Hepatocellular Carcinoma In High-risk Patients Research Articles

Interventions to Improve Surveillance for Hepatocellular Carcinoma in High-Risk Patients: A Scoping Review.

Hepatocellular carcinoma (HCC) is most often a sequela of chronic liver disease or chronic hepatitis B infection. Among high-risk patients, surveillance for HCC every 6months is recommended by international guidelines. However, rates of HCC surveillance are suboptimal (11-64%). Barriers at the patient, provider, and healthcare delivery system levels have been identified. We performed a systemic scoping review to identify and characterize interventions to improve HCC surveillance that has previously been evaluated. Searches using key terms in PubMed and Embase were performed to identify studies examining interventions designed to improve the surveillance rate for HCC in patients with cirrhosis or chronic liver disease that were published in English between January 1990 and September 2021. Included studies (14) had the following study designs: (1) randomized clinical trials (3, 21.4%), (2) quasi-experimental (2, 14.3%), (3) prospective cohort (6, 42.8%), and (4) retrospective cohort (3, 21.4%). Interventions included mailed outreach invitations, nursing outreach, patient education with or without printed materials, provider education, patient navigation, chronic disease management programs, nursing-led protocols for image ordering, automated reminders to physicians and nurses, web-based clinical management tools, HCC surveillance databases, provider compliance reports, radiology-led surveillance programs, subsidized HCC surveillance, and the use of oral medications. It was found that HCC surveillance rates increased after intervention implementation in all studies. Despite improvements in HCC surveillance rates with intervention, compliance remained suboptimal. Further analysis of which interventions yield the greatest increases in HCC surveillance, design of multi-pronged strategies, and improved implementation are needed.

FRI-278 - Alternative surveillance using CT/MR improves clinical outcomes by detecting early-stage hepatocellular carcinoma in High-risk patients with chronic hepatitis B

FRI-278 - Alternative surveillance using CT/MR improves clinical outcomes by detecting early-stage hepatocellular carcinoma in High-risk patients with chronic hepatitis B

Prognostic and Immunological Significance of the Molecular Subtypes and Risk Signatures Based on Cuproptosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) remains a challenging medical problem. Cuproptosis is a novel form of cell death that plays a crucial role in tumorigenesis, angiogenesis, and metastasis. However, it remains unclear whether cuproptosis-related genes (CRGs) influence the outcomes and immune microenvironment of HCC patients. From The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, we obtained the mRNA expression file and related clinical information of HCC patients. We selected 19 CRGs as candidate genes for this study according to previous literature. We performed a differential expression analysis of the 19 CRGs between malignant and precancerous tissue. Based on the 19 CRGs, we enrolled cluster analysis to identify cuproptosis-related subtypes of HCC patients. A prognostic risk signature was created utilizing univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. We employed independent and stratification survival analyses to investigate the predictive value of this model. The functional enrichment features, mutation signatures, immune profile, and response to immunotherapy of HCC patients were also investigated according to the two molecular subtypes and the prognostic signature. We found that 17 CRGs significantly differed in HCC versus normal samples. Cluster analysis showed two distinct molecular subtypes of cuproptosis. Cluster 1 is preferentially related to poor prognosis, high activity of immune response signaling, high mutant frequency of TP53, and distinct immune cell infiltration versus cluster 2. Through univariate and LASSO Cox regression analyses, we created a cuproptosis-related prognostic risk signature containing LIPT1, DLAT, MTF1, GLS, and CDKN2A. High-risk HCC patients were shown to have a worse prognosis. The risk signature was proved to be an independent predictor of prognosis in both the TCGA and ICGC datasets, according to multivariate analysis. The signature also performed well in different stratification of clinical features. The immune cells, which included regulatory T cells (Treg), B cells, macrophages, mast cells, NK cells, and aDCs, as well as immune functions containing cytolytic activity, MHC class I, and type II IFN response, were remarkably distinct between the high-risk and low-risk groups. The tumor immune dysfunction and exclusion (TIDE) score suggested that high-risk patients had a higher response rate to immune checkpoint inhibitors than low-risk patients. This research discovered the potential prognostic and immunological significance of cuproptosis in HCC, improved the understanding of cuproptosis, and may deliver new directions for developing more efficacious therapeutic techniques for HCC patients.

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response.

Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive. Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells' pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes' expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation. Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-Ⅱ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines. Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time.

