Hepatocellular Carcinoma Group Research Articles

Analysis of Serum Exosome Metabolites Identifies Potential Biomarkers for Human Hepatocellular Carcinoma.

Currently, the clinical cure rate for primary liver cancer remains low. Effective screening and early diagnosis of hepatocellular carcinoma (HCC) remain clinical challenges. Exosomes are intimately associated with tumor development and their contents have the potential to serve as highly sensitive tumor-specific markers. A comprehensive untargeted metabolomics study was conducted using exosome samples extracted from the serum of 48 subjects (36 HCC patients and 12 healthy controls) via a commercial kit. An ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) strategy was used to identify the metabolic compounds. A total of 18 differential metabolites were identified using the non-targeted metabolomics approach of UPLC-QTOF-MS/MS. Pathway analysis revealed significant alterations in the arachidonic acid metabolism, linoleic acid metabolism, and unsaturated fatty acid metabolism pathways. ROC analysis indicated that three metabolites with AUC values exceeding 0.900 were selected as potential biomarkers: caprylic acid and linoleic acid were upregulated in the HCC group, whereas pentadecanoic acid was downregulated. Linoleic acid, caprylic acid, and pentadecanoic acid are potential biomarkers for diagnosing HCC. The significant alterations in these three metabolic pathways offer new insights into the mechanisms underlying HCC formation and progression.

Acetazolamide suppresses the progression of hepatocellular carcinoma induced by diethylnitrosamine in Wistar albino rats.

Hepatocellular carcinoma (HCC) continues to be the most prevalent type of liver cancer worldwide. Diethylnitrosamine (DEN)-induced HCC is an extensively used hepatic cancer model in experimental animals. Acetazolamide (AZA) is a carbonic anhydrase enzyme inhibitor. This study aimed to assess the therapeutic mechanism of AZA against DEN-induced HCC. Thirty male Wistar albino rats were divided equally into three groups. Group I (C): control group, Group II (HCC): DEN-induced HCC, and Group III (HCC/AZA): AZA-treated HCC. Verification of the HCC induced by DEN was confirmed by elevated liver enzymes' activities, and increased α-fetoprotein (AFP) levels, as well as distinct liver architecture changes. On the other hand, the AZA-treated HCC group experienced decreases in the activities of serum liver enzymes and AFP levels, as well as, regulated liver architecture. Additionally, it downregulated p-p38 MAPK/p-JNK1/JNK2/p-C-Jun/p-NF-κB p65 protein expressions. Moreover, it ameliorated autophagy by controlling the expression of the p-AMPK/p-mTOR1/LC3 I/II proteins. Furthermore, it downregulated the relative gene expressions of carbonic anhydrase-IX (CAIX) and hexokinase-II (HKII). Histopathological examination of AZA-treated HCC liver tissues supported these findings. Conclusion: AZA provides a new dimension in ameliorating experimentally induced HCC through regulation of hepatic biomarkers, antioxidant status, inflammatory markers, and autophagy, mediated by amelioration of CAIX and HKII gene expressions.

Dexmedetomidine induces IL-10 secretion by B lymphocytes in the peripheral blood of patients with hepatocellular carcinoma

