Insulin Use and The Risk of Hepatocellular Carcinoma: Insights and Implications.

In recent years, the incidence of diabetes mellitus and hepatocellular carcinoma (HCC) has been increasing worldwide, in the context of an increasing prevalence of non-alcoholic fatty liver disease (NAFLD). In patients with diabetes mellitus, exogenous insulin is commonly prescribed and used in long-term settings. Recent studies suggest that insulin use may elevate the risk of HCC. A substantial body of work seeks to unpack the association between insulin use and the risk of developing HCC, although there may be conflicting evidence. Further validation is necessary to clarify the true relationship between insulin mechanisms and its hepatocarcinogenic effect. Given the burden of diabetic patients developing HCC, diabetologists and hepatologists must collaborate, particularly regarding the prevention and surveillance of HCC in diabetic patients.

Shear-wave elastography to predict hepatocellular carcinoma after hepatitis C virus eradication: A systematic review and meta-analysis.

BACKGROUND: Direct-acting antiviral agents (DAAs) are highly effective treatment for chronic hepatitis C (CHC) with a significant rate of sustained virologic response (SVR). The achievement of SVR is crucial to prevent additional liver damage and slow down fibrosis progression. The assessment of fibrosis degree can be performed with transient elastography, magnetic resonance elastography or shear-wave elastography (SWE). Liver elastography could function as a predictor for hepatocellular carcinoma (HCC) in CHC patients treated with DAAs. AIM: To explore the predictive value of SWE for HCC development after complete clearance of hepatitis C virus (HCV). METHODS: A comprehensive literature search of clinical studies was performed to identify the ability of SWE to predict HCC occurrence after HCV clearance. In accordance with the study protocol, a qualitative and quantitative analysis of the evidence was planned. RESULTS: At baseline and after 12 wk of follow-up, a trend was shown towards greater liver stiffness (LS) in those who go on to develop HCC compared to those who do not [baseline LS standardized mean difference (SMD): 1.15, 95% confidence interval (95%CI): 020-2.50; LS SMD after 12 wk: 0.83, 95%CI: 0.33-1.98]. The absence of a statistically significant difference between the mean LS in those who developed HCC or not may be related to the inability to correct for confounding factors and the absence of raw source data. There was a statistically significant LS SMD at 24 wk of follow-up between patients who developed HCC vs not (0.64; 95%CI: 0.04-1.24). CONCLUSION: SWE could be a promising tool for prediction of HCC occurrence in patients treated with DAAs. Further studies with larger cohorts and standardized timing of elastographic evaluation are needed to confirm these data.

Associations between type 2 diabetes mellitus and chronic liver diseases: evidence from a Mendelian ranldomization study in Europeans and East Asians.

Objective: Multiple observational studies have demonstrated an association between type 2 diabetes mellitus (T2DM) and chronic liver diseases (CLDs). However, the causality of T2DM on CLDs remained unknown in various ethnic groups. Methods: We obtained instrumental variables for T2DM and conducted a two-sample mendelian randomization (MR) study to examine the causal effect on nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), viral hepatitis, hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection risk in Europeans and East Asians. The primary analysis utilized the inverse variance weighting (IVW) technique to evaluate the causal relationship between T2DM and CLDs. In addition, we conducted a series of rigorous analyses to bolster the reliability of our MR results. Results: In Europeans, we found that genetic liability to T2DM has been linked with increased risk of NAFLD (IVW : OR =1.3654, 95% confidence interval [CI], 1.2250-1.5219, p=1.85e-8), viral hepatitis (IVW : OR =1.1173, 95%CI, 1.0271-1.2154, p=0.0098), and a suggestive positive association between T2DM and HCC (IVW : OR=1.2671, 95%CI, 1.0471-1.5333, p=0.0150), HBV (IVW : OR=1.1908, 95% CI, 1.0368-1.3677, p=0.0134). No causal association between T2DM and HCV was discovered. Among East Asians, however, there was a significant inverse association between T2DM and the proxies of NAFLD (ALT: IVW OR=0.9752, 95%CI 0.9597-0.9909, p=0.0021; AST: IVW OR=0.9673, 95%CI, 0.9528-0.9821, p=1.67e-5), and HCV (IVW: OR=0.9289, 95%CI, 0.8852-0.9747, p=0.0027). Notably, no causal association was found between T2DM and HCC, viral hepatitis, or HBV. Conclusion: Our MR analysis revealed varying causal associations between T2DM and CLDs in East Asians and Europeans. Further research is required to investigate the potential mechanisms in various ethnic groups, which could yield new insights into early screening and prevention strategies for CLDs in T2DM patients.

Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial.

Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown. Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD. Design, Setting, and Participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023. Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months. Main Outcomes and Measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified. Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn. Conclusions and Relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04031729.

Histidine-rich glycoprotein in metabolic dysfunction-associated steatohepatitis-related disease progression and liver carcinogenesis.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously non-alcoholic fatty liver disease (NAFLD), is a leading cause of chronic liver disease worldwide. In 20%-30% of MASLD patients, the disease progresses to metabolic dysfunction-associated steatohepatitis (MASH, previously NASH) which can lead to fibrosis/cirrhosis, liver failure as well as hepatocellular carcinoma (HCC). Here we investigated the role of histidine-rich glycoprotein (HRG), a plasma protein produced by hepatocytes, in MASLD/MASH progression and HCC development. Methods: The role of HRG was investigated by morphological, cellular, and molecular biology approaches in (a) HRG knock-out mice (HRG-/- mice) fed on a CDAA dietary protocol or a MASH related diethyl-nitrosamine/CDAA protocol of hepatocarcinogenesis, (b) THP1 monocytic cells treated with purified HRG, and (c) well-characterized cohorts of MASLD patients with or without HCC. Results: In non-neoplastic settings, murine and clinical data indicate that HRG increases significantly in parallel with disease progression. In particular, in MASLD/MASH patients, higher levels of HRG plasma levels were detected in subjects with extensive fibrosis/cirrhosis. When submitted to the pro-carcinogenic protocol, HRG-/- mice showed a significant decrease in the volume and number of HCC nodules in relation to decreased infiltration of macrophages producing pro-inflammatory mediators, including IL-1ß, IL-6, IL-12, IL-10, and VEGF as well as impaired angiogenesis. The histopathological analysis (H-score) of MASH-related HCC indicate that the higher HRG positivity in peritumoral tissue significantly correlates with a lower overall patient survival and an increased recurrence. Moreover, a significant increase in HRG plasma levels was detected in cirrhotic (F4) patients and in patients carrying HCC vs. F0/F1 patients. Conclusion: Murine and clinical data indicate that HRG plays a significant role in MASLD/MASH progression to HCC by supporting a specific population of tumor-associated macrophages with pro-inflammatory response and pro-angiogenetic capabilities which critically support cancer cell survival. Furthermore, our data suggest HRG as a possible prognostic predictor in HCC patients with MASLD/MASH-related HCCs.

Meta-analysis: Incidence of cirrhosis and hepatocellular carcinoma in patients with Fontan palliation.

BACKGROUND AND AIMS: The Fontan palliation is the final stage of surgery for many children born with univentricular physiology. Almost all Fontan patients develop liver fibrosis which may eventually lead to cirrhosis and hepatocellular carcinoma (HCC). These are important causes of morbidity and mortality in these patients. We performed a systematic review and meta-analysis to assess the incidence of cirrhosis and HCC in Fontan patients and stratify it based on time since surgery. METHODS: A literature search of seven databases identified 1158 records. Studies reporting the number of cirrhosis and HCC cases in Fontan patients and time since Fontan surgery were included. In the cirrhosis cohort, we included only those studies where all patients underwent liver biopsy. RESULTS: A total of 23 studies were included: 12 and 13 studies in the cirrhosis and HCC cohorts, respectively, with two studies included in both cohorts. The incidence of cirrhosis was 0.97 per 100 patient-years (95% CI 0.57-1.63), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 1.61 per 100 patient-years (95% CI 1.24-2.08) and 32.2% (95% CI 25.8%-39.4%), respectively. The incidence of HCC was 0.12 per 100 patient-years (95% CI 0.07-0.21), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 0.20 per 100 patient-years (95% CI 0.12-0.35) and 3.9% (95% CI 2.2%-6.8%), respectively. Only about 70% of patients with HCC (20/28) had underlying cirrhosis. CONCLUSION: The incidence of cirrhosis and HCC increases over time, especially at ≥20 years post Fontan surgery. Studies are needed to further identify at-risk patients in order to streamline surveillance for these highly morbid conditions.

Non-liver-related mortality in the DAA era: Insights from post-SVR patients with and without previous HCC history.