Intraindividual Comparison of Contrast-Enhanced Ultrasound Using Perfluorobutane With Modified Criteria Versus CT/MRI LI-RADS Version 2018 for Diagnosing HCC in High-Risk Patients.

BACKGROUND. Previously proposed modifications to LI-RADS criteria for contrast-enhanced ultrasound (CEUS) performed using perfluorobutane contrast agent yielded increased sensitivity for hepatocellular carcinoma (HCC) without a significant decrease in specificity. OBJECTIVE. The purpose of our study was to compare the diagnostic performance of CEUS with perfluorobutane using modified LI-RADS criteria versus contrast-enhanced CT or MRI using LI-RADS version 2018 (v2018) for characterizing lesions as HCC in high-risk patients. METHODS. This retrospective study included 171 patients (140 men, 31 women; mean age, 54 ± 12 [SD] years) at high-risk for HCC with a pathologically confirmed liver observation evaluated by both CEUS using perfluorobutane and contrast-enhanced CT or MRI between March 2020 and May 2021. A matching algorithm was used to select two patients with HCC for each patient with a non-HCC lesion. Two readers evaluated observations using previously proposed modifications to CEUS LI-RADS version 2017 that classify certain observations as LR-5 rather than as LR-4 or LR-M on the basis of the presence of Kupffer phase defect after perfluorobutane administration; two different readers evaluated observations using CT/MRI LI-RADS v2018. Each reader pair reached consensus. Diagnostic performance was evaluated. RESULTS. A total of 114 patients had HCC, 43 had a non-HCC malignancy, and 14 had a benign lesion. Modified CEUS criteria using perfluorobutane and CT/MRI LI-RADS v2018 showed no significant difference (p > .05) in sensitivity (92.1% vs 89.5%), specificity (87.7% vs 84.2%), or accuracy (90.6% vs 87.7%) of LR-5 for diagnosis of HCC. Of six observations assessed as LR-4 only by CT/MRI LI-RADS v2018, modified CEUS criteria using perfluorobutane assessed one as LR-3 (benign lesion) and five as LR-5 (all HCC). Of seven observations assessed as LR-M only by CT/MRI LI-RADS v2018, modified CEUS criteria using perfluorobutane assessed one as LR-3 (non-HCC malignancy) and six as LR-5 (all HCC). Eight of 12 observations assessed as LR-5 only by CT/MRI LI-RADS v2018 and 11 of 13 observations assessed as LR-5 only by modified CEUS criteria using perfluorobutane were HCC. CONCLUSION. The diagnostic performance of LR-5 for HCC diagnosis was not significantly different between modified CEUS criteria using perfluorobutane and CT/MRI LI-RADS v2018. CLINICAL IMPACT. The findings support the application of modified CEUS criteria using perfluorobutane for diagnosing HCC in high-risk patients.

Performance of Contrast-enhanced Ultrasound Liver Imaging Reporting and Data System LR-5 in the Diagnosis of Hepatocellular Carcinoma:A Meta-analysis

Objective To evaluate the performance of contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system (LI-RADS) LR-5 in the diagnosis of hepatocellular carcinoma (HCC). Methods The clinical research reports with the application of CEUS LI-RADS in the diagnosis of HCC were collected from PubMed,Embase,Cochrane Library,CNKI,and Wanfang Data from inception to November 14,2021.Two researchers respectively screened the literature and extracted relevant information.The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) was used to evaluate the quality of all the included articles.RevMan 5.4,Meta disc 1.4,and Stata 16.0 were employed to analyze the diagnostic performance of LR-5 for HCC in high-risk patients. Results Twenty original studies were included,involving a total of 6131 lesions,of which 5142 were HCC.The results of meta-analysis showed that the LR-5 in CEUS LI-RADS for diagnosing HCC in the high-risk population had the overall sensitivity of 0.72 (95%CI=0.66-0.77),the overall specificity of 0.93 (95%CI=0.87-0.96),the overall positive likelihood ratio of 9.89 (95%CI=5.31-18.41),the overall negative likelihood ratio of 0.30 (95%CI=0.25-0.37),and the area under the summary receiver operating characteristic curve of 0.88 (95%CI=0.85-0.91).There was heterogeneity among the included studies (I2=95.31,P<0.001).The funnel plot indicated the existence of publication bias (P=0.04). Conclusion The CEUS LI-RADS can effectively diagnose HCC in high-risk patients based on the LR-5 criteria.

