This was a narrative review of select studies published through September of 2024. We review the shift toward multi-dimensional scores such as HCC early detection screening (HES), GALAD, ASAP, and mt-HBT represents a significant advancement in biomarker research for hepatocellular carcinoma (HCC) detection. Unlike single biomarker approaches, these scores integrate various clinical and biochemical factors to enhance predictive accuracy by reflecting different complementary aspects of disease progression and HCC oncogenesis. Proper testing and validation of biomarker scores in phase 3 biomarker studies is essential before wide use can be recommended. We also review the comparative performance of biomarker scores in phase 3 studies. The new version of HES (HES V2.0) which includes AFP, AFP L3, DCP, and changes in their levels the past one year, if available, in addition to age, platelets, albumin, ALT and underlying liver disease etiology outperforms GALAD in detecting early-stage HCC with overall 6.7% higher sensitivity, and ASAP with 13.4%-18.0% higher sensitivity, both at fixed 90% specificity. HES V2.0 is a leading candidate biomarker score for prospective testing in clinical studies of early HCC detection.

Abbreviated MRI (AMRI) has been proposed as an alternative to ultrasound for hepatocellular carcinoma (HCC) surveillance; however, comparative data for AMRI and ultrasound are needed. Thus, we evaluated the sensitivity and specificity of dynamic contrast-enhanced (DCE)-AMRI and ultrasound for early-stage HCC detection in patients with cirrhosis.

We conducted a multicenter retrospective case-control study among patients with cirrhosis (cases with early-stage HCC as per Milan Criteria; controls without HCC) who underwent an ultrasound and a DCE-MRI within a 6-month period between 2012 and 2019. HCC diagnosis was confirmed by imaging alone in 85% and by histopathology in 15% of patients. Dynamic AMRI examinations were simulated from the full MRI by selecting relevant sequences. Independent, blinded interpretations of ultrasounds and AMRI results were performed using Liver Imaging Reporting and Data System algorithms. Ultrasounds were considered positive if US-3 observations were detected. AMRI was considered positive if LR-4, LR-5, or LR-M were detected. Per-patient sensitivity and specificity for early-stage HCC detection were estimated, and cross-modality differences were tested.

We included 216 cases and 432 controls. Patient-level sensitivity and specificity of AMRI were significantly higher compared with ultrasound: 80.1% (95% CI 76.1-83.6) vs. 71.1% (95% CI 66.6-75.2), p <0.001, and 91.9% (95% CI 89.9-93.5) vs. 72.3% (95% CI 69.3-75.2), p <0.001, respectively. AMRI sensitivity was significantly higher compared with ultrasound among patients with Child-Pugh B cirrhosis (80.8% vs. 57.4%, p <0.001) but not among those with Child-Pugh A (84.7% vs. 78.6%, p = 0.07) or Child-Pugh C cirrhosis (52.6% vs. 68.4%, p = 0.18).

Dynamic AMRI may be more sensitive and specific for early-stage HCC detection in patients with cirrhosis compared with ultrasound, although its relative benefit might be smaller in patients with Child-Pugh A cirrhosis. Larger direct comparative data sets are needed, particularly among patients with Child-Pugh C cirrhosis who may benefit from alternative surveillance strategies.

Abbreviated MRI (AMRI) is increasingly recognized as an alternative to ultrasound for hepatocellular carcinoma (HCC) surveillance. However, existing data are limited by single-center samples, spectrum bias, and lack of comparative data for AMRI vs. ultrasound. We found that AMRI had significantly higher per-patient sensitivity and specificity compared with ultrasound for the detection of early-stage HCC, although its relative benefit might be smaller in patients with Child-Pugh A cirrhosis, and both modalities underperformed in patients with Child-Pugh C cirrhosis. If sufficiently validated, AMRI could be adopted into practice guidelines for HCC surveillance and serve as a preferred alternative in select subgroups of patients.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. This study evaluates how strongly socioeconomic factors associate with diagnostics, treatment, and survival among patients with HCC in Sweden.

All adult patients registered with a diagnosis of HCC in the Swedish quality register for liver cancer between 2011 and 2021 were included. Household income was classified as low (first quartile; poorest), medium (second or third quartile), or high (in fourth quartile; wealthiest) based on the overall distribution of household income across all household in Sweden. Outcomes included likelihood of diagnosis under surveillance, early-stage diagnosis (Barcelona Clinic Liver Cancer [BCLC] staging 0-A), and receipt of curative treatment (ablation, resection or liver transplantation), as well as mortality risk.

Among 5490 patients, a significant association was found between low household income and decreased likelihood of diagnosis while under surveillance (adjusted odds ratio [aOR] 0·63; 95% confidence interval [CI]: 0·50-0·80), early-stage diagnosis (aOR 0·58; 95% CI: 0·51-0·67), and curative treatment receipt (aOR 0·65; 95% CI: 0·50-0·85). After adjustments for all variables in the BCLC, other sociodemographic variables, comorbidities, and cirrhosis status, patients with low household income had an adjusted hazard ratio for mortality of 1·29 (95% CI: 1·15-1·45) compared to patients with high household income.

Socioeconomic disparities associate markedly with more advanced stage at HCC diagnosis, less curative treatment, and poorer survival in Sweden. Addressing these disparities through targeted public health interventions may improve HCC care and outcomes in socioeconomically disadvantaged populations.