Background/aimTo investigate the distribution of subpopulations of peripheral blood B lymphocytes in individuals with hepatocellular carcinoma (HCC), and to evaluate the effect of dexmedetomidine (DEX) on B lymphocyte differentiation in patients with HCC in vitro. MethodsPeripheral blood mononuclear cells (PBMCs) were collected from the HCC group and the healthy group, and the distribution of peripheral blood B-lymphocyte subpopulations in the two groups was examined by Flow Cytometry (FCM). B lymphocytes extracted from the peripheral blood of the HCC group were divided into D0, D1, D2 and D4 groups according to the different dose of DEX in the culture medium (0 μM, 1 μM, 2 μM and 4 μM). After 72 h of in vitro culture, FCM was used to detect differences in the percentage of apoptotic B lymphocytes and the percentage of B lymphocytes that can express interleukin 10(IL-10) and transforming growth factor-β (TGF-β) in each group. ResultsIn contrast to the healthy group, the HCC group exhibited a statistically significant increase in the proportion of CD19 + CD73 + B lymphocyte subpopulation (P<0.05). In the in vitro culture experiment, the differences in apoptosis of B lymphocytes and the percentage of TGF-β expression in each group were not statistically significant; When compared to the control group, there was a significant increase in the percentage of B lymphocytes expressing IL-10 across the D1, D2, and D4 groups (P<0.05). ConclusionThe peripheral blood of HCC patients is characterized by an elevated presence of CD19 + CD73 + B lymphocyte subpopulations; DEX may have an immunosuppressive effect by promoting IL-10 secretion from peripheral blood B lymphocytes of HCC patients.

NOD1 and NOD2 genetic variants: Impact on hepatocellular carcinoma susceptibility and progression in Moroccan population

BackgroundNucleotide-binding oligomerization domain 1 (NOD1) and NOD2 are involved in carcinogenic processes by recognizing bacterial cell wall components and triggering inflammation. This study explored the association between genetic variations in NOD1 and NOD2 and susceptibility to hepatocellular carcinoma (HCC) and its progression in a Moroccan population. MethodsGenotyping of NOD1 rs2075820 (C>T) and NOD2 rs718226 (A>G) was performed using the TaqMan allelic discrimination assay in 467 Moroccan individuals. The cohort included 156 patients with hepatocellular carcinoma (HCC), 155 patients with liver cirrhosis (LC) diagnosed with HBV, HCV, or MASLD, and 156 controls. ResultsThe NOD1 rs2075820 variant showed no association with HCC susceptibility or progression, which is consistent with in silico predictions. However, the NOD2 rs718226 G allele and GG genotype were more common in the HCC group compared to the cirrhosis and control groups. Individuals with the homozygous G variant had a 2-fold higher risk for HCC (ORad = 2.12; CI=1.01–4.44; Pad = 0.04). Those with the GG genotype also had an increased risk of HCC (GG vs. AG+AA ORad = 2.28; CI=1.15–4.54; Pad = 0.016). Furthermore, GG genotype carriers had a significantly higher risk of HCC progression (ORad = 2.58; CI=1.26–5.31; Pad​ = 0.031). Individuals with the rs718226 minor allele had a significantly elevated risk of progressing from LC to HCC (ORad = 1.50; CI=1.07–2.09; Pad = 0.016). Stratification analysis indicated that men had a higher risk of HCC progression compared to women (ORad = 4.63; CI=1.53–14.00 vs. ORad = 2.73; CI=1.05–7.09). ConclusionThe NOD1 rs2075820 polymorphism does not appear to be a genetic risk factor for susceptibility to HCC. In contrast, the non-coding NOD2 rs718226 variant significantly increases HCC susceptibility and promotes liver cancer progression in the Moroccan population. Further studies involving larger cohorts are warranted to definitively confirm or refute the effects of NOD1 and NOD2 genetic variants on liver cancer susceptibility and progression.

Gd-EOB-DTPA enhanced MRI nomogram model to differentiate hepatocellular carcinoma and focal nodular hyperplasia both showing iso- or hyperintensity in the hepatobiliary phase

