HCC

Liver Stiffness for HCC Risk in MASLD: Hepatology | July 2026

Introduction: Metabolic dysfunction–associated steatotic liver disease (MASLD) is now the fastest-growing cause of hepatocellular carcinoma (HCC). Because a substantial proportion of MASLD-related HCC develops before cirrhosis, better tools are needed to identify high-risk patients who may benefit from surveillance. This study evaluated whether liver stiffness measurement (LSM) by transient elastography can improve HCC risk stratification in MASLD. Why was this study needed? HCC increasingly develops in patients with MASLD, including those without cirrhosis. Current surveillance strategies miss many high-risk noncirrhotic patients. Reliable, noninvasive biomarkers for HCC risk stratification are lacking. Defining LSM thresholds could enable more cost-effective surveillance. Results: This retrospective study included more than 30,000 patients with MASLD from the Veterans Analysis of Liver Disease (VALID) cohort. HCC risk increased progressively with increasing liver stiffness, with every 5 kPa rise in LSM associated with an 18% increase in HCC risk. Patients with higher LSM values demonstrated stepwise increases in annual HCC incidence, reaching nearly 1% per year among those with LSM ≥25 kPa. Importantly, among patients without cirrhosis or clinically significant portal hypertension, those with diabetes and an LSM ≥10 kPa had an annual HCC incidence exceeding the accepted threshold for cost-effective HCC surveillance. Clinical Impact: LSM may become an important noninvasive tool for individualized HCC surveillance in MASLD. Rather than relying solely on cirrhosis status, integrating liver stiffness and diabetes status could identify high-risk noncirrhotic patients who are currently overlooked by existing surveillance recommendations. This approach may improve early HCC detection while optimizing resource utilization. Bottom Line: Liver stiffness is a strong predictor of HCC risk in MASLD. Noncirrhotic patients with MASLD, diabetes, and an LSM ≥10 kPa may be appropriate candidates for HCC surveillance.

Durvalumab Plus Tremelimumab in Real-World HCC: JGH | May 2026

Introduction: The HIMALAYA trial established durvalumab plus tremelimumab (STRIDE) as a first-line treatment for unresectable hepatocellular carcinoma (HCC). However, many real-world patients do not meet the strict eligibility criteria of clinical trials. This multicenter study evaluated the effectiveness and safety of STRIDE in routine clinical practice. Why was this study needed? Many patients treated in routine practice would not have qualified for the HIMALAYA trial. Real-world effectiveness of STRIDE outside trial criteria remains uncertain. Better predictors of treatment outcomes are needed. Liver function may be more important than trial eligibility alone. Real-world data are essential to guide everyday clinical decision-making. Results: Patients meeting the HIMALAYA eligibility criteria achieved longer progression-free and overall survival than those who did not meet trial criteria. Among patients outside the HIMALAYA criteria, those with preserved liver function (ALBI Grade 1) achieved survival outcomes comparable to trial-eligible patients. Poor liver function (ALBI ≥2), impaired performance status, and portal vein invasion were associated with worse clinical outcomes, emphasizing the importance of careful patient selection. Clinical Impact: This real-world study demonstrates that STRIDE remains effective beyond the strict HIMALAYA trial population, particularly in patients with well-preserved liver function. ALBI grade may be a more practical tool than trial eligibility alone when selecting patients for immunotherapy. Bottom Line: Preserved liver function—not simply trial eligibility—is the key determinant of successful STRIDE therapy. Patients with ALBI Grade 1 may derive meaningful benefit from durvalumab plus tremelimumab even if they would not have met the original HIMALAYA trial inclusion criteria.

ALBI Grade and Sarcopenia in Unresectable HCC: IJG | July 2026

Introduction: Prognosis in unresectable hepatocellular carcinoma (HCC) depends not only on tumor burden but also on liver function and nutritional status. This study evaluated the prognostic value of ALBI grade, EZ-ALBI grade, and sarcopenia in patients with intermediate- and advanced-stage HCC treated with TACE alone or TACE plus lenvatinib. Why was this study needed? Reliable prognostic markers are needed to personalize treatment in unresectable HCC. ALBI and EZ-ALBI provide objective assessment of liver function. Sarcopenia is increasingly recognized as an important determinant of cancer outcomes. Their combined prognostic value in TACE-based therapy remains unclear. Better risk stratification may improve treatment selection and follow-up. Results: ALBI and EZ-ALBI grades accurately predicted treatment response, disease progression, and progression-free survival in both intermediate-stage HCC treated with TACE and advanced-stage HCC treated with TACE plus lenvatinib. Sarcopenia was associated with poorer treatment response and shorter progression-free survival in advanced HCC, but showed limited prognostic value in intermediate-stage disease treated with TACE alone. These findings highlight the complementary role of liver reserve and muscle mass in predicting outcomes after locoregional and systemic therapy. Clinical Impact: Routine assessment of ALBI/EZ-ALBI grades and sarcopenia may improve prognostic stratification in unresectable HCC. While ALBI-based scores appear useful across disease stages, assessment of sarcopenia may be particularly valuable in patients receiving combination therapy with TACE and lenvatinib. Bottom Line: ALBI and EZ-ALBI are simple, effective prognostic tools for unresectable HCC. In advanced disease, sarcopenia identifies patients with poorer outcomes, emphasizing the importance of integrating nutritional and functional assessment into routine HCC management.

HCC Surveillance Saves Lives: Frontline Gastroenterology | July 2026

Introduction: Hepatocellular carcinoma (HCC) surveillance enables earlier diagnosis and improves survival. This largest UK multicenter study evaluated how patients are diagnosed in routine clinical practice and identified major gaps in the surveillance pathway. Why was this study needed? Early HCC detection remains suboptimal despite established surveillance guidelines. Real-world data on surveillance performance across the UK have been limited. Understanding where surveillance fails is essential to improve outcomes. Earlier diagnosis increases eligibility for curative treatment. Better surveillance pathways could reduce HCC-related mortality. Results: Only 28% of HCC cases were detected through surveillance, while nearly half of patients presented with symptoms, reflecting missed opportunities for early diagnosis. Surveillance identified smaller tumors at an earlier stage, resulting in substantially lower 1-year mortality compared with incidental or symptomatic presentation. Failures occurred throughout the surveillance pathway, including missed cirrhosis diagnosis, failure to enroll eligible patients, and inadequate surveillance delivery. Clinical Impact: This study highlights that the greatest opportunity to improve HCC outcomes lies before the cancer develops—by identifying patients with cirrhosis, enrolling them into surveillance programs, and ensuring regular high-quality follow-up. Strengthening every step of the surveillance pathway could substantially increase early detection and access to curative therapies. Bottom Line: HCC surveillance works—but it is underutilized. Fewer than 1 in 3 high-risk patients are diagnosed through surveillance, despite clear evidence that earlier detection saves lives. Improving surveillance implementation should be a major priority in HCC care.

Yttrium-90 Radioembolization for HCC: The Lancet Regional Health | July 2026

Introduction: Selective internal radiation therapy (SIRT) using yttrium-90 (Y90) glass microspheres is an established locoregional treatment for hepatocellular carcinoma (HCC), but guideline recommendations remain inconsistent. This large prospective multicenter study evaluated the real-world effectiveness, safety, quality of life, and survival outcomes of Y90 radioembolization. Why was this study needed? High-quality prospective real-world data on Y90 radioembolization are limited. Current international guidelines differ regarding the role of Y90 in HCC. The impact of personalized dosimetry on survival remains uncertain. More evidence is needed in patients with portal vein tumor thrombosis (PVT). The potential role of Y90 as a bridge to curative surgery requires further validation. Results: Y90 radioembolization achieved encouraging overall survival with a favorable safety profile across all BCLC stages, including patients with portal vein tumor thrombosis. Higher radiation doses to the tumor (especially ≥400 Gy) were associated with significantly longer survival, supporting personalized dosimetry-guided treatment. Approximately 1 in 10 patients were successfully downstaged to curative surgery after Y90, achieving excellent long-term survival, while quality of life remained well preserved. Clinical Impact: This landmark real-world study strengthens the role of dosimetry-guided Y90 radioembolization as an effective and safe treatment for selected patients with HCC. It also highlights Y90 as an important downstaging strategy before curative surgery and supports broader incorporation into future treatment guidelines. Bottom Line: Personalized Y90 radioembolization delivers meaningful survival with low toxicity in HCC. Higher tumor radiation doses improve outcomes, and successful downstaging to surgery offers the best long-term survival, reinforcing the importance of dosimetry-guided treatment planning.

Bleeding Risk with Immunotherapy in Advanced HCC: JHEP Reports | July 2026

Introduction: Atezolizumab–bevacizumab (A/B) and durvalumab–tremelimumab (STRIDE) are preferred first-line treatments for advanced hepatocellular carcinoma (HCC). Because bevacizumab inhibits VEGF, concerns remain regarding bleeding and thromboembolic complications in patients with underlying cirrhosis and portal hypertension. Why was this study needed? Direct real-world safety comparisons between A/B and STRIDE are limited. The anti-VEGF component of bevacizumab may increase bleeding risk. Clinicians need evidence to guide treatment selection in patients at high bleeding risk. The comparative risk of variceal bleeding and thromboembolic events remains uncertain. Better safety data are needed to individualize first-line immunotherapy. Results: Atezolizumab–bevacizumab was associated with significantly more overall and severe bleeding events, which also occurred earlier than with durvalumab–tremelimumab. Variceal bleeding and thromboembolic event rates were similar between the two treatment groups despite the higher overall bleeding risk with A/B. Treatment with A/B independently predicted bleeding risk, suggesting that the VEGF inhibitor contributes to this increased risk. Clinical Impact: These findings suggest that STRIDE may be the preferred first-line immunotherapy in patients with advanced HCC who have a high baseline bleeding risk, particularly those with portal hypertension or previous bleeding episodes. As this was a retrospective study, treatment decisions should still be individualized pending prospective confirmation. Bottom Line: Atezolizumab–bevacizumab increases overall bleeding risk compared with durvalumab–tremelimumab, while variceal bleeding and thromboembolic events remain similar. Careful bleeding risk assessment should guide first-line immunotherapy selection in advanced HCC.

AGA Updates HCC Risk Stratification and Surveillance : Gastroenterology | Jun 2026

Introduction: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality among patients with chronic liver disease and cirrhosis. Outcomes are substantially better when HCC is detected at an early stage, allowing access to potentially curative therapies. However, surveillance remains underutilized, and currently recommended tools have important limitations in sensitivity and implementation. As the epidemiology of liver disease shifts toward metabolic dysfunction–associated steatotic liver disease (MASLD) and alcohol-associated liver disease, there is growing interest in improving risk stratification and surveillance strategies. Problem Statement: Current HCC surveillance relies primarily on semiannual ultrasound with α-fetoprotein (AFP), but this approach fails to detect a significant proportion of early-stage tumors. At the same time, numerous emerging biomarkers, risk prediction models, and imaging approaches have been proposed, creating uncertainty regarding their role in routine clinical practice. Clear guidance is needed on how these evolving tools should be incorporated into patient care. Summary: In this AGA Clinical Practice Update, experts reaffirm that semiannual ultrasound combined with AFP remains the preferred surveillance strategy for patients at risk of HCC, particularly those with cirrhosis and selected patients with chronic hepatitis B infection. The document emphasizes that prevention of cirrhosis through viral hepatitis treatment, alcohol use disorder management, and metabolic risk factor control remains the most effective strategy for reducing HCC-related morbidity and mortality. While several promising blood-based and radiologic biomarkers, including GALAD, are undergoing clinical validation, current evidence is insufficient to support their routine use as replacements for guideline-recommended surveillance. Similarly, multicancer blood-based screening panels are not recommended for HCC surveillance at present. The update also highlights the growing need for individualized risk stratification as HCC increasingly arises in patients with nonviral liver disease, where annual cancer risk may differ substantially from traditional viral hepatitis populations. Although numerous HCC risk prediction models have been developed, few have demonstrated sufficient validation for widespread clinical use. An exception is chronic hepatitis B without cirrhosis, where PAGE-B and REAL-B scores may help identify patients at higher future risk. Overall, the guidance advocates for evidence-based surveillance while encouraging continued development and validation of novel biomarkers and precision risk-stratification tools to improve early HCC detection.

PRISM Study: Real-World Outcomes for Unresectable HCC: Liver Cancer | May 2026

PRISM is one of the largest prospective real-world studies evaluating systemic therapy for unresectable hepatocellular carcinoma in routine clinical practice across Japan. This analysis reports outcomes from the first 1,000 prospectively enrolled patients, providing important validation of results seen in clinical trials. Among evaluable patients, the vast majority received atezolizumab plus bevacizumab (82.8%), while 15.2% received lenvatinib as first-line therapy. Median overall survival reached 21.8 months with Atezo+Bev and 20.8 months with lenvatinib, demonstrating excellent real-world outcomes. Survival outcomes were numerically better than those reported in the original registration trials, suggesting that careful patient selection, multidisciplinary management, and effective sequential therapy may be improving outcomes in practice. Progression-free survival remained consistent with clinical trial data at 7.7 months for Atezo+Bev and 6.7 months for lenvatinib. Objective response rates were impressive for both regimens, confirming that real-world effectiveness closely mirrors clinical trial efficacy. Sorafenib was rarely used and showed substantially lower response rates compared with modern first-line therapies. Grade 3 or higher treatment-related adverse events occurred in approximately 22% of patients, with no unexpected safety concerns. Importantly, nearly 50% of patients were able to receive second-line therapy, highlighting the growing importance of sequential treatment strategies in advanced HCC. The most common sequencing pattern was: Atezolizumab + bevacizumab → lenvatinib Lenvatinib → atezolizumab + bevacizumab Second-line therapy provided a median progression-free survival of approximately 4 months, while benefit progressively decreased with later treatment lines. The study demonstrates that modern systemic therapies can be safely delivered to a broad real-world population, not just highly selected clinical trial patients. PRISM also highlights the importance of maintaining liver function and performance status to allow access to sequential therapies, which likely contributes significantly to prolonged survival. Future analyses are expected to provide valuable information regarding special populations, including elderly patients, those with impaired liver function, and different molecular or clinical subgroups. Bottom line: The PRISM study confirms that atezolizumab plus bevacizumab and lenvatinib achieve reproducible real-world outcomes in unresectable HCC, with median overall survival exceeding 20 months and nearly half of patients successfully receiving subsequent lines of therapy.