The Swedish Cancer Society-Cancerfonden.

The epidemiological landscape of hepatocellular carcinoma (HCC) in Europe is evolving. This study aims to provide an updated description of the current epidemiology of liver cancer in Spain.

This multicenter prospective study collected demographic and clinical data on primary liver cancer between October 2022 and January 2023. We conducted descriptive and comparative analyses with data collected in 2008 and 2014.

Of the 767 cases of primary liver cancer collected from 52 centers, 91% were diagnosed as HCC. The majority of patients were male (83.3%), average age 68 years, 80.7% had cirrhosis. The primary causes were alcohol (29.9% alone, 55% combined with other etiologies), liver disease related to metabolic syndrome (LDrMS, 23%) and hepatitis C (17.3%). Treatments included ablation (15.7%), systemic therapy (14.7%), and chemoembolization (14.6%). Data from 29 centers (n = 1,351) across three registries revealed a significant increase in LDrMS (from 4.9% to 24%) and HCC in non-cirrhotic livers (from 4.2% to 7.9%). Meanwhile, hepatitis C decreased sharply (from 43% to 17.5%). Alcohol-related cases remained stable. There was a slight increase in male patients and hypertension, diabetes, and obesity. Patients with cirrhosis diagnosed outside of screening programs presented with larger tumors and more advanced disease. This led to fewer evaluations for curative treatments.

Alcohol accounts for 30% of HCC cases and is the main etiology. The registry shows a decrease in hepatitis C-related HCC, an increase in LDrMS and HCC in non-cirrhotic livers. Surveillance was implemented in ∼80% of the recommended population. There is a need for improved screening and prevention strategies, particularly for alcohol abuse and LDrMS, to enhance HCC management.

Our study showcases the involvement of numerous reference centers across Spain and examines over 1,300 patients to track the changing epidemiology of hepatocellular carcinoma (HCC) over 14 years. In patients with known liver cirrhosis, more than 80% of HCC diagnoses were made through screening leading to early-stage identification and curative treatment opportunities. Notably, there has been a shift in HCC etiology within the registries from hepatitis C to liver disease related to metabolic syndrome, with an increase in cases without cirrhosis. Findings indicate a need for the prevention and early detection of HCC, particularly focusing on alcohol and liver disease related to metabolic syndrome, along with greater involvement of health authorities, to improve the participation of at-risk patients in screening programs.

Alcohol-related liver disease is the third leading cause of hepatocellular carcinoma worldwide and the leading cause in Europe. Additionally, the recent definition of metabolic dysfunction-associated steatotic liver disease with increased alcohol intake (MetALD) will enrich this population with a more nuanced phenotype, reflecting recent epidemiological trends. In these patients, the hepatocellular carcinoma diagnosis is often delayed and less frequently detected through screening programmes. Moreover, at the time of diagnosis, patients with alcohol-related hepatocellular carcinoma tend to have a poorer general condition, more severely impaired liver function, and a higher prevalence of comorbidities, leading to increased competitive mortality. However, when hepatocellular carcinoma is diagnosed during surveillance programmes in patients with alcohol-related liver disease or MetALD, the rate of allocation to first-line curative treatments is high (56%) and comparable to that of patients with virus-related hepatocellular carcinoma. As a consequence, the aetiology of the underlying cirrhosis cannot be considered an independent prognostic factor in patients with hepatocellular carcinoma. Instead, prognosis is driven by liver function, general condition, and tumour burden. This underscores the crucial role of early diagnosis through periodic surveillance in patients with alcohol- or MetALD-related cirrhosis.

Actionable candidates of hepatocarcinogenesis remain elusive, and tools for early detection are suboptimal. Our aim was to demonstrate that serum metabolome profiles reflect the initiation of hepatocellular carcinoma (HCC) and enable the identification of biomarkers for early HCC detection and actionable candidates for chemoprevention.

This global cohort study included 654 patients and 801 biospecimens. Following serum metabolome profiling across the spectrum of hepatocarcinogenesis, we conducted a phase II biomarker case-control study for early HCC detection. Findings were independently validated through in silico analysis, mRNA sequencing, and proteome profiling of primary HCC and non-tumoral tissue, and in vitro experiments.

Aspartic acid, glutamic acid, taurine, and hypoxanthine were differentially abundant in the serum across chronic liver disease, cirrhosis, initial HCC, and progressed HCC, independent of sex, age, and etiology. In a phase II biomarker case-control study, a blood-based metabolite signature yielded an AUC of 94% to discriminate between patients with early-stage HCC and controls with cirrhosis, including independent validation. Unsupervised biclustering (MoSBi), lipid network analysis (LINEX2), and pathway enrichment analysis confirmed alterations in amino acid-, lipid-, and nucleotide-related pathways. In tumor tissue, these pathways were significantly deregulated regarding gene and protein expression in two independent datasets, including actionable targets RRM2, GMPS, BCAT1, PYCR2, and NEU1. In vitro knockdown confirmed a functional role in proliferation and migration, as exemplified for PYCR2.

These findings demonstrate that serum metabolome profiling indicates deregulated metabolites and pathways during hepatocarcinogenesis. Our liquid biopsy approach accurately detects early-stage HCC outperforming currently recommended surveillance tools and facilitates identification of actionable candidates for chemoprevention.

