Risk Factor For Hepatocellular Carcinoma Research Articles

Development of machine learning-based personalized predictive models for risk evaluation of hepatocellular carcinoma in hepatitis B virus-related cirrhosis patients with low levels of serum alpha-fetoprotein

Introduction and ObjectivesThe increasing incidence of hepatocellular carcinoma (HCC) in China is an urgent issue, necessitating early diagnosis and treatment. This study aimed to develop personalized predictive models by combining machine learning (ML) technology with a demographic, medical history, and noninvasive biomarker data. These models can enhance the decision-making capabilities of physicians for HCC in hepatitis B virus (HBV)-related cirrhosis patients with low serum alpha-fetoprotein (AFP) levels. Patients and MethodsA total of 6,980 patients treated between January 2012 and December 2018 were included. Pre-treatment laboratory tests and clinical data were obtained. The significant risk factors for HCC were identified, and the relative risk of each variable affecting its diagnosis was calculated using ML and univariate regression analysis. The data set was then randomly partitioned into validation (20 %) and training sets (80 %) to develop the ML models. ResultsTwelve independent risk factors for HCC were identified using Gaussian naïve Bayes, extreme gradient boosting (XGBoost), random forest, and least absolute shrinkage and selection operation regression models. Multivariate analysis revealed that male sex, age >60 years, alkaline phosphate >150 U/L, AFP >25 ng/mL, carcinoembryonic antigen >5 ng/mL, and fibrinogen >4 g/L were the risk factors, whereas hypertension, calcium <2.25 mmol/L, potassium ≤3.5 mmol/L, direct bilirubin >6.8 μmol/L, hemoglobin <110 g/L, and glutamic-pyruvic transaminase >40 U/L were the protective factors in HCC patients. Based on these factors, a nomogram was constructed, showing an area under the curve (AUC) of 0.746 (sensitivity = 0.710, specificity=0.646), which was significantly higher than AFP AUC of 0.658 (sensitivity = 0.462, specificity=0.766). Compared with several ML algorithms, the XGBoost model had an AUC of 0.832 (sensitivity = 0.745, specificity=0.766) and an independent validation AUC of 0.829 (sensitivity = 0.766, specificity = 0.737), making it the top-performing model in both sets. The external validation results have proven the accuracy of the XGBoost model. ConclusionsThe proposed XGBoost demonstrated a promising ability for individualized prediction of HCC in HBV-related cirrhosis patients with low-level AFP.

ZFC3H1 as an Indicator of Poor Prognosis in Hepatocellular Carcinoma: Bioinformatic Analysis and Experimental Verification.

Zinc finger C3H1-type containing (ZFC3H1) might regulate RNA processes. However, research lacks the prognostic value of ZFC3H1 in hepatocellular carcinoma (HCC). The study analyzed ZFC3H1 expression in HCC cells and its correlation with patient prognosis using transcriptomics, immunohistochemistry, and quantitative real-time reverse transcription PCR, as well as single-cell RNA expression data. Additionally, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were used to investigate the potential ZFC3H1-related cellular functions and signaling pathways. The impact of ZFC3H1 expression on the tumor microenvironment and tumor mutational burden (TMB) was assessed using the ESTIMATE algorithm. Cell-based assays, including cell counting kit 8, proliferation, colony formation, cell cycle, wound healing, and Transwell assays, were conducted to evaluate the influence of ZFC3H1 on hepatocellular carcinoma proliferation and migration. ZFC3H1 is upregulated in HCC and linked to tumor progression. High ZFC3H1 expression is a prognostic risk factor for HCC, according to Kaplan-Meier and Cox regression analyses. ESTIMATE analysis suggested that ZFC3H1 reduces immune cell infiltration and increases the TMB. Patients with low ZFC3H1 expression might respond better to immunotherapy. High ZFC3H1 expression is associated with increased half-maximal inhibitory concentration (IC50) of sorafenib. Functional experiments demonstrated that reducing ZFC3H1 expression inhibited HCC cell proliferation and migration. ZFC3H1 is upregulated in HCC, promoting the proliferation and migration of liver cancer cells, impacting the prognosis of HCC patients and the effectiveness of immunotherapy. ZFC3H1 might serve as a therapeutic target and biomarker for HCC.

Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis.

Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 inenhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.

Metabolic syndrome and cancer risk: A two-sample Mendelian randomization study of European ancestry.

The relationship between Metabolic Syndrome and cancer remains controversial. We aimed to assess the association between Metabolic Syndrome and cancer risk at different locations using a Mendelian randomization approach. We extracted single nucleotide polymorphisms (SNPs) of MetS and its components from public databases for populations of European ancestry. Causal effects were estimated using inverse variance weighting, MR-Egger, weighted median, and MR-PRESSO. Sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots. In addition, we calculated the Statistical power. Finally, we applied the False Discovery Rate (FDR) to correct our results. IVW methods showed that Genetically predicted Metabolic Syndrome may be a potential risk factor for hepatocellular carcinoma (P=0.031, P-FDR=0.093). Metabolic Syndrome was not causally associated with cancers at other sites (lung, thyroid, breast, prostate, kidney, bladder, colorectal, oesophagus, and stomach). In further analyses, WC may increase the risk of lung (P=0.003, P-FDR=0.018), and oesophageal (P=0.011, P-FDR=0.066) cancers and decrease the risk of prostate cancer (P=0.006, P-FDR=0.001). Furthermore, hypertension may reduce the risk of Hepatic cancer (P=0.014, P-FDR=0.084). Our study suggests that genetically predicted Metabolic Syndrome may increase the risk of some cancers. Prevention and treatment of Metabolic Syndrome may help to prevent the development of related cancers.

Development of a Cancer-associated Fibroblast Signature for Evaluating Immunotherapy Response and Prognosis of Hepatocellular Carcinoma.

Alcohol abuse, non-alcoholic fatty liver disease (NAFLD), and hepatitis B and C are the main pathogenic factors of hepatocellular carcinoma (HCC). Though the current understanding of risk factors for HCC has been improved, patients with this type of cancer are normally diagnosed at advanced stages, posing significant challenges to effective treatment. This study analyzed the HCC datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database (GSE14520 and GSE116174). Stromal and immune cell infiltration in the tumor microenvironment (TME) was quantified by the ESTIMATE algorithm. To identify gene modules associated with cancer-associated fibroblasts (CAFs), weighted gene co-expression network analysis (WGCNA) was performed to develop gene co-expression networks. A CAF prognosis score (CAFPS) model was established based on the prognostic CAF genes screened by univariate and multivariate Cox regression analyses. To determine the role of the genes in the vital module in HCC, we conducted Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Finally, the relationship between CAFPS and drug sensitivity was analyzed using Genomic Data for Cancer Drug Sensitivity (GDSC). In this study, we found significant differences in immune scores, stromal scores, CAFs scores, and CD4/8 T-cell scores between normal samples and samples with different TNM staging. In particular, the proportion of CAFs was higher than all other cells in normal samples. Gene modules related to CAFs were identified by developing a gene co-expression network using WGCNA analysis. The lightyellow and greenyellow modules showed the highest correlation with CAF scores. Univariate COX analysis identified 12 genes related to HCC prognosis from a total of 191 genes in the two modules. The Kaplan-Meier (KM) survival analysis revealed that a high expression of these genes was associated with a lower survival chance. Based on the 12 genes obtained by univariate COX analysis, multivariate COX analysis was performed to construct a risk score model for the characteristics of CAFs (CAFPS). The KM survival curves of patients in the high CAFPS and low CAFPS groups showed that patients in the low CAFPS group had better survival. CAFs played a crucial role in the pathogenesis and treatment response of HCC. Targeting the CAFs milieu may provide therapeutic benefits, highlighting the importance of CAFS in developing a personalized treatment for HCC patients. Further studies are required to verify the current findings and explore their implications in clinical settings.