ICI Before Liver Transplant in HCC: irAEs Signal Rejection Risk: Gut | June 2026

* Immune checkpoint inhibitors are increasingly used in patients with hepatocellular carcinoma before liver transplantation, but post-transplant allograft rejection remains a major concern. * This multicenter Chinese retrospective study evaluated 209 patients with HCC who received immune checkpoint inhibitors before liver transplantation. * Allograft rejection occurred in 17.2% of patients, highlighting that rejection is a clinically meaningful risk after pretransplant immunotherapy. * Rejection was much more frequent in patients who developed immune-related adverse events before transplant. * Patients with irAEs had a rejection rate of 58.3%, compared with 13.3% in those without irAEs. * Any-grade irAE was the strongest independent predictor of allograft rejection, suggesting that irAEs may reflect a heightened immune activation state. * Other independent risk factors included younger age below 40 years and a short ICI washout interval of less than 30 days. * A predictive model combining irAEs, age, and ICI washout interval performed better than any individual factor alone. * Importantly, rejection was not just a laboratory or histological event; it was associated with worse survival. * One-year survival was significantly lower in patients who developed allograft rejection. * The study suggests that irAEs should be considered a practical pretransplant biomarker of immune risk. * Patients with irAEs may require longer washout intervals, closer perioperative immune monitoring, and individualized immunosuppression strategies. * The findings support a more cautious transplant selection pathway for HCC patients previously exposed to ICIs. * This does not mean that ICIs should be avoided in all transplant candidates, but they should be used with careful planning and multidisciplinary coordination. * Prospective validation is needed before universal cutoffs for washout period or immunosuppression protocols can be standardized. Bottom line: In HCC patients receiving immune checkpoint inhibitors before liver transplantation, the development of immune-related adverse events strongly predicts post-transplant allograft rejection and may help guide washout timing, monitoring intensity, and immunosuppressive strategy.

CRAFITY Score May Guide First-Line Therapy Selection in Unresectable HCC: Liver Cancer | June 2026

* Atezolizumab plus bevacizumab remains the most widely used first-line therapy for unresectable hepatocellular carcinoma, while lenvatinib continues to be an important alternative. * This international multicenter study evaluated whether the CRAFITY score can help identify which patients may benefit more from one treatment over the other. * The CRAFITY score is based on two simple biomarkers: * CRP ≥1 mg/dL * AFP ≥100 ng/mL Patients receive a score of 0, 1, or 2. * The analysis included 994 patients treated across Japan and Taiwan, making it one of the largest real-world comparisons of Atezo+Bev and lenvatinib stratified by CRAFITY score. * In patients with CRAFITY score 0, progression-free survival and overall survival were similar between Atezo+Bev and lenvatinib. * Similar results were observed in patients with CRAFITY score 1, suggesting both treatment options remain reasonable choices in this group. * The key finding emerged in patients with CRAFITY score 2, representing the highest-risk subgroup. * In CRAFITY-2 patients, lenvatinib achieved significantly longer progression-free survival compared with Atezo+Bev. * This suggests that highly inflammatory, biologically aggressive HCC characterized by elevated CRP and AFP may respond less favorably to immunotherapy-based treatment. * Overall survival did not differ significantly between the two treatment groups, but progression control clearly favored lenvatinib in the CRAFITY-2 population. * The study demonstrated a significant interaction between CRAFITY score and treatment efficacy, supporting the concept of biomarker-driven treatment selection. * One major advantage of the CRAFITY score is its simplicity. Both CRP and AFP are routinely available worldwide and do not require expensive molecular testing. * These findings challenge the current “one-size-fits-all” approach in first-line HCC treatment and suggest that not every patient may derive the same benefit from Atezo+Bev. * Before changing routine practice, prospective validation studies are required because this analysis was retrospective. * Nevertheless, the study provides one of the strongest signals to date that a simple clinical biomarker score may help personalize first-line therapy in advanced HCC. Bottom line: In unresectable HCC patients with a CRAFITY score of 2, lenvatinib achieved superior progression-free survival compared with atezolizumab plus bevacizumab, suggesting that CRAFITY may become a practical tool for first-line treatment selection.

PRISM Study: Real-World Outcomes of First-Line Systemic Therapy for Unresectable HCC: Liver Cancer | May 2026

* PRISM is one of the largest prospective real-world studies evaluating systemic therapy for unresectable hepatocellular carcinoma in routine clinical practice across Japan. * This analysis reports outcomes from the first 1,000 prospectively enrolled patients, providing important validation of results seen in clinical trials. * Among evaluable patients, the vast majority received atezolizumab plus bevacizumab (82.8%), while 15.2% received lenvatinib as first-line therapy. * Median overall survival reached 21.8 months with Atezo+Bev and 20.8 months with lenvatinib, demonstrating excellent real-world outcomes. * Survival outcomes were numerically better than those reported in the original registration trials, suggesting that careful patient selection, multidisciplinary management, and effective sequential therapy may be improving outcomes in practice. * Progression-free survival remained consistent with clinical trial data at 7.7 months for Atezo+Bev and 6.7 months for lenvatinib. * Objective response rates were impressive for both regimens, confirming that real-world effectiveness closely mirrors clinical trial efficacy. * Sorafenib was rarely used and showed substantially lower response rates compared with modern first-line therapies. * Grade 3 or higher treatment-related adverse events occurred in approximately 22% of patients, with no unexpected safety concerns. * Importantly, nearly 50% of patients were able to receive second-line therapy, highlighting the growing importance of sequential treatment strategies in advanced HCC. * The most common sequencing pattern was: * Atezolizumab + bevacizumab → lenvatinib * Lenvatinib → atezolizumab + bevacizumab * Second-line therapy provided a median progression-free survival of approximately 4 months, while benefit progressively decreased with later treatment lines. * The study demonstrates that modern systemic therapies can be safely delivered to a broad real-world population, not just highly selected clinical trial patients. * PRISM also highlights the importance of maintaining liver function and performance status to allow access to sequential therapies, which likely contributes significantly to prolonged survival. * Future analyses are expected to provide valuable information regarding special populations, including elderly patients, those with impaired liver function, and different molecular or clinical subgroups. Bottom line: The PRISM study confirms that atezolizumab plus bevacizumab and lenvatinib achieve reproducible real-world outcomes in unresectable HCC, with median overall survival exceeding 20 months and nearly half of patients successfully receiving subsequent lines of therapy.

ARTE Score Predicts Decompensation on Atezo-Bev : J Hepatol | May 2026

Introduction: Introduction: Atezolizumab plus bevacizumab (Atezo-Bev) is the standard first-line systemic therapy for many patients with unresectable hepatocellular carcinoma (uHCC). However, treatment success depends not only on tumor control but also on preservation of liver function. Hepatic decompensation remains a major cause of treatment interruption, reduced survival, and impaired quality of life. Identifying patients at greatest risk before therapy initiation is therefore crucial for optimal treatment selection and monitoring. Problem Statement: Problem Statement: Existing prognostic models primarily focus on survival outcomes and do not specifically predict hepatic decompensation during Atezo-Bev therapy. Clinicians lack a simple, validated tool that can identify patients at increased risk of liver failure despite having Child-Pugh A liver function at treatment initiation. Summary: Summary: This multicenter study analyzed 453 Child-Pugh A patients with unresectable HCC receiving first-line atezolizumab plus bevacizumab from the ARTE database and externally validated findings in an independent cohort of 292 patients from the AB-real database. During a median follow-up of 14 months, hepatic decompensation occurred in 16.3% of patients. Multivariable Cox regression identified three independent predictors of decompensation: neoplastic portal vein thrombosis, elevated bilirubin levels, and thrombocytopenia. These variables were integrated into a simple point-based risk stratification model termed the ARTE Score. Based on the cumulative score, patients were classified into three risk categories: Low risk (0–1 points) Intermediate risk (2 points) High risk (3–4 points) The model demonstrated clear separation of decompensation risk across all categories. Compared with low-risk patients, intermediate-risk patients experienced nearly a twofold increase in decompensation risk, while high-risk patients had more than a fourfold increased risk. Decompensation-free survival showed marked differences between groups. At 12 months, decompensation-free survival remained high in low-risk patients but progressively declined in intermediate- and high-risk groups. These differences persisted at 24 months, highlighting the score’s ability to identify clinically meaningful long-term risk. Importantly, the model maintained its predictive performance in the independent external validation cohort, supporting its reproducibility and generalizability across different clinical settings. The biological rationale behind the score is intuitive. Portal vein tumor thrombosis reflects advanced tumor burden and impaired hepatic perfusion. Elevated bilirubin indicates reduced hepatic reserve even within Child-Pugh A patients. Thrombocytopenia serves as a surrogate marker of clinically significant portal hypertension and advanced underlying cirrhosis. Together, these variables capture the combined impact of tumor aggressiveness and baseline liver vulnerability. Clinically, the ARTE Score may assist in treatment planning before initiating Atezo-Bev. High-risk patients may benefit from closer laboratory surveillance, earlier recognition of liver deterioration, optimization of portal hypertension management, and consideration of alternative therapeutic strategies when appropriate. The score is particularly valuable because it relies exclusively on routinely available clinical variables, making implementation feasible in everyday practice without specialized testing or biomarkers. Overall, this study introduces the ARTE Score as a simple, externally validated tool for predicting hepatic decompensation in patients with unresectable HCC receiving atezolizumab plus bevacizumab, providing an important step toward more personalized risk assessment and treatment decision-making in advanced liver cancer.

Carbon-Ion Radiotherapy Matches Surgery in Early HCC : Hepatol Commun | June 2026

Introduction: Hepatocellular Carcinoma surgical resection remains a standard curative treatment for early-stage disease, but many patients are poor surgical candidates because of cirrhosis, portal hypertension, advanced age, or comorbidities. Carbon-ion radiotherapy (CIRT), an advanced particle radiotherapy technique with superior dose localization and enhanced biological effectiveness, has emerged as a potential non-surgical curative option for HCC. Problem Statement: Despite increasing interest in particle therapy, comparative real-world data evaluating long-term oncologic outcomes between CIRT and surgical resection are limited. Whether CIRT can provide equivalent survival and disease control to surgery in early-stage HCC remains uncertain, particularly after adjusting for differences in baseline patient characteristics. Summary: This multicenter Japanese retrospective study compared clinical outcomes between 116 patients treated with carbon-ion radiotherapy and 947 patients undergoing surgical resection for HCC between 2010 and 2022. Because patients selected for CIRT often differ significantly from surgical candidates, the investigators used inverse probability of treatment weighting (IPTW) analysis to balance baseline characteristics and improve comparability between groups. Before adjustment, recurrence-free survival was similar between surgery and CIRT, with median recurrence-free survival of approximately 2.3 years in both groups. Although unadjusted overall survival initially appeared superior with surgical resection, this difference disappeared after IPTW adjustment, suggesting that baseline patient selection rather than treatment efficacy largely explained the survival disparity. Following adjustment, neither recurrence-free survival nor overall survival differed significantly between surgical resection and CIRT. Importantly, multivariable analyses confirmed that treatment modality itself was not an independent predictor of recurrence or survival outcomes. These findings suggest that CIRT may offer oncologic outcomes comparable to surgery in appropriately selected patients with early-stage HCC. The study is clinically important because many HCC patients have limited hepatic reserve or comorbidities that increase operative risk. Unlike surgery, CIRT is non-invasive and can deliver highly conformal radiation with minimal damage to surrounding liver tissue, making it particularly attractive in cirrhotic patients or those unsuitable for resection. The results also support the growing role of advanced radiotherapy as a definitive treatment strategy rather than merely a bridge or palliative option. Carbon-ion therapy possesses unique radiobiological advantages over conventional photon radiotherapy, including higher relative biological effectiveness and improved targeting precision through the Bragg peak phenomenon, potentially enhancing tumor control while preserving non-tumorous liver parenchyma. Although recurrence rates remained substantial in both groups, reflecting the multicentric carcinogenic nature of HCC in cirrhosis, survival equivalence suggests that local tumor control with CIRT is clinically meaningful. The study further reinforces the evolving multidisciplinary management paradigm in HCC, where surgery, ablation, transplantation, and particle radiotherapy may increasingly function as complementary curative strategies tailored to patient-specific hepatic reserve, tumor anatomy, and comorbidity profile. Limitations include the retrospective design, relatively smaller CIRT cohort, and potential residual confounding despite IPTW adjustment. In addition, accessibility and cost remain major barriers to widespread CIRT implementation globally. Overall, this study provides important real-world evidence that carbon-ion radiotherapy can achieve survival and recurrence outcomes comparable to surgical resection in selected patients with early-stage HCC, supporting its role as a potentially curative non-surgical treatment modality.

Immune-Related Adverse Events Strongly Predict Post-Transplant Rejection After Pretransplant Immunotherapy in HCC : Gut | May 2026

Introduction Hepatocellular Carcinoma management increasingly incorporates Immune Checkpoint Inhibitors for downstaging and bridging prior to Liver Transplantation. Although checkpoint inhibitors can successfully expand transplant eligibility and improve tumor control, they also create a major immunological dilemma because persistent immune activation may increase the risk of catastrophic post-transplant allograft rejection. Problem Statement Reliable predictors of post-transplant rejection after pretransplant immune checkpoint inhibitor exposure remain poorly defined, limiting safe patient selection and peri-transplant immunotherapy planning. Summary This national multicentre retrospective study evaluated predictors of allograft rejection in hepatocellular carcinoma patients receiving immune checkpoint inhibitors before liver transplantation, with particular emphasis on the role of immune-related adverse events (irAEs). The study identified immune-related adverse events as the strongest independent predictor of post-transplant rejection. Patients experiencing irAEs during checkpoint inhibitor therapy had an approximately ninefold higher risk of subsequent allograft rejection after transplantation. This is a highly important and clinically actionable observation because irAEs may represent a real-time biomarker of sustained systemic immune activation. Post-transplant rejection occurred in 17% of patients overall, typically developing early after transplantation, with a median onset of only 10 days. This rapid temporal pattern supports the concept that pre-existing activated immune pathways persist into the peri-transplant period despite surgical organ replacement and immunosuppression. Additional independent risk factors included younger recipient age and shorter washout intervals below 30 days between checkpoint inhibitor exposure and transplantation. These findings align with previous concerns that insufficient immune de-escalation time before transplantation may leave residual T-cell activation capable of targeting the allograft. Importantly, the study moved beyond clinical associations and explored mechanistic correlates through a prospective observational cohort. Patients developing irAEs demonstrated significantly increased circulating CD8+ T-cell populations and elevated inflammatory cytokines including IFN-α and TNF-α, suggesting a hyperactivated cytotoxic immune phenotype. These data provide biologic plausibility for the observed clinical association between irAEs and rejection risk. Immune-related toxicities may not merely reflect isolated organ-specific inflammation but instead indicate a globally primed immune system capable of heightened alloimmune reactivity. Clinically, the findings have major implications for transplant hepatology and multidisciplinary tumor boards. Occurrence of irAEs during checkpoint inhibitor therapy may need to be incorporated into transplant eligibility assessment, perioperative risk counseling and individualized immunosuppression planning. The predictive model generated in the study achieved good discriminatory performance, suggesting that integrated risk stratification incorporating irAEs, recipient age and washout duration may help identify patients at particularly high rejection risk. The study also contributes to the evolving discussion regarding optimal timing of transplantation after checkpoint inhibitor therapy. Although no universally accepted washout interval exists, these findings support caution with very short intervals, especially in patients who experienced clinically significant immune toxicities. From an oncologic perspective, the work highlights the increasingly complex balance between maximizing antitumor immunity and preserving transplant tolerance. Checkpoint inhibitors may simultaneously improve tumor control while destabilizing alloimmune equilibrium. The findings are especially relevant because checkpoint inhibitors are increasingly being used earlier in HCC treatment algorithms, including neoadjuvant and bridging settings. As immunotherapy exposure before transplantation becomes more common, reliable biomarkers for rejection prediction will become critically important. The study further underscores the need for close collaboration between oncology, transplant hepatology and transplant immunology teams when managing these patients. Decisions regarding checkpoint inhibitor selection, duration, toxicity management and transplantation timing will likely require increasingly individualized approaches. Overall, this multicentre study identifies immune-related adverse events as a powerful predictor of post-transplant rejection in HCC patients exposed to pretransplant checkpoint inhibitors. The findings suggest that irAEs may serve as clinically accessible markers of persistent immune activation and provide an important framework for risk stratification and peri-transplant immunotherapy management.