Deregulated cellular metabolism is a hallmark of cancer. In smaller studies, circulating metabolite profiles have been associated with HCC, although mainly in the context of fatty liver disease. Translation strategies for primary prevention or early detection are lacking. In this global study, we present an unsupervised landscape of the altered serum metabolome profile during hepatocarcinogenesis, independent of age, sex, and etiology. We provide a blood-based metabolite signature that accurately identifies early-stage HCC in a phase II biomarker study including independent validation. Further RRM2, GMPS, BCAT1, PYCR2, and NEU1 are identified in tumor tissue as actionable candidates for prevention. Our data provide the rationale for clinical trials testing liquid biopsy metabolome-based signatures for early HCC detection and the development of chemoprevention strategies.

Hepatocellular carcinoma (HCC) most commonly occurs in a cirrhotic liver. In France, a screening rate of 20 % to 35 % has been reported in clinical cohorts. In these studies, patients were generally enrolled in centers of the same category (university or general hospitals). The aim of this study was to prospectively investigate the circumstances of HCC diagnosis and the causes of HCC screening failure in a cohort of patients from a regional network.

This prospective multicenter study enrolled patients with newly diagnosed HCC from October 2022 to July 2024. Investigators were from one university hospital, two private clinics, and three general hospitals.

Two hundred patients were included. Diagnosis was made by screening in 31.0 % of cases. Most patients had comorbidities that could lead to screening for liver fibrosis: current or past history of alcohol consumption (74.6 %), diabetes (51.4 %), hypertension (75.7 %), dyslipidemia (47.4 %). The FIB-4 score was ≥ 2.67 in 74.5 % of patients in the "in screening" group and 63.9 % in the "not in -screening" group. Among the 138 patient in the "not in screening" group, 115 (83.3 %), 34 (24.6), 23 (16.7 %) and 13 (9.4 %) declared they had visited a general practionner, a cardiologist, a gastroenterologist, and/or an endocrinologist within the 12 months prior to HCC diagnosis, respectively.

Recognition by general practitioners of patients at risk of chronic liver disease and identification of advanced fibrosis are major areas for optimization of HCC screening.

Pseudouridine synthases (PUSs) are associated with the development and progression of various cancers. However, the role of pseudouridine synthase 1 (PUS1) on HCC is unclear. The purpose of this study is to explore the biological role and mechanism of PUS1 in HCC growth and progression. We identified the expression of PUS1 in HCC. The biological roles and downstream cell signaling pathways of PUS1 were explored to clarify the molecular mechanism of PUS1 in the growth and development of HCC. The results showed that the expression of PUS1 was correlated with HCC progression, metastasis, and poor survival. In addition, the knockdown of PUS1 dramatically inhibited cell proliferation and colony formation and promoted cell apoptosis. GSEA analysis revealed that c-MYC, DNA repair, and mTORC1 pathways were significantly enriched in patients with high PUS1 expression. An intersection of the PUS1-dependent Ψ modification genes and c-MYC or mTORC1 pathway genes was performed. The expression of a part of these genes changed after PUS1 knockdown. Meanwhile, the expression of c-MYC and mTOR were down-regulated after PUS1 knockdown, but the inhibitory effect of PUS1 on cell growth capacity was not enhanced after inhibiting c-MYC or mTOR pathways. In conclusion, PUS1 regulates the occurrence and development of HCC through c-MYC and mTOR-related signaling pathways. It could be a novel molecule for clinical diagnosis, progression surveillance, prognosis assessment and therapeutic target of HCC.

Hepatocellular carcinoma remains a significant cause of mortality worldwide, particularly among patients with liver cirrhosis. In most cases, surveillance in cirrhotic patients is neglected, leading to a diagnosis when the neoplasm is at an advanced stage. Within this context, Zhou et al carried out a network meta-analysis to demonstrate the effectiveness of hepatic arterial infusion chemotherapy, concluding that it is a superior approach compared to sorafenib and transarterial chemoembolization in the treatment of advanced hepatocellular carcinoma. Unfortunately, the meta-analysis in question lacks methodological rigor, preventing the authors from making more definitive assertions. Additionally, we understand that transarterial chemoembolization, when properly indicated, is a highly effective therapeutic option, and that sorafenib, given the results of new therapies based on immune checkpoint inhibitors, is no longer the recommended drug for the treatment of these patients. Therefore, we believe the use of hepatic arterial infusion chemotherapy is increasingly limited and lacks strong scientific support.

Hepatocellular carcinoma (HCC) remains a deadly cancer in the UK despite advancements in curative therapies. Societal conditions and health inequalities influence the development of chronic liver disease and outcomes from complications including HCC. Scoping this emergent evidence-base is required to inform research and solutions for the NHS.

A PRISMA scoping review was performed up to September 2023. Articles exploring health inequalities in HCC involving the UK population were included.

This review has characterised axes of health inequality and their impact across the HCC care continuum in the UK. Studies predominantly employed a cohort design or population-based analyses, with meta-analyses of surveillance utilisation including only a single UK study. These methodologies provided an appropriate lens to understand longitudinal trends and identify disadvantaged groups. However, important evidence gaps remain, including exploration of patient perspectives, intersectional analyses, and statistical measures of socioeconomic inequity in HCC.

HCC is a rapidly growing cause of cancer mortality and disproportionally affects underserved groups, presenting a major public health concern. Further research is required to innovate and evaluate surveillance and management pathways to reduce systemic inequities. Direction is needed at the national level to improve prevention, early diagnosis and access to curative treatment.