Hepatocellular Carcinoma in Asia: Physician and Patient Perspectives on Surveillance, Diagnosis, and Treatment

PurposeIn several Asian countries, hepatocellular carcinoma (HCC) is a leading cause of cancer deaths. HCC risk factors in Asia differ from those elsewhere and are changing with the treatment landscape as systemic treatment options increase. This study was conducted to gain insight from physicians and patients into HCC screening, diagnosis, and treatment strategies in Indonesia, Korea, Malaysia, Singapore, Taiwan, Thailand, and Vietnam.MethodsTwo cross-sectional, anonymized, online surveys were completed between July and December 2022 by physicians diagnosing and treating HCC (55 questions on risk factors, surveillance, diagnosis, and treatment) and patients ≥ 18 years old diagnosed with HCC (36 questions on disease knowledge, quality of life, and experiences of diagnosis and treatment).ResultsResponses were received from 276 physicians in all 7 countries and 130 patients in Thailand, Taiwan, and Vietnam. From the physician’s perspective, surveillance programs are widespread but identify insufficient HCC cases; only 18% are early-stage HCC at diagnosis. From the patient’s perspective, knowledge of risk factors increases after diagnosis, but few seek support from patient associations; patients would benefit from better communication from their doctors. Treatment affordability and side effects are key issues for patients.ConclusionsAwareness of the risk factors for HCC should be raised in primary care and the general population, and surveillance should identify early-stage HCC. Because patients rely on their doctors for support, doctors should better understand their patients’ needs, and patients could be supported by trained nurses or case managers. Programs are needed to increase patients’ access to proven HCC treatments.

Predictive Risk Factors and Scoring Systems Associated with the Development of Hepatocellular Carcinoma in Chronic Hepatitis B.

Chronic hepatitis B (CHB) infection constitutes a leading cause of hepatocellular carcinoma (HCC) development. The identification of HCC risk factors and the development of prognostic risk scores are essential for early diagnosis and prognosis. The aim of this observational, retrospective study was to evaluate baseline risk factors associated with HCC in CHB. Six hundred thirty-two consecutive adults with CHB (n = 632) [median age: 46 (IQR: 24)], attending the outpatients' Hepatology clinics between 01/1993-09/2020 were evaluated. Core promoter mutations and cirrhosis-HCC (GAG-HCC), Chinese University-HCC (CU-HCC), risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B), Fibrosis-4 (FIB-4), and Platelet Age Gender-HBV (PAGE-B) prognostic scores were calculated, and receiver operating curves were used to assess their prognostic performance. HCC was developed in 34 (5.38%) patients. In the multivariable Cox regression analysis, advanced age (HR: 1.086, 95% CI: 1.037-1.137), male sex (HR: 7.696, 95% CI: 1.971-30.046), alcohol abuse (HR: 2.903, 95% CI: 1.222-6.987) and cirrhosis (HR: 21.239, 95% CI: 6.001-75.167) at baseline were independently associated with the development of HCC. GAG-HCC and PAGE-B showed the highest performance with c-statistics of 0.895 (95% CI: 0.829-0.961) and 0.857 (95% CI: 0.791-0.924), respectively. In the subgroup of patients with cirrhosis, the performance of all scores declined. When treated and untreated patients were studied separately, the discriminatory ability of the scores differed. In conclusion, HCC development was independently associated with advanced age, male sex, alcohol abuse, and baseline cirrhosis among a diverse population with CHB. GAG-HCC and PAGE-B showed high discriminatory performance to assess the risk of HCC development in these patients, but these performances declined in the subgroup of patients with cirrhosis. Further research to develop scores more specific to certain CHB subgroups is needed.

Associations between modifiable risk factors and hepatocellular carcinoma: a trans-ancestry Mendelian randomization study

BackgroundPotentially modifiable risk factors for hepatocellular carcinoma (HCC) have been investigated in observational epidemiology studies in East Asian and European populations, whereas the causal associations of most of these risk factors remain unclear.MethodsWe collected genome-wide association summary statistics of 22 modifiable risk factors in East Asians and 33 risk factors in Europeans. Genetic summary statistics of HCC were sourced from the Biobank Japan study (1,866 cases and 195,745 controls) for East Asians, and the deCODE genetics study (406 cases and 49,302 controls) and the UK Biobank (168 cases and 372 016 controls) for Europeans. Two-sample Mendelian randomization (MR) analyses were performed independently for East Asian and European populations.ResultsIn East Asians, genetically predicted alcohol frequency, ever drinkers, aspartate aminotransferase (AST), hypothyroidism, chronic hepatitis B, and chronic hepatitis C, metabolic dysfunction-associated steatotic liver disease (MASLD), and autoimmune hepatitis were significantly associated with an increased HCC risk (P < 0.05/22). Among European population, alanine transaminase, AST, MASLD, percent liver fat, and liver iron content were significantly associated with a higher risk of HCC (P < 0.05/33). The replication dataset and meta-analysis further confirmed these results.ConclusionsAlthough East Asian and European populations have different factors for HCC, their common modifiable risk factors AST and MASLD for HCC, offer valuable insights for targeted intervention strategies to mitigate society burden of HCC.