Chemical Biopsy for GNMT as Noninvasive and Tumorigenesis-Relevant Diagnosis of Liver Cancer.

Early diagnosis of hepatocellular carcinoma (HCC) is difficult; the lack of convenient biomarker-based diagnostic modalities renders high-risk HCC patients burdened by life-long periodical examinations. Here, a new chemical biopsy approach was developed for noninvasive diagnosis of HCC using urine samples. Bioinformatic screening for tumor suppressors yielded glycine N-methyltransferase (GNMT) as a biomarker with clinical relevance to HCC tumorigenesis. A liquid chromatography-mass spectrometry (LC-MS)-based chemical biopsy detecting nonradioactive 13C-sarcosine from 13C-glycine was designed to noninvasively assess liver GNMT activity extrahepatically. 13C-Sarcosine showed a strong correlation with GNMT in normal and cancerous liver cells. In an autochthonous animal model developing visible cancer nodules at 17 weeks, the urinary 13C-sarcosine chemical biopsy exhibited notable changes as early as 8 weeks, showing significant correlations with liver GNMT and molecular pathological changes. Our chemical biopsy approach should facilitate early and noninvasive diagnosis of HCC, with direct relevance to tumorigenesis, which can be straightforwardly applied to other diseases.

S1336 Role of FIB-4 Score in Predicting Risk of Hepatocellular Carcinoma in Patients With Cirrhosis due to Nonalcoholic Steatohepatitis

Introduction: Hepatocellular carcinoma (HCC) represents the main cause of death in patients with nonalcoholic steatohepatitis (NASH) cirrhosis and is a leading indication for liver transplantation. Identification of high-risk patients for HCC is essential for long term monitoring of disease progression, early detection, and effective intervention. Fibrosis-4 (FIB-4) is a noninvasive index of readily available laboratory measurements and is widely validated for predicting cirrhosis and HCC. We sought to determine if FIB-4 score is associated with high risk of HCC among patients with NASH cirrhosis. Methods: We conducted a retrospective cohort study of adult patients with NASH cirrhosis (n=1,441) who were evaluated at our medical center between 2005 and 2015. Those who developed HCC were identified via ICD codes until the end of September 2021. At day of index NASH cirrhosis diagnosis, clinical and biochemical measurements were recorded on each patient. Descriptive statistics were calculated for all factors. Kaplan-Meier analysis was performed to evaluate time to HCC event. Cox regression models were used to evaluate associations between HCC and factors of interest. Models were adjusted for age, sex, number of comorbidities, and laboratory values. Results: During a median follow-up time of 8.3 years, 218 (15%) patients with NASH cirrhosis developed HCC. At index visit, the study population had a median age 57 years, 44% males, 78.6% White, median BMI 31.5 kg/m2, 26.7% had diabetes mellitus, 10.4% current smokers, mean FIB-4 score 4.2, and mean MELD score 8.1. Multivariable Cox regression models revealed that age, sex, race/ethnicity, BMI and FIB-4 were independent factors associated with development of HCC in patients with NASH cirrhosis (Table). Compared to patients with FIB-4 < 1.45, patients with FIB-4 between 1.45-3.25 had a similar risk of HCC (95% CI: 0.61-1.86, p=0.82). Patients with FIB-4 > 3.25 had a 2.51 (95% CI: 1.53-4.12, p< 0.001) increased hazard of HCC (Figure). Conclusion: Age, sex, race/ethnicity, BMI and FIB-4 were independently associated with HCC in NASH cirrhosis. We found that FIB-4 > 3.25 was an independent predictor of HCC risk. Providers should pay attention to FIB-4 for long term monitoring of disease progression. An inexpensive, available, validated marker like FIB-4 is a promising tool for identification of high-risk patients and may be used in routine clinical practice as a simple screening strategy for HCC risk in patients with NASH cirrhosis.Figure 1.: Kaplan-Meier estimates of developing HCC in patients with NASH cirrhosis by FIB-4 score within 5 years of follow up Table 1. - Factors Associated with HCC in NASH Cirrhosis: Univariate and Multivariable Analyses Univariate Multivariable Factors Unadjusted Hazard Ratio (95% Confidence Interval) p-value Adjusted Hazard Ratio (95% Confidence Interval) p-value Age group, yrs <49 1 [reference] 1 [reference] >49-59 1.40 (0.96-2.04) 0.08 1.22 (0.74-2.04) 0.43 >59-69 2.13 (1.47-3.11) 0.000 1.72 (1.02-2.90) 0.04 >69 4.26 (2.66-6.80) 0.000 3.03 (1.57-5.88) 0.001 Sex Female 1 [reference] 1 [reference] Male 2.13 (1.62-2.8) 0.000 2.00 (1.37-2.91) 0.000 Race and ethnicity Hispanic 0.72 (0.29-1.7) 0.46 0.42 (0.10-1.74) 0.23 Non-Hispanic White 1 [reference] 1 [reference] Black 0.62 (0.42-0.91) 0.01 0.70 (0.43-1.13) 0.15 Other* 0.59 (0.19-1.8) 0.36 0.50 (0.12-2.06) 0.34 BMI, Kg/m2 0.989 (0.97-1.01) 0.24 BMI category, Kg/m2 < 18.5 0.95 (0.22-4.16) 0.95 1.52 (0.34-6.85) 0.59 18.5–24.9 1 [reference] 1 [reference] 25.0–29.9 1.73 (0.96-3.11) 0.07 1.69 (0.89-3.20) 0.11 30.0–34.9 1.49 (0.81-2.7) 0.20 1.46 (0.76-2.81) 0.26 35.0–39.9 1.59 (0.83-3.02) 0.16 1.63 (0.82-3.26) 0.16 >40 0.95 (0.47-1.91) 0.89 1.16 (0.53-2.50) 0.71 Diabetes 0.76 (0.55-1.06) 0.11 Total cholesterol, mg/dL 125-200 1 [reference] >200 0.78 (0.39-1.6) 0.50 LDL, mg/dL < 130 1 [reference] >130 0.42 (0.17-1.01) 0.05 MELD score <20 1 [reference] >20 1.14 (0.60-2.16) 0.68 FIB-4 score < 1.45 1 [reference] 1 [reference] 1.45-3.25 1.22 (0.79-1.9) 0.37 1.07 (0.61-1.86) 0.82 > 3.25 2.74 (1.89-3.97) 0.000 2.51 (1.53-4.12) 0.000 Albumin, g/dL 0.685 (0.566-0.828) 0.000 INR 1.52 (1.19-1.95) 0.001 Creatinine, mg/dL 0.91 (0.77-1.07) 0.26 Total Bilirubin, mg/dL 1.04 (1.01-1.07) 0.01 Platelet count, ×109/L 0.997 (0.996-0.999) 0.001 *Other category included Asian, American Indian-Alaskan or other.