Patient, clinician, and system-related barriers may affect adherence to hepatocellular carcinoma (HCC) surveillance programmes. The impact of a dedicated automated recall HCC surveillance programme on retention rates in patients eligible for screening is unknown. We aimed to describe and evaluate a large HCC surveillance programme in a publicly funded healthcare system.

Data were collected from January 1, 2013, to December 31, 2022, from a retrospective cohort of subjects enrolled in a publicly funded automated recall semi-annual surveillance programme as per the American Association for the Study of Liver Disease HCC guidance in the Calgary Health Zone (~1.6 million), Canada. Patients were excluded if there was incomplete data or did not meet indications for surveillance. Cox regression was used to identify predictors of non-retention to surveillance.

A total of 7269 patients were included. The median was age 55.5 years (IQR: 45.5-63.8), 60% were male, 46% were of Asian descent, 51% had HBV infection, and 36% had cirrhosis (35% alcohol-related). Median follow-up was 4.9 years (IQR: 1.5-7.2). Overall, 52% (n = 3768) of patients were retained in the surveillance programme, while 8.3% (n = 603) left for potential medical reasons, and 40% (n = 2898) were lost in follow-up. The median time in the programme for those lost in follow-up was 0.81 years (IQR: 0.0-2.8) compared to 6.75 years if retained (IQR: 5.6-8.6; p < 0.001). In multivariable Cox regression analysis, HCV aetiology (HR 1.41; CI 1.23-1.62, p < 0.01), African ethnicity (HR 1.20, CI 1.02-1.42, p = 0.03), and cirrhosis (HR 1.16, CI 1.05-1.28, p < 0.01) increased risk of dropout. On interaction analysis, Hepatitis B amongst cirrhotic patients also increased risk of dropout (HR 1.48, CI 1.05-2.07, p = 0.02).

A dedicated automated recall HCC surveillance programme has a high retention rate in a large multi-ethnic cohort of patients while identifying certain marginalised patient populations, such as those with viral liver disease, cirrhosis, or African ethnicity, as particularly vulnerable to loss to follow-up.

Patients with cirrhosis are at high risk for hepatocellular carcinoma (HCC), but few undergo guideline-recommended semi-annual screening. Randomized clinical trials (RCTs) demonstrate that mailed outreach can increase screening versus visit-based screening. We estimated the costs and cost-effectiveness of an outreach strategy versus usual care.

We built a 10-year Markov chain Monte Carlo microsimulation model to conduct a cost-effectiveness analysis comparing a mailed outreach program versus usual care for HCC screening in a cohort of 10,000 patients with cirrhosis. Model inputs were based on literature review (2005-current), and costs were based on inflation-adjusted estimates from Surveillance, Epidemiology, and End Results (SEER)-Medicare claims data. We conducted one-way sensitivity analyses for HCC incidence, outreach costs, efficacy of the outreach strategy to increase screening, and efficacy of curative (versus palliative) HCC treatments.

Mailed outreach was estimated to cost $32.45 per patient in the first year and $21.90 per patient in subsequent years. The outreach program increased the number of HCC patients detected at an early stage by 48.4% and increased quality-adjusted life years (QALYs) by 300. Cost savings from these increases offset the costs of mailed outreach. Mailed outreach remained cost-effective across a wide range of HCC incidence rates, outreach costs, efficacy of the outreach strategy to increase screening, and the efficacy of curative HCC treatments. Annual out-of-pocket patient costs in the outreach arm were low at $13 per year.

Mailed outreach to encourage HCC screening in patients with cirrhosis dominates usual care and should be considered for implementation in routine practice.

National Cancer Institute and Cancer Prevention Research Institute of Texas.

Primary liver cancer (PLC) is projected to be the third leading cause of cancer mortality in the United States in 2040. We examine the burden of PLC in the United States, stratified by sex, state and aetiological risk factors.

Data on PLC prevalence, incidence, death and disability-adjusted life years (DALYs) were extracted from the Global Burden of Disease Study 2021. Changes in these parameters were calculated using the Joinpoint regression model.

There were 47,970 cases, 31,450 incident cases, 24,770 deaths and 576,920 DALYs from PLC in the United States. The highest prevalence (16,980), incidence (12,040), death (9840) and DALYs (213,410) from PLC were due to chronic hepatitis C virus infection. From 2000 to 2021, PLC incidences increased by 141%, and PLC deaths increased by 136%. Age-standardised incidence rates (ASIRs) and death rates (ASDRs) per 100,000 population for PLC increased, primarily driven by alcohol-related liver disease (ALD) (ASIR: annual percent change [APC]: +2.40%; ASDR: APC: +2.22%) and metabolic dysfunction-associated steatotic liver disease (MASLD) (ASIR: APC: +2.32%; ASDR: APC: +2.04%).

The burden of PLC in the United States has risen in the past two decades, driven mainly by ALD and followed by MASLD. These findings offer policymakers an accurate assessment of the PLC burden and emphasise the need for targeted risk factor mitigation, especially regarding alcohol related policy.

Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis.

Molecular (prognostic liver secretome signature with α-fetoprotein) and clinical (aMAP [age, male sex, albumin-bilirubin, and platelets] score) variable-based scores were integrated into PAaM (prognostic liver secretome signature with α-fetoprotein plus age, male sex, albumin-bilirubin, and platelets), which was subsequently validated in 2 phase 3 biomarker validation studies: the statewide Texas HCC Consortium and nationwide HCC Early Detection Strategy prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events.