BACKGROUND AND AIMS: Mortality after sustained virological response (SVR) with interferon-free direct-acting antiviral (IFN-free DAA) therapy is crucial for optimizing post-SVR patient care, but it remains unclear, especially regarding non-liver-related mortality. METHODS: Consecutive post-SVR patients from 14 institutions were stratified into three cohorts: A (without advanced fibrosis and without prior HCC), B (with advanced fibrosis and without prior HCC), and C (curative HCC treatment). We assessed mortality (per 1000 person-years [/1000PY]) post-SVR. Mortality rates were compared between cohorts A and B and the general population using age- and sex-adjusted standardized mortality ratio (SMR). Comparison of survival between each cohort was performed using propensity-score (PS) matching with sex, age, and comorbidity. RESULTS: In cohort A (n = 762; median age, 65 years), 22 patients died (median follow-up, 36 months); all-cause mortality was 10.0/1000PY, with 86.4% non-liver-related deaths. In cohort B (n = 519; median age, 73 years), 27 patients died (median follow-up, 39 months); all-cause mortality was 16.7/1000PY, with 88.9% non-liver-related deaths. In both cohorts, malignant neoplasm was the most common cause of death; all-cause mortality was comparable to that of the general population (SMR: 0.96 and 0.92). In cohort C (n = 108; median age, 75 years), 15 patients died (median follow-up, 51 months); all-cause mortality was 36.0/1000PY, with 53.3% liver-related deaths. PS matching showed no significant survival differences between cohorts A and B, both of which had better survival than cohort C. CONCLUSIONS: Mortality varies based on HCC history in the DAA era; nevertheless, attention should be paid to non-liver-related deaths in all post-SVR patients.

CAMP-B score predicts the risk of hepatocellular carcinoma in patients with chronic hepatitis B after HBsAg seroclearance.

BACKGROUND: Risk of hepatocellular carcinoma (HCC) persists after hepatitis B surface antigen (HBsAg) seroclearance in patients with chronic hepatitis B (CHB). AIMS: To identify risk factors and construct a predictive model for HCC development. METHODS: We retrospectively analysed patients with CHB with HBsAg seroclearance. Primary outcome was HCC development. Factors identified from a multivariate Cox model in the training cohort, consisting of 3476 patients from two Korean hospitals, were used to construct the prediction model. External validation was performed using data from 5255 patients in Hong Kong. RESULTS: In the training cohort, HCC occurred in 102 patients during 24,019 person-years of observation (0.43%/year). Risk scores were assigned to cirrhosis (C:3), age ≥50 years (A:2), male sex (M:3) and platelet count <150,000/mm3 (P:1); all were independently associated with an increased risk of HCC in multivariate analysis The time-dependent area under receiver operating characteristic curves for 5, 10 and 15 years in the training and validation cohorts were 0.782, 0.817 and 0.825 and 0.785, 0.771 and 0.796, respectively. In the validation cohort, 85 patients developed HCC (0.24%/year). The corresponding incidence of HCC in the low-, intermediate- and high-risk groups were 0.07%, 0.37% and 0.90%, respectively. CONCLUSIONS: The CAMP-B score (cirrhosis, age ≥50 years, male sex and platelet count <150,000/mm3/L) was significantly associated with HCC development after HBsAg seroclearance. CAMP-B score can be easily implemented in real-world clinical practice and helps stratify HCC risk in patients with CHB following HBsAg seroclearance.

Causal relationship between psychological factors and hepatocellular carcinoma as revealed by Mendelian randomization.

PURPOSE: The impact of psychological factors on the incidence of hepatocellular carcinoma (HCC) in humans remains unclear. Mendelian randomization (MR) study is a novel approach aimed at unbiased detection of causal effects. Therefore, we conducted a two-sample MR to determine if there is a causal relationship between psychological distress (PD), participation in leisure/social activities of religious groups (LARG), and HCC. METHODS: The genetic summary data of exposures and outcome were retrieved from genome-wide association studies (GWAS). We used PD and LARG as exposures and HCC as outcome. Five MR methods were used to investigate the causal relationship between PD, LARG, and HCC. The result of inverse variance weighted (IVW) method was deemed as principal result. Besides, we performed a comprehensive sensitivity analysis to verify the robustness of the results. RESULTS: The IVW results showed that PD [odds ratio (OR) 1.006, 95% confidence interval (CI) 1.000-1.011, P = 0.033] and LARG (OR 0.994, 95% CI 0.988-1.000, P = 0.035) were causally associated with the incidence of HCC. Sensitivity analysis did not identify any bias in the results. CONCLUSION: PD turned out to be a mild risk factor for HCC. In contrast, LARG is a protective factor for HCC. Therefore, it is highly recommended that people with PD are seeking positive leisure activities such as participation in formal religious social activities, which may help them reduce the risk of HCC.