Liver Transplantation Defines Long-Term Survival in HCC : Hepatol Commun | May 2026

Introduction Hepatocellular Carcinoma remains one of the leading causes of cancer-related mortality worldwide. Although curative-intent therapies such as liver transplantation, surgical resection and ablation can achieve durable disease control, long-term survival remains limited by tumor recurrence, progressive cirrhosis and competing liver-related complications. Data defining predictors of true long-term survival beyond 10 years have remained scarce. Problem Statement Most HCC outcome studies focus on short- or intermediate-term survival, whereas determinants of ≥10-year survival are poorly characterized. In particular, the relative long-term impact of liver transplantation compared with resection or ablation in real-world populations requires further clarification. Summary This large National Cancer Database analysis evaluated nearly 250,000 patients diagnosed with HCC between 2004 and 2022 to identify factors associated with survival beyond 10 years. Long-term outcomes remained poor overall, with only 3.3% of patients achieving ≥10-year survival, emphasizing the aggressive biologic and cirrhotic burden associated with HCC. Among all treatment modalities, Liver Transplantation emerged as the dominant determinant of long-term survival. Compared with ablation, liver transplantation increased the odds of surviving ≥10 years nearly twelvefold, substantially outperforming surgical resection and all non-curative therapies. Decision-tree analyses further confirmed transplantation as the single most important predictor of durable survival. The superiority of transplantation likely reflects its unique ability to simultaneously eliminate both tumor burden and the underlying cirrhotic liver substrate responsible for de novo carcinogenesis and hepatic decompensation. In contrast, resection and ablation remove or destroy focal tumors while leaving the diseased liver in place, allowing continued risk for recurrence and liver-related mortality. Surgical resection also significantly improved long-term survival compared with ablation, although the magnitude of benefit remained considerably lower than transplantation. Non-curative therapies were associated with substantially worse outcomes, underscoring the importance of early-stage diagnosis and access to definitive treatment strategies whenever feasible. One of the most important findings was the persistence of racial disparities in transplant access and survival. Black patients demonstrated lower odds of receiving liver transplantation and correspondingly lower likelihood of ≥10-year survival. These observations reinforce longstanding concerns regarding inequities in transplant referral, waitlist access, socioeconomic barriers and healthcare delivery within HCC management pathways. Clinically, the study reinforces that long-term cure in HCC depends not only on oncologic control but also on management of the underlying liver disease. The exceptional survival associated with transplantation highlights the central importance of careful candidate selection, surveillance-based early detection and equitable access to transplant evaluation. The findings additionally support ongoing efforts to expand transplant eligibility through downstaging protocols, improved locoregional bridging therapies and optimized organ allocation systems. As systemic therapies improve and multidisciplinary HCC care evolves, transplantation may become increasingly integrated into broader biologic treatment algorithms rather than purely anatomy-based selection models. Overall, this large national analysis demonstrates that liver transplantation provides the greatest likelihood of achieving ≥10-year survival in HCC, far surpassing other curative-intent therapies. The study also highlights persistent disparities in transplant access and emphasizes that equitable delivery of transplantation remains essential for improving long-term outcomes in hepatocellular carcinoma.

IMbrave050 Update Questions Adjuvant Atezo-Bev in HCC : J Hepatol | May 2026

Introduction Recurrence after curative-intent resection or ablation remains one of the greatest challenges in Hepatocellular Carcinoma management, with early relapse rates remaining high even after apparently successful treatment. Following the landmark IMbrave150 study, the combination of Atezolizumab plus Bevacizumab became standard first-line therapy for unresectable HCC, generating major interest in extending this strategy into the adjuvant setting for high-risk disease. Problem Statement The initial interim analysis of the IMbrave050 trial demonstrated a significant recurrence-free survival benefit with adjuvant atezolizumab plus bevacizumab after curative-intent therapy for high-risk HCC. However, whether this early benefit would remain durable with longer follow-up and ultimately translate into overall survival improvement remained uncertain. Summary IMbrave050 randomized patients with high-risk HCC following curative-intent resection or ablation to receive one year of adjuvant atezolizumab plus bevacizumab or active surveillance. The original interim analysis generated considerable enthusiasm after demonstrating improved recurrence-free survival with combination immunotherapy and antiangiogenic therapy. However, this updated analysis substantially alters interpretation of the study. With longer follow-up, the initially observed recurrence-free survival advantage was no longer sustained. The updated recurrence-free survival hazard ratio moved from the previously significant 0.72 to 0.90, indicating loss of the earlier statistical and clinical benefit signal. Overall survival data also remained immature at the second interim analysis, with no evidence of survival advantage emerging thus far. Importantly, the overall survival hazard ratio numerically favored the surveillance arm, although confidence intervals remained wide and definitive conclusions cannot yet be drawn because of limited event maturity. Despite the disappointing efficacy update, the long-term safety profile remained manageable and consistent with known toxicities of both agents. No unexpected safety concerns emerged with prolonged follow-up, reinforcing the relative tolerability of the regimen in appropriately selected patients with preserved liver function. These findings are highly important because IMbrave050 represented the first positive immunotherapy-based adjuvant trial in HCC at initial reporting and had raised hopes for a paradigm shift in postoperative management. The updated results now emphasize the complexity of interpreting early recurrence-free survival signals in immunotherapy studies and highlight the necessity of mature longitudinal follow-up before widespread adoption of perioperative strategies. Biologically, the findings suggest that residual micrometastatic disease after curative-intent HCC therapy may possess heterogeneous immune sensitivity. It is also possible that recurrence dynamics in HCC are influenced not only by metastatic relapse but also by de novo carcinogenesis within chronically diseased cirrhotic liver tissue, potentially limiting the durability of adjuvant immune-based approaches. Importantly, exploratory subgroup analyses suggested that certain patient subsets may still derive benefit, indicating that biomarker-guided perioperative immunotherapy strategies remain an important future research direction. Effective perioperative therapy continues to represent a major unmet need in HCC given persistently high recurrence rates after surgery or ablation. Overall, the updated IMbrave050 analysis does not support routine use of adjuvant atezolizumab plus bevacizumab for all patients with high-risk HCC following curative-intent treatment. The study nevertheless provides critical lessons for future perioperative immunotherapy trial design and reinforces the importance of refined patient selection strategies in early-stage hepatocellular carcinoma.

EBRT Achieves Competitive Survival in Early HCC : J Clin Oncol | May 2026

Introduction External Beam Radiation Therapy has historically played a limited role in the management of Hepatocellular Carcinoma because of concerns regarding radiation-induced liver injury and limited survival data. However, advances in image guidance, stereotactic body radiotherapy and conformal radiation delivery have substantially improved precision and safety. Despite increasing integration into treatment algorithms, robust multinational survival data supporting EBRT as a first-line curative-intent modality have remained limited. Problem Statement Although modern EBRT demonstrates excellent local tumor control in HCC, uncertainty persists regarding long-term survival outcomes compared with established curative therapies such as resection and thermal ablation. The absence of large individual patient-level datasets has limited broader incorporation of EBRT into global HCC treatment algorithms. Summary This multinational collaborative analysis evaluated individual patient data from 4,913 patients with HCC treated using technically validated EBRT protocols, representing the largest international EBRT cohort reported to date. Patients were stratified according to Barcelona Clinic Liver Cancer (BCLC) stage and prior treatment exposure to assess long-term overall survival outcomes. Survival outcomes for very early- and early-stage HCC were particularly notable. Median overall survival reached 6.8 years for BCLC-0 disease and 4.6 years for BCLC-A disease. Among treatment-naïve patients, outcomes were even more impressive, with median survival not reached in BCLC-0 patients and exceeding five years in BCLC-A disease. These results compare favorably with many contemporary surgical and ablative series and strongly support EBRT as a potentially curative locoregional strategy in selected patients. Multivariable analyses identified several prognostic determinants consistent with established HCC biology. Advanced BCLC stage, higher tumor burden, impaired performance status and Child-Pugh B/C cirrhosis independently predicted worse survival outcomes. Conversely, delivery of ablative radiation doses and treatment in more recent eras were associated with improved survival, likely reflecting ongoing technological advancements in radiation planning and patient selection. Importantly, the study reinforces the evolving role of EBRT within multidisciplinary HCC management. Modern radiation therapy offers several advantages in patients unsuitable for surgery or thermal ablation, including treatment of lesions adjacent to vascular structures, biliary anatomy or subdiaphragmatic regions where ablative approaches may be technically difficult or high risk. The findings further challenge historical perceptions that radiation therapy should remain only a salvage or palliative modality in HCC. The study additionally highlights the growing convergence between radiation oncology and hepatology within contemporary liver cancer care. Improved survival associated with ablative dosing strategies suggests that biologically effective dose escalation and stereotactic techniques may further optimize outcomes in early-stage disease. Overall, this landmark multinational individual patient-level analysis provides strong evidence that modern EBRT achieves survival outcomes comparable to other curative locoregional therapies for selected early-stage HCC patients. The findings strongly support broader incorporation of EBRT into BCLC clinical decision-making pathways and reinforce its emerging role as a first-line treatment option within multidisciplinary hepatocellular carcinoma management.

Precision Genomics in Refractory PLC : J Hepatol | May 2026

Introduction Advanced Hepatocellular Carcinoma, Cholangiocarcinoma and rare primary liver cancers remain therapeutically challenging after progression on standard systemic therapy. Conventional targeted next-generation sequencing panels identify actionable alterations in only a minority of patients, particularly outside biliary tract cancers. This multicenter French Genomic Medicine 2025 (FMG2025) initiative evaluated whether comprehensive molecular profiling using whole-genome sequencing (WGS), whole-exome sequencing (WES) and RNA sequencing could expand precision oncology opportunities in advanced primary liver cancers. Problem Statement Precision medicine approaches in primary liver cancers are limited by inadequate genomic characterization, delayed profiling and restricted access to actionable biomarkers beyond standard panels. The clinical utility of broad genomic sequencing in refractory liver cancers, especially HCC and rare histologies, remains insufficiently defined. Summary This nationwide French initiative enrolled 120 patients with advanced or refractory primary liver cancers across eight tertiary centers. The cohort included HCC, cholangiocarcinoma, combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and rare tumors such as fibrolamellar carcinoma and hepatic epithelioid hemangioendothelioma. Comprehensive genomic profiling was successfully completed in 86% of tumors using integrated WGS, WES and RNA sequencing. Actionable molecular alterations were identified in 65% of patients, substantially exceeding the yield achievable with standard targeted sequencing panels. Common alterations included TP53, TERT and CTNNB1 in HCC, while cholangiocarcinoma demonstrated frequent TP53, ARID1A, BAP1 and FGFR2 alterations. cHCC-CCA displayed hybrid genomic signatures involving TP53 and PI3K pathway abnormalities. RNA sequencing added clinically meaningful information through identification of oncogenic pathway activation, immune-related transcriptomic signatures and fusion transcripts. Among 67 patients with actionable alterations, 31 ultimately received genomically matched therapies, predominantly directed against ESCAT II–III targets involving FGFR, MET, ERBB2, PI3K–AKT–mTOR, homologous recombination deficiency and cell-cycle pathways. Disease control was achieved in 32.3% overall and exclusively occurred in patients treated for ESCAT I–III alterations, while ESCAT IV-directed therapies failed to demonstrate clinical benefit. Disease control rates were particularly notable in cholangiocarcinoma and cHCC-CCA. Median progression-free survival was significantly longer in responders compared with non-responders (11.8 vs 2.4 months). The study also highlighted important translational insights. Whole-genome analysis identified mutational signatures linked to aflatoxin exposure and aristolochic acid carcinogenesis, while germline cancer-predisposition variants were detected in 5% of patients. Importantly, many patients could not receive matched therapies because of progressive liver failure or clinical deterioration before genomic results became available, emphasizing the need for earlier molecular profiling in liver cancers. Overall, this landmark real-world study demonstrates that broad genomic profiling in advanced primary liver cancers is feasible and clinically relevant, particularly for identifying therapeutically actionable ESCAT II–III alterations beyond standard sequencing panels. The findings support earlier integration of comprehensive molecular profiling into hepatobiliary oncology workflows and reinforce the emerging role of precision oncology in advanced liver cancers.

Liver Function Dominates Risk Prediction After HCC Locoregional Therapy : Liver Transpl | May 2026

Introduction Locoregional therapy (LRT) remains a cornerstone treatment strategy for patients with early- and intermediate-stage Hepatocellular Carcinoma. Although procedures such as transarterial chemoembolization and ablative therapies are routinely performed, post-procedural hepatic decompensation remains a major determinant of morbidity, treatment interruption and mortality. Identifying patients at highest risk for short-term liver dysfunction is therefore essential for treatment selection and peri-procedural planning. Problem Statement Current risk assessment for LRT often incorporates tumor burden, demographic variables and clinician judgment, but the relative contribution of hepatic reserve versus tumor-related factors in predicting post-LRT liver failure remains uncertain. Reliable prediction models for short-term hepatic dysfunction following LRT are still lacking in routine clinical practice. Summary This retrospective Veterans Health Administration cohort study evaluated 1,183 patients with early- to intermediate-stage HCC undergoing locoregional therapy to determine predictors of severe liver dysfunction within 30 and 90 days after treatment. Multiple clinical, laboratory and tumor-related variables were assessed for prognostic performance using discrimination and calibration analyses. Measures of baseline hepatic reserve consistently outperformed tumor-related and demographic factors in predicting post-LRT liver dysfunction. Among all evaluated metrics, the MELD=3.78ln(bilirubin)+11.2ln(INR)+9.57ln(creatinine)+6.43 score demonstrated the strongest predictive discrimination for both 30-day and 90-day outcomes, followed closely by MELD-Na and serum bilirubin levels. In contrast, total tumor diameter and demographic characteristics provided limited prognostic value. Model calibration remained acceptable across multiple risk strata, supporting the robustness of liver function–based prediction approaches. The findings reinforce the concept that hepatic reserve, rather than tumor burden alone, is the principal determinant of peri-procedural vulnerability following LRT. Even among patients with relatively early-stage HCC, impaired baseline liver function substantially increased the likelihood of post-treatment decompensation. These data support prioritization of liver severity metrics when selecting candidates for locoregional therapies and may help refine multidisciplinary decision-making regarding treatment intensity, monitoring and transplant referral timing. Overall, this study provides important real-world evidence that objective liver function assessment should remain central to procedural risk stratification in HCC and highlights the need for future prospective models integrating dynamic hepatic reserve measurements into LRT treatment algorithms.