Of 2156 patients with cirrhosis in the Texas HCC Consortium, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared with low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios for incident HCC of 7.51 (95% CI, 4.42-12.8) and 4.20 (95% CI, 2.52-7.01), respectively. Of 1328 patients with cirrhosis in the HCC early detection strategy, PAaM identified 201 high-risk (15%), 540 intermediate-risk (41%), and 587 low-risk (44%) patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate-risk groups were associated with sub-distribution hazard ratios for incident HCC of 6.54 (95% CI, 3.85-11.1) and 1.77 (95% CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease and cured hepatitis C infection.

PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies.

Hepatocellular carcinoma (HCC) represents a significant portion of global cancer incidence and mortality. Screening with ultrasound with or without alpha-fetoprotein is recommended for those at high-risk. Although screening can lead to earlier treatment and better outcomes, existing screening paradigms have several flaws. Ultrasound does not capture all early lesions and has lower efficacy in specific populations such as patients with obesity or those with metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, individuals with noncirrhotic MASLD and chronic hepatitis C also develop HCC, although not at high enough rates to justify screening based on current standards. These individuals, however, represent a substantial proportion of new HCC cases given rising MASLD rates and the endemic nature of hepatitis C in certain regions. Risk-stratifying these populations may reveal subsets that are higher risk and warrant screening. Several imaging advances, including contrast-enhanced ultrasound and abbreviated MRI protocols, may improve detection compared with the current approach. Evaluation of risk stratification and validation of these new imaging methods via clinical trials would likely lead to adjusting screening guidelines. This narrative review provides a diagnostic and interventional radiology-focused summary of the HCC screening guidelines and their recent evolution and highlights emerging imaging methods as potential screening tools of the future.

Prognosis in patients with HCC is largely determined by stage at diagnosis, highlighting the importance of effective early detection strategies. HCC surveillance is associated with increased early detection and reduced HCC-related mortality and is currently recommended in patients with cirrhosis or chronic HBV infection.

We performed a targeted literature review to identify limitations of current HCC surveillance practices and strategies for improvement.

Semi-annual ultrasound continues as the cornerstone modality for HCC surveillance but has limited sensitivity for detecting early-stage HCC, particularly in patients with obesity and non-viral etiologies. Although sensitivity for early-stage HCC can be improved by using ultrasound with alpha fetoprotein, this strategy misses over one-third of HCC at an early stage. Emerging imaging and biomarker-based surveillance strategies currently remain in varying stages of validation and are not yet ready for routine use in practice. The cost-effectiveness of surveillance in patients with non-cirrhotic liver disease related to hepatitis C or metabolic dysfunction-associated steatotic liver disease continues to be debated, although subgroups with advanced fibrosis may warrant surveillance. Finally, the effectiveness of surveillance is diminished by underuse in clinical practice, particularly in racial minority and low-income groups, highlighting a need for interventions to increase utilization.

Metabolic dysfunction-associated steatotic liver disease (MASLD), a progressive liver disease frequently associated with metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity, has the potential to progress symptomatically to liver cirrhosis and, in some cases, hepatocellular carcinoma. Hence, an urgent need arises to identify and approve new therapeutic options to improve patient outcomes. Research efforts have focused on either developing dedicated molecules or repurposing drugs already approved for other conditions, such as metabolic diseases. Among the latter, antidiabetic and anti-obesity agents have received the most extensive attention, with pivotal trial results anticipated shortly. However, the primary focus underlying successful regulatory approvals is demonstrating a substantial efficacy in improving liver fibrosis and preventing or ameliorating cirrhosis, the key advanced outcomes within MASLD progression. Besides liver steatosis, the ideal therapeutic candidate should reduce inflammation and fibrosis effectively. Although some agents have shown promise in lowering MASLD-related parameters, evidence of their impact on fibrosis and cirrhosis remains limited. This review aims to evaluate whether antidiabetic and anti-obesity drugs can be safely and effectively used in MASLD-related advanced fibrosis or cirrhosis in patients with T2DM. Our paper discusses the molecules closest to regulatory approval and the expectation that they can address the unmet needs of this increasingly prevalent disease.

Hepatocellular carcinoma (HCC) disproportionately affects racial/ethnic minorities. We evaluated the impact of income and geography on racial/ethnic disparities across the HCC care cascade in the United States.

Using NCI registry data spanning 2000 to 2020, adults with HCC were evaluated to determine race/ethnicity-specific differences in tumor stage at diagnosis, delays and gaps in treatment, and survival. Adjusted regression models evaluated predictors of HCC outcomes.

Among 112,389 adults with HCC, cohort characteristics were as follows: 49.8% non-Hispanic White (NHW), 12.0% African American(AA), 20.5% Hispanic, 16.5% Asian/Pacific Islander, and 1.1% American Indian/Alaska Native. Compared with NHW patients, AA patients had lower odds of localized-stage HCC at diagnosis [adjusted odds ratio (aOR), 0.84], lower odds of HCC treatment receipt (aOR, 0.77), greater odds of treatment delays (aOR, 1.12), and significantly greater risk of death [adjusted hazards ratio (aHR), 1.10]. Compared with NHW patients from large metro areas, AA patients from large metro areas had 8% higher mortality risk (aHR, 1.08), whereas AA patients from small-medium metro areas had 17% higher mortality risk (aHR, 1.17; all P < 0.05).