Screening immune-related blood biomarkers for DKD-related HCC using machine learning.

Background: Diabetes mellitus is a significant health problem worldwide, often leading to diabetic kidney disease (DKD), which may also influence the occurrence of hepatocellular carcinoma (HCC). However, the relationship and diagnostic biomarkers between DKD and HCC are unclear. Methods: Using public database data, we screened DKD secretory RNAs and HCC essential genes by limma and WGCNA. Potential mechanisms, drugs, and biomarkers for DKD-associated HCC were identified using PPI, functional enrichment, cMAP, and machine learning algorithms, and a diagnostic nomogram was constructed. Then, ROC, calibration, and decision curves were used to evaluate the diagnostic performance of the nomograms. In addition, immune cell infiltration in HCC was explored using CIBERSORT. Finally, the detectability of critical genes in blood was verified by qPCR. Results: 104 DEGs associated with HCC using WGCNA were identified. 101 DEGs from DKD were predicated on secreting into the bloodstream with Exorbase datasets. PPI analysis identified three critical modules considered causative genes for DKD-associated HCC, primarily involved in inflammation and immune regulation. Using lasso and RM, four hub genes associated with DKD-associated HCC were identified, and a diagnostic nomogram confirmed by DCA curves was established. The results of immune cell infiltration showed immune dysregulation in HCC, which was associated with the expression of four essential genes. PLVAP was validated by qPCR as a possible blood-based diagnostic marker for DKD-related HCC. Conclusion: We revealed the inflammatory immune pathways of DKD-related HCC and developed a diagnostic nomogram for HCC based on PLVAP, C7, COL15A1, and MS4A6A. We confirmed with qPCR that PLVAP can be used as a blood marker to assess the risk of HCC in DKD patients.

Current Perspectives on the Molecular and Clinical Relationships between Primary Biliary Cholangitis and Hepatocellular Carcinoma.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.g., HBV and HCV, non-response to UDCA, and high alcohol intake, as well as some metabolic-associated factors. Overall, HCC development is significantly more frequent in patients with advanced histological stages, being related to liver cirrhosis. It seems to be of fundamental importance to unravel eventual dysfunctional molecular pathways in PBC patients that may be used as biomarkers for HCC development. In the near future, this will possibly take advantage of artificial intelligence-designed algorithms.

Local recurrence following a complete radiologic response in hepatocellular carcinoma patients: comparison of transarterial chemoembolisation and transarterial radioembolisation.

AIM: To evaluate and compare the rates of local recurrence in hepatocellular carcinoma (HCC) patients who undergo selective transarterial radioembolisation (TARE) or transarterial chemoembolisation (TACE) and achieve a complete response (CR) radiologically. MATERIALS AND METHODS: All patients undergoing treatment with TARE or TACE at a single academic institution were reviewed retrospectively. Those who had been treated previously, presented with multifocal disease, had non-selective TARE or TACE, or did not achieve a complete response (CR) radiologically were excluded. RESULTS: In total 110 patients were included (TACE n=60 [54.5%]; TARE n=50 [45.5%]). TARE patients were older (66.4 ± 9.4 versus 61.2 ± 5.6 years, p<0.001) and had larger tumours (4.4 ± 2.2 versus 3 ± 1.4 cm, p=0.002). TACE patients were significantly more likely to suffer a local recurrence (31/60, 51.7% versus 9/50, 18%, p<0.001) and had a significantly shorter time to recurrence (median 8.3 {interquartile range [IQR]}: 12 versus median 17.9 [IQR: 23.5] months, p=0.001). A local time to progression (TTP) Kaplan-Meier curve demonstrated TACE patients had a significantly shorter local TTP (hazard ratio [HR]: 7.2; 95% confidence interval [CI]: 3.64-14.24; p<0.001) and treatment modality (TACE or TARE; HR: 0.05; 95% CI: 0.005-0.5; p=0.01) was found to be associated with local recurrences on multivariate Cox proportional HR analysis. When overall TTP was evaluated, again TACE patients were found to have a significantly shorter TTP (HR: 2.13 [1.28-3.53], p=0.004). CONCLUSION: In HCC patients undergoing selective treatment who achieve a CR radiologically, those treated with TARE may be less likely to suffer recurrence, either local or general, than those treated with TACE.