BackgroundTo develop and validate a nomogram model based on Gd-EOB-DTPA enhanced MRI for differentiation between hepatocellular carcinoma (HCC) and focal nodular hyperplasia (FNH) showing iso- or hyperintensity in the hepatobiliary phase (HBP).MethodsA total of 75 patients with 49 HCCs and 26 FNHs randomly divided into a training cohort (n = 52: 34 HCC; 18 FNH) and an internal validation cohort (n = 23: 15 HCC; 8 FNH). A total of 37 patients (n = 37: 25 HCC; 12 FNH) acted as an external test cohort. The clinical and imaging characteristics between HCC and FNH groups in the training cohort were compared. The statistically significant parameters were included into the FAE software, and a multivariate logistic regression classifier was used to identify independent predictors and establish a nomogram model. Receiver operating characteristic (ROC) curves were used to evaluate the prediction ability of the model, while the calibration and decision curves were used for model validation. Subanalysis was used to compare qualitative and quantitative characteristics of patients with chronic hepatitis and cirrhosis between the HCC and FNH groups.ResultsIn the training cohort, gender, age, enhancement rate in the arterial phase (AP), focal defects in uptake were significant predictors for HCC showing iso- or hyperintensity in the HBP. In the training cohort, area under the curve (AUC), sensitivity and specificity of the nomogram model were 0.989(95%CI: 0.967-1.000), 97.1% and 94.4%. In the internal validation cohort, the above three indicators were 0.917(95%CI: 0.782-1.000), 93.3% and 87.5%. In the external test cohort, the above three indicators were 0.960(95%CI: 0.905-1.000), 84.0% and 100.0%. The results of subanalysis showed that age was the independent predictor in the patients with chronic hepatitis and cirrhosis between HCC and FNH groups.ConclusionsGd-EOB-DTPA enhanced MRI nomogram model may be useful for discriminating HCC and FNH showing iso- or hyperintensity in the HBP before surgery.

Comprehensive analysis of CXCL10 and MIP-3a reveals their potential clinical application in hepatocellular carcinoma

Chemokines play a crucial role in the pathogenesis of patients with hepatocellular carcinoma (HCC). The expression levels of interferon-γ-induced protein-10 (CXCL10) and macrophage inflammatory protein-3α (MIP-3a) were investigated to clarify their clinical significance in HCC.The protein levels of CXCL10 and MIP-3a in the serum of 105 HBV-associated HCC patients, 50 patients with liver cirrhosis (LC), 50 patients with chronic hepatitis B (CHB) and 50 healthy donors (HC) were detected by liquid chip technology (Luminex) or ELISA. In addition, their mRNA levels were also determined in liver cancer and adjacent cancer tissue (paracancer; ParaCa) from 65 HCC patients. The online database UALCAN was used to analyze the association between CXCL10 and pathological manifestations of liver cancer. In addition, the diagnostic value of CXCL10/MIP-3a and AFP in HCC patients was determined by analyzing the Receiver Operating Characteristic Curve (ROC).The protein concentrations of CXCL10 and MIP-3a were significantly higher in the HCC group than in the LC, CHB and HC groups. CXCL10 in sera and liver cancer tissues is significantly positively correlated with ALT, but no significance between CXCL10 in ParaCa tissues and sera-ALT. Their mRNA is significantly higher in cancer tissues than in ParaCa tissues. The areas under the ROC curve of CXCL10, MIP-3a, CXCL10 and MIP-3a combined and AFP were 0.9169, 0.9261, 0.9299 and 0.7880, respectively. Elevated chemokines CXCL10 and MIP-3a in HCC patients may be associated with the clinical manifestation of HCC and could be a potential molecular marker for prognostic evaluation or a therapeutic target for HCC.

Assessment of Hepatocellular Carcinoma Patients Infected with Covid-19 Infection during the Pandemic

Hepatocellular carcinoma (HCC) patients are more susceptible to decompensation if they get Coronavirus disease 2019 (COVID-19) infection that leads to significant reduction in HCC related health services, reduction in surveillance activities and progression of HCC. On the other hand, symptoms of covid-19 infection are usually severe in HCC patients. Assessment of severity of covid-19 infection in HCC patients. And assessment of clinical course and outcome of HCC patients when they get infected by Covid-19. This is a retrospective case control study including 100 HCC patients (50 of them were infected by covid-19 while the other 50 were not infected). All patients were Egyptians presented to HCC clinic in national hepatology &amp; tropical research institute (NHTMRI) from 1/2022 to 1/2023 assessed for covid-19 infection (by typical CT chest, covid swab and covid symptoms) and assessed for HCC staging (by Barcelona clinic liver cancer BCLC), clinical course over six months (by Child Pugh score) and mortality rates. Most of Covid-19 infected HCC patients had severe covid symptoms and progressive HCC course with mortality 72%, while low percentage of covid-19 HCC infected group were mild with stationary course. On the other hand, high percentage of non-infected HCC group have stationary HCC course with low mortality 24%. COVID-19 infection seems to have a significant effect on clinical course and outcome of HCC. Also, HCC patients are vulnerable to have more severe COVID-19 symptoms.