Multinational EBRT Data Support Curative-Intent Role in Early HCC : J Clin Oncol | May 2026

Introduction External Beam Radiation Therapy has historically played a limited role in the management of Hepatocellular Carcinoma because of concerns regarding hepatic toxicity and limited survival data. However, advances in stereotactic body radiation therapy, image guidance and conformal radiation planning have substantially improved the safety and precision of liver-directed radiotherapy. Despite growing incorporation of EBRT into international guidelines, robust multinational survival data comparable to surgery or ablation have remained limited. Problem Statement The absence of large individual patient-level datasets has hindered accurate assessment of long-term survival outcomes following EBRT in HCC. Whether EBRT can provide outcomes comparable to established curative-intent therapies such as resection or thermal ablation—particularly in early-stage disease—has remained controversial. Summary This multinational individual patient data analysis evaluated outcomes in nearly 5,000 patients with HCC treated using EBRT across multiple international centers, representing the largest collaborative dataset reported to date. Survival outcomes were stratified according to Barcelona Clinic Liver Cancer (BCLC) stage and prior treatment status. Patients with very early-stage and early-stage disease demonstrated particularly favorable outcomes. Median overall survival reached 6.8 years in BCLC-0 disease and 4.6 years in BCLC-A disease. Among treatment-naïve patients, survival outcomes were even more impressive, with median overall survival not reached in BCLC-0 patients and exceeding five years in BCLC-A disease. Multivariable analysis identified established prognostic factors associated with mortality, including advanced BCLC stage, greater tumor burden, impaired performance status and poorer liver function. Importantly, delivery of ablative radiation doses and more contemporary treatment eras were independently associated with improved survival, highlighting the impact of modern radiation techniques and evolving patient selection strategies. The study provides compelling evidence that modern EBRT can achieve long-term survival outcomes in very early and early-stage HCC that appear comparable to established curative locoregional therapies including resection and thermal ablation. These findings are particularly relevant for patients unsuitable for surgery or ablation because of tumor location, vascular proximity, comorbidity or impaired hepatic reserve. Overall, this landmark multinational analysis strengthens the evidence base supporting EBRT as a legitimate curative-intent treatment modality in selected patients with early-stage HCC. The findings further reinforce the integration of EBRT into contemporary BCLC treatment algorithms and multidisciplinary HCC decision-making pathways.

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.

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.

Neoadjuvant Nivolumab–Ipilimumab in Resectable HCC- J Hepatol Feb.26

Immune checkpoint inhibitors have transformed the treatment of advanced hepatocellular carcinoma (HCC), but their role in potentially resectable disease remains under active investigation. This single-arm study evaluated nivolumab plus ipilimumab as neoadjuvant therapy, followed by surgery when feasible, and explored biological markers associated with treatment response. Patients with potentially resectable HCC received combination immunotherapy before reassessment for curative surgery. Nearly half of the treated patients ultimately underwent resection, demonstrating the feasibility of integrating dual immune checkpoint blockade into a perioperative strategy. Importantly, a meaningful proportion of resected tumours showed major pathological response, indicating deep antitumor activity prior to surgery. Long-term follow-up revealed encouraging progression-free and overall survival, suggesting that this approach may translate into durable clinical benefit. Beyond clinical outcomes, the study provides important mechanistic insights. Tumours responding to immunotherapy showed increased interferon-γ signalling and formation of tertiary lymphoid structures (TLS), specialised immune aggregates that support sustained antitumor immunity. Preclinical experiments confirmed that B cells are critical for the efficacy of combined PD-1 and CTLA-4 blockade, reinforcing the functional relevance of TLS. Additionally, profiling of peripheral blood demonstrated that patterns of T-cell activation and exhaustion, assessed with advanced flow cytometry and computational analysis, correlated with response and survival. In summary, neoadjuvant nivolumab plus ipilimumab followed by surgery is feasible and may offer long-term benefit in selected patients with resectable HCC. The identification of TLS and peripheral immune signatures highlights promising biomarkers to guide patient selection and future perioperative immunotherapy strategies.

Lenvatinib After Atezolizumab–Bevacizumab Failure in Advanced HCC- J Hepatol Feb.26

Atezolizumab plus bevacizumab is the established first-line treatment for unresectable hepatocellular carcinoma (HCC). However, most patients eventually progress, and the optimal second-line therapy after atezo-bev failure remains uncertain, with limited prospective data to guide clinical decisions. This multicenter, investigator-initiated phase II trial evaluated lenvatinib as a second-line treatment in patients with unresectable HCC who had progressed on first-line atezo-bev. Patients received weight-based oral lenvatinib until disease progression or unacceptable toxicity. The study focused on progression-free survival as the primary endpoint, with overall survival, tumor response, and safety as secondary outcomes. The study demonstrated that lenvatinib provides meaningful disease control in the post–atezo-bev setting. Progression-free survival exceeded the predefined efficacy threshold, and overall survival outcomes were clinically relevant in a population with limited therapeutic options. Tumor responses were modest but durable in responders, and disease stabilization was achieved in the majority of patients. Importantly, outcomes were driven by response to lenvatinib itself rather than prior response duration to atezo-bev or underlying disease etiology. The safety profile was consistent with known effects of lenvatinib and was generally manageable with dose modifications and supportive care, despite a substantial rate of higher-grade adverse events. In summary, this study provides the first prospective evidence supporting lenvatinib as a viable second-line option after atezolizumab–bevacizumab failure in advanced HCC, helping to define a treatment pathway in a rapidly evolving therapeutic landscape.

HBV Reactivation Risk With ICIs vs TKIs in Liver Cancer

Hepatitis B virus (HBV) reactivation is a recognized risk during systemic therapy for liver cancer, particularly in high-endemic regions where HBV is a leading cause of hepatocellular carcinoma (HCC). The comparison of HBV reactivation risk between immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) is a critical area of investigation. ### Key Findings on HBV Reactivation Risk: 1. **No Excess Risk With ICIs Compared to TKIs**: - Studies indicate that the use of ICIs does not increase the risk of HBV reactivation compared to TKIs, which are widely used systemic therapies for advanced liver cancer. This suggests that ICIs are as safe as TKIs in terms of HBV reactivation risk when proper prophylactic measures are employed. 2. **Consistency Across ICI Regimens**: - Different types of ICIs, such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapies, show similar profiles regarding HBV reactivation risk. This consistency highlights the general safety of ICIs in HBV-endemic populations under routine antiviral prophylaxis. 3. **Low Overall Reactivation Risk**: - Routine antiviral prophylaxis significantly reduces HBV reactivation risk across both ICIs and TKIs. However, while prophylaxis is protective, it does not completely eliminate the risk, necessitating ongoing surveillance. 4. **Mechanistic Considerations**: - ICIs theoretically raise concerns for HBV reactivation due to their immunological effects, such as enhancing immune responses that could impact latent HBV reservoirs in liver cells. Despite this, real-world evidence does not show an increased reactivation risk compared to TKIs. 5. **Patients With Past HBV Infection**: - Individuals with resolved HBV infection (negative HBV surface antigen but positive HBV core antibody) are more vulnerable to reactivation than those with active infection. This is due to the persistence of latent viral reservoirs in liver cells, which can be triggered under immunotherapy. 6. **Antiviral Prophylaxis**: - Preventive antiviral therapy is essential for reducing HBV reactivation risk in patients receiving systemic therapy for liver cancer. However, antiviral prophylaxis is less consistently prescribed for patients with past HBV infection, leaving them at higher risk. 7. **Role of Surveillance**: - Even with antiviral prophylaxis, ongoing monitoring of HBV DNA and liver function is necessary to detect reactivation early and manage potential complications. 8. **Impact of Prior Liver Procedures**: - Patients who have undergone transarterial chemoembolization (TACE) or other invasive liver procedures may have increased susceptibility to HBV reactivation during systemic therapy, regardless of whether they are on ICIs or TKIs. ### Clinical Implications: - Systematic HBV screening is critical before initiating ICIs or TKIs in patients with liver cancer, particularly in HBV-endemic regions. - Proactive antiviral prophylaxis should be implemented for all patients at risk, including those with resolved HBV infection, to minimize reactivation risk. - Regular surveillance of HBV DNA and liver enzymes is essential for detecting reactivation or immune-related liver toxicity during therapy. ### Conclusion: Under routine antiviral prophylaxis, ICIs do not pose an excess risk of HBV reactivation compared to TKIs for liver cancer treatment. However, patients with past HBV infection and those with a history of liver procedures require heightened vigilance due to their increased susceptibility. Comprehensive screening, prophylaxis, and surveillance are key to safe and effective management of HBV reactivation risk during systemic therapy in HCC.

CARES-009 phase 2/3 trial

The CARES-009 phase 2/3 trial investigated the efficacy of perioperative camrelizumab plus rivoceranib in patients with hepatocellular carcinoma (HCC) at intermediate or high risk of relapse. The trial aimed to determine whether combining immunotherapy and targeted therapy before and after surgery could improve outcomes compared to surgery alone. In the study, 294 patients were randomly assigned to two groups: one receiving perioperative therapy (neoadjuvant and adjuvant camrelizumab plus rivoceranib) and the other undergoing surgery alone. Results showed that patients in the perioperative therapy group had significantly improved event-free survival (EFS) with a median of 42.1 months compared to 19.4 months in the surgery-alone group (HR 0.59, p=0.0040). However, adverse events of grade 3 or higher occurred in 38% of patients receiving perioperative therapy, including two treatment-related deaths during neoadjuvant therapy. This trial highlights the potential benefits of perioperative immunotherapy but underscores the importance of managing associated risks.

Recurrent HCC followingTACE

Recurrent hepatocellular carcinoma (HCC) following transarterial chemoembolisation (TACE) is a significant clinical challenge. TACE is widely used as a treatment modality for HCC, particularly for patients with intermediate-stage disease or as an adjuvant therapy after curative resection to target residual microscopic disease. However, recurrence remains a common issue, and understanding the factors contributing to recurrence, as well as strategies for managing recurrent HCC, is essential for improving patient outcomes. ### Factors Contributing to Recurrence Following TACE: 1. **Tumour Biology**: Aggressive tumour characteristics, such as poor differentiation, vascular invasion, or high alpha-fetoprotein (AFP) levels, are associated with a higher risk of recurrence. 2. **Incomplete Tumour Necrosis**: TACE relies on selective embolisation of tumour-feeding arteries, but incomplete necrosis of the tumour may leave residual viable cancer cells that can proliferate. 3. **Micrometastases**: Occult micrometastases that are not detectable at the time of initial treatment can lead to recurrence. 4. **Liver Function**: Patients with compromised liver function (e.g., cirrhosis) may have a higher risk of recurrence due to reduced ability to tolerate treatment and impaired immune surveillance. 5. **TACE Technique**: Variability in the technical execution of TACE, such as insufficient embolisation or suboptimal drug delivery, can contribute to recurrence. ### Patterns of Recurrence: Recurrent HCC after TACE can manifest as: - **Intrahepatic Recurrence**: New tumour nodules within the liver, either near the original site or in different segments of the liver. - **Extrahepatic Metastasis**: Spread to distant organs, such as lungs, bones, or lymph nodes, which is less common but associated with worse prognosis. ### Management of Recurrent HCC Following TACE: 1. **Repeat TACE**: - Patients with recurrent HCC confined to the liver may benefit from repeat TACE, provided liver function is preserved and the tumour burden remains manageable. - The interval between TACE sessions and the patient's tolerance to treatment should be considered. 2. **Systemic Therapy**: - Targeted therapies such as sorafenib, lenvatinib, or other tyrosine kinase inhibitors (TKIs) may be used for patients with advanced or recurrent HCC. - Immunotherapy with immune checkpoint inhibitors (e.g., atezolizumab plus bevacizumab) has emerged as a promising option for recurrent HCC. 3. **Surgical Resection**: - If the recurrence is localized and the patient is a suitable surgical candidate, re-resection may be considered. - This option is typically reserved for patients with good liver function and limited tumour burden. 4. **Liver Transplantation**: - In cases of recurrent HCC meeting Milan or UCSF criteria, liver transplantation may offer a curative option, particularly for patients with underlying cirrhosis. 5. **Ablative Therapies**: - Techniques such as radiofrequency ablation (RFA) or microwave ablation (MWA) may be used for small, localized recurrent tumours. 6. **Combination Approaches**: - Combining locoregional therapies (e.g., TACE plus RFA) or systemic therapies with TACE may enhance outcomes and reduce recurrence rates. ### Prognostic Tools and Risk Stratification: To guide management decisions, predictive models and tools, such as the online calculator mentioned in the context, can be used to estimate recurrence risk and tailor treatment strategies. These tools integrate tumour-related factors, surgical details, and patient characteristics to provide personalised recommendations. ### Preventive Strategies: 1. **Optimising TACE Protocols**: Ensuring adequate embolisation and drug delivery during the initial TACE procedure can reduce the risk of recurrence. 2. **Adjuvant Therapies**: In high-risk patients, adjuvant therapies such as systemic agents or combination locoregional treatments may be considered to prevent recurrence. 3. **Surveillance**: Regular imaging and AFP monitoring post-TACE are critical for early detection and management of recurrence. ### Conclusion: Recurrent HCC following TACE is a complex issue influenced by tumour biology, treatment efficacy, and patient factors. Management requires a multidisciplinary approach, incorporating locoregional therapies, systemic treatments, and predictive tools to optimise outcomes. Advances in risk stratification and treatment modalities hold promise for reducing recurrence and improving survival in patients with HCC.