Among a population-based cohort of US adults with HCC, significant race/ethnicity-specific disparities across the HCC care continuum were observed. Lower household income and more rural geography among racial/ethnic minorities are also associated with disparities in HCC outcomes, particularly among AA patients.

Our study shows that lower income and less urban/more rural geography among racial/ethnic minorities are also associated with disparities in HCC outcomes, particularly among AA patients with HCC. This contextualizes the complex relationship between sociodemographic factors and HCC outcomes through an intersectional lens.

The value of hepatocellular carcinoma screening is defined by the balance of benefits from early tumor detection vs harms because of false-positive results. We evaluated the value of a mailed outreach strategy for hepatocellular carcinoma screening in patients with cirrhosis.

We conducted a multicenter pragmatic randomized clinical trial comparing mailed outreach for hepatocellular carcinoma screening (n = 1436) and usual care with visit-based screening (n = 1436) among patients with cirrhosis at 3 health systems from March 2018 to September 2021. Outcomes of interest were early stage hepatocellular carcinoma detection (ie, screening benefit) and diagnostic evaluation for false-positive or indeterminate results (ie, screening harm). Screening harm was categorized as mild, moderate, and severe based on number and type of diagnostic exams. All patients were included in intention-to-screen analyses.

Of 125 patients diagnosed with hepatocellular carcinoma (67 outreach and 58 usual care), 71.2% were found at an early stage per the Milan criteria. Early tumor detection did not statistically significantly differ between the outreach and usual care arms (64.2% vs 79.3%; P = .06). The proportion of patients with physical harms also did not differ between the outreach and usual care arms (10.8% vs 10.7%; P = .95) with 5.9% in both arms having mild harms; 4.0% and 3.8%, respectively, with moderate harms; and 0.9% and 1.0%, respectively, with severe harms.

Most patients enrolled in hepatocellular carcinoma screening were detected at an early stage, and a minority experienced physical harms. A mailed outreach strategy did not increase early hepatocellular carcinoma detection or physical harms compared with usual care.

NCT02582918 and NCT03756051.

Transplant oncology encompasses and utilizes liver transplantation (LT) in combination with other aspects of cancer care to offer improved long-term outcomes for patients with liver cancer, but not all patients have equal access and ability to undergo LT. Social determinants of health may negatively impact a patient's ability to receive liver-related oncologic care, including LT. This review highlights recent work exposing gaps in access to LT, including transplant oncology, and interventions to ameliorate these disparities.

Members of racial and ethnic minorities and indigenous groups, females, socioeconomically disadvantaged persons, and patients from rural areas are less likely to undergo LT. Recent studies have also described programs that have successfully mitigated some of the barriers in access to transplant oncology that these patients experience, including targeted outreach programs and access to virtual healthcare.

Disparities in access to LT for liver cancer are increasingly well described, but additional research is needed to find effective ways to ameliorate these differences.

Better surveillance tests for hepatocellular carcinoma (HCC) are needed. The GALAD score (gender, age, α-fetoprotein [AFP] L3, AFP, and des-γ carboxyprothrombin) has been shown to have excellent sensitivity and specificity for HCC in phase 2 studies. We performed a phase 3 biomarker validation study to compare GALAD with AFP in detecting HCC.

This is a prospective study of patients with cirrhosis enrolled at 7 centers. Surveillance for HCC was performed every 6 months at each site, and HCC diagnosis was confirmed per American Association for the Study of Liver Diseases guidelines. Blood for biomarker research was obtained at each follow-up visit and stored in a biorepository. Measurements of AFP, AFP-L3, and des-γ carboxyprothrombin) were performed in a FujiFilm laboratory by staff blinded to clinical data. The performance of GALAD in detecting HCC was retrospectively evaluated within 12 months before the clinical diagnosis. All analyses were conducted by an unblinded statistician in the Early Detection Research Network data management and coordinating center.

A total of 1,558 patients with cirrhosis were enrolled and followed for a median of 2.2 years. A total of 109 patients developed HCC (76 very early or early stage), with an annual incident rate of 2.4%. The areas under the curve for AFP and GALAD within 12 months before HCC were 0.66 and 0.78 (P < .001), respectively. Using a cutoff for GALAD of -1.36, the specificity was 82%, and the sensitivity at 12 months before HCC diagnosis was 62%. For comparison, performance of AFP at 82% specificity showed 41% sensitivity at 12 months before HCC diagnosis (P = .001).

GALAD score, compared to AFP, improves the detection of HCC within 12 months before the actual diagnosis.

