Development Of Hepatocellular Carcinoma In Cirrhotic Patients Research Articles

Early warning of hepatocellular carcinoma in cirrhotic patients by three-phase CT-based deep learning radiomics model: a retrospective, multicentre, cohort study

The diagnosis of hepatocellular carcinoma (HCC) often experiences latency, ultimately leading to unfavorable patient outcomes due to delayed therapeutic interventions. Our study is designed to develop and validate a model that employs triple-phase computerized tomography (CT)-based deep learning radiomics and clinical variables for early warning of HCC in patients with cirrhosis. We studied 1858 patients with cirrhosis primarily from the PreCar cohort (NCT03588442) between June 2018 and January 2020at 11 centres, and collected triple-phase CT images and laboratory results 3-12 months prior to HCC diagnosis or non-HCC final follow-up. Using radiomics and deep learning techniques, early warning model was developed in the discovery cohort (n=924), and then validated in an internal validation cohort (n=231), and an external validation cohort from 10 external centres (n=703). We developed a hybrid model, named ALARM model, which integrates deep learning radiomics with clinical variables, enabling early warning of the majority of HCC cases. The ALARM model effectively predicted short-term HCC development in cirrhotic patients with area under the curve (AUC) of 0.929 (95% confidence interval 0.918-0.941) in the discovery cohort, 0.902 (0.818-0.987) in the internal validation cohort, and 0.918 (0.898-0.961) in the external validation cohort. By applying optimal thresholds of 0.21 and 0.65, the high-risk (n=221, 11.9%) and medium-risk (n=433, 23.3%) groups, which covered 94.4% (84/89) of the patients who developed HCC, had significantly higher rates of HCC occurrence compared to the low-risk group (n=1204, 64.8%) (24.3% vs 6.4% vs 0.42%, P<0.001). Furthermore, ALARM also demonstrated consistent performance in subgroup analysis. The novel ALARM model, based on deep learning radiomics with clinical variables, provides reliable estimates of short-term HCC development for cirrhotic patients, and may have the potential to improve the precision in clinical decision-making and early initiation of HCC treatments. This work was supported by National Key Research and Development Program of China (2022YFC2303600, 2022YFC2304800), and the National Natural Science Foundation of China (82170610), Guangdong Basic and Applied Basic Research Foundation (2023A1515011211).

Single-cell RNA-seq Revealed that Altered Tumor Infiltrating Lymphocytes in Cirrhotic Liver Indicate Development of Hepatocellular Carcinoma.

Cirrhosis is the precursor lesion for most hepatocellular carcinoma (HCC) cases. However, no biomarker effectively predicted HCC initiation before diagnosis by imaging. We aimed to investigate the hallmarks of immune microenvironments in healthy, cirrhotic livers and HCC tumor tissues and to identify immune biomarkers of cirrhosis-HCC transition. Expression matrices of single-cell RNA sequencing studies were downloaded and integrated with Seurat package vignettes. Clustering was performed to analyze the immune cell compositions of different sample types. The cirrhotic liver and HCC tumors had distinct immune microenvironments, but the immune landscape of cirrhotic livers was not markedly modified compared with healthy livers. Two subsets of B cells and three subsets of T cells were identified in the samples. Among the T cells, naïve T cells were more prominent in the cirrhotic and healthy liver samples than in the HCC samples. In contrast, the neutrophil count was lower in cirrhotic livers. Two macrophage clusters were identified, one that actively interacted with T cells and B cells and was enriched in cirrhotic blood compared with HCC blood samples. Decreased naïve T cell infiltration and increased neutrophil infiltration in the liver may indicate the development of HCC in cirrhotic patients. Alterations in blood-resident immune cells may also be a sign of HCC development in cirrhotic patients. The dynamics of the immune cell subsets may serve as novel biomarkers to predict the transition from cirrhosis to HCC.

Bone Densities Assessed by Hounsfield Units at L5 in Computed Tomography Image Independently Predict Hepatocellular Carcinoma Development in Cirrhotic Patients.