Risk factors of hepatocellular carcinoma associated with nonalcoholic fatty liver disease: Systematic review and meta-analysis.

Nonalcoholic fatty liver disease (NAFLD) is currently an important chronic liver disease threatening human life and health. To investigate the risk factors of hepatocellular carcinoma (HCC) associated with nonalcoholic fatty liver disease (NAFLD) by systematic review. We conducted a systematic review and meta-analysis. A systematic search of Chinese and English databases (PubMed, Web of Science, Cochrane Library, China national knowledge infrastructure (CNKI), Wanfang database, and VIP database) was performed until June 30, 2023. Studies were included to investigate the risk factors for HCC in patients with NAFLD. Quality evaluation was performed using the Newcastle-Ottawa Literature Quality Evaluation Scale, and then hazard ratios (HRs) for different influencing factors were combined. We reviewed the results of 12 high-quality cohort studies involving 738,934 patients with NAFLD and 1,480 developed HCC. A meta-analysis based on a random-effects model showed that advanced age (HR = 1.81, 95% CI: 1.51-2.17), male gender (HR = 2.51, 95% CI: 1.67-3.78), hypertension (HR = 1.87, 95% CI: 1.05-3.33), and diabetes (HR = 2.27, 95% CI: 1.63-3.16) were risk factors for HCC in NAFLD, and the differences were statistically significant. However, there was no statistically significant effect of current smoking (HR = 1.45, 95% CI: 0.72-2.92) and dyslipidemia (HR = 1.03, 95% CI: 0.72-1.47) on HCC incidence in this study. Age, sex, hypertension and diabetes are risk factors for HCC in NAFLD patients. Diabetic NAFLD patients have a 2.27-fold increased risk of HCC, and health education and intervention for elderly, male, NAFLD patients with diabetes and hypertension need to be strengthened to promote a reduction in the risk of HCC.

Evaluation the Role of Lipocalin 2 as a New Non-Invasive Diagnostic Marker for Hepatocellular Carcinoma in Egyptian Cirrhotic Patients

Abstract Background Hepatocellular carcinoma (HCC) represents the sixth most common cancer worldwide. In Egypt, it represents the fourth common cancer. Significant risk factors for hepatocellular carcinoma include viral hepatitis (hepatitis B and hepatitis C), alcoholic liver disease, and non-alcoholic liver steatohepatitis/non-alcoholic fatty liver disease. HCC occurs in 80%-90% of patients with cirrhosis. The annual incidence of HCC in patients with cirrhosis is 2-4%. Aim of the Work The aim of this study is to evaluate the role of lipocalin 2 (LCN 2) as a diagnostic marker in HCC Egyptian patients. Patients and Methods A case-control study in Ain- Shams University Hospital for 6 months period and the study will be conducted on 96 Egyptian patients (32 HCC patients, 32 liver cirrhosis without HCC, 32 normal control persons). Res1ults We found that LCN 2 level ranged from 150 to 380 in HCC group with mean±SD = 292.750±50.940, from 88 to 280 in cirrhotic patients with mean± SD = 129.313±36.605, from 40 to 62 in control group with mean± SD = 53.250± 4.958, being statistically significant higher in HCC group more than both cirrhotic group and control group and in cirrhotic patients more than control group (p-value = &amp;lt;0.001). The results showing sensitivity of 96.87% and specificity 96.87% of LCN 2 as a marker for HCC with accuracy of 98.4%,with cut off &amp;gt; 160. The presence of (LCN-2) in blood and urine, in combination with α-Fetoprotein (AFP), is a biomarker of early stages of HCC. LCN 2 is a promising serum tumor marker for HCC diagnosis. Conclusion We concluded from this study that: Serum LCN 2 level was significantly higher in patients with HCC and mildly elevated in patients with liver cirrhosis compared to the control group. So it can be used as a tumor marker for HCC diagnosis. Use of LCN 2 with AFP or possibly other markers will improve the diagnostic field and can help in early detection of HCC in surveillance programms. We need further studies on large number of HCC patients of different etiologies and on metastaic liver tumors to clarify the accuracy and potential diagnostic role of LCN 2 in the future.