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.

Role of Α-L-Fucosidase as a Diagnostic Marker versus Α-Fetoprotein in HCC Post Viral Cirrhotic Patients

Abstract Background Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third cause of cancer-related mortality world- wide. The incidence of HCC is on the increase, and it is a major threat to our modern life. Epidemiological studies have indicated that HCC are related to chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infection. Aim of the Work To evaluate the role of AFU as a diagnostic marker versus AFP in HCC post viral cirrhotic Egyptian patients. Patients and Methods This study had been carried out on 90 subjects, age range 21-75 year selected from Internal medicine and Hepatology outpatient clinics and inpatient wards at Ain shams university hospitals from January 2022 to June 2022. Results We found that serum levels of AFU were highest in patients of group A with HCC (129.867 ± 32.997 μl U/ml) compared to those with liver cirrhosis (33.433± 14.818 μl U/ml) with P value &amp;lt; 0.001 and the control groups (3.177 ± 1.199 μl U/ml) with P value &amp;lt; 0.001. Similarly alpha fetoprotein its serum levels were much higher in the HCC group (4688.223±11490.009 ng/ml) compared to the cirrhotic patients (4.407±3.107 ng/ml) with P value 0.02 Also, compared to healthy individuals (2.623±1.566 ng/ml) with p value 1.00. We found that there is No significant statistical correlation between serum AFP and AFU in our studied HCC and cirrhotic patients (R 0.332, P 0.073 for HCC and R 0.222, P 0.238 for cirrhotic). Regarding the negative correlation between serum AFU level and AFP level in order to predict the diagnostic value, sensitivity and specificity of both of them in term of tumor size, our study show that for AFU when the best cut off value was &amp;gt;52μl U/ml the sensitivity was 100% and specificity was 90% while for AFP when the best cut off value was &amp;gt; 10.5 ng/ml the sensitivity was 96.67% and specificity 96.67%. AFU is a promising serum tumor marker for HCC diagnosis and can be combined with AFP. Conclusion We concluded from this study that: Serum AFP was highly significant increase in HCC patients compared to cirrhotic and healthy controls, this is in agreement with many several reports that consider AFP in high serum levels as diagnostic for HCC combined with triphasic CT abdomen or dynamic MRI. Serum AFU levels were 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. No correlation between AFU and laboratory data and child score. AFU was not influenced by clinical condition of the liver itself but with HCC. Around 40% of HCC patients have normal or low AFP level so AFU may be useful as a diagnostic marker in those patients. Serum AFP is the standard tumor marker used in clinical practice for diagnosis and surveillance of HCC in cirrhotic patients in spite of normal and low AFP HCC patients that may reach 40%. Sensitivity and specificity of AFU was nearly similar to sensitivity and specificity of AFP. Combined use of AFU with AFP or possibly other markers will improve the diagnostic field and can help in early detection of HCC in surveillance programms.