Nutrition in Hepatocellular Carcinoma - J of JGH - Jan,26

The topic of nutrition in hepatocellular carcinoma (HCC) is highly relevant and extensively studied due to the profound impact of malnutrition on patient outcomes. While I cannot access specific articles such as "Nutrition in Hepatocellular Carcinoma - J of JGH - Jan, 26," I can provide a detailed overview based on the context and current knowledge related to nutrition in HCC. **Overview of Nutrition in Hepatocellular Carcinoma (HCC):** 1. **Prevalence of Malnutrition**: - Malnutrition is exceedingly common in patients with HCC, significantly contributing to morbidity, mortality, and poor clinical outcomes. - Unlike other cancers, malnutrition in HCC often begins early in the disease course due to the compounding effects of chronic liver disease. 2. **Drivers of Nutritional Decline**: - **Hepatic Dysfunction**: Chronic liver disease and cirrhosis associated with HCC disrupt carbohydrate, protein, and lipid metabolism, leading to a hypercatabolic state. - **Insulin Resistance**: Impaired glycogen storage and early gluconeogenesis result in muscle breakdown and energy imbalance. - **Protein Catabolism**: Negative nitrogen balance and preferential skeletal muscle degradation accelerate sarcopenia. - **Impaired Fat Absorption**: Cholestasis and reduced bile acid synthesis hinder fat absorption, resulting in energy deficits and fat-soluble vitamin deficiencies. - **Micronutrient Deficiencies**: Vitamins A, D, E, K, and trace element deficiencies contribute to complications like coagulopathy, bone disease, and neuromuscular dysfunction. 3. **Key Features of Malnutrition in HCC**: - **Sarcopenia**: Loss of skeletal muscle mass is a hallmark feature in HCC patients and independently predicts poorer survival, higher complication rates, and reduced tolerance to treatments. - **Cachexia**: Chronic systemic inflammation drives anorexia, hypermetabolism, and cancer-related cachexia, further worsening nutritional status. - **High Energy Expenditure**: Many patients with HCC exhibit increased resting energy expenditure, exacerbating the gap between nutritional intake and metabolic demands. 4. **Prognostic Implications**: - Malnutrition and sarcopenia are strongly associated with reduced overall survival, increased recurrence rates, and higher postoperative risks. - Addressing nutritional deficits early and comprehensively can improve clinical outcomes. 5. **Assessment of Nutritional Status**: - **Validated Screening Tools**: Tools such as NRS-2002, MUST, PG-SGA, and GLIM are essential for identifying patients at nutritional risk. - **Muscle Mass Evaluation**: CT imaging at the L3 vertebra is a gold-standard method for assessing skeletal muscle mass. - **Functional Status**: Handgrip strength provides a practical measure of muscle function and complements structural assessments. - **Limitations of Laboratory Markers**: Serum albumin and prealbumin are unreliable indicators due to hepatic dysfunction and systemic inflammation. 6. **Nutritional Management**: - **Individualized Targets**: Energy and protein requirements should be tailored to the disease stage, severity of cirrhosis, and treatment modalities. - **Oral Nutritional Supplements**: Supplements enriched with branched-chain amino acids are beneficial for maintaining protein balance and improving clinical outcomes. - **Enteral Nutrition**: Preferred over parenteral nutrition if gastrointestinal function is preserved. - **Exercise**: Resistance and aerobic exercise programs help mitigate sarcopenia and functional decline when integrated with nutritional support. - **Multidisciplinary Care**: Coordinated care involving hepatologists, oncologists, dietitians, and physiotherapists is essential for optimal management. 7. **Emerging Research and Guidelines**: - The field continues to evolve with ongoing research into the role of specific nutrients, exercise regimens, and novel interventions to address malnutrition and sarcopenia in HCC. - Journals like the "Journal of Gastroenterology and Hepatology" (JGH) often publish cutting-edge studies and guidelines on this topic. If you are looking for specific insights or findings from the January 26 article in JGH, I recommend accessing the journal directly through medical databases such as PubMed, Wiley Online Library, or institutional subscriptions. Let me know if you'd like guidance on how to access such resources!

Engineered T-Cell Therapy and HCC - J of Hepatology. Jan 26

Engineered T-cell therapy is a precision immunotherapy approach designed to treat cancer by modifying a patient's T cells to enhance their ability to target and destroy cancer cells. This therapy involves genetic engineering of T cells to recognize tumor-associated antigens (TAAs) and improve their survival and function in the body. The most successful example of engineered T-cell therapy is chimeric antigen receptor-T cell (CAR-T) therapy, which has shown remarkable efficacy in treating hematological malignancies like refractory B-cell lymphoma/leukemia and multiple myeloma. ### Basis of Engineered T-cell Therapy in Hepatocellular Carcinoma (HCC) Hepatocellular carcinoma (HCC) is a challenging cancer to treat using engineered T-cell therapy due to the complexities of solid tumors. These challenges include: 1. **Lack of Suitable Tumor-Associated Antigens:** Unlike hematological malignancies, HCC lacks well-defined and universally expressed TAAs that can be targeted effectively. 2. **Tumor Microenvironment:** HCC tumors create an immunosuppressive microenvironment characterized by hypoxia, immunosuppressive cells, and cytokines, which hinder T-cell activity. 3. **Tumor Stroma:** The dense stroma within solid tumors obstructs effective trafficking of T cells to the tumor site. ### Alpha-Fetoprotein (AFP) Targeting TCR-T Therapy in HCC In a clinical trial reported by Meyer et al., researchers explored T-cell receptor (TCR)-T therapy targeting alpha-fetoprotein (AFP), a protein expressed in some HCC tumors. This therapy used ADP-A2AFP cells, which are engineered T cells designed to recognize AFP complexed with HLA-A*02:01. The trial enrolled 21 patients with AFP-expressing advanced solid tumors (20 with advanced HCC and 1 with gastric hepatoid carcinoma). The treatment involved lymphodepleting chemotherapy followed by infusion of the engineered T cells. ### Key Findings from the Trial: 1. **Safety and Adverse Events:** - Dose-limiting toxicity was observed in one patient (grade 4 atrial fibrillation), who later died due to cholangitis unrelated to the therapy. - Cytokine release syndrome (CRS) occurred in six patients, with one experiencing severe grade 4 CRS. - Grade 3-4 leukopenia was observed in 10 patients, likely due to the lymphodepleting chemotherapy. 2. **Efficacy:** - The overall response rate was 9.5%, with one complete responder and one partial responder. - The trial highlighted difficulties in achieving satisfactory efficacy, partly due to variability in AFP expression among tumors and challenges in patient enrollment. 3. **Challenges:** - Enrollment was limited due to the specific HLA haplotype required for the therapy and safety concerns associated with lymphodepleting chemotherapy in patients with cirrhosis. - The prolonged time required for screening and cell preparation meant that only patients with slower tumor progression could participate. ### Lessons Learned and Future Directions: 1. **Tumor-Associated Antigen Variability:** The variability of AFP expression in tumors complicates the correlation between antigen expression and treatment efficacy. More precise diagnostic tools are needed to select patients who are likely to benefit from therapy. 2. **Improving T-cell Design:** Novel T-cell constructs or higher cell doses may enhance efficacy while maintaining safety. 3. **Targeting Multiple Antigens:** Engineering T cells to target multiple TAAs could improve specificity and reduce resistance due to antigen escape. 4. **Overcoming Tumor Microenvironment:** Strategies like incorporating interleukin-15 constructs or dominant-negative transforming growth factor-β receptors into CAR-T cells have shown promise in overcoming the immunosuppressive tumor microenvironment of HCC. 5. **Patient Selection:** T cells from less heavily pretreated patients may exhibit higher antitumor activity, and the phenotypes of engineered T cells should be optimized for trafficking and cytotoxicity. ### Advances in Engineered T-cell Therapy for Solid Tumors: While engineered T-cell therapy for hematological malignancies has been highly successful, progress in treating solid tumors like HCC has been slower. Recent trials targeting glypican 3 (a membranous glycoprotein expressed in HCC) using CAR-T therapy have demonstrated promising antitumor activity and acceptable safety profiles. For example: - CAR-T cells engineered with interleukin-15 constructs improved T-cell survival and function. - CAR-T cells with dominant-negative transforming growth factor-β receptors helped overcome the immunosuppressive tumor microenvironment. ### Conclusion: The clinical trial by Meyer et al. represents an important effort to develop precision immunotherapy for HCC. Although the efficacy of ADP-A2AFP therapy was limited, the study provides valuable insights into the challenges and opportunities in engineered T-cell therapy for HCC. Advances in cell engineering technologies and a better understanding of the interactions between engineered T cells, cancer cells, and the tumor microenvironment will be critical to driving progress in this field.

Serum N-Glycomics analysis and HBV - Hepatology Jan.2026

Serum N-glycomics analysis refers to the study of N-linked glycans (complex sugar molecules attached to proteins) present in serum. This analytical approach focuses on profiling and identifying specific glycan structures that may be associated with various diseases, including hepatocellular carcinoma (HCC) linked to chronic hepatitis B virus (HBV) infection. N-glycomics analysis uses advanced techniques such as mass spectrometry and machine learning to quantify and characterize glycan patterns in biological samples. ### How N-glycomics Analysis Helps in HCC Diagnosis in HBV Infection: 1. **Enhanced Sensitivity and Specificity**: - Traditional diagnostic markers for HCC, such as alpha-fetoprotein (AFP) and Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II), often lack sufficient sensitivity and specificity, particularly in early-stage HCC detection. - N-glycomics analysis identifies unique glycan profiles associated with HCC, providing more accurate diagnostic models. In the study, machine learning-based models (Random Forest and Support Vector Machine) demonstrated significantly higher diagnostic accuracy with AUC values of 0.967 and 0.908, compared to AFP (0.687) and PIVKA-II (0.665). 2. **Early Detection of HCC**: - N-glycomics models can detect HCC earlier than imaging techniques, which is crucial for timely intervention and improving patient outcomes. - The study showed that the N-glycomics-based diagnostic models outperformed conventional markers in subgroup analyses and external validation, making them highly reliable for early screening. 3. **Prognostic Value**: - Beyond diagnosis, N-glycomics analysis aids in monitoring disease progression and recurrence. The prognostic model (prog-G) developed in the study was able to predict recurrence in patients with HCC after curative treatment. - During follow-up, the prog-G model identified all recurrent HCC cases before imaging findings, outperforming AFP and PIVKA-II. This capability allows for earlier therapeutic intervention to manage recurrence. 4. **Precision Medicine**: - By leveraging N-glycomics profiling, clinicians can make more informed decisions tailored to individual patients. This promotes precision treatment strategies for HCC in HBV-infected individuals, improving overall clinical outcomes. 5. **Non-Invasive and Scalable**: - Serum N-glycomics analysis is a non-invasive diagnostic method, making it suitable for routine clinical use and large-scale screening of at-risk populations, including those with chronic HBV-related cirrhosis. ### Conclusion: Serum N-glycomics analysis represents a promising advancement in the diagnosis and management of HCC in patients with HBV infection. By providing highly sensitive and specific models for early detection and recurrence monitoring, it addresses the limitations of conventional markers like AFP and PIVKA-II. The integration of N-glycomics into clinical practice has the potential to improve decision-making, enhance precision treatment, and ultimately reduce the global health burden of HBV-related HCC.

HCC risk in PSC (Hepatology Jan. 26)

Introduction: Primary sclerosing cholangitis (PSC) is a chronic liver disease that can lead to complications, including hepatocellular carcinoma (HCC). However, the actual risk of developing HCC in PSC patients has been unclear, leading to questions about the necessity of current HCC surveillance guidelines. Problem Statement: A study involving 3071 PSC patients across 12 university hospitals was conducted to better understand the risk of HCC. Patients were followed for an average total of 38,387 person-years, from PSC diagnosis until death, liver transplantation, or other significant events. The study aimed to identify factors associated with HCC development, such as age and cirrhosis status, to refine surveillance strategies. Conclusion: The study found that HCC is relatively rare in PSC patients, especially in those without cirrhosis and under the age of 50. Cirrhosis was a significant risk factor for HCC, with most cases occurring in cirrhotic patients. Age also increased the risk, but for non-cirrhotic patients, the risk remained low across all age groups. These findings suggest that HCC surveillance in PSC patients can be tailored based on individual risk factors like age and cirrhosis status, potentially reducing unnecessary monitoring in low-risk groups.

MASLD and HCC

Metabolic dysfunction–associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC) are closely interconnected, with MASLD emerging as a significant risk factor and contributor to the development of HCC. Below is a detailed explanation of MASLD and its relationship with HCC: ### **Understanding MASLD** MASLD is the most common chronic liver disease globally, affecting over a billion people. It was previously referred to as non-alcoholic fatty liver disease (NAFLD), but the terminology has been updated to better reflect the metabolic dysfunctions associated with the condition. MASLD is characterized by the accumulation of fat in liver cells (steatosis) in individuals who do not consume excessive alcohol and who have at least one of five cardiometabolic risk factors, such as: - Obesity - Type 2 diabetes mellitus (T2DM) - Hypertension - Dyslipidemia - Insulin resistance MASLD progresses through several stages: 1. **Simple steatosis**: Fat accumulation in the liver without significant inflammation or damage. 2. **Metabolic dysfunction–associated steatohepatitis (MASH)**: A more severe form of MASLD marked by inflammation, liver cell injury (ballooning), and fibrosis. MASH can lead to cirrhosis. 3. **Cirrhosis**: Advanced scarring of the liver, which impairs liver function and increases the risk of complications. 4. **Hepatocellular carcinoma (HCC)**: The most serious complication, MASLD-related liver cancer, which can occur with or without cirrhosis. ### **HCC Overview** HCC is the most common type of primary liver cancer and represents the fifth most common cancer globally. It is also the second leading cause of cancer-related deaths worldwide. HCC can develop due to chronic liver diseases such as MASLD, viral hepatitis (HBV, HCV), alcoholic liver disease, and autoimmune liver conditions. ### **MASLD as a Driver of HCC** MASLD is increasingly recognized as a major contributor to HCC due to the global rise in metabolic disorders such as obesity and T2DM. Key aspects include: 1. **Epidemiology**: - MASLD is rapidly becoming the leading indication for liver transplantation among patients listed for HCC. - Studies from the USA, Europe, South Korea, and Southeast Asia show that MASLD is the fastest-growing cause of HCC. 2. **Risk Factors**: - Obesity and T2DM are significant drivers of MASLD progression to HCC. - Advanced age, male sex, and Latino/Latina ethnicity are associated with higher risks of MASLD progression and HCC development. 3. **Pathogenesis**: - Chronic inflammation, oxidative stress, and metabolic dysfunction in MASLD contribute to DNA damage, genetic mutations, and liver cell proliferation, which can ultimately lead to HCC. - Unlike other causes of HCC, MASLD-HCC can develop without cirrhosis in 36.6%–54.0% of cases, complicating early detection and treatment. ### **Challenges in Diagnosis and Management** 1. **Early Detection**: - Diagnosing MASLD and MASLD-related HCC (MASLD-HCC) in the early stages is challenging, particularly in patients without cirrhosis. - Current screening strategies for MASLD patients at risk of HCC are still under debate, and there is no universal consensus on optimal approaches. 2. **Risk Evaluation**: - Assessing the risk of MASLD progression to HCC requires identifying high-risk patients based on metabolic factors, liver fibrosis, and genetic predispositions. - Advanced imaging techniques and biomarkers are being explored for early detection, but their implementation in clinical practice remains limited. 3. **Therapeutic Challenges**: - MASLD-HCC treatment is highly complex due to the multifactorial nature of the disease and its pathogenesis. - While therapies such as liver transplantation, surgical resection, and systemic treatments (e.g., immunotherapy, targeted therapy) are available, their effectiveness can vary depending on the stage of HCC and the presence of underlying metabolic dysfunctions. - Preventive strategies, including lifestyle modifications (e.g., weight loss, exercise, and dietary changes), are crucial in managing MASLD and reducing the risk of HCC. ### **Current Advancements** Recent research focuses on improving early detection and risk stratification for MASLD and MASLD-HCC patients. Key advancements include: - **Biomarkers**: Identifying molecular and genetic markers to predict MASLD progression and HCC risk. - **Imaging**: Enhanced imaging techniques such as MRI elastography and contrast-enhanced ultrasound for non-invasive liver fibrosis assessment. - **Therapeutics**: Development of novel drugs targeting metabolic pathways, inflammation, and fibrosis in MASLD, which may help prevent progression to HCC. ### **Conclusion** MASLD is a rapidly emerging cause of HCC due to the global increase in metabolic disorders such as obesity and T2DM. Early detection, risk evaluation, and effective management of MASLD are critical to preventing progression to HCC and improving patient outcomes. However, challenges remain in diagnosing MASLD-HCC, particularly in patients without cirrhosis, and in developing optimal therapeutic strategies. Continued research and advancements in screening, biomarkers, and targeted therapies are essential to address the growing burden of MASLD-related HCC.