Multi-omics data integration for hepatocellular carcinoma subtyping with multi-kernel learning.

Hepatocellular carcinoma (HCC) is a leading malignant liver tumor with high mortality and morbidity. Patients at the same stage can be defined as different molecular subtypes associated with specific genomic disorders and clinical features. Thus, identifying subtypes is essential to realize efficient treatment and improve survival outcomes of HCC patients. Here, we applied a regularized multiple kernel learning with locality preserving projections method to integrate mRNA, miRNA and DNA methylation data of HCC patients to identify subtypes. We identified two HCC subtypes significantly correlated with the overall survival. The patient 3-years mortality rates in the high-risk and low-risk group was 51.0% and 23.5%, respectively. The high-risk group HCC patients were 3.37 times higher in death risk compared to the low-risk group after adjusting for clinically relevant covariates. A total of 196 differentially expressed mRNAs, 2,151 differentially methylated genes and 58 differentially expressed miRNAs were identified between the two subtypes. Additionally, pathway activity analysis showed that the activities of six pathways between the two subtypes were significantly different. Immune cell infiltration analysis revealed that the abundance of nine immune cells differed significantly between the two subtypes. We further applied the weighted gene co-expression network analysis to identify gene modules that may affect patients prognosis. Among the identified modules, the key module genes significantly associated with prognosis were found to be involved in multiple biological processes and pathways, revealing the mechanism underlying the progression of HCC. Hub gene analysis showed that the expression levels of CDK1, CDCA8, TACC3, and NCAPG were significantly associated with HCC prognosis. Our findings may bring novel insights into the subtypes of HCC and promote the realization of precision medicine.

Multiarterial Phase Acquisition in Gadoxetic Acid-Enhanced Liver MRI for the Detection of Hypervascular Hepatocellular Carcinoma in High-Risk Patients: Comparison of Compressed Sensing Versus View Sharing Techniques.