Diagnostic Value of Plasma Methylated Septin 9 in Detection of Hepatocellular Carcinoma in Egyptian Patient with Post Hepatitis C Liver Cirrhosis in Comparison to Serum Level of Alphafeto Protein

Abstract Background Egypt has the highest hepatitis C virus (HCV) prevalence worldwide. Cirrhosis secondary to HCV is associated with the highest annual risk for developing hepatocellular carcinoma. The burden of HCC has been increasing in Egypt with a doubling in the incidence rate in the past 10 years. HCC contributes to 14.8% of all cancer mortality in Egypt. Most HCCs (80%) arise in a cirrhotic liver, a situation where there has been longstanding hepatocyte damage and chronic inflammation leading to fibrosis. Aim of the Work This study aims to evaluate the diagnostic value of plasma mSEPT9 assay in detection of HCC in Egyptian patients with post hepatitis C liver cirrhosis in comparison to serum level of α-fetoprotein (AFP). Patients and Methods This is a prospective case-control study conducted at the Gastroenterology department in Ain Shams University Hospital. The study population consisted of 80 subjects, divided into three groups: 40 patients with hepatocellular carcinoma, 20 patients with liver cirrhosis, and 20 healthy subjects as controls with matched age and gender. Results The study found that hepatocellular carcinoma (HCC) was more frequent in male patients and that the age of HCC patients was statistically significantly higher than patients with cirrhosis and healthy controls. Patients with HCC and cirrhosis had a higher Child Pugh score than healthy controls. Portal hypertension and portal vein thrombosis were more frequent in HCC and cirrhosis patients than in the control group. Liver enzymes were higher in patients with HCC and cirrhosis compared to healthy controls, while hemoglobin and platelet levels were lower in patients with HCC. Hepatitis C antibody and PCR were positive in HCC and cirrhosis patient groups. AFP and Methylated Septin 9 levels were higher in patients with HCC and cirrhosis than in healthy controls, and AFP had better diagnostic accuracy than Methylated Septin 9. Both AFP and Methylated Septin 9 levels were positively correlated with age, Child Score, liver enzymes, and coagulation profile and negatively correlated with platelet count and hemoglobin level. AFP level was positively correlated with the number of focal lesions and liver size. Conclusion This study demonstrated that plasma Methylated Septin 9 can be a promising noninvasive and circulating epigenetic biomarker for HCC diagnosis at the individual level. However, our results showed that AFP was superior than Methylated Septin 9 in the detection of HCC, Methylated Septin 9 has higher Sensitivity. It was suggested that the combination of plasma mSEPT9 and AFP could enhance the sensitivity of Methylated Septin 9 or AFP alone in the diagnosis of HCC. Further comparative studies with larger sample size and longer follow-up are needed to confirm our results and to identify risk factors of adverse events.

Clinical Utility of CTNNB1 (c.121A&amp;gt;G) Mutation in Circulating Tumor DNA in Egyptian Patients with Hepatocellular Carcinoma: A Case-Control Study

Abstract Background Hepatocellular carcinoma (HCC) is the most common malignancy of the liver and with 782,000 new cases annually and 600,000 deaths/year globally. In Egypt, HCC causes a significant public health problem with a rising incidence as it is strongly linked to viral hepatitis mainly HCV. CTNNB1 mutations is one of the most common genetic alterations in HCC. Our aim is to investigate the clinical utility of CTNNB1 (rs121913412) single nucleotide variation (SNV) in ctDNA in patients with early and late-stage HCC in comparison to chronic HCV patients and healthy controls. Methods All participants were subjected to history taking, clinical evaluation, laboratory investigations including liver profile, kidney function tests, alfa-fetoprotein. Additionally, complete blood counts and coagulation profile were done. Child and Model for End-Stage Liver Disease (MELD) scores were calculated, BCLC staging was done for each patient and radiological protocol for HCC (spiral triphasic CT or MRI). Genotyping of rs121913412 CTNNB1 (c.121A&amp;gt;G) on extracted DNA from blood samples was done using Real Time PCR System. Results Thirty patients with HCC on top of HCV were recruited including 14 early HCC and 16 with advanced HCC in addition to non-HCC group including 10 HCV-positive patients and 10 healthy controls. All participants have undergone laboratory investigations and radiological protocol for HCC cases. Genotyping of rs121913412 CTNNB1 (c.121A&amp;gt;G) in peripheral blood samples using RT-PCR for all cases was done. The genotype AA was detected in 27out of 30 (30%) of the cases while 3 HCC cases out of 30 (10 %) were positive for the CTNNB1 p.T41A mutation; AG phenotype (heterozygous), no cases showed GG phenotype. In HCV- positive patients’ group and healthy controls none were positive for the CTNNB1 mutation all showed wild AA genotype. No significant differences in the genotype (AA, AG, GG) distribution between HCC and non-HCC groups (χ2=3.619, p = 0.0571). The frequency of AA vs AG + GG genotype was considerably higher in cases when compared to controls however no statistical significance was detected (χ2=3.619, p = 0.0571). Distribution of A vs G allele in cases compared to controls showed statistically significant difference (χ2=4.571, p = 0.0325). Conclusion In this study we were not able to prove the clinical utility of CTNNB1 rs121913412 in Egyptian HCC patients. Further large multi-centric studies are needed to explore the clinical utility of ctDNA in assessment of tumor-specific hotspot somatic mutations in genes including CTNNB1, TERT and TP53 genes that can be identified in the peripheral blood of HCC patients. Comparison studies utilizing both ctDNA and DNA extracted from HCC tissue samples are recommended.

