carcinoma (HCC) and combined hepatocellular–cholangiocarcinoma (cHCC–CCA), encompassing 2,372 HCC and 150 mixed histology cases profiled using clinical-grade next-generation sequencing (FoundationOne platform). What was done Comprehensive genomic profiling assessed >290 cancer-related genes, tumour mutational burden (TMB), and microsatellite status across five genetic ancestries and both sexes. Key findings Sex-based differences: Women had lower rates of TERT, MYC, and CTNNB1 alterations, but higher BAP1 mutations. Ancestry-linked variation: East Asian patients showed higher frequencies of TP53, MUTYH, and TET2 alterations, along with more TMB-high tumours—suggesting biologically distinct molecular subgroups. cHCC–CCA is molecularly distinct: Compared with classic HCC, mixed tumours had significantly higher rates of IDH1, IDH2, and FGFR2 alterations, many of which are therapeutically actionable. Actionable alterations: Potentially targetable genomic events were identified in: 19.5% of HCC 34.7% of cHCC–CCA Diagnostic refinement: In 37 cases, genomic findings prompted re-evaluation and revision of the original histological diagnosis—highlighting the diagnostic power of NGS. Clinical implications This study reinforces that integrated molecular diagnostics should become standard of care in cHCC–CCA and considered in advanced HCC, not only to identify therapeutic targets but also to refine diagnosis. Precision oncology in liver cancer is no longer theoretical—it is becoming clinically relevant.

CHANCE2202 for HCC- eClinicalMedicine Feb. 2026

The CHANCE2202 study evaluated whether combining TACE with immune checkpoint inhibitors (ICIs) plus VEGF inhibitors or TKIs improves outcomes compared to TACE alone in intermediate-stage hepatocellular carcinoma (HCC). Using a rigorous target trial emulation framework, this nationwide Chinese multicenter cohort (n=941) attempted to replicate the design principles of a randomised controlled trial while minimising immortal-time and selection bias. Among 941 patients, 308 received combination therapy, and 633 received TACE monotherapy. Median overall survival (OS) was significantly longer with combination therapy (32.9 vs 23.0 months), with a restricted mean survival time (RMST) gain of 9.2 months and HR 0.57. Median progression-free survival (PFS) was also superior (18.0 vs 12.9 months; RMST difference 6.7 months; HR 0.70). Objective response rate (mRECIST) was higher in the combination group (60.5% vs 44.3%). Grade ≥3 adverse events were more frequent in the combination arm (20.8% vs 6.8%) but were considered manageable. Key Takeaways Real-world evidence suggests meaningful OS and PFS improvement with TACE + ICI + VEGF/TKI. Benefit was consistent across clinically relevant subgroups. The safety profile was acceptable, though higher toxicity requires monitoring. Phase III trials show PFS benefit, but OS data remain immature. Current evidence is promising but insufficient to change standard BCLC practice pending prospective confirmation. This study strengthens the biological rationale for integrating locoregional and systemic therapy in intermediate-stage HCC but highlights the need for definitive randomized survival data.

Real-World Evidence Favours Immunotherapy Over Lenvatinib in Advanced HCC- Hepatology Feb.26

Immune checkpoint inhibitor–based regimens have become central to the treatment of advanced hepatocellular carcinoma (HCC), but comparative effectiveness against tyrosine kinase inhibitors in real-world practice remains an important clinical question. This study used a target trial emulation approach to compare outcomes of first-line immunotherapy versus lenvatinib in patients with advanced HCC treated in routine clinical settings. Using a large U.S. healthcare database, the investigators identified patients who received either immunotherapy-based combinations (atezolizumab plus bevacizumab or durvalumab plus tremelimumab) or lenvatinib as initial systemic therapy. By applying rigorous propensity score matching, the study aimed to minimize bias and approximate the conditions of a randomized trial. Overall survival was the primary outcome. The analysis showed that immunotherapy was associated with longer overall survival compared with lenvatinib in the overall cohort. When specific regimens were examined, atezolizumab plus bevacizumab demonstrated a clear survival advantage over lenvatinib, while durvalumab plus tremelimumab showed a favorable trend that did not reach statistical significance, likely due to smaller sample size. Importantly, the benefit of immunotherapy was most pronounced in patients with viral hepatitis–related and alcohol-associated HCC, whereas no clear survival difference was observed in patients with metabolic dysfunction–associated steatotic liver disease. These findings reinforce current guideline recommendations supporting immunotherapy as first-line treatment for advanced HCC and highlight the potential importance of disease etiology in treatment response. While observational in nature, this study provides strong real-world evidence that complements randomized trial data and supports immunotherapy as the preferred initial systemic therapy for most patients with advanced HCC.

SBRT for Extensive Macrovascular Invasion in HCC- J Hepatol Feb.26

Macrovascular invasion (MVI) in hepatocellular carcinoma (HCC), particularly involving the hepatic veins, inferior vena cava, or right atrium, is associated with extremely poor prognosis and limited treatment options. Systemic therapy is the standard of care, but many patients with extensive MVI experience rapid deterioration in liver function, making systemic treatment poorly tolerated or infeasible. Evidence to guide management in this subgroup is sparse, as such patients are often excluded from clinical trials. This report highlights the role of stereotactic body radiotherapy (SBRT) as an effective local therapy for extensive MVI. In the described case, SBRT targeting the vascular tumor thrombus resulted in marked radiologic response, substantial reduction in tumour burden, and—critically—improvement in liver function, allowing safe reintroduction of systemic therapy. Tumor markers fell dramatically, and durable local control of the macrovascular disease was achieved. The case is supported by growing evidence from retrospective series and prospective trials showing that SBRT achieves high local control rates in HCC with MVI, with acceptable toxicity. Importantly, radiation to macrovascular tumour thrombus can restore or preserve hepatic blood flow, stabilise liver function, and create an opportunity for sequential systemic therapy. Randomised data suggest that combining radiotherapy with other treatments improves outcomes compared with systemic therapy alone. In summary, SBRT is a valuable treatment option for HCC with extensive MVI, even in advanced cases. By controlling vascular invasion and improving liver function, SBRT may expand therapeutic possibilities and improve outcomes in a population with otherwise very limited options.