The aim of this study was to compare compressed sensing (CS) and view sharing (VS) techniques for single breath-hold multiarterial phase imaging with respect to image quality and focal liver observation detectability during gadoxetic acid-enhanced magnetic resonance imaging in patients at high risk for hepatocellular carcinoma (HCC). A total of 385 patients who underwent gadoxetic acid-enhanced magnetic resonance imaging, including triple arterial phases using either CS (n = 224) or VS (n = 161) techniques, were retrospectively included. Among them, 117 patients had 171 focal liver observations (median diameter, 1.3 cm), which were classified according to Liver Imaging Reporting and Data System version 2018. The acquisition rate of optimally timed late arterial phase (LAP) was assessed, and image quality, including respiratory motion artifact and observation conspicuity, was rated on a 4-point scale by 3 radiologists. The Mann-Whitney U test and nonparametric test for repeated measures data were used for image quality and observation conspicuity analysis. The jackknife alternative free-response receiver operating characteristics method was used to compare the observation detectability between the 2 techniques. The CS technique showed significantly higher acquisition rate of optimally timed LAP without transient severe motion (82.1% [184/224] vs 71.4% [115/161]; P = 0.013) than the VS technique. The CS technique also demonstrated significantly improved overall image quality (3.42 ± 0.70 vs 2.97 ± 0.61; P < 0.001) compared with the VS technique. Regarding the detection of hyperenhancing observations, there was no significant difference between the figure of merits of CS and VS techniques (0.660 vs 0.665; P = 0.890). However, the CS technique showed a higher detection rate in Liver Imaging Reporting and Data System M (LR-M, probably or definitely malignant but not HCC specific) observations than the VS technique (100.0% [9/9] vs 44.4% [8/18]; P = 0.009). The CS technique tended to provide optimally timed LAP without transient severe motion and demonstrated greater detection rate of LR-M observations than the VS technique in patients at high risk of HCC.

Utility of PIVKA-II and AFP in Differentiating Hepatocellular Carcinoma from Non-Malignant High-Risk Patients.

Background and Objectives: We aim to compare the diagnostic performance of Protein induced by vitamin K absence-II (PIVKA-II), a biomarker for hepatocellular carcinoma (HCC), and alpha-fetoprotein (AFP) in differentiating HCC and non-malignant high-risk (NMHR) groups and to determine their cut-off values. Materials and Methods: A total of 163 patients, including 40 with HCC and 123 with NMHR (100 with liver cirrhosis and 23 with non-cirrhotic high-risk patients) were prospectively enrolled. The levels of AFP and PIVKA-II were measured, and their cut-off values were determined. We calculated and compared the areas under the receiver operating characteristic (AUROC) curves of PIVKA-II, AFP, and their combination. Results: The levels of PIVKA-II and AFP were found to be significantly higher in the HCC compared to NMHR patients (p < 0.0001). For the differentiation of HCC from NMHR, the optimal cutoff values for PIVKA-II and AFP were 36.7 mAU/mL (90% sensitivity; 82.1% specificity) and 14.2 ng/mL (75% sensitivity; 93.5% specificity), respectively. The AUROC of PIVKA-II (0.905, p < 0.0001) was higher compared to AFP (0.869, p < 0.0001), but the combination of PIVKA–II and AFP gave the highest AUROC value (0.911, p < 0.0001). However, their differences were not statistically significant (AFP vs. PIVKA; p = 0.4775, AFP vs. Combination; p = 0.3808, PIVKA vs. Combination; p = 0.2268). Conclusions: PIVKA-II and AFP showed equal performance in detecting HCC in high-risk patients. AFP as a screening marker for HCC may be adequate, and replacing or adding the PIVKA-II test in current clinical practice may be of little value.

Development and Validation of a Novel Ferroptosis-Related Gene Signature for Prognosis and Immunotherapy in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a cancer that is sensitive to ferroptosis, and immunotherapy has emerged as a promising treatment for HCC patients. However, the prognostic potential of ferroptosis-related genes (FRGs) and the effect of ferroptosis on the tumor immune microenvironment in HCC remain largely obscure. Here, we analyzed the expression pattern of FRGs using the TCGA, ICGC and GEO databases. The expression of most FRGs was upregulated in HCC tissues compared with normal liver tissues. Three independent clusters were determined by consensus clustering analysis based on FRG expression in HCC. Cluster 3 exhibited higher expression, unfavorable prognosis, and higher histological tumor stage and grade than clusters 1 and 2. CIBERSORT analysis indicated different infiltrating levels of various immune cells among the three clusters. Moreover, most immune checkpoint genes were highly expressed in cluster 3. Univariate Cox regression and LASSO regression analyses were performed to develop a five FRG-based prognostic risk model using the TCGA and ICGC datasets. Kaplan–Meier analysis and ROC curves were performed to verify the prognostic potential of the risk model. A nomogram containing independent prognostic factors was further developed. Compared with low-risk patients, high-risk HCC patients exhibited worse overall survival (OS). In addition, this risk model was significantly correlated with the infiltrating levels of six major types of immune cells in HCC. Finally, the relationships between the five FRGs and drug sensitivity were investigated. The present study suggests that the five FRGs could elucidate the molecular mechanisms of HCC and lead to a new direction for the improvement of predictive, preventive, and personalized medicine for HCC.