The Combination of Gd-EOB-DTPA Enhanced T1 Mapping with Apparent Diffusion Coefficient could Improve the Diagnostic Efficacy of Hepatocellular Carcinoma Grading.

Accurately predicting the hepatocellular carcinoma (HCC) grade may facilitate the rational selection of treatment strategies. The diagnostic efficacy of the combination of Gadolinium ethoxybenzy diethylenetriamine pentaacetic (Gd-EOB-DTPA) enhancement T1 mapping and apparent diffusion coefficient (ADC) values in predicting HCC grade needs further validation. This study aimed to assess the capacity of Gd-EOB-DTPA-enhanced T1 mapping and ADC values, both individually and in combination, to discriminate between different grades of HCC. From July 2017 to February 2020, 96 patients (male, 83; mean age, 53.67 years; age range, 29-71 years) clinically diagnosed with HCC were included in the present study. All patients underwent Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI, including T1 mapping sequence) before surgery or biopsy. All the patients were categorized into 3 groups according to the pathological results (including 24 cases of well-differentiated HCCs, 59 cases of moderately differentiated HCCs, 13 cases of and poorly differentiated HCCs). The mean Gd-EOB-DTPA enhanced T1 values (&#916;T1=[(T1pre-T1post)/T1pre]×100%) and ADC values between different grading groups of HCC were calculated and compared. The area under the characteristics curve (AUC), the diagnostic threshold, sensitivity, and specificity of &#916;T1 and ADC for differential diagnosis were analyzed. Mean &#916;T1 was 58% for well-differentiated HCCs, 50% for moderately-differentiated HCCs, and 43% for poorly-differentiated HCCs. &#916;T1 showed statistical differences between the groups (P<0.001). The mean ADC values of the 3 groups were 1.11×10-3 mm2/s, 0.91×10-3 mm2/s, and 0.80×10-3mm2/s, respectively. ADC showed statistical differences between the groups (P<0.001). In discriminating well- differentiated group from the moderately differentiated group, the AUC of &#916;T1 was 0.751 (95% CI: 0.642, 0.859), the AUC of ADC was 0.782 (95% CI: 0.671, 0.894), the AUC of combined model was 0.811 (95% CI: 0.709, 0.914). In discriminating the poorly differentiated group from the moderately differentiated group, the AUC of &#916;T1 was 0.768 (95% CI: 0.634, 0.902), the AUC of ADC was 0.754 (95% CI: 0.603, 0.904), and the AUC of the combined model was 0.841 (95% CI: 0.729, 0.953). Gd-EOB-DTPA enhanced T1 mapping, and ADC values have complementary effects on the sensitivity and specificity for identifying different HCC grades. A combined model of Gd-EOB-DTPA-enhanced MRI T1 mapping and ADC values could improve diagnostic performance for predicting HCC grades.</p>.