Persistently high HBsAg levels during HBeAg-seropositive stage predict lower risk of hepatocellular carcinoma in chronic hepatitis B patients.

BACKGROUND: High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg-positive CHB patients remains unknown. METHOD: HBeAg-positive CHB participants from the REVEAL-HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group-based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg-positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p-value less than 0.05 was considered statistically significant. RESULTS: A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non-stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow-up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj [95% CI] = 4.11 [2.26-7.48]), genotype C (HRadj [95% CI] = 4.39 [1.96-9.81]) and the non-stationary group (HRadj [95% CI] = 3.50 [1.49-8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj [95% CI] = 32.75 [5.41-198.42]). CONCLUSION: Patients with persistently high HBsAg levels during HBeAg-seropositive stage represent a unique population with low risk of HCC development.

Regulatory T cell: a double-edged sword from metabolic-dysfunction-associated steatohepatitis to hepatocellular carcinoma.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is becoming a leading cause of end-stage liver disease globally. Metabolic-dysfunction-associated steatohepatitis (MASH) represents a progressive inflammatory manifestation of MASLD. MASH underlies a versatile and dynamic inflammatory microenvironment, accompanied by aberrant metabolism and ongoing liver regeneration, establishing itself as a significant risk factor for hepatocellular carcinoma (HCC). The mechanisms underlying the escape and survival of malignant cells within the extensive inflammatory microenvironment of MASH remain elusive. Regulatory T cells (Tregs) play a crucial role in maintaining homeostasis and preventing excessive immune responses in the liver. Paradoxically, Tregs have been implicated in inhibiting tumour-promoting inflammation and facilitating the evasion of cancer cells. Recent studies have unveiled distinct behaviours of Tregs at different stages of MASLD, suggesting a dual role in the pathogenesis. In this review, we explore the fate of Tregs from MASLD to HCC, offering recent insights into potential targets for clinical intervention.

Impact of the COVID-19 pandemic on hospitalizations with hepatocellular carcinoma in the United States.

BACKGROUND: We studied the temporal trends of hepatocellular carcinoma (HCC)-related hospitalizations and potential predictors of in-hospital mortality around the COVID-19 pandemic. RESEARCH DESIGN AND METHODS: Using the International Classification of Diseases code, we used the National Inpatient Sample 2019-2020 and defined HCC and its underlying etiology. To assess the impact of the COVID-19 pandemic on hospitalization and in-hospital mortality, the study period was divided into the pre-COVID-19 era (2019 Q1-2020 Q1) and the COVID-19 era (2020 Q2-2020 Q4). Quarterly trends in etiology-based hospitalizations with HCC and predictors of in-hospital mortality among hospitalizations with HCC were determined. RESULTS: Hospitalization rates for HCC, as well as viral hepatitis-related HCC hospitalization rates, remained stable, while hospitalizations with alcohol-related liver disease (ALD, quarterly percentage change [QPC]: 2.1%; 95% confidence interval [CI]: 0.1%-4.2%) increased steadily. Hospitalization related to nonalcoholic fatty liver disease (NAFLD)-related HCC increased significantly steeper in the COVID-19 era (QPC: 6.6%; 95% CI: 4.0%-9.3%) than in the pre-COVID-19 era (QPC: 0.7%; 95% CI: 0.2%-1.3%). COVID-19 infection was independently associated with in-hospital mortality among hospitalizations with HCC (odds ratio: 1.94, 95% CI: 1.30-2.88). CONCLUSION: Hospitalization rates for viral hepatitis-related HCC remained stable, while those for HCC due to ALD and NAFLD increased during the COVID-19 pandemic.

Prediagnostic plasma metabolite concentrations and liver cancer risk: a population-based study of Chinese men.