Curative Analysis of Patients with Hepatocellular Carcinoma Using Transcatheter Arterial Chemoembolization Combined with Radiofrequency Ablation.

BackgroundTranscatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) can improve the survival of patients with hepatocellular carcinoma (HCC). The purpose was to explore the characteristics of high-risk and low-risk groups of HCC patients receiving combination therapy using a decision tree model.Material/MethodsThis retrospective cohort study investigated HCC patients treated with a combination of TACE and RFA at our hospital from 2012 to 2018. Decision tree analysis was used to study the 1-year prognosis of patients, and patients were divided into high-risk and low-risk groups.ResultsWe included a total of 142 patients with HCC, 21.83% female and 78.17% male, with the median age of 60 years old. The median follow-up was 13.5 months; 39.44% of patients had progressive disease or death (high-risk group) and 60.56% of patients did not have progressive disease or survival (low-risk group). The area under the curve (AUC) of the decision tree model was 0.846. There were significant differences in sex (P=0.003), age (P=0.038), tumor number (P=0.043), number of RFAs in the first treatment cycle (P<0.001), alanine transaminase (ALT) (P<0.001), and aspartate transaminase (AST) (P=0.041) between the high-risk and the low-risk groups. Risk of progressive disease or death in the high-risk group was 12.232 times higher than in the low-risk group.ConclusionsTo improve individual survival, clinicians should pay attention to the identification of high-risk HCC patients receiving combination therapy, especially those with less frequent use of RFA during the first treatment and higher ALT and AST levels.

Inflammatory Response-Related Long Non-Coding RNA Signature Predicts the Prognosis of Hepatocellular Carcinoma.

Background Hepatocellular carcinoma (HCC) is a high mortality malignant tumor with genetic and phenotypic heterogeneity, making predicting prognosis challenging. Meanwhile, the inflammatory response is an indispensable player in the tumorigenesis process and regulates the tumor microenvironment, which can affect the prognosis of tumor patients. Methods Using HCC samples in the TCGA-LIHC dataset, we explored lncRNA expression profiles associated with the inflammatory response. The inflammatory response-related lncRNA signature was constructed by univariate Cox regression, LASSO regression, and multivariate Cox regression methods based on inflammatory response-related differentially expressed lncRNAs in HCC. Results Seven inflammatory response-related lncRNA signatures were identified in predicting HCC prognosis. Kaplan–Meier (K-M) survival analysis indicated that high-risk group HCC patients were associated with poor prognosis. The utility of the inflammatory response-related lncRNA signatures was proved by the AUC and DCA analysis. The nomogram further confirmed the accuracy of the novel signature in predicting HCC patients' prognoses. In validation, our novel signature is more accurate than traditional clinicopathological performance for prognosis prediction of HCC patients. GSEA analysis further elucidated the underlying mechanisms and pathways of HCC progression in the low- and high-risk groups. Moreover, immune cells infiltration responses and immune function analyses revealed a significant difference between high- and low-risk groups in cytolytic activity, MHC class I, type I INF response, type II INF response, inflammation-promoting, and T cell coinhibition. Finally, HHLA2, NRP1, CD276, TNFRSF9, TNFSF4, CD80, and VTCN1 were expressed higher in high-risk groups in the immune checkpoint analysis. Conclusions A novel inflammatory response-related lncRNA signature (AC145207.5, POLHAS1, AL928654.1, MKLN1AS, AL031985.3, PRRT3AS1, and AC023157.2) is capable of predicting the prognosis of HCC patients and providing new immune targeted therapies insight.

Clinical versus radiographical factors associated with hepatocellular carcinoma diagnosis in high-risk patients: sizes matter.

