The current review aims to summarize the benefits and limitations of the novel multicancer detection tests (MCD) for diagnosing gastrointestinal (GI) malignancies.

Traditional cancer screening methods can reduce deaths in malignancies involving the GI tract. For GI cancers, screening options vary by type and often involve invasive techniques with limited sensitivity. MCDs offer a promising, non-invasive (simple blood draw) alternative by analyzing biomarkers such as cell-free DNA and RNA using advanced techniques and machine learning to detect cancers across multiple organ sites. Large studies like the PATHFINDER trial and THUNDER study have demonstrated the feasibility and accuracy of MCD assays in identifying cancer signals, with high sensitivity and specificity in some GI organs that lack routine screening tests (e.g., liver, pancreas, and stomach). Despite these advancements, MCD testing faces challenges, including high costs, lack of FDA approval, false positives, and limited data on clinical utility in reducing cancer-specific mortality. MCD should not be a substitute for age-appropriate cancer screenings but may complement existing methods, particularly for cancers with no current screening tools, such as cholangiocarcinoma and pancreatic cancer. Clinicians need to discuss the limitations of MCDs, including the potential for overdiagnosis, patient anxiety, and financial burden due to insurance coverage gaps. MCD is a promising, non-invasive test that can augment traditional cancer screening. As the role of MCD in cancer detection evolves, further research is essential to establish how it will be integrated into clinical practice, ensuring informed, shared decision-making with patients.

Major society guidelines recommend the fibrosis-4 index (FIB-4) as the initial step to risk stratifying people with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to evaluate the proportion of people with MASLD-related hepatocellular carcinoma (HCC) and a low FIB-4.

This cohort study included 613 consecutive adults (33% female) diagnosed with MASLD-related HCC from January 2008 to August 2023 at seven international centres in Australia, India, Japan, South Korea, Singapore and the United States. The primary objective was to determine the proportion of participants with a low FIB-4, defined as FIB-4 < 1.3, or < 2 if age > 65 years, in people without cirrhosis.

The mean (±SD) age and body mass index were 71 (±11) years and 27 (±7) kg/m2, respectively. Overall, 235 participants (38%) did not have known cirrhosis. The median FIB-4 was 3.90 (IQR 2.42-6.42). A total of 78 participants (13%) had a low FIB-4. Among participants without known cirrhosis (n = 235), 62 participants (26%) had a low FIB-4. Participants with a low FIB-4 had larger median total tumour diameter (p < 0.001) and lower median serum alpha-fetoprotein (p = 0.005), compared to participants without a low FIB-4. Cirrhosis was associated with lower odds of low FIB-4, but not other factors such as male sex, type 2 diabetes, or obesity.

More than a quarter of those with MASLD-related HCC without cirrhosis have a low FIB-4. The proposed clinical care pathways may not identify these people for further evaluation.

Hepatocellular carcinoma (HCC) represents the predominant form of primary liver cancer, yet early, precise, and noninvasive detection continues to pose a considerable clinical challenge. Glypican-3 (GPC3), a membrane-bound proteoglycan, is markedly overexpressed in most HCC cases, while exhibiting low expression in normal and hepatitis-affected liver tissues. Given its crucial role in malignant transformation and tumor progression, GPC3 emerges as a compelling target for imaging. In this study, we developed and evaluated 2 68Ga-labeled GPC3-targeted positron emission tomography (PET) probes, each incorporating either polyethylene glycol (PEG) or 4-(p-methylphenyl)butanoic acid (an albumin-binding moiety). Comparative analyses revealed that 68Ga-ALB-GBP, which includes the albumin-binding moiety, exhibited superior in vivo stability, enhanced tumor uptake, and an improved tumor-to-liver ratio relative to 68Ga-PEG2-GBP in subcutaneous HCC mouse models. Micro-PET/computed tomography imaging of orthotopic liver cancer with 68Ga-ALB-GBP demonstrated a tumor-to-liver ratio of 2.29 ± 0.13 and a tumor-to-muscle ratio of 13.03 ± 1.63 at 3 h postinjection, outperforming the performance of the clinically used 18F-fluorodeoxyglucose PET imaging. These findings suggest that 68Ga-ALB-GBP is a promising diagnostic tool for HCC and a strong candidate for clinical translation with potential utility in both diagnostic and therapeutic settings. Moreover, the incorporation of an albumin-binding moiety into PET tracers significantly extends blood circulation time, thereby enhancing bioavailability and facilitating high-contrast PET imaging.