Hepatocellular carcinoma (HCC) is a major global burden, ranking as the third leading cause of cancer-related mortality. HCC due to chronic hepatitis B virus (HBV) or C virus (HCV) infection has decreased due to universal vaccination for HBV and effective antiviral therapy for both HBV and HCV, but HCC related to metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease is increasing. Biannual liver ultrasonography and serum α-fetoprotein are the primary surveillance tools for early HCC detection among high-risk patients (e.g., cirrhosis, chronic HBV). Alternative surveillance tools such as blood-based biomarker panels and abbreviated magnetic resonance imaging (MRI) are being investigated. Multiphasic computed tomography or MRI is the standard for HCC diagnosis, but histological confirmation should be considered, especially when inconclusive findings are seen on cross-sectional imaging. Staging and treatment decisions are complex and should be made in multidisciplinary settings, incorporating multiple factors including tumor burden, degree of liver dysfunction, patient performance status, available expertise, and patient preferences. Early-stage HCC is best treated with curative options such as resection, ablation, or transplantation. For intermediate-stage disease, locoregional therapies are primarily recommended although systemic therapies may be preferred for patients with large intrahepatic tumor burden. In advanced-stage disease, immune checkpoint inhibitor-based therapy is the preferred treatment regimen. In this review article, we discuss the recent global epidemiology, risk factors, and HCC care continuum encompassing surveillance, diagnosis, staging, and treatments.

In recent years, novel findings have progressively and promisingly supported the potential role of Artificial intelligence (AI) in transforming the management of various neoplasms, including hepatocellular carcinoma (HCC). HCC represents the most common primary liver cancer. Alarmingly, the HCC incidence is dramatically increasing worldwide due to the simultaneous "pandemic" spreading of metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD currently constitutes the leading cause of chronic hepatic damage (steatosis and steatohepatitis), fibrosis, and liver cirrhosis, configuring a scenario where an HCC onset has been reported even in the early disease stage. On the other hand, HCC represents a serious plague, significantly burdening the outcomes of chronic hepatitis B (HBV) and hepatitis C (HCV) virus-infected patients. Despite the recent progress in the management of this cancer, the overall prognosis for advanced-stage HCC patients continues to be poor, suggesting the absolute need to develop personalized healthcare strategies further. In this "cold war", machine learning techniques and neural networks are emerging as weapons, able to identify the patterns and biomarkers that would have normally escaped human observation. Using advanced algorithms, AI can analyze large volumes of clinical data and medical images (including routinely obtained ultrasound data) with an elevated accuracy, facilitating early diagnosis, improving the performance of predictive models, and supporting the multidisciplinary (oncologist, gastroenterologist, surgeon, radiologist) team in opting for the best "tailored" individual treatment. Additionally, AI can significantly contribute to enhancing the effectiveness of metabolomics-radiomics-based models, promoting the identification of specific HCC-pathogenetic molecules as new targets for realizing novel therapeutic regimens. In the era of precision medicine, integrating AI into routine clinical practice appears as a promising frontier, opening new avenues for liver cancer research and treatment.

Preventive interventions are expected to substantially improve the prognosis of patients with primary liver cancer, predominantly HCC and cholangiocarcinoma. HCC prevention is challenging in the face of the evolving etiological landscape, particularly the sharp increase in obesity-associated metabolic disorders, including metabolic dysfunction-associated steatotic liver disease. Next-generation anti-HCV and HBV drugs have substantially reduced, but not eliminated, the risk of HCC and have given way to new challenges in identifying at-risk patients. The recent development of new therapeutic agents and modalities has opened unprecedented opportunities to refine primary, secondary, and tertiary HCC prevention strategies. For primary prevention (before exposure to risk factors), public health policies, such as universal HBV vaccination, have had a substantial prognostic impact. Secondary prevention (after or during active exposure to risk factors) includes regular HCC screening and chemoprevention. Emerging biomarkers and imaging modalities for HCC risk stratification and detection may enable individual risk-based personalized and cost-effective HCC screening. Clinical studies have suggested the potential utility of lipid-lowering, antidiabetic/obesity, and anti-inflammatory agents for secondary prevention, and some of them are being evaluated in prospective clinical trials. Computational and experimental studies have identified potential chemopreventive strategies directed at diverse molecular, cellular, and systemic targets for etiology-specific and/or agnostic interventions. Tertiary prevention (in conjunction with curative-intent therapies for HCC) is an area of active research with the development of new immune-based neoadjuvant/adjuvant therapies. Cholangiocarcinoma prevention may advance with recent efforts to elucidate risk factors. These advances will collectively lead to substantial improvements in liver cancer mortality rates.

This systematic literature review of qualitative findings aims to identify the perceived barriers and enablers for hepatocellular carcinoma (HCC) surveillance from patient and clinician perspectives.

A systematic search of databases using key term combinations with the following inclusion criteria: 1) qualitative and quantitative (survey) studies exploring barriers and enablers of HCC surveillance, and 2) qualitative and quantitative (survey) studies exploring barriers and enablers of enagagement in clinical care for patients with cirrhosis and/or viral hepatitis.

The search returned 445 citations: 371 did not meet the study criteria and were excluded. 74 studies proceeded to full-text review, leading to 21 included studies (15 studies from searching with a further six studies from citation review) progressing to data extraction by two independent reviewers. Results from studies exploring patients' perspectives reinforce that barriers are experienced by patients across different health settings, cultures, and regions. Logistical barriers including costs and transportation, and knowledge/awareness barriers were commonly identified. Studies that included clinician perspectives highlighted the need for healthcare provider education and system-level interventions to optimize HCC surveillance uptake in clinical practice.

These findings highlight the critical need for interventions that enable engagement in HCC surveillance in health services.

Steatotic liver disease (SLD) is an emerging liver disease that has been associated with an increased risk for hepatocellular carcinoma (HCC). The impact of concurrent SLD on the prognosis of HCC remains unknown. This study investigates how concurrent SLD affects the outcomes of patients with HCC undergoing curative radiofrequency ablation (RFA) therapy.