Aim:This study aimed to evaluate if clinical or radiographic findings can be used for hepatocellular carcinoma (HCC) diagnosis particularly in high-risk patients.Methods:This was a prospective study and evaluated factors associated with HCC.Results:There were 260 patients met the study criteria: 219 patients (84.23%) were HCC. Two factors significantly associated with HCC: portal vein invasion and the largest mass size. The cutoff point for the largest mass size of 2 cm or over gave sensitivity and specificity for HCC of 83.56 and 87.80%, respectively.Conclusion:Portal vein invasion and the largest liver mass of 2 cm or over may be diagnostic factors for HCC in high-risk patients, while clinical factors were not suggestive for HCC.

Association Between Nonselective Beta-Blocker Use and Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Without Cirrhosis and Decompensation.

Background: Nonselective beta-blockers (NSBBs) can reduce the incidence or mortality of certain types of cancers, and NSBBs exert a protective effect on hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the potential preventive effect of NSBBs has not yet been investigated in patients with chronic hepatitis B (CHB) who have a high HCC risk regardless of the presence of underlying cirrhosis. Aim: This study evaluated the association between NSBB use and HCC incidence in patients with CHB without cirrhosis and decompensation. Methods: From the 2000 Longitudinal Generation Tracking Database, we enrolled patients who were newly diagnosed as having CHB from January 2001 to December 2011 and then followed them up for at least 5 years. To estimate the causal effect of NSBBs on the time-to-event outcomes of HCC, a marginal Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: After adjustment, no significant benefit of HCC risk reduction was observed between the NSBB users and nonusers (adjusted HR, 0.82; 95% CI, 0.52–1.31). The cumulative defined daily dose (cDDD) analysis revealed no significant dose correlation among the three groups [adjusted HR (95% CI): 1.08, (0.56–2.05), 0.54 (0.17–1.77), and 0.76 (0.40–1.42) in the <90 cDDD, 90 to <180 cDDD, and ≥180 cDDD groups, respectively]. Duration-dependent associations were not observed. Multivariable stratified analysis results demonstrated that HCC risk markedly decreased in the patients aged >55 years (adjusted HR, 0.49; 95% CI, 0.25–0.96; p = 0.04). Conclusion: NSBB did not significantly prevent HCC in the patients with CHB infection without cirrhosis and decompensation. This study provided one of valuable results that it is not clinically required to use NSBBs as recommended chemoprevention for HCC in high-risk patients who have CHB.

Abbreviated magnetic resonance imaging vs ultrasound for surveillance of hepatocellular carcinoma in high-risk patients.

We aimed to compare the performance of gadoxetic acid-enhanced abbreviated MRI (AMRI)-based surveillance and ultrasound-only surveillance in high-risk patients for hepatocellular carcinoma (HCC). Prospectively recruited high-risk patients (>5% annual risk of HCC) who underwent one to three rounds of complete gadoxetic acid-enhanced MRI (CMRI) and ultrasound at 6-months intervals were retrospectively analysed. AMRI consisted of diffusion-weighted, T2-weighted, and hepatobiliary phase imaging. The sensitivity, specificity, and accuracy of CMRI followed by AMRI (CAA), AMRI-only (AAA), and ultrasound-only (US) were compared using generalized estimating equations. Image quality was assessed. In 382 patients, HCC was diagnosed in 43 (11.3%), including 42 with early-stage HCCs. The sensitivities of CAA (90.7%, 39/43) and AAA (86.0%, 37/43) were higher than US (27.9% [12/43]; P<0.001), whereas the sensitivities of the two MRI approaches did not significantly differ (P=0.56). The specificity of CAA (97.1%, 983/1012) was higher than AAA (95.6% [967/1012]; P=0.01) and not significantly different from US (96.3% [975/1012]; P=0.59). The CAA approach had the best accuracy of 96.9% (1022/1055), higher than the AAA approach (95.2% [1004/1055]; P=0.01) and the US approach (93.6% [987/1055]; P=0.01). Image quality was inadequate in 33.7% (356/1055) of US examinations but in only 10.0% (105/1055) of the AAA and 11.1% (117/1055) of the CAA approach. In high-risk patients, AMRI-based surveillance approaches had higher sensitivities than ultrasound-only surveillance for early-stage HCC. A sequential MRI approach of CMRI followed by AMRIs showed superior accuracy than the AMRI-only or ultrasound-only approach.