BACKGROUND: Previous metabolic profiling of liver cancer has mostly used untargeted metabolomic approaches and was unable to quantitate the absolute concentrations of metabolites. In this study, we examined the association between the concentrations of 186 targeted metabolites and liver cancer risk using prediagnostic plasma samples collected up to 14 years prior to the clinical diagnosis of liver cancer. METHODS: We conducted a nested case-control study (n = 322 liver cancer cases, n = 322 matched controls) within the Shanghai Men's Health Study. Conditional logistic regression models adjusted for demographics, lifestyle factors, dietary habits, and related medical histories were used to estimate the odds ratios. Restricted cubic spline functions were used to characterise the dose-response relationships between metabolite concentrations and liver cancer risk. FINDINGS: After adjusting for potential confounders and correcting for multiple testing, 28 metabolites were associated with liver cancer risk. Significant non-linear relationships were observed for 22 metabolites. The primary bile acid biosynthesis and phenylalanine, tyrosine and tryptophan biosynthesis were found to be important pathways involved in the aetiology of liver cancer. A metabolic score consisting of 10 metabolites significantly improved the predictive ability of traditional epidemiological risk factors for liver cancer, with an optimism-corrected AUC increased from 0.84 (95% CI: 0.81-0.87) to 0.89 (95% CI: 0.86-0.91). INTERPRETATION: This study characterised the dose-response relationships between metabolites and liver cancer risk, providing insights into the complex metabolic perturbations prior to the clinical diagnosis of liver cancer. The metabolic score may serve as a candidate risk predictor for liver cancer. FUNDING: National Key Project of Research and Development Program of China [2021YFC2500404, 2021YFC2500405]; US National Institutes of Health [subcontract of UM1 CA173640].

Incidence of immunotherapy-related hyperprogressive disease (HPD) across HPD definitions and cancer types in observational studies: A systematic review and meta-analysis.

BACKGROUND: While evidence of hyperprogressive disease (HPD) continues to grow, the lack of a consensual definition obscures a proper characterization of HPD incidence. We examined how HPD incidence varies by the tumor type or the type of definition used. METHODS: We searched PubMed, Embase, the Cochrane Library of Systematic Reviews, and Web of Science from database inception to June 21, 2022. Observational studies reporting HPD incidence, in patients diagnosed with solid malignant tumors and treated with immune checkpoint inhibitors (ICI), were included. Random-effects meta-analyses were performed, and all statistical tests were 2-sided. RESULTS: HPD incidence was 12.4% (95% CI 10.2%-15.0%) with evidence of heterogeneity (Q = 119.32, p < 0.001). Meta-regression showed that the risk of developing HPD was higher in patients with advanced gastric cancer (adjusted odds ratio [OR], 10.83; 95% CI, 2.14-54.65; p < 0.001), hepatocellular carcinoma (adjusted OR, 7.99; 95% CI, 1.68-38.13; p = 0.006), non-small cell lung cancer (adjusted OR, 7.14; 95% CI, 1.58-32.29; p = 0.005), and mixed or other types (adjusted OR, 5.09; 95% CI, 1.12-23.14, p = 0.018) than in patients with renal cell carcinoma. Across definitions, HPD defined as a tumor growth kinetics ratio ≥ 2 (adjusted OR, 1.82; 95% CI, 1.08-3.07; p = 0.025) based on the Response Evaluation Criteria in Solid Tumors (RECIST) reported higher incidence than when HPD was defined as RECIST-defined progressive disease and a change in the tumor growth rate (TGR) exceeding 50% (∆TGR > 50). CONCLUSIONS: The incidence of immunotherapy-related HPD may vary across tumor types and definitions used, supporting the argument for a uniform and improved method of HPD evaluation for informed clinical decision-making.

Dietary restriction and hepatic cancer: Systematic review and meta-analysis of animal studies.

The effect of calorie restriction, fasting, and ketogenic diets on the treatment of liver cancer remains uncertain. Therefore, we conducted a systematic review to evaluate the effect of restrictive diets on the development and progression of liver cancer in animal models. We did a meta-analysis using the Cochrane Collaboration's Review Manager software, with the random effects model and the inverse variance technique. We examined 19 studies that were conducted between 1983 and 2020. Of these, 63.2% investigated calorie restriction, 21.0% experimented with a ketogenic diet, and 15.8% investigated the effects of fasting. The intervention lasted anything from 48 h to 221 weeks. Results showed that restrictive diets may reduce tumor incidence and progression, with a significant reduction in the risk of liver cancer development. Thereby, our results suggest that putting limits on what you eat may help treat liver cancer in more ways than one.