To compare therapeutic outcomes of predicted proliferative and nonproliferative hepatocellular carcinoma (HCC) after microwave ablation (MWA) using a previously developed imaging-based predictive model, the SMARS score.

This multicenter retrospective study included consecutive 635 patients with unresectable HCC who underwent MWA between August 2013 and September 2020. Patients were stratified into predicted proliferative and nonproliferative phenotypes according to the SMARS score. Overall survival (OS) and recurrence-free survival (RFS) were compared between the predicted proliferative and nonproliferative HCCs before and after propensity score matching (PSM). OS and RFS were also compared between the two groups in subgroups of tumor size smaller than 30 mm and tumor size 30-50 mm.

The SMARS score classified 127 and 508 patients into predicted proliferative and nonproliferative HCCs, respectively. The predicted proliferative HCCs exhibited worse RFS but equivalent OS when compared with nonproliferative HCCs before (p < 0.001 for RFS; p = 0.166 for OS) and after (p < 0.001 for RFS; p = 0.456 for OS) matching. Regarding subgroups of tumor size smaller than 30 mm (p = 0.098) and tumor size 30-50 mm (p = 0.680), the OSs were similar between the two groups. However, predicted proliferative HCCs had worse RFS compared to nonproliferative HCCs in the subgroup of tumor size 30-50 mm (p < 0.001), while the RFS did not differ in the subgroup of tumor size smaller than 30 mm (p = 0.141).

Predicted proliferative HCCs have worse RFS than nonproliferative ones after MWA, especially in tumor size larger than 30 mm. However, the phenotype of the tumor may not affect the OS.

Before performing microwave ablation for hepatocellular carcinoma, the tumor phenotype should be considered because it may affect the therapeutic outcome.

Proliferative hepatocellular carcinoma (HCC) may be identified using the SMARS score, an imaging-based predictive model. SMARS predicted proliferative HCCs have worse recurrence-free and equivalent overall survival compared to nonproliferative HCC after microwave ablation. Tumor phenotype should be considered before performing microwave ablation.

Hepatocellular carcinoma (HCC) remains one of the leading causes of death among many associated liver diseases. Various conventional strategies have been utilized for treatment, ranging from invasive surgeries and liver transplants to radiation therapy, but fail due to advanced disease progression, late screening/staging, and the various etiologies of HCC. This is especially evident within racially distinct populations, where incidence rates are higher and treatment outcomes are worse for racial/ethnic minorities than their Caucasian counterparts. However, with the rapid development of genetic engineering and molecular and synthetic biology, many novel strategies have presented promising results and have provided potential treatment options. In this review, we summarize past treatments, how they have shaped current treatments, and potential treatment strategies for HCC that may prove more effective in the future.

Ultrasound (US) is associated with severe visualization limitations (US Liver Imaging Reporting and Data System visualization score C) in one-third of patients with nonalcoholic fatty liver disease (NAFLD) cirrhosis undergoing hepatocellular carcinoma (HCC) screening. Data suggest abbreviated MRI (aMRI) may improve HCC screening efficacy. This study analyzed the cost-effectiveness of HCC screening strategies, including an US visualization score-based approach with aMRI, in patients with NAFLD cirrhosis.

We constructed a Markov model simulating adults with compensated NAFLD cirrhosis in the United States undergoing HCC screening, comparing strategies of US plus visualization score, US alone, or no surveillance. We modeled aMRI in patients with visualization score C and negative US, while patients with scores A/B did US alone. We performed a sensitivity analysis comparing US plus visualization score with US plus alpha fetoprotein or no surveillance. The primary outcome was the incremental cost-effectiveness ratio (ICER), with a willingness-to-pay threshold of $100,000 per quality-adjusted life-year. Sensitivity analyses were performed for all variables.

US plus visualization score was the most cost-effective strategy, with an ICER of $59,005 relative to no surveillance. The ICER for US alone to US plus visualization score was $822,500. On sensitivity analysis, screening using US plus visualization score remained preferred across several parameters. Even with alpha fetoprotein added to US, the US plus visualization score strategy remained cost-effective, with an ICER of $62,799 compared with no surveillance.