CT/MRI LI-RADS version 2018 versus CEUS LI-RADS version 2017 in the diagnosis of primary hepatic nodules in patients with high-risk hepatocellular carcinoma.

BackgroundThis study aimed to explore the application value of computed tomography/magnetic resonance imaging (CT/MRI) liver imaging reporting and data system (LI-RADS) version 2018 and contrast-enhanced ultrasound (CEUS) LI-RADS version 2017 in high-risk hepatocellular carcinoma (HCC) patients and to conduct a comparative analysis.MethodsThis study enrolled 250 high-risk HCC patients with 259 primary hepatic nodules from June 2017 to June 2020. Two investigators used a single-blind method to classify all nodules. The u-test, t-test, and Kappa test were performed. The sensitivity, specificity, positive predictive value (PPV), negative predictive value and receiver operating characteristic curves of LR-5 and LR-M in the diagnosis of HCC and non-HCC malignancy were respectively calculated.ResultsCT/MRI LI-RADS v2018 and CEUS LI-RADS v2017 showed substantial agreement inter-observers, and there was a moderate agreement inter-modality. The specificity and PPV of HCC and non-HCC malignancies in CT/MRI LR-5/M were higher than CEUS. The areas under the curve (AUC) of CT/MRI LR-5 and LR-M were 0.794 and 0.777, and the AUC of CEUS LR-5 and LR-M were 0.720 and 0.718, respectively.ConclusionsTwo modalities have substantial agreement inter-observers and moderate agreement inter-modalities. The diagnostic accuracy of HCC of CT/MRI LR-5 and non-HCC malignancy of CT/MRI LR-M are higher than CEUS.

Risk assessment and management of hepatocellular carcinoma occurrence in patients with chronic hepatitis B in the era of antiviral therapy

Chronic hepatitis B (CHB) virus infection remains the leading cause of hepatocellular carcinoma (HCC) in China. Oral antiviral drugs have been shown to significantly reduce the HCC risk in CHB patients, but it cannot completely eliminate the HCC occurrence. Therefore, accurate HCC risk assessment and standardized screening in CHB patients are essential for early diagnosis and improved prognosis. In recent years, medical researchers have established a variety of HCC risk prediction models for CHB patients, providing clinicians with a good assessment method. However, due to the differences in the baseline characteristics of each model when deriving and verifying the population, the applicable population and prediction effectiveness are still different, and it is difficult to achieve a "one-size-fits all" . To this end, this paper reviews the common HCC risk assessment model for CHB patients during antiviral therapy, and introduces the monitoring and screening strategies of domestic and foreign guidelines for high-risk HCC patients in order to help clinicians better manage such patients.

Development of a novel lipid metabolism-based risk score model in hepatocellular carcinoma patients

BackgroundLiver cancer is one of the most common malignancies worldwide. HCC (hepatocellular carcinoma) is the predominant pathological type of liver cancer, accounting for approximately 75–85 % of all liver cancers. Lipid metabolic reprogramming has emerged as an important feature of HCC. However, the influence of lipid metabolism-related gene expression in HCC patient prognosis remains unknown. In this study, we performed a comprehensive analysis of HCC gene expression data from TCGA (The Cancer Genome Atlas) to acquire further insight into the role of lipid metabolism-related genes in HCC patient prognosis.MethodsWe analyzed the mRNA expression profiles of 424 HCC patients from the TCGA database. GSEA(Gene Set Enrichment Analysis) was performed to identify lipid metabolism-related gene sets associated with HCC. We performed univariate Cox regression and LASSO(least absolute shrinkage and selection operator) regression analyses to identify genes with prognostic value and develop a prognostic model, which was tested in a validation cohort. We performed Kaplan-Meier survival and ROC (receiver operating characteristic) analyses to evaluate the performance of the model.ResultsWe identified three lipid metabolism-related genes (ME1, MED10, MED22) with prognostic value in HCC and used them to calculate a risk score for each HCC patient. High-risk HCC patients exhibited a significantly lower survival rate than low-risk patients. Multivariate Cox regression analysis revealed that the 3-gene signature was an independent prognostic factor in HCC. Furthermore, the signature provided a highly accurate prediction of HCC patient prognosis.ConclusionsWe identified three lipid-metabolism-related genes that are upregulated in HCC tissues and established a 3-gene signature-based risk model that can accurately predict HCC patient prognosis. Our findings support the strong links between lipid metabolism and HCC and may facilitate the development of new metabolism-targeted treatment approaches for HCC.