AHCTF1 Promotes Tumor Progression in Hepatocellular Carcinoma

Yes, AHCTF1 plays a significant role in promoting tumor progression in hepatocellular carcinoma (HCC). Below is a detailed explanation of how AHCTF1 contributes to HCC progression based on the provided context: ### 1. **Upregulation of AHCTF1 in HCC** - AHCTF1 expression is significantly higher in HCC tissues compared to normal liver tissues. - This upregulation is associated with poor clinical outcomes, as patients with elevated AHCTF1 levels exhibit reduced overall survival. - AHCTF1 expression increases progressively from early to advanced clinical stages of HCC, indicating its involvement in tumor progression. ### 2. **Clinical Relevance Validated by TCGA** - Bioinformatics analyses using The Cancer Genome Atlas (TCGA) datasets confirmed the clinical significance of AHCTF1 in HCC. - Genes associated with AHCTF1 were enriched in cancer-related signaling pathways, further emphasizing its role in tumor biology. ### 3. **Proliferation, Migration, and Invasion** - Overexpression of AHCTF1 significantly enhances HCC cell proliferation, migration, and invasion in vitro. - This indicates that AHCTF1 contributes to the aggressive behavior of HCC cells. ### 4. **Promotion of Tumorigenic Potential** - AHCTF1 overexpression increases colony formation in HCC cells, highlighting its role in enhancing tumorigenic potential. ### 5. **Epithelial–Mesenchymal Transition (EMT) Activation** - AHCTF1 promotes EMT, a critical process in cancer metastasis. This is evidenced by: - Downregulation of E-cadherin (an epithelial marker). - Upregulation of N-cadherin and vimentin (mesenchymal markers). - EMT activation by AHCTF1 facilitates tumor cell invasion and dissemination. ### 6. **In Vivo Tumor Growth and Metastasis** - In xenograft mouse models, AHCTF1 overexpression significantly increases tumor volume and weight. - AHCTF1 also enhances lung metastasis in vivo, confirming its role in promoting HCC dissemination. ### 7. **Key Signaling Pathways Involved** - **PI3K–Akt Signaling Pathway**: AHCTF1-associated genes are enriched in this pathway, which is known to regulate cell growth, survival, and proliferation in cancer. - **Hedgehog Signaling Pathway**: AHCTF1-associated genes are also enriched in this pathway, which is linked to tumor progression and stemness. - **Glycolysis Pathway**: AHCTF1-related gene signatures are enriched in glycolysis pathways, suggesting that AHCTF1 supports metabolic reprogramming in HCC cells to sustain rapid tumor growth. - **Cell Adhesion Processes**: Bioinformatics analysis showed that AHCTF1 regulates genes involved in cell adhesion, which is crucial for metastasis. ### 8. **Knockdown of AHCTF1 Suppresses Tumor Progression** - Silencing AHCTF1 in HCC cells inhibits proliferation, migration, invasion, and EMT-related changes. - This demonstrates that AHCTF1 is essential for maintaining the aggressive phenotype of HCC cells. ### 9. **Therapeutic Potential** - Given its significant role in promoting HCC progression and metastasis, AHCTF1 represents a promising prognostic biomarker. - Targeting AHCTF1 could provide a novel therapeutic strategy for HCC treatment, potentially improving patient outcomes. ### Conclusion: AHCTF1 is a key driver of tumor progression in hepatocellular carcinoma through its ability to enhance proliferation, migration, invasion, EMT, and metabolic reprogramming. Its involvement in critical signaling pathways like PI3K–Akt and Hedgehog further underscores its importance in HCC biology. These findings highlight AHCTF1 as a potential therapeutic target and prognostic biomarker for managing HCC.

Liver Decompensation With Atezolizumab–Bevacizumab in Hepatocellular Carcinoma

The study on atezolizumab–bevacizumab treatment for advanced or unresectable hepatocellular carcinoma (HCC) provides valuable insights into liver decompensation as a key clinical consideration. Below is a detailed analysis of liver decompensation in this context: ### **Incidence of Liver Decompensation** - Approximately **one-quarter of patients** developed liver decompensation during treatment with atezolizumab–bevacizumab. - Decompensation events were more frequent in patients with **Child Pugh B** liver function compared to those with **Child Pugh A**. ### **Common Manifestations of Liver Decompensation** The most frequent clinical presentations of liver decompensation observed during therapy included: 1. **Ascites** (fluid accumulation in the abdominal cavity), 2. **Jaundice** (yellowing of the skin and eyes due to elevated bilirubin), 3. **Hepatic encephalopathy** (brain dysfunction caused by liver failure). ### **Risk Factors for Liver Decompensation** - **Baseline liver function** is a critical determinant. Patients with worse liver function (e.g., Child Pugh B or ALBI grade 3) were at higher risk of decompensation. - **Portal hypertension**, identified at baseline, was an independent risk factor for liver decompensation during therapy. ### **Time to Decompensation** - The study introduced **time to decompensation** as a novel and clinically relevant safety endpoint. This metric is important for assessing the timing and progression of liver-related complications during treatment. ### **Impact of Liver Decompensation on Treatment and Survival** 1. **Resumption of Therapy:** - Despite liver decompensation, over **40% of patients** were able to resume atezolizumab–bevacizumab therapy. - Patients who restarted treatment after decompensation demonstrated overall survival outcomes comparable to those who never experienced decompensation. 2. **Discontinuation of Therapy:** - Permanent discontinuation of treatment after liver decompensation was associated with **markedly worse survival outcomes**. 3. **Reversibility of Liver Function:** - Some patients with Child Pugh B liver function experienced an **improvement in liver function**, reverting to Child Pugh A during treatment. - This suggests that liver decompensation does not always signify irreversible liver failure or treatment failure. ### **Clinical Implications** - **Liver decompensation should not automatically be considered treatment failure or disease progression.** Instead, it requires careful evaluation and management. - Multidisciplinary hepato-oncologic care is essential for the safe continuation or resumption of therapy in patients experiencing liver decompensation. - Patients with **mild-to-moderate liver dysfunction** (e.g., Child Pugh B) should not be excluded from atezolizumab–bevacizumab treatment, as meaningful outcomes can still be achieved. ### **Prognostic Stratification** - The **albumin–bilirubin (ALBI) score** was found to be a stronger tool for prognostic stratification than the Child Pugh class. - Patients with **ALBI grade 3** had significantly poorer survival and a higher risk of liver decompensation compared to those with better ALBI grades. ### **Conclusion** Liver decompensation is a notable complication during atezolizumab–bevacizumab therapy for HCC, particularly in patients with impaired baseline liver function. However, it should not preclude treatment continuation or resumption, as many patients achieve meaningful survival outcomes. Multidisciplinary care and individualized management strategies are crucial for optimizing outcomes in these patients.

Perioperative nursing coordination and complication management in Yttrium-90 radioactive microsphere therapy for hepatocellular carcinoma

Perioperative nursing coordination and complication management in Yttrium-90 (Y-90) radioactive microsphere therapy for hepatocellular carcinoma (HCC) is a highly structured and multidisciplinary process aimed at ensuring patient safety, optimizing treatment outcomes, and minimizing complications. Y-90 therapy, a form of internal radiation therapy delivered via interventional radiology, requires precise nursing care, radiation safety measures, and seamless collaboration among healthcare professionals. Below is a detailed breakdown of the perioperative nursing coordination and complication management framework as described in the study: ### **1. Preoperative Phase** The preoperative phase is critical for preparing the patient, the medical team, and the environment for Y-90 therapy. Key nursing responsibilities during this phase include: - **Multidisciplinary Evaluation:** Nurses participate in the evaluation of the patient's suitability for Y-90 therapy. This includes collaborating with oncologists, interventional radiologists, and other specialists to assess the patient's condition. - **Patient Education and Psychological Support:** Nurses educate patients about the procedure, potential risks, and expected outcomes. Psychological support is provided to alleviate anxiety and improve compliance. - **Nutritional Risk Assessment:** Nurses assess the patient's nutritional status to optimize their physical condition before the therapy. - **Vascular Anatomy Verification:** Nurses assist in verifying the patient’s vascular anatomy to ensure accurate delivery of the radioactive microspheres to the tumor site. - **Radiation Dosimetry Preparation:** Nurses support the preparation of radiation dosimetry, which calculates the appropriate dose of Y-90 to be administered. - **Patient Counseling and Rehearsal:** Nurses conduct counseling sessions and procedural rehearsals with the medical team to enhance patient understanding and readiness. - **Radiation Safety and Emergency Planning:** Strict preparation of radiation-protective equipment and emergency response plans ensures a safe environment for both patients and staff. ### **2. Intraoperative Phase** During the intraoperative phase, nursing care focuses on coordination, monitoring, and maintaining safety. Responsibilities include: - **Patient Positioning and Vascular Access Assistance:** Nurses ensure proper patient positioning and assist with vascular access for the delivery of Y-90 microspheres. - **Real-Time Vital Sign Monitoring:** Continuous monitoring of the patient's vital signs is essential to detect and address any immediate complications. - **Radiation Protection Measures:** Nurses implement rigorous radiation safety protocols to minimize exposure to both the patient and healthcare staff. This includes contamination control, handling of radioactive materials, and proper disposal of radioactive waste. - **Contamination Control:** Nurses take precautions to prevent contamination during the procedure, ensuring that all radioactive materials are managed safely. ### **3. Postoperative Phase** Postoperative care focuses on managing radiation safety, preventing complications, and supporting recovery. Key nursing interventions include: - **Radiation Safety Management:** Nurses ensure that radiation safety protocols are followed, including monitoring for residual radiation exposure and providing guidance on safe interactions with others. - **Symptom Prevention and Liver Protection:** Nurses monitor and manage symptoms such as pain, nausea, and fatigue. They also focus on protecting liver function, as the liver may be affected by both the therapy and the underlying disease. - **Hydration Support:** Adequate hydration is maintained to support overall recovery and mitigate potential side effects. - **Dynamic Monitoring with Early-Warning Systems:** Nurses use early-warning systems to detect and address complications promptly. This includes monitoring for signs of radiation-induced liver disease, vascular injury, or other adverse effects. - **Tiered Complication Management:** Complications are managed using a tiered approach based on standardized grading. This allows for early detection and timely intervention, reducing the risk of severe outcomes. ### **4. Follow-Up Care** Long-term follow-up care is essential for monitoring the patient’s recovery and addressing any delayed complications. Nursing responsibilities include: - **Rehabilitation Guidance:** Nurses provide guidance on physical rehabilitation to help patients regain strength and function. - **Nutritional Management:** Nutritional support is continued to promote healing and maintain overall health. - **Psychological Support:** Ongoing psychological support is offered to help patients cope with the emotional and mental challenges of cancer treatment. - **Long-Term Monitoring:** Nurses play a key role in coordinating follow-up appointments, imaging studies, and laboratory tests to monitor the patient’s response to therapy and detect any recurrence or complications. ### **Key Outcomes** The structured perioperative nursing coordination model and complication management framework described in the study are designed to: - Improve the safety and standardization of Y-90 therapy. - Enhance patient compliance and procedural readiness. - Minimize radiation exposure and occupational hazards. - Enable early detection and management of complications. - Optimize clinical outcomes and quality of life for patients with hepatocellular carcinoma. ### **Conclusion** Perioperative nursing coordination and structured complication management are essential for the successful implementation of Y-90 radioactive microsphere therapy in hepatocellular carcinoma. By adhering to a standardized protocol and leveraging multidisciplinary collaboration, nursing teams can ensure the safety, effectiveness, and reproducibility of this advanced treatment modality, particularly in settings where it is newly adopted.

HCC surveillance: minimum standards

Hepatocellular carcinoma (HCC) surveillance is crucial for early detection and improved survival rates, particularly in at-risk populations such as those with chronic liver disease or cirrhosis. To ensure effective surveillance, minimum standards have been established focusing on patient engagement, diagnostic accuracy, and system efficiency. 1. **Target Population**: Surveillance should be offered to individuals at high risk of HCC, including those with cirrhosis due to hepatitis B or C, alcohol-related liver disease, non-alcoholic fatty liver disease (NAFLD), and other chronic liver conditions. 2. **Surveillance Intervals**: Surveillance should be conducted at 6-month intervals, as evidence shows this frequency balances the benefits of early detection with resource utilization. 3. **Diagnostic Tools**: The recommended surveillance method is a combination of abdominal ultrasound and serum alpha-fetoprotein (AFP) testing. Ultrasound is the primary tool, while AFP serves as an adjunct to improve sensitivity. However, AFP alone is not sufficient due to its variability and limited specificity. 4. **Integrated Systems**: A robust, digital call-recall system is essential to track eligible patients and ensure timely surveillance. This system should automatically flag missed appointments and facilitate re-engagement. 5. **Patient Engagement**: Education and communication are critical to improve adherence. A multifaceted approach, including culturally sensitive materials, personalized reminders, and patient navigation support, can address barriers to participation. 6. **Quality Assurance**: Surveillance programs should have mechanisms for regular monitoring, auditing, and feedback to ensure adherence to guidelines and optimize outcomes. By meeting these minimum standards, healthcare systems can enhance HCC surveillance, improve early diagnosis, and ultimately reduce mortality rates associated with this aggressive cancer.