HCC surveillance using US visualization score-based approach, using aMRI for visualization score C, seems to be the most cost-effective strategy in patients with NAFLD cirrhosis.

The prevention and early diagnosis of liver cancer remains a global medical challenge. During the malignant transformation of hepatocytes, a variety of oncogenic cellular signalling molecules, such as novel high mobility group-Box 3, angiopoietin-2, Golgi protein 73, glypican-3, Wnt3a (a signalling molecule in the Wnt/β-catenin pathway), and secretory clusterin, can be expressed and secreted into the blood. These signalling molecules are derived from different signalling pathways and may not only participate in the malignant transformation of hepatocytes but also become early diagnostic indicators of hepatocarcinogenesis or specific targeted molecules for hepatocellular carcinoma therapy. This article reviews recent progress in the study of several signalling molecules as sensitive biomarkers for monitoring hepatocarcinogenesis.

Lysyl oxidase-like 2 (LOXL2) mediates the crosslinking of extracellular collagen, reflecting qualitative changes in liver fibrosis. This study aimed to validate the utility of serum LOXL2 levels as a predictive biomarker for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection who achieved a sustained virological response (SVR). This retrospective study included 137 patients with chronic HCV infection without history of HCC development and who achieved SVR via direct-acting antiviral therapy. Median LOXL2 levels decreased significantly after SVR achievement (pre-Tx, 2.33 ng/mL; post-Tx, 1.31 ng/mL, p < 0.001). Post-Tx LOXL2 levels, fibrosis-4 index, platelet counts, Wisteria floribunda agglutinin-positive human Mac-2 binding protein levels, and alpha-fetoprotein (AFP) levels were identified as independent predictive factors for post-SVR HCC development in the univariate analysis. The incidence of post-SVR HCC development was significantly higher in patients with post-Tx LOXL2 levels ≥ 2.08 ng/mL and AFP levels ≥ 5.0 ng/mL than in patients with elevated levels of either marker or with lower marker levels. Serum LOXL2 levels can serve as a predictive biomarker for HCC development after achieving SVR. The combination of serum LOXL2 and AFP levels provides robust risk stratification for HCC development after SVR, suggesting an enhanced surveillance strategy.

The precise assessment of liver fibrosis degree is imperative for monitoring and managing chronic liver diseases. Traditionally, liver biopsy and quantitative blood biomarkers have been the mainstays for fibrosis assessment, albeit each with its inherent limitations. However, the emergence of elastography presents a promising non-invasive alternative, potentially supplanting or complementing traditional biomarkers. In contrast to conventional biomarkers, elastography offers several advantages. Firstly, it is non-invasive, sidestepping the risks and discomfort associated with liver biopsy. Secondly, this technique provides real-time and intuitive fibrosis assessments, characterized by user-friendly operation and high reproducibility. Thirdly, elastography excels in diagnosing moderate to severe fibrosis, is vital for determining treatment strategies and monitoring disease progression. Notably, MRE stands out as the most accurate non-invasive method for fibrosis assessment, especially suitable for advanced fibrotic stages. This article provides an overview of the advancements in elastography as a viable quantitative biomarker for chronic liver disease fibrosis burden.

Non-alcoholic fatty liver disease (NAFLD), with its progressive form, non-alcoholic steatohepatitis (NASH), has emerged as a significant public health concern, affecting over 30% of the global population. Hepatocellular carcinoma (HCC), a complication associated with both cirrhotic and non-cirrhotic NAFLD, has shown a significant increase in incidence. A substantial proportion of NAFLD-related HCC occurs in non-cirrhotic livers, highlighting the need for improved risk stratification and surveillance strategies. This comprehensive review explores the potential role of liver ultrasound elastography as a risk assessment tool for HCC development in NAFLD and highlights the importance of effective screening tools for early, cost-effective detection and improved management of NAFLD-related HCC. The integration of non-invasive tools and algorithms into risk stratification strategies could have the capacity to enhance NAFLD-related HCC screening and surveillance effectiveness. Alongside exploring the potential advancement of non-invasive tools and algorithms for effectively stratifying HCC risk in NAFLD, we offer essential perspectives that could enable readers to improve the personalized assessment of NAFLD-related HCC risk through a more methodical screening approach.