X-ray Repair Cross Complementing 1 (XRCC1) Gene Polymorphism in Hepatocellular Carcinoma (HCC)

Abstract Background Several risk factors for hepatocellular carcinoma (HCC) have been identified, including chronic infection of hepatitis B virus (HBV) and hepatitis C virus (HCV). Nevertheless, only a fraction of infected patients develops HCC during their lifetime suggesting that genetic factors might modulate HCC development. The human X-ray repair cross- complementing protein 1 (XRCC1) gene encodes for one of the major repair factors involved in base excision repair (BER), which is reported to be associated with the risk of several cancers. A few studies have explored the association between risk of hepatocellular carcinoma (HCC) and single-nucleotide polymorphisms (SNPs) in different DNA repair genes. Aim of the Work to investigate the possible association between XRCC1-G28152A (rs25487) single nucleotide polymorphism (SNP) and hepatocellular carcinoma (HCC) in chronic hepatitis C patients. Patients and Methods The study included 35 patients who had HCC and 15 patients who had liver cirrhosis. XRCC1 gene polymorphism was done to all participants by RT-PCR After collection of relevant clinical data and basic laboratory tests. Results A statistically higher frequency of XRCC1 (GG, GA) genotypes and increased (G) allele frequency in patients with HCC was found in comparison to cirrhotic HCV patients as well as control group but Our results revealed that the genotypic and allelic frequencies of XRCC1 gene polymorphism rs25487 didn’t show statistically significant difference between HCC patients group and liver cirrhosis control group. Conclusion The present study had demonstrated that there was no significant association between XRCC1 gene polymorphism (rs25487) and HCC in the sample of Egyptian population included in our study. Also, non-significant differences among the XRCC1 genotypes and alleles were found regarding age, sex, BMI and laboratory data including CBC, AFP, coagulation profile (PT, INR), liver function test ( total protein, albumin, AST, total bilirubin and direct bilirubin), BCLC and Milan criteria. While a statistically significant difference was observed as regards PTT and ALT between genotypes.

Modifiable Risk Factors for Hepatocellular Carcinoma in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-Analysis

Background and AimsThe increasing incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has led to a gradual increase in MASLD-related hepatocellular carcinomas (HCC). In this context, we aimed to investigate the association between modifiable factors and the risk of incident HCC in patients with MASLD. MethodsTwo authors independently searched electronic databases (PubMed, Embase, and the Cochrane Library) from their inception to April 1, 2023. Observational studies reporting an association between modifiable risk factors and MASLD-related HCC were eligible for inclusion. The effect size on the study outcomes was calculated using a random-effects model and was presented as a risk ratio with 95% confidence interval. ResultsA total of 31 studies covering 1.02 million individuals were included. Regarding lifestyle factors, smoking and alcohol consumption were associated with 30% (1.30 [1.08-1.57]) and 140% (2.41 [1.03-5.65]) risk increase of MASLD-related HCC. Regarding metabolic risk factors, patients with MASLD who were overweight or obese (1.31 [1.13-1.52]), had diabetes (2.08 [1.71-2.53]) and hypertension (1.42 [1.12-1.80]) had a higher risk of developing HCC, while dyslipidemia was negatively associated with MASLD-HCC (0.78 [0.65-0.93]). The use of metformin, statin, and aspirin was associated with 18% (0.82 [0.68-0.98]), 55% (0.45 [0.36-0.56]), and 36% (0.64 [0.44-0.92]) risk reduction in incident HCC, respectively. ConclusionsThis comprehensive systematic review and meta-analysis showed statistically significant increases in the risk of incident HCC inpatients with MASLD due to smoking, alcohol use, obesity, diabetes, and hypertension, whereas metformin, statin, and aspirin therapy might modify disease progression.