Immune- and metabolism-related gene signature analysis uncovers the prognostic and immune microenvironments of hepatocellular carcinoma

BackgroundMetabolic reprogramming is an emerging hallmark that influences the tumour microenvironment (TME) by regulating the behavior of cancer cells and immune cells. The relationship between metabolism and immunity remains elusive. The purpose of this study was to explore the predictive value of immune- and metabolism-related genes in hepatocellular carcinoma (HCC) and their intricate interplay with TME.MethodsWe established the immune- and metabolism-related signature (IMRPS) based on the LIHC cohort from The Cancer Genome Atlas (TCGA) dataset. Kaplan–Meier analysis, receiver operating characteristic (ROC) curve analysis and Cox regression analysis confirmed the prognostic value of IMRPS. We investigated differences in immune cell infiltration, clinical features, and therapeutic response between risk groups. The quantitative real-time PCR (qPCR) was used to confirm the expression of signature genes. Immunohistochemical staining was performed to evaluate immune infiltration features in HCC tissue samples. We conducted cell experiments including gene knockout, cell counting kit-8 (CCK-8), and flow cytometry to explore the role of the IMRPS key gene UCK2 in HCC. RNA-seq was used to further investigate the potential underlying mechanism involved.ResultsThe IMRPS, composed of four genes, SMS, UCK2, PFKFB4 and MAPT, exhibited significant correlations with survival, immune cell infiltration, clinical features, immune checkpoints and therapeutic response. The IMRPS was shown to be an excellent predictor of HCC prognosis. It could stratify patients appropriately and characterize the TME accurately. The high-risk HCC group exhibited an immunosuppressive microenvironment with abundant M2-like macrophage infiltration, which was confirmed by the immunohistochemistry results. The results of qPCR revealed that the expression of signature genes in 20 HCC tissues was significantly greater than that in adjacent normal tissues. After the key gene UCK2 was knocked out, the proliferation of the Huh7 cell line was significantly inhibited, and monocyte-derived macrophages polarized towards an M1-like phenotype in the coculture system. RNA-seq and GSEA suggested that the phenotypes were closely related to the negative regulation of growth and regulation of macrophage chemotaxis.ConclusionsThis study established a new IMRS for the accurate prediction of patient prognosis and the TME, which is also helpful for identifying new targets for the treatment of HCC.

Evaluating anticancer activity of emodin by enhancing antioxidant activities and affecting PKC/ADAMTS4 pathway in thioacetamide-induced hepatocellular carcinoma in rats

ABSTRACT Emodin is a naturally occurring anthraquinone derivative with a wide range of pharmacological activities, including neuroprotective and anti-inflammatory activities. We aim to assess the anticancer activity of emodin against hepatocellular carcinoma (HCC) in rat models using the proliferation, invasion, and angiogenesis biomarkers. After induction of HCC, assessment of the liver impairment and the histopathology of liver sections were investigated. Hepatic expression of both mRNA and protein of the oxidative stress biomarkers, HO-1, Nrf2; the mitogenic activation biomarkers, ERK5, PKCδ; the tissue destruction biomarker, ADAMTS4; the tissue homeostasis biomarker, aggregan; the cellular fibrinolytic biomarker, MMP3; and of the cellular angiogenesis biomarker, VEGF were measured. Emodin increased the survival percentage and reduced the number of hepatic nodules compared to the HCC group. Besides, emodin reduced the elevated expression of both mRNA and proteins of all PKC, ERK5, ADAMTS4, MMP3, and VEGF compared with the HCC group. On the other hand, emodin increased the expression of mRNA and proteins of Nrf2, HO-1, and aggrecan compared with the HCC group. Therefore, emodin is a promising anticancer agent against HCC preventing the cancer prognosis and infiltration. It works through many mechanisms of action, such as blocking oxidative stress, proliferation, invasion, and angiogenesis.