A previous study identified that bone density (BD) assessed by Hounsfield unit (HU) at T12 in computed tomography (CT) image was a predictor for hepatocellular carcinoma (HCC) development in cirrhotic patients. Here, we conducted a verification study, where clinical variables together with BDs (assessed from three different bone areas: T12, L5, and femur trochanter) were assessed for their predictive values for time-to-HCC development in cirrhotic patients. Univariate Cox proportional hazard analysis showed that age (p = 0.017), T12 BD (p = 0.013) and L5 BD (p = 0.005), but not femur BD, were significant predictors. Multivariate analysis revealed that L5 BD was the only independent factor associated with time-to-HCC development (adjusted p = 0.007). Kaplan-Meier analysis confirmed that BD which was lower than median HU was associated with a shorter time-to-HCC development for both T12 BD and L5 BD (p = 0.001 each). Longitudinal follow-ups for BDs in HCC patients having received serial CT imaging studies unveiled a significantly rapid reduction in BD, right before HCC was diagnosed (p = 0.025 when compared with the average BD reduction rate). In conclusion, BD assessed by HU at L5 was an independent predictor for HCC development in cirrhotic patients. Rapid BD reduction during CT scan follow-ups could serve as a warning sign for HCC development.

Clinical usefulness of noninvasive fibrosis indices for predicting hepatocellular carcinoma in treatment-naïve patients with chronic hepatitis B following entecavir therapy.

This study aimed to evaluate the clinical usefulness of the aminotransferase to platelet ratio index (APRI), fibrosis-4 (FIB-4), and modified FIB-4 (mFIB-4) indices in predicting hepatocellular carcinoma (HCC) in patients receiving entecavir (ETV) treatment. Among 1955 patients treated with ETV, a total of 857 treatment-naive chronic hepatitis B patients (424 with liver cirrhosis [LC], 433 without cirrhosis) treated with ETV for more than 1 year were analyzed. Of the 857 patients, 85 (9.9%) patients (77 in the LC group and 8 in the non-LC group) developed HCC during the follow-up period. The median observation period was 6.9 years. Multivariate regression analysis of HCC incidence revealed that the initial mFIB-4 index (hazard ratio [HR] 1.058; 95% confidence interval [CI], 1.007-1.112; p=0.027) and improvement in the FIB-4 index after 1 year of ETV treatment (HR 0.531; 95% CI, 0.339-0.831; p=0.006) were independent prognostic factors in the entire cohort. In the LC group, the improvement of the FIB-4 index following ETV treatment (HR 0.491; 95% CI, 0.280-0.861; p=0.013) was negatively correlated with incidence of HCC. However, the area under the receiver operating characteristic curve of specific cut-off values of the FIB-4 index at baseline and 1 year after ETV treatment were 0.572 (95% CI, 0.504-0.640) and 0.615 (95% CI, 0.546-0.684), respectively. In the non-LC group, none of the invasive fibrosis indices could predict HCC incidence. The specific cut-off value of the FIB-4 index was not suitable for predicting HCC. However, the improvement in the FIB-4 index after 1year of ETV therapy could be a predictor of HCC development in cirrhotic patients.

Genetic polymorphism of epidermal growth factor gene as a predictor of hepatocellular carcinoma in hepatitis C cirrhotic patients

ObjectivesTo investigate the correlation between the epidermal growth factor (EGF) polymorphism and the risk of hepatocellular carcinoma (HCC) in hepatitis C viral (HCV)-related cirrhotic patients as well as its relation to EGF protein expression in HCC tissue.BackgroundIn Egypt, the incidence of HCC is ∼4.7% in chronic liver disease patients because of HCV infection. EGF plays an important role in hepatocyte regeneration and also plays a role in malignant transformation. A functional polymorphism in EGF was identified recently as the G/G genotype was associated with a higher risk of HCC and increased EGF expression in serum and liver tissue from HCC patients.Patients and methodsThis case–control study was carried out on 100 patients in the HCC clinic of the National Liver Institute, Menoufia University. Routine investigations and EGF genotyping were performed in 50 HCC patients (group I) subdivided into 25 patients with resectable HCC (subgroup IA) and 25 patients with advanced unrespectable HCC (subgroup IB). Twenty-five cirrhotic HCV patients did not have HCC (group II). There were a total of 25 healthy individuals (group III). Immunohistochemical detection of EGF was performed in HCC tissue biopsy from patients who underwent surgical resection.ResultsThe GG genotype was associated with a significantly increased risk of HCC compared with the AG and AA genotypes (P = 0.031) in the cirrhotic group. The G allele led to a highly significant risk of HCC compared with allele A in recessive model GG versus AG + AA (P = 0.036) rather than in the dominant model GG + AG versus AA (P = 0.66). EGF expression in tumor tissue was statistically different only between GG and AG genotypes in the resectable HCC group (group IA) (P = 0.032).ConclusionThe EGF gene polymorphism (GG genotype) led to a significant risk of HCC development in cirrhotic patients more than the AG and AA genotypes.