A retrospective analysis of patients with early-stage HCC receiving curative RFA at a tertiary medical center was conducted. Laboratory data and HCC characteristics were recorded and analyzed by a Cox proportional hazards regression model to predict recurrence and all-cause mortality after RFA.

A total of 598 patients with HCC were included between 2005 and 2015, with 139 and 459 classified in SLD and non-SLD groups, respectively. The SLD group exhibited a significantly better liver reserve and a lower cumulative incidence of HCC recurrence and liver-related and all-cause mortality after a median follow-up of 51 months. After adjusting for metabolic dysfunction, liver reserve, and HCC characteristics, the presence of SLD reduced all-cause mortality (adjusted hazard ratio [aHR], 0.67; 95% confidence interval [CI], 0.45-0.996; p = .048), which was supported by inverse probability weighting analysis (aHR, 0.65; 95% CI, 0.42-1.00; p = .049). Poor liver functional reserve (high albumin-bilirubin grades) increased all-cause mortality dose dependently. Barcelona Clinic Liver Cancer staging and a higher Fibrosis-4 index were predictors for HCC recurrence, whereas SLD was not.

Among patients with HCC undergoing curative RFA, those with concurrent SLD had a lower risk of all-cause mortality compared to those with poor liver functional reserve.

The present research demonstrated that patients with both liver cancer and steatotic liver disease who received curative radiofrequency ablation for liver cancer survived longer compared to those without steatotic liver disease. Maintaining good liver function is an important prognostic factor for survival.

This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To estimate the diagnostic accuracy of des-gamma-carboxy prothrombin, GALAD (Gender, Age, Lens culinaris agglutinin-reactive AFP, AFP and DCP), and alpha-foetoprotein for the diagnosis of hepatocellular carcinoma of any size, and at any stage, in adults with chronic liver disease, in either a surveillance programme or a clinical setting. We acknowledge the possibility that theoretically, the accuracy of the tests in a surveillance programme may differ from that in a clinical setting due to variation in inclusion criteria and the prevalence of the target condition. However, we do not plan a separate analysis for surveillance and clinical settings, as they are not clearly distinct in current clinical practice (Forner 2018; Poustchi 2011). In routine evaluation of people with chronic liver disease, index tests, as well as ultrasound, are already part of standard procedure. Given that HCC typically presents with no symptoms and is often asymptomatic, suspicion of the disease is typically based solely on the presence of advanced chronic liver disease. However, we do plan to consider the study setting as a potential source of heterogeneity. To compare the diagnostic accuracy of des-gamma-carboxy prothrombin (DCP) alone or GALAD alone versus alpha-foetoprotein (AFP), for the diagnosis of hepatocellular carcinoma (HCC) of any size, at any stage; in adults with chronic liver disease, either in a surveillance programme or a clinical setting. Secondary objectives To estimate the diagnostic accuracy of DCP or GALAD versus AFP, for resectable HCC in people with chronic liver disease, in a surveillance programme and a clinical setting. To investigate the following predefined sources of heterogeneity for each of the index tests: study design (case-control studies compared to cross-sectional studies); inclusion of participants without cirrhosis (studies including more than 10% of participants without cirrhosis compared to studies including less than 10% of participants without cirrhosis); study location (population differences): studies conducted in North and South America and Europe compared to Asia and Africa; prevalence of the target condition (studies with hepatocellular carcinoma prevalence more than 10% compared to studies with hepatocellular carcinoma prevalence less than 10%); participant selection (participants recruited from planned surveillance programmes compared to clinical cohorts); different reference standards (histology of the explanted liver compared to liver biopsy compared to another reference standard); different aetiology: studies including at least 90% of participants with chronic viral hepatitis compared to studies including less than 90% of participants with chronic viral hepatitis.

This study aimed to evaluate the cost-effectiveness (CE) of 4 hepatocellular carcinoma (HCC) surveillance strategies in the United Kingdom, the GAAD algorithm, which combines Gender (biological sex) and Age with Elecsys® biomarker assays, alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (previously Des-γ-carboxy prothrombin); ultrasound (US); US + AFP and GAAD + US.

A de novo microsimulation state-transition Markov model was developed in Microsoft Excel® from the perspective of the United Kingdom National Health Service to calculate life-years, quality-adjusted life-years (QALYs), costs, incremental CE ratios, and net monetary benefits. Parameters were sourced from peer-reviewed published literature, national guidelines, and public cost databases. Sensitivity and scenario analyses were performed to evaluate the impact of parameter and structural uncertainty on the results.

In a simulated cohort of 100 000 patients, discounted costs and QALYs per patient were £8663 and 6·066 for US, £9095 and 6·076 for US + AFP, £8719 and 6·078 for GAAD alone, and £9114 and 6·086 for GAAD + US. At a CE threshold of £20 000/QALY, GAAD was the most cost-effective strategy; however, although most costly, GAAD + US was the most clinically effective. Sensitivity and scenario analyses indicated that HCC incidence along with costs associated with diagnostic performance influence CE.

Considering the cost of US and low incidence of HCC in the United Kingdom, this study suggests that GAAD alone or in combination with US are cost-effective surveillance strategies compared with US and US + AFP. Although GAAD + US showed the highest QALY increase, GAAD alone is considered preferable regarding CE; however, better performance estimates for GAAD + US are needed to confirm.