Therapeutic targets of SphK1 and SphK2 in hepatocellular carcinoma

SphK1 and SphK2 are critical therapeutic targets in hepatocellular carcinoma (HCC) due to their involvement in tumor progression, survival, and resistance mechanisms. Below is a detailed overview of their therapeutic implications: ### **1. SphK1 as a Therapeutic Target** SphK1 plays a significant oncogenic role in HCC by promoting tumor proliferation, migration, angiogenesis, and chemoresistance. Its therapeutic targeting focuses on inhibiting its activity and disrupting its signaling pathways: - **Mechanisms of Action:** - SphK1 activates PI3K/AKT/mTOR and MAPK/ERK signaling pathways, driving tumor growth and survival. - It enhances NF-κB signaling, epithelial–mesenchymal transition (EMT), and chemoresistance, contributing to tumor aggressiveness. - SphK1 upregulation increases VEGF secretion, promoting angiogenesis and linking lipid metabolism to tumor vascularization. - **Therapeutic Strategies:** - **Selective SphK1 Inhibitors:** - **PF-543**: Potently inhibits SphK1 activity, suppressing sphingosine-1-phosphate (S1P) production and reducing tumor invasion. - **SKI-178**: Induces apoptosis and inhibits tumor proliferation in preclinical models. - **Dual Inhibition Approaches:** - Combined blockade of SphK1 and SphK2 (e.g., SKI-II, SKI-349) enhances apoptosis, suppresses FAK/IGF-1R and AKT/mTOR signaling, and improves chemosensitivity. - **Immunotherapy Potential:** - Inhibiting SphK1/S1P signaling may reactivate tumor necrosis factor (TNF)-mediated apoptosis and enhance immune checkpoint inhibitor responses. ### **2. SphK2 as a Therapeutic Target** SphK2 has a unique role in HCC by regulating nuclear gene transcription, mitochondrial function, and metabolic reprogramming. Its inhibition has shown promise in overcoming resistance and reducing tumor progression: - **Mechanisms of Action:** - Nuclear SphK2-generated S1P enhances histone acetyltransferase activity, promoting oncogene transcription (e.g., c-Myc) and metabolic reprogramming. - Mitochondrial SphK2 maintains telomere activity by stabilizing telomerase (hTERT) structure, supporting tumor cell survival and resistance to regorafenib. - SphK2 modulates mTORC2 signaling and very-low-density lipoprotein (VLDL) secretion, contributing to HCC cell survival and lipid metabolism. - **Therapeutic Strategies:** - **Selective SphK2 Inhibitors:** - **ABC294640 (Opaganib)**: Selectively inhibits SphK2, reducing MAPK/ERK pathway activation and showing synergy with sorafenib in HCC models. - **Dual Inhibition Approaches:** - Combined targeting of SphK1 and SphK2 enhances apoptosis and suppresses key survival pathways, such as AKT/mTOR. - **Regorafenib Resistance Overcoming:** - SphK2 inhibition can restore drug efficacy by blocking NF-κB/STAT3 activation, which contributes to regorafenib resistance. - **Metabolic Reprogramming:** - SphK2 inhibition induces lipotoxic stress and cell death by disrupting mTORC2 signaling and lipid secretion. ### **3. Diagnostic and Biomarker Potential** - Elevated serum levels of S1P and C16-ceramide are being investigated as potential early biomarkers for malignant transformation in liver diseases, including HCC. These biomarkers could guide therapeutic targeting of SphK1 and SphK2. ### **4. Future Directions in Therapy** - **Isoform-Specific Inhibitors:** Developing highly specific inhibitors for SphK1 and SphK2 to minimize off-target effects and maximize therapeutic efficacy. - **Combination Therapies:** Integrating SphK inhibitors with immune checkpoint inhibitors, chemotherapy, or targeted therapies (e.g., sorafenib or regorafenib) for enhanced outcomes. - **Multi-Omics Analysis:** Utilizing genomics, proteomics, and metabolomics to tailor precision therapies targeting SphK isoforms in HCC. - **Metabolism–Immune Targeting:** Combining SphK inhibition with therapies targeting immune modulation and metabolic reprogramming. ### **Summary** Targeting SphK1 and SphK2 in HCC offers promising therapeutic opportunities by disrupting key oncogenic pathways, overcoming drug resistance, and inducing tumor cell apoptosis. Selective inhibitors like PF-543, SKI-178, and ABC294640 have demonstrated preclinical efficacy, while dual inhibition strategies and combination therapies hold potential for clinical application. Additionally, diagnostic biomarkers and precision medicine approaches are advancing the field of SphK-targeted therapies in HCC.

Key Differences in Y90 vs. SBRT Dosing in HCC

**Role of Radiotherapy in HCC (Hepatocellular Carcinoma):** Radiotherapy plays a critical role in treating HCC, particularly for patients who are not candidates for surgery or liver transplantation. It aims to deliver targeted radiation to destroy tumor cells while sparing healthy liver tissue. Advanced techniques, such as SBRT and Y90 radioembolization, are commonly used for localized disease and provide non-invasive tumor control with minimal systemic side effects. **What is Y90?** Y90 (Yttrium-90) radioembolization is a locoregional therapy that involves injecting radioactive microspheres directly into the hepatic artery, targeting liver tumors. These microspheres lodge in the tumor's arterioles and emit beta radiation, delivering a highly localized dose over several days. The radiation penetrates only 2–3 mm into tissue, resulting in a heterogeneous dose distribution within the tumor. **What is SBRT?** SBRT (Stereotactic Body Radiation Therapy) is a highly precise form of external beam radiation therapy that delivers intense doses of radiation to the tumor in a few sessions, typically over a few minutes per session. SBRT is known for delivering a uniform dose of radiation, with high tumor control rates due to its precision and ability to spare surrounding healthy tissue. **Key Differences in Y90 vs. SBRT Dosing in HCC:** 1. **Dose Uniformity:** SBRT delivers a uniform dose across the tumor, while Y90 provides a highly heterogeneous dose due to microsphere deposition in arterioles with limited penetration (2–3 mm). 2. **Dose Distribution:** Y90 doses vary significantly within the tumor mass, whereas SBRT provides consistent dosing throughout the target region. 3. **Dose Rate:** SBRT administers radiation over minutes per session, while Y90 delivers radiation gradually over several days due to Y90's half-life (~64 hours). 4. **Biological Effect:** Y90's slower radiation delivery allows cellular repair of sublethal DNA damage during treatment, reducing its biological effectiveness per Gy compared to SBRT. 5. **Dose Equivalence:** A Y90 dose of ~400 Gy corresponds to an SBRT dose of 40–50 Gy in terms of tumoricidal effect due to the temporal protraction effect. **Summary of the Text:** Radiotherapy is crucial for treating HCC, especially for patients ineligible for surgery. Y90 is a locoregional therapy using radioactive microspheres to deliver heterogeneous radiation over days, while SBRT is a precise external beam therapy delivering uniform radiation in minutes. Key differences include dose uniformity, distribution, rate, biological effects, and equivalence, with Y90's 400 Gy being biologically similar to SBRT's 40–50 Gy.

Chemoprevention of Hepatocellular Carcinoma

Chemoprevention of hepatocellular carcinoma (HCC) refers to the use of medications, vaccines, or supplements to prevent or delay the development of HCC, particularly in individuals at high risk due to chronic liver disease (CLD). This concept was introduced over 50 years ago and remains a critical strategy for addressing HCC, given its long latency period and the global burden of the disease. ### Key Drivers of HCC HCC is primarily driven by: 1. **Chronic Viral Hepatitis**: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are leading causes of HCC worldwide. 2. **Alcohol Use**: Chronic alcohol consumption contributes to liver cirrhosis and HCC development. 3. **Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD/MASH)**: Previously known as non-alcoholic fatty liver disease (NAFLD/NASH), metabolic dysfunction is becoming an increasingly significant contributor to HCC due to the global rise in obesity and diabetes. ### Chemopreventive Strategies 1. **HBV Vaccination**: - Universal HBV vaccination is the most successful example of chemoprevention, reducing HBV-related HCC by 80–90% among children and young adults. - HBV vaccination is considered the first true "anti-cancer vaccine." 2. **Antiviral Therapies**: - **HBV**: Nucleos(t)ide analogues such as entecavir, tenofovir, and lamivudine, as well as interferon therapy, significantly reduce HCC risk in HBV patients, with hazard ratios around 0.5. - **HCV**: Direct-acting antivirals (DAAs) for HCV have revolutionized treatment, reducing HCC incidence by 70–80% through viral eradication, which is the most effective chemopreventive strategy. 3. **Aspirin**: - Observational studies show aspirin use is associated with a 24–41% reduced risk of HCC, likely due to its anti-inflammatory effects and COX-2 inhibition. - However, the risk of bleeding limits its universal application for HCC prevention. 4. **Non-Aspirin NSAIDs**: - Non-aspirin NSAIDs and COX-2 inhibitors, such as meloxicam, have shown inconsistent or minimal HCC risk reduction in clinical trials, making them less promising for chemoprevention. 5. **Statins**: - Statins are consistently associated with a 30–50% lower HCC incidence across HBV, HCV, and MASLD patients. - Lipophilic statins (e.g., simvastatin, atorvastatin) appear more effective than hydrophilic statins due to their greater hepatic and systemic action. 6. **Metformin**: - Metformin shows a 40–50% reduction in HCC risk among patients with type 2 diabetes, although results vary when adjusted for concurrent use of statins or aspirin. - Current guidelines do not recommend metformin solely for HCC prevention. 7. **New Antidiabetic Drugs**: - **GLP-1 receptor agonists** (e.g., liraglutide, semaglutide) and **SGLT2 inhibitors** (e.g., dapagliflozin, canagliflozin) show promise in reducing steatosis and potentially HCC risk in MASH models, although clinical validation is required. - **Thiazolidinediones (TZDs)** and **DPP4 inhibitors** may reduce liver inflammation and fibrosis, but evidence for HCC prevention remains weak and inconsistent. 8. **Antihypertensive Drugs**: - ACE inhibitors, ARBs, and beta-blockers may have anti-fibrotic or anti-angiogenic effects, but current human data do not support their use specifically for HCC chemoprevention. - Non-selective beta-blockers like nadolol and carvedilol show potential HCC risk reduction in cirrhotic patients, while propranolol has not demonstrated clear benefit. 9. **Targeted Agents**: - Erlotinib (EGFR inhibitor) and mTOR inhibitors (sirolimus, everolimus) show HCC-preventive potential in preclinical models, but clinical trial validation in non-cancer populations is lacking. 10. **Dietary and Lifestyle Modifications**: - **Coffee Consumption**: Drinking more than two cups of coffee per day is associated with a 35–40% lower HCC risk due to its anti-inflammatory and antioxidant properties. - **Mediterranean Diet**: Foods such as fish, white meat, fiber, and olive oil show protective associations. - **Vitamin and Supplementation**: Vitamins D and E, branched-chain amino acids, and selenium supplementation may reduce HCC risk in deficient populations, but applicability is limited. ### Guidelines and Recommendations The American Association for the Study of Liver Diseases (AASLD) provides the following recommendations for HCC prevention: - **Encouraged**: Antiviral therapy for HBV and HCV, coffee consumption, and metabolic control. - **Discouraged**: Routine use of aspirin, metformin, or statins solely for chemoprevention due to insufficient evidence or associated risks. ### Conclusion The most effective strategies for HCC chemoprevention are controlling viral hepatitis through vaccination and antiviral therapies and implementing lifestyle modifications, including coffee consumption and metabolic control. While drugs like statins, aspirin, and GLP-1 receptor agonists show promise, further large-scale clinical validation is needed.

Phosphatidylethanol Testing in Clinical Practice for the Identification of MASLD Subtypes

Phosphatidylethanol (PEth) testing is increasingly recognized as a valuable tool in clinical practice for distinguishing subtypes of steatotic liver disease (SLD), particularly in the context of the updated 2023 nomenclature. Accurate identification of SLD subtypes — MASLD (metabolic dysfunction–associated SLD), ALD (alcohol-associated liver disease), and MetALD (metabolic dysfunction and alcohol-associated liver disease) — is essential for tailoring treatment strategies to individual patients, and PEth testing plays a critical role in quantifying alcohol intake objectively. ### Why PEth Testing is Important in SLD Classification 1. **Objective Alcohol Intake Measurement**: PEth is a direct biomarker of alcohol consumption, formed in the presence of ethanol in red blood cells. It provides a reliable indication of alcohol use over the prior 2–4 weeks, offering a more objective assessment compared to self-reported alcohol intake, which can be influenced by underreporting or recall bias. 2. **Threshold-Based Subtype Differentiation**: The updated SLD classification relies on weekly alcohol thresholds to differentiate between MASLD, MetALD, and ALD: - MASLD vs. MetALD: >140 g/week for women or >210 g/week for men. - MetALD vs. ALD: >350 g/week for women or >420 g/week for men. PEth levels can help determine whether a patient’s alcohol consumption exceeds these thresholds, ensuring accurate subtype classification. 3. **Synergistic Role of Alcohol and Metabolic Dysfunction**: MetALD represents a hybrid subtype where both metabolic dysfunction and alcohol intake contribute to liver damage. PEth testing can help identify patients whose alcohol use is significant enough to shift their diagnosis from MASLD to MetALD, emphasizing the need for tailored interventions addressing both metabolic and alcohol-related factors. ### Advantages of PEth Testing in Clinical Practice - **High Sensitivity and Specificity**: PEth testing has superior sensitivity and specificity compared to other alcohol biomarkers (e.g., ethyl glucuronide [EtG], carbohydrate-deficient transferrin [CDT]). It is particularly useful for detecting moderate-to-heavy alcohol use. - **Correlation with Alcohol Dose**: PEth levels correlate strongly with the amount of alcohol consumed, making it a quantitative tool for assessing whether a patient’s intake exceeds the thresholds for SLD subtype differentiation. - **Non-Invasive and Convenient**: PEth testing involves a simple blood draw, making it a practical option for routine clinical use. ### Clinical Implementation of PEth Testing 1. **Routine Use in SLD Diagnosis**: Incorporating PEth testing into the diagnostic workup for patients with suspected SLD can improve the accuracy of subtype classification and guide treatment decisions. 2. **Monitoring Alcohol Intake**: For patients with MetALD or ALD, PEth testing can be used to monitor adherence to alcohol reduction or abstinence goals during treatment. 3. **Integration with Other Biomarkers**: PEth testing can complement other clinical assessments, such as liver function tests, imaging, and metabolic evaluations, to provide a comprehensive picture of disease etiology and progression. ### Limitations and Considerations - **Cost and Accessibility**: PEth testing may not be universally available or covered by all healthcare systems, potentially limiting its use in some settings. - **Interpretation Challenges**: While PEth provides a reliable measure of alcohol intake, clinicians must consider individual variability in alcohol metabolism and the potential influence of comorbid conditions when interpreting results. ### Conclusion Phosphatidylethanol testing represents a powerful tool for identifying MASLD subtypes and guiding personalized management strategies for steatotic liver disease. Its ability to objectively quantify alcohol intake is particularly important in distinguishing MASLD from MetALD and ALD, ensuring that patients receive appropriate interventions targeting both metabolic dysfunction and alcohol-related liver damage. As clinical awareness of the updated SLD classification grows, PEth testing is likely to become a cornerstone of diagnostic and therapeutic decision-making in liver disease management.