Matrix stiffening facilitates stemness of liver cancer stem cells by YAP activation and BMF inhibition

Matrix stiffening is one of the major risk factors for hepatocellular carcinoma (HCC) and drives tumor progression. The extracellular matrix (ECM) stiffness of HCC displays mechanical heterogeneity, with stiffness increasing from the core to the invasive frontier. The distribution of liver cancer stem cells (CSCs) is related to this mechanical property. However, it is not sufficiently understood how heterogeneous matrix stiffness regulates the stemness of CSCs. In this study, we developed an adjustable gelatin/alginate hydrogel to investigate the effect of various matrix stiffnesses on CSC stemness under three-dimensional culture conditions. Gelatin/alginate hydrogel with the stiffness of soft (5 kPa), medium (16 kPa), and stiff (81 kPa) were prepared by altering the concentration of calcium ions. It was found that a stiffer matrix promoted stemness-associated gene expression, reduced drug sensitivity, enhanced sphere-forming and clonogenic ability, and tumorigenic potential. Mechanistically, matrix stiffening facilitates CSC stemness by increasing Yes-associated protein (YAP) activity and inhibiting Bcl-2 modifying factor (BMF) expression. Knockdown of YAP or overexpression of BMF significantly attenuated matrix stiffening-induced stemness, suggesting the involvement of YAP and BMF in this process. Together, our results unravel the regulatory mechanism of heterogeneous matrix stiffness on CSC stemness and also provide a novel therapeutic strategy for eradicating CSCs and improving the efficiency of HCC treatment.

Analysis of Risk Factors for Hepatocellular Carcinoma Caused by Hepatitis

Analysis of Risk Factors for Hepatocellular Carcinoma Caused by Hepatitis

Body mass index (BMI) as a prelude to hepatocellular carcinoma (HCC) and metabolic dysfunction–associated steatohepatitis (MASH) risk factors in patients with no identified risk factor for developing hepatocellular carcinoma (HCC).

e16193 Background: Common risk factors for hepatocellular carcinoma (HCC) include viral hepatitis (hepatitis B and hepatitis C), alcoholic liver disease, and metabolic dysfunction-associated steatohepatitis (MASH). Non-risk factored HCC has been suggested where patients who do not have common risk factors develop HCC (Journal of Clinical Oncology Volume 35, Number 15_suppl, May 2017). This is described more commonly among young, females more than males. Is this a misdiagnosis or a truly non-factored risk? Methods: Patients diagnosed with histology confirmed HCC between years 2014 and 2017 with none of the known HCC risk factors, were assessed part of our previous effort add to more recent gathered data at Memorial Sloan Kettering (MSK). In an institutional IRB approved retrospective study, demographic and treatment data in addition to DNA sequencing were compiled and evaluated. Detailed clinical and genomic information was abstracted from the medical record. Pathology data was reviewed (AS). Results: A total of 428 patients diagnosed with HCC were identified, of whom 18 (4.2%) patients had no identifiable HCC risk factors. Fourteen patients were females (78%), and four were males (22%). Median age at diagnosis was 59 years (range 18-77 years). All 18 patients did not meet any of the clinical and/or radiologic alleged criteria for a diagnosis of MASH. The average body mass index (BMI) was 27.9 kg/m2 (16.7-54.4). Six patients (33%) had BMI greater than 30 kg/m2, and five (28%) patients had BMI ranging from 25 to 29.9 kg/m2. Three patients had diabetes mellitus. With the lack of non-tumorous liver cancer surrounding tissue, only three patients had mild steatosis documented on pathology. At the molecular level, few somatic mutations were detected including TERT and CTNNB1 in 37% of cases. No germline mutations were identified in 4 tested patients. Conclusions: Among 18 patients diagnosed with HCC with presumed no or unknown risk factors we previously reported, average BMI was 27.9 kg/m2. This is in the absence of any clinical and/or radiologic alleged criteria for a diagnosis of MASH. In the presence of subtle clinical and/or radiologic findings suggestive of MASH, evaluating patient’s BMI may be considered as an added variable for evaluation of patients with HCC. We clinicians need to be aware of increased BMI as a possible prelude for MASH and HCC. This is added to an invitation for acquired biopsies to include tumor and normal tissue to assess liver cirrhosis or fibrosis.

Comparison of Clinical Manifestations and Related Factors of Hepatocellular Carcinoma with Chronic Hepatitis B.