Genetic Polymorphism of Epidermal Growth Factor Gene as a Predictor of Hepatocellular Carcinoma in Hepatitis C Cirrhotic Patients.

Background:In Egypt, the incidence of hepatocellular carcinoma (HCC) is approximately 4.7% of chronic liver disease patients due to (HCV) infection. Epidermal growth factor (EGF) plays an important role in hepatocyte regeneration. A functional polymorphism in EGF 61A>G was identified; itwas associated with higher risk of HCC. Objectives:to investigate the correlation between the epidermal growth factor (EGF) polymorphism and the risk of hepatocellular carcinoma (HCC) in hepatitis C viral (HCV) cirrhotic patients as well as its relation to EGF protein expression in HCC tissue. Patients and methods:this casecontrol study was conducted on 75 HCV cirrhotic patients including 50 HCC patients (25 withresectable HCC and 25 with advanced unresectable HCC) and 25 healthy persons were included. EGF genotype was detected by restriction fragment length polymorphism. EGF expression in HCC tissue biopsiesfrom patientswhounderwent surgical resection was done by immunohistochemical examination. Results:The GG genotype was associated with significant increased risk of HCC compared to AA genotypes (P=0.031) in cirrhotic group. The G allele had a highly significant risk of HCC compared to allele Ain recessive model GG vs. AG+AA (P=0.036) rather than in the dominant model GG +AG vs. AA (P=0.66). There was significant increased expression of EGF in tumour tissues in patients with GG genotype compared to AG genotype and AA genotype p= 0.019. Conclusion: EGF gene polymorphism (GG genotype) had a significant risk of HCC development in cirrhotic patients. This is confirmed by increased EGF expression in liver tumor tissue from HCC patients.

ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA-enriched extracellular vesicles

Excessive alcohol consumption is one of the major causes of hepatocellular carcinoma (HCC). Approximately 30-40% of the Asian population are deficient for aldehyde dehydrogenase 2 (ALDH2), a key enzyme that detoxifies the ethanol metabolite acetaldehyde. However, how ALDH2 deficiency affects alcohol-related HCC remains unclear. ALDH2 polymorphisms were studied in 646 patients with viral hepatitis B (HBV) infection, who did or did not drink alcohol. A new model of HCC induced by chronic carbon tetrachloride (CCl4) and alcohol administration was developed and studied in 3 lines of Aldh2-deficient mice: including Aldh2 global knockout (KO) mice, Aldh2*1/*2 knock-in mutant mice, and liver-specific Aldh2 KO mice. We demonstrated that ALDH2 deficiency was not associated with liver disease progression but was associated with an increased risk of HCC development in cirrhotic patients with HBV who consumed excessive alcohol. The mechanisms underlying HCC development associated with cirrhosis and alcohol consumption were studied in Aldh2-deficient mice. We found that all 3 lines of Aldh2-deficient mice were more susceptible to CCl4 plus alcohol-associated liver fibrosis and HCC development. Furthermore, our results from in vivo and in vitro mechanistic studies revealed that after CCl4 plus ethanol exposure, Aldh2-deficient hepatocytes produced a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which were then transferred into neighboring HCC cells and together with acetaldehyde activated multiple oncogenic pathways (JNK, STAT3, BCL-2, and TAZ), thereby promoting HCC. ALDH2 deficiency is associated with an increased risk of alcohol-related HCC development from fibrosis in patients and in mice. Mechanistic studies reveal a novel mechanism that Aldh2-deficient hepatocytes promote alcohol-associated HCC by transferring harmful oxidized mitochondrial DNA-enriched extracellular vesicles into HCC and subsequently activating multiple oncogenic pathways in HCC. Alcoholics with an ALDH2 polymorphism have an increased risk of digestive tract cancer development, however, the link between ALDH2 deficiency and hepatocellular carcinoma (HCC) development has not been well established. In this study, we show that ALDH2 deficiency exacerbates alcohol-associated HCC development both in patients and mouse models. Mechanistic studies revealed that after chronic alcohol exposure, Aldh2-deficient hepatocytes produce a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which can be delivered into neighboring HCC cells and subsequently activate multiple oncogenic pathways, promoting HCC.