GUIDANCE001 study

The GUIDANCE001 study appears to be a research initiative focused on evaluating the efficacy and safety of combining transarterial chemoembolization (TACE) with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for the treatment of unresectable hepatocellular carcinoma (HCC). Below is a detailed breakdown based on the study's context: ### **Purpose of the GUIDANCE001 Study** The study aimed to determine whether triple therapy (TACE + TKI + ICI) offers improved clinical outcomes compared to TACE alone in patients with unresectable HCC. Specifically, the study sought to assess whether this combination could enhance survival, increase the likelihood of surgical resection (hepatectomy), and improve tumor response rates. --- ### **Study Design** - **Type of Study**: Multicenter, retrospective cohort analysis. - **Patient Population**: A total of 802 patients with unresectable HCC were included: - 459 patients received TACE alone. - 343 patients received the triple therapy (TACE + TKI + ICI). - **Endpoints**: - **Primary Endpoint**: Overall survival (OS). - **Secondary Endpoints**: Progression-free survival (PFS), hepatectomy conversion rate, treatment-related adverse events (TRAEs), and pathologic complete response (pCR). --- ### **Key Findings** 1. **Overall Survival (OS) Benefit**: - Triple therapy significantly improved overall survival compared to TACE alone. - **Hazard Ratio (HR)**: 0.43 (95% CI 0.35–0.53), corresponding to a **57% reduction in mortality risk**. 2. **Progression-Free Survival (PFS)**: - Median PFS was almost **doubled** in the triple therapy group: - Triple therapy: **15.9 months**. - TACE alone: **8.0 months**. - This improvement was statistically significant (**p < 0.001**). 3. **Stage-Specific Efficacy**: - Survival benefits from triple therapy were observed in patients with **intermediate (BCLC B)** and **advanced (BCLC C)** stage disease. - No significant benefit was seen in patients with early-stage disease (**BCLC A**). 4. **Hepatectomy Conversion Rate**: - Triple therapy increased the likelihood of patients becoming eligible for surgical resection: - Triple therapy: **36.4%**. - TACE alone: **23.5%**. - This difference was statistically significant (**p < 0.001**). 5. **Pathologic Complete Response (pCR)**: - Among patients who underwent surgery post-treatment, triple therapy achieved a much higher rate of complete tumor response: - Triple therapy: **32.1%**. - TACE alone: **11.1%**. - This was also statistically significant (**p < 0.001**). 6. **Safety Profile**: - Triple therapy was associated with a higher incidence of **grade ≥3 treatment-related adverse events (TRAEs)**: - Triple therapy: **35.6%**. - TACE alone: **27.0%**. - This indicates an increased risk of toxicity, necessitating careful management. --- ### **Clinical Implications** The findings from the GUIDANCE001 study suggest that combining TACE with TKIs and ICIs provides **substantial survival and conversion benefits** for patients with intermediate to advanced unresectable HCC. Specifically: - **Intermediate (BCLC B)** and **Advanced (BCLC C)** stage patients should be prioritized for this triple therapy approach. - The improved survival, PFS, and hepatectomy conversion rates make triple therapy a promising option for these patient groups. - However, the **higher toxicity risk** associated with triple therapy underscores the need for **careful patient selection and management** to mitigate adverse events. --- ### **Conclusion** The GUIDANCE001 study highlights the clinical potential of triple therapy (TACE + TKI + ICI) in improving outcomes for patients with unresectable HCC, particularly in intermediate and advanced stages. While effective, the increased toxicity risk requires balancing the benefits of treatment against potential adverse events. This study provides valuable evidence to guide treatment strategies in this challenging patient population.

Hepatocellular Carcinoma (HCC): Classification Systems

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is closely linked to chronic liver diseases such as viral hepatitis, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease (MASLD, previously referred to as NAFLD/NASH). Accurate classification of HCC is critical for diagnosis, prognosis, and treatment planning. Various classification systems for HCC have been developed, focusing on tumor burden, liver function, and patient performance status. Additionally, biomarker-based tools such as the **GALAD score** have emerged as valuable resources for early detection of HCC. Here is a detailed overview of the **classification systems for HCC**: --- ### **1. Staging Systems for HCC** Staging systems for HCC aim to assess tumor burden, liver function, and patient performance status to determine prognosis and guide therapeutic decisions. Key staging systems include: #### **A. Barcelona Clinic Liver Cancer (BCLC) Staging System** The **BCLC staging system** is the most widely used staging framework for HCC. It integrates tumor burden, liver function (Child-Pugh score), and patient performance status (ECOG) to guide treatment decisions. | **Stage** | **Tumor Burden** | **Liver Function** | **Performance Status (ECOG)** | **Treatment Options** | |-----------------|---------------------------------------|--------------------|------------------------------|-----------------------------------------| | **Stage 0 (Very Early)** | Single tumor ≤2 cm, no vascular invasion | Child-Pugh A | 0 | Resection, ablation | | **Stage A (Early)** | ≤3 nodules, each ≤3 cm or single tumor >2 cm | Child-Pugh A/B | 0 | Resection, ablation, transplant | | **Stage B (Intermediate)** | Multinodular tumors without vascular invasion | Child-Pugh A/B | 0 | Transarterial chemoembolization (TACE) | | **Stage C (Advanced)** | Portal invasion or extrahepatic spread | Child-Pugh A/B | 1–2 | Systemic therapy (e.g., sorafenib, atezolizumab + bevacizumab) | | **Stage D (Terminal)** | Any tumor burden | Child-Pugh C | ≥3 | Best supportive care | The BCLC system is highly regarded for its ability to guide treatment strategies, ranging from curative (e.g., resection, transplantation) to palliative (e.g., systemic therapies, supportive care). --- #### **B. TNM Staging System (AJCC 8th Edition)** The **TNM staging system**, developed by the American Joint Committee on Cancer (AJCC), focuses on tumor size, vascular invasion, lymph node involvement, and metastasis. It is primarily used for surgically resected HCC and provides prognostic information. | **Stage** | **T (Tumor)** | **N (Nodes)** | **M (Metastasis)** | |-----------|-------------------------------------------|---------------|---------------------| | **Stage I** | Single tumor, no vascular invasion | N0 | M0 | | **Stage II** | Single tumor with vascular invasion | N0 | M0 | | **Stage IIIA** | Multiple tumors >5 cm | N0 | M0 | | **Stage IIIB** | Tumor invades major vascular structures | N0 | M0 | | **Stage IVA** | Any T, regional lymph node involvement | N1 | M0 | | **Stage IVB** | Any T, any N, distant metastasis | Any N | M1 | The TNM system is particularly useful in evaluating prognosis after surgical resection. --- #### **C. Child-Pugh Classification** The **Child-Pugh classification** evaluates liver function in patients with cirrhosis, which is critical because most HCC cases occur in the context of chronic liver disease. It is based on five clinical parameters: bilirubin, albumin, prothrombin time (INR), ascites, and hepatic encephalopathy. | **Score** | **Points** | **Prognosis** | |------------------|------------|------------------------| | **Class A** | 5–6 | Well-compensated liver | | **Class B** | 7–9 | Significant compromise | | **Class C** | 10–15 | Decompensated liver | The Child-Pugh score is commonly used alongside other staging systems to assess liver function and guide treatment decisions. --- #### **D. Cancer of the Liver Italian Program (CLIP) Score** The **CLIP score** combines tumor stage, liver function, and portal vein thrombosis to provide prognostic information. | **Parameter** | **Score** | |------------------------------|-----------| | **Child-Pugh Class** | A: 0, B: 1, C: 2 | | **Tumor Morphology** | Uninodular: 0, Multinodular <50%: 1, Massive >50%: 2 | | **AFP Levels** | <400 ng/mL: 0, ≥400 ng/mL: 1 | | **Portal Vein Thrombosis** | Absent: 0, Present: 1 | The CLIP score is particularly useful in prognostication and treatment planning. --- #### **E. Other Staging Systems** 1. **Okuda Classification**: - Focuses on tumor size, ascites, albumin, and bilirubin. - Historically significant but less commonly used today. 2. **Japanese Integrated Staging (JIS) Score**: - Combines **TNM staging** and **Child-Pugh class**. 3. **Hong Kong Liver Cancer (HKLC) Staging**: - Developed for Asian populations, incorporates tumor burden, liver function, and performance status. --- ### **2. Biomarker-Based Classification: The GALAD Score** The **GALAD score** is a diagnostic and risk prediction model for HCC that uses serum biomarkers and patient demographics. It is particularly valuable for detecting early-stage HCC in patients with chronic liver disease, including non-alcoholic steatohepatitis (NASH). #### **Components of the GALAD Score**: The GALAD score integrates: 1. **G**ender 2. **A**ge 3. **L**ectin-bound alpha-fetoprotein (AFP-L3%) 4. **A**lpha-fetoprotein (AFP) 5. **D**es-gamma-carboxy prothrombin (DCP, also known as PIVKA-II) #### **Formula**: The GALAD score uses a logistic regression model: ``` GALAD = -10.08 + (0.09 × Age) + (1.67 × Sex) + (2.34 × log10(AFP)) + (0.04 × AFP-L3%) + (1.33 × log10(DCP)) ``` - **Sex**: Male = 1, Female = 0. - The output is a probability value indicating the likelihood of HCC. #### **Utility of the GALAD Score**: - **Early Detection**: - High sensitivity and specificity for identifying early-stage HCC. - **Comparison with Imaging**: - The GALAD score performs better than ultrasound or AFP alone. - **GALADUS Score**: - Combines the GALAD score with ultrasound findings for improved diagnostic accuracy. #### **Validation**: The GALAD score has been validated across diverse populations and is particularly effective in detecting HCC in NASH-related liver disease. --- ### **3. Gross and Microscopic Classification of HCC** #### **A. Gross Classification**: HCC can be classified based on its macroscopic appearance into: 1. **Nodular Type**: - Most common. - Appears as a single nodule or multiple nodules. 2. **Massive Type**: - A single large tumor, often with central necrosis. 3. **Diffuse Type**: - Tumor infiltrates large portions of the liver. #### **B. Microscopic Classification**: - **Well-Differentiated**: - Resembles normal hepatocytes; less aggressive. - **Moderately Differentiated**: - Intermediate features. - **Poorly Differentiated**: - Highly aggressive, with poor prognosis. --- ### **Summary of HCC Classification Systems** | **Classification System** | **Focus** | |--------------------------------|---------------------------------------------------------------------------| | **BCLC** | Tumor burden, liver function, and performance status. Guides treatment. | | **TNM (AJCC)** | Tumor size, vascular invasion, lymph node, and metastasis staging. | | **Child-Pugh** | Liver function assessment (cirrhosis severity). | | **CLIP** | Combines liver function, tumor stage, and portal vein thrombosis. | | **GALAD Score** | Biomarker-based model for early HCC detection. | | **Okuda, JIS, HKLC** | Regional or historical staging systems. | --- ### **Take-Home Points** - Accurate classification of HCC is essential for prognosis and treatment planning. - The **BCLC staging system** is the most commonly used, integrating tumor burden, liver function, and performance status. - The **GALAD score** is a promising biomarker-based tool for **early detection of HCC**, particularly in patients with chronic liver disease. - Combining staging systems with biomarker models improves diagnostic accuracy and enhances treatment strategies.

Benign liver masses - Management strategies

Management strategies for benign liver masses depend on the type of lesion, its size, symptoms, and associated risks (e.g., bleeding, malignant transformation). Below is a detailed overview of the management approaches for the most common types of benign liver masses: --- ### **1. Hemangiomas** - **General Features**: - Most common benign liver tumor. - Typically asymptomatic and stable over time. - Rarely associated with complications like rupture or Kasabach-Merritt syndrome (consumptive coagulopathy). - **Management**: - **Small, Asymptomatic Hemangiomas**: - No treatment or follow-up is needed. - **Large or Symptomatic Hemangiomas**: - May cause pain, mass effect, or complications. - Options include: - **Surgical Resection or Enucleation**: For symptomatic or complicated cases. - **Embolization or Ablation**: For patients not suitable for surgery. - Surgery is rare and reserved for select cases. - **Hormonal Considerations**: Monitor for growth during pregnancy or in patients exposed to hormonal therapies (e.g., oral contraceptives). --- ### **2. Focal Nodular Hyperplasia (FNH)** - **General Features**: - Second most common benign liver tumor. - Usually affects young to middle-aged women. - No risk of malignant transformation or significant complications. - **Management**: - **Asymptomatic FNH**: - No treatment or surveillance is required. - **Symptomatic or Atypical Lesions**: - Biopsy or surgical resection may be considered in rare cases, especially if diagnosis is uncertain or symptoms persist. - **Role of Imaging**: - MRI with hepatobiliary contrast typically confirms the diagnosis, avoiding unnecessary interventions. --- ### **3. Hepatic Adenomas** - **General Features**: - Associated with risk factors like oral contraceptives, anabolic steroids, obesity, and metabolic syndrome. - Risk of complications includes bleeding (spontaneous rupture) and malignant transformation to hepatocellular carcinoma (HCC). - **Management**: - **Small, Stable Adenomas (<5 cm)**: - Women: MRI surveillance every 6–12 months. - Discontinue risk factors (e.g., oral contraceptives, weight loss for obesity). - **Large Adenomas (>5 cm)**: - Surgical resection is typically recommended due to higher risks of bleeding and malignant transformation. - **High-Risk Adenomas**: - **β-Catenin–Mutated Subtypes**: High risk for HCC; surgical resection is advised. - **Men with Adenomas**: Resection is generally recommended, regardless of size, due to elevated malignancy risk. - **Pregnancy**: Avoid pregnancy if adenomas are large or high-risk due to increased bleeding risk. --- ### **4. Simple Hepatic Cysts** - **General Features**: - Common, asymptomatic, and benign. - No risk of malignant transformation. - **Management**: - **Asymptomatic Cysts**: - No surveillance or treatment is required. - **Symptomatic Cysts**: - May cause pain, mass effect, or complications. - Options include: - Aspiration (temporary relief but high recurrence rate). - Surgical deroofing or resection for definitive management. --- ### **5. Complex Cysts** - **Mucinous Cystic Neoplasms (MCNs)**: - Carry a risk of malignant transformation. - **Management**: Surgical resection is recommended. - **Hydatid Cysts (Echinococcal Infection)**: - Infectious risk due to parasitic origin. - **Management**: - Antiparasitic therapy (e.g., albendazole). - Surgical resection or drainage in select cases. --- ### **6. Inherited Cystic Disorders** - **Polycystic Liver Disease (PLD)**: - Often associated with polycystic kidney disease (PKD). - **Management**: - Treat symptoms like pain, infection, or bleeding. - Surgical intervention (e.g., fenestration, liver transplantation) for severe cases. - **Caroli’s Disease**: - Associated with bile duct dilation and complications like cholangitis or stones. - **Management**: - Treat complications (e.g., antibiotics for infection). - Resection or liver transplantation for severe cases. --- ### **7. Rare Benign Tumors** - **Angiomyolipoma, Mesenchymal Hamartoma, Schwannoma, Hemangioendothelioma**: - Rare and often require biopsy for diagnosis. - **Management**: - Asymptomatic lesions may be monitored. - Symptomatic or uncertain lesions may require surgical resection. --- ### **8. Symptomatic Lesions** - Symptoms like pain, early satiety, nausea, or mass effect may necessitate intervention regardless of the lesion type. - **Management**: - Individualized decision-making with input from hepatologists, radiologists, and surgeons. - Avoid overtreatment for asymptomatic lesions. --- ### **9. Risk Context** - **Patients with Cirrhosis**: - Benign lesions in cirrhotic livers should be interpreted with caution due to overlapping imaging features with hepatocellular carcinoma (HCC). - Multidisciplinary evaluation is critical. - **Patients with Known Malignancy**: - Imaging findings of benign lesions may mimic metastatic disease, requiring careful differentiation. --- ### **10. Multidisciplinary Care** - Optimal management involves collaboration between hepatologists, radiologists, and surgeons. - Decisions should balance the risks of intervention against the natural history of the lesion. --- ### **11. Future Outlook** - Advances in molecular subclassification of adenomas and imaging algorithms (e.g., hepatocyte-specific MRI) are expected to: - Enhance diagnostic accuracy. - Reduce the need for biopsy. - Allow better identification of lesions at risk of complications like bleeding or malignant transformation. --- In summary, the management of benign liver masses is highly individualized, with most lesions requiring no treatment or surveillance. Intervention is reserved for symptomatic cases, high-risk lesions, or when malignancy cannot be excluded.