The aim of this study was to describe the demographic and clinical characteristics of hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC), analyse the risk factors associated with HBV-associated HCC, and to provide some references to the diagnosis and treatment of HCC. This study retrospectively enrolled 730 patients, including 390 patients with chronic hepatitis B (CHB) as controls, and 340 patients with CHB complicated with HCC as patients. Relevant information and medical records of these participants were collected, including age, sex, cigarette smoking, alcoholism, diabetes mellitus (DM), hypertension, coronary heart disease (CHD), cirrhosis, occupation, ascites, HBV-DNA load, the qualitative analysis of HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb serological markers, and levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), gamma-glutamyltransferase (GGT), TNM stage, tumor size and tumor number. The T test, Chi-square test, non-parametric rank-sum test, logistic regression analyses were used to explore the influencing factors and their degree of association with HCC in patients with HBV. The proportion of smoking, alcoholism, married status, DM, hypertension, and the rate of HBV-DNA with a viral load of ≥500 copies/mL were significantly higher in the HCC group than in the controls (all p<0.05). Cirrhosis was more common among patients with CHB+HCC than in controls (p=0.013). The proportion of patients with HBsAg, HBeAb, and HBcAb positive was greater in CHB+HCC group than that in CHB group. Logistic regression analysis indicated that age ≥60 years (OR: 1.835, 95% CI: 1.020-3.302, p=0.043), HBeAb positive (OR: 9.105, 95% CI: 4.796-17.288, p<0.001), antiviral treatment with entecavir (OR: 2.209, 95% CI: 1.106-4.409, p=0.025), and GGT (OR: 1.004, 95% CI: 1.001-1.007, p=0.002) were risk factors for HCC in patients with CHB. Advanced age, HBeAb positive, antiviral treatment with entecavir, and GGT were independent risk factors for HCC in HBV patients.

Hepatocellular carcinoma etiology drives survival outcomes: A population-based analysis.

e16142 Background: Previous studies on survival differences according to etiology of hepatocellular carcinoma (HCC) (5-year observed survival of 23%) are limited to hospital-based series and restricted cohorts. We performed a population-based survival analysis by major HCC etiologies, inclusive of hepatitis-C virus (HCV), hepatitis-B virus (HBV), alcohol-related liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD) as singular causes, in addition to unexplored dual etiological groups, (HCV&amp;HBV, HCV&amp;ALD, and HBV&amp;ALD), and accounting for age at diagnosis, tumor characteristics, and socio-demographics. Methods: All 19,956 cases of HCC diagnosed in Florida during 2005–2018 from the Florida cancer registry were linked for HCC etiology using Agency for Healthcare Administration and Florida Department of Health viral hepatitis data. Survival analysis was performed for the 15,759 linked HCC cases, comparing HCC etiologic groups (4 single and 3 dual). Results included age-adjusted 5-year survival, Kaplan-Meier curves, and adjusted hazard ratios from Cox regression models. Results: The leading single etiology was ‘HCV only’ (n=4,983; 31.6%); the leading dual etiology was ‘HCV&amp;ALD’ (n=2,694; 17.1%). The age-adjusted 5-year survival was low (&lt;22%) across all HCC etiologies; however, non-ALD causes showed higher survival [‘HCV only’ (21.5%; 95%CI:20.2%–22.8%), ‘HBV only’ (20.2%; 95%CI:16.6%–23.9%), ‘NAFLD only’ (19.9%; 95%CI:18.7%–21.2%)] than ALD-related etiologies [‘ALD only’ (14.4%; 95%CI:12.7%–16.0%), ‘HCV&amp;ALD’ (10.4%; 95%CI:9.0%–11.9%), ‘HBV&amp;ALD’ (8.1%; 95%CI:2.2%–14.1%)]. Compared to the reference category ‘HCV only,’ age-adjusted hazard ratios were 1.69 (95%CI: 1.41–2.03; p-value&lt;0.0001) for ‘HBV&amp;ALD,’ 1.33 (95%CI:1.26–1.40; p-value&lt;0.0001) for ‘HCV&amp;ALD,’ and 1.35 (95%CI:1.28–1.43; p-value&lt;0.0001) for ‘ALD only.’ Multivariable analysis including additional factors showed minimal variation from these results. Conclusions: Significant differences in survival based on HCC etiology are important for prevention, surveillance, and targeted treatments based on etiologic-specific biomarkers. Specific pathophysiological mechanisms for ALD in addition to viral hepatitis could be responsible for poorer outcomes for dual etiologies involving alcohol use, compared to viral etiology alone. To increase overall survival, improved screening is needed for patients with multiple HCC risk factors. [Table: see text]