TIPS Is Not Associated with a Higher Risk of Developing HCC in Cirrhotic Patients: A Systematic Review and Meta-analysis.

Background and Aims: The association between portal-systemic shunt and hepatocellular carcinoma (HCC) development in patients who have cirrhosis is still controversial. This systematic review with meta-analysis was performed to systematically clarify the potential role of portal-systemic shunt in the development of HCC.Methods: The PubMed, Embase, and Cochrane Library databases were searched for potentially eligible literature. Meta-analysis with random-effects model was performed to combine the incidence rates of HCC after portal-systemic shunt. Finally, seven studies were included. In the present review, we mainly focused on 859 patients (365 in the transjugular intrahepatic portal-systemic shunt (TIPS) group and 494 in the non-TIPS group) from five studies to analyze incidence rates after TIPS.Results: At the end of follow-up, there were 66 (18%, 66/365) patients who developed HCC after TIPS intervention and 63 (13%, 63/494) patients who developed HCC after non-TIPS treatments. Pooled estimates with random-effects model did not demonstrate a significant increase of incidence of HCC after TIPS (risk ratio: 1.37 [confidence interval (CI): 0.96 to 1.97]; p = 0.08) compared with non-TIPS treatments. Subgroup analyses for those patients with transplanted liver also did not detect a significant difference between the TIPS group and non-TIPS group (risk ratio: 1.10 [CI: 0.59 to 2.07]; p = 0.75).Conclusions: Current evidence suggests that portal-systemic shunt is not associated with a higher risk of HCC development in cirrhotic patients.

Predictive value of the preoperative neutrophil-to-lymphocyte ratio for the development of hepatocellular carcinoma in HBV-associated cirrhotic patients after splenectomy.

The neutrophil to lymphocyte ratio (NLR), a simple marker of inflammation, has recently been showed to predict tumor recurrence in hepatocellular carcinoma (HCC) patients after hepatic resection or liver transplantation. However, whether it can be used to predict HCC development in cirrhotic patients remained unknown. The aim of this study was to evaluate the predictive value of the preoperative NLR for the development of HCC in cirrhotic patients who underwent splenectomy. A total of 230 HBV-associated cirrhotic patients who underwent splenectomy in our hospital from January 2000 to December 2012 were included in this study. Detailed clinical data included patients’ general characteristics, laboratory tests and imaging studies, surgical procedures and complications. Information on patients’ follow-up data was also obtained. We found that 38 (16.52%) patients developed HCC after splenectomy during the follow-up period. An elevated preoperative NLR was associated with increased risk of developing HCC in cirrhotic patients after splenectomy. The optimal cutoff value of NLR for HCC development was 2.27. In patients who developed HCC during the follow-up period, NLR scores showed no predictive value in overall survival after splenectomy. However, NLR scores appeared to have a much better predictive value in overall survival in patients who did not develop HCC. In conclusion, cirrhotic patients who underwent splenectomy remain at a relatively high risk of developing HCC, and an elevated preoperative NLR is associated with HCC development in cirrhotic patients who underwent splenectomy for hypersplenism.

PWE-125 Stratification Of Hepatocellular Carcinoma Risk in Primary Biliary Cirrhosis by Biochemical Response to Treatment

Introduction AimsTo review patterns of hepatocellular carcinoma (HCC) presentation in patients with primary biliary cirrhosis (PBC) in the context of disease severity and biochemical response to treatment.MethodsPatients with confirmed PBC...