Assessment of Helicobacter Pylori Status and Serum Gastrin Level as Risk Factors for Hepatocellular Carcinoma in Patients with HCV-Related Liver Cirrhosis

Assessment of Helicobacter Pylori Status and Serum Gastrin Level as Risk Factors for Hepatocellular Carcinoma in Patients with HCV-Related Liver Cirrhosis

Value of Sonazoid-enhanced ultrasonography in characterizing indeterminate focal liver lesions on gadoxetic acid-enhanced liver MRI in patients without risk factors for hepatocellular carcinoma.

To evaluate the added value of contrast-enhanced ultrasonography (CEUS) using Sonazoid in characterizing focal liver lesions (FLLs) with indeterminate findings on gadoxetic acid-enhanced liver MRI in patients without risk factors for hepatocellular carcinoma (HCC). Patients who underwent CEUS using Sonazoid for characterizing indeterminate FLLs on gadoxetic acid-enhanced liver MRI were. The indeterminate FLLs were classified according to the degree of malignancy on a 5-point scale on MRI and combined MRI and CEUS. The final diagnosis was made either pathologically or based on more than one-year follow-up. The diagnostic performance was assessed using a receiver operating characteristic (ROC) curve analysis, and the net reclassification improvement (NRI) was calculated. A total of 97 patients (mean age, 49 years ± 16, 41 men, 80 benign and 17 malignant lesions) were included. When CEUS was added to MRI, the area under the ROC curve increased, but the difference was not statistically significant (0.87 [95% confidence interval {CI}, 0.77-0.98] for MRI vs 0.93 [95% CI, 0.87-0.99] for CEUS added to MRI, P = 0.296). The overall NRI was 0.473 (95% CI, 0.100-0.845; P = 0.013): 33.8% (27/80) of benign lesions and 41.2% (7/17) of malignant lesions were appropriately reclassified, whereas 10.0% (8/80) of benign lesions and 17.6% (3/17) of malignant lesions were incorrectly reclassified. Although performing CEUS with Sonazoid did not significantly improve the overall diagnostic performance in characterizing indeterminate FLLs on gadoxetic acid-enhanced liver MRI in patients without risk factors for HCC, it may increase radiologist's confidence in classifying FLLs.

MRTO4 Enhances Glycolysis to Facilitate HCC Progression by Inhibiting ALDOB.

BACKGROUND MRT4 Homolog, Ribosome Maturation Factor (MRTO4) is often upregulated in cancer cells. However, its impact in hepatocellular carcinoma (HCC) is less well understood. Herein, we explored the prognostic and energy metabolism reprogramming role of MRTO4 in HCC. MATERIAL AND METHODS Clinical data were obtained from The Cancer Genome Atlas (TCGA), and the expression of MRTO4 in clinical samples was analyzed. The association between different variables and overall survival (OS) was studied, as well as their potential as independent prognostic factors, using Cox regression analysis. We constructed a nomogram including clinical pathological variables and MRTO4 expression to provide a predictive model for prognosis. Heatmaps, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the relationship between energy metabolism pathways and MRTO4. We used classic molecular biology research methods, including RT-qPCR, Western blotting, CCK8, TUNEL, Clone formation, Transwell assay, ELISA, and immunohistochemistry, to study the role of MRTO4 in promoting the progression of HCC through glycolysis regulation. RESULTS Our study showed that MRTO4 is an independent prognostic risk factor for HCC and that MRTO4 accelerates glycolysis of HCC cells, promotes proliferation and invasion, and suppresses apoptosis of HCC cells. The underlying mechanism involves MRTO4 promoting glycolysis and accelerating HCC by inhibiting ALDOB. CONCLUSIONS Our study revealed a novel mechanism by which MRTO4 promotes glycolysis and accelerates HCC progression, and suggests that inhibiting MRTO4 could be a potential therapeutic strategy for HCC.