Value of magnetic resonance imaging for diagnosis of LR‑3 and LR-4 lesions coexisting with hepatocellular carcinoma.

To explore which preoperative clinical data and conventional magnetic resonance imaging (MRI) features may indicate the presence of hepatocellular carcinoma (HCC) in HCC patients coexisting with LR-3 and LR-4 lesions. HCC Patients coexisting with LR-3 and LR-4 lesions who participated in a prospective clinical trial (XX) were included in this study. Two radiologists independently assessed the preoperative MRI features and each lesion was assigned according to the liver imaging reporting and data system (LI-RADS). The preoperative clinical data were also evaluated. The relative values of these parameters were assessed as potential predictors of HCC for coexisting LR-3 and LR-4 lesions. We enrolled 102 HCC patients (58.1 ± 11.5years; 84.3% males) coexisting with 110 LR-3 and LR-4 lesions (HCCs group [n = 66]; non-HCCs group [n = 44]). The presence of restricted diffusion (OR: 18.590, p < 0.001), delayed enhancement (OR: 0.113, p < 0.001), and mild-moderate T2 hyperintensity (OR: 3.084, p = 0.048) were found to be independent predictors of HCC diagnosis. The sensitivity and specificity of the above independent variables for the diagnosis of HCC ranged from 66.7 to 80.3% and 56.8 to 88.6%, respectively. ROC analysis showed that, in discriminating HCC, the AUCs of the above factors were 0.777, 0.686, and 0.670, respectively. Combining these three findings for the prediction of HCC resulted in a specificity greater than 97%, and the AUC further increased to 0.874. The presence of restricted diffusion, delayed enhancement, and mild-moderate T2 hyperintensity can be useful features for risk stratification of coexisting LR-3 and LR-4 lesions in HCC patients. Trial registration a prospective clinical trial (ChiCTR2000036201).

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.

Evaluation of the risk of developing hepatocellular carcinoma in chronic Hepatitis C patients receiving antiviral treatment.

Chronic HC leads to the development of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The treatment of chronic HC with DAAs reduces mortality from LC and HCC.The study aimed to investigate the serological markers specific to HCC (PIVKA-II and AFP) in patients with chronic HC before and after DAA treatment. The study involved 35 HCV patients (mean age: 56.23 ± 1.45) divided into two groups. Group 1 included 15 HCV + HCC patients and Group 2 included 20 HCV non-HCC patients. At the end of treatment all the patients were HCV RNA negative. Three months after the end of antiviral treatment, HCV RNA was undetectable in all patients, while a complete biochemical and virological response was observed in 66.7% of HCV + HCC patients and 85.0% of HCV non-HCC patients. PIVKA-II levels before the initiation of antiviral treatment were high in all patients. At the end of the treatment, in the HCV non-HCC group, normalization of PIVKA-II levels was observed only in 20.0% cases, and in 60.0% of cases 3 months after the treatment. Meanwhile, in patients with HCC and chronic HCV, PIVKA-II levels were within the normal range 3 months after treatment in only 13.3% of patients. It is necessary to monitor HCV patients with cirrhosis (F4) and severe fibrosis (F3) without HCC, who have high PIVKA-II and AFP levels and/or ALT activity despite obtaining sustained virologic response 3 months after treatment with DAAs.

The elevated expression of serum glutathione reductase in hepatocellular carcinoma and its role in assessing the therapeutic efficacy and prognosis of transarterial chemoembolization

BackgroundCurrently, there is a scarcity of reliable biomarkers that can accurately forecast the outcome and prognosis of transarterial chemoembolization (TACE). In this study, we assessed the diagnostic efficacy of serum glutathione reductase (GR) as a biomarker for hepatocellular carcinoma (HCC) and its practicality in predicting TACE treatment response. MethodsThe baseline positive rate and level of serum GR were analyzed and compared between HCC group and control group. Serum GR levels were assessed at three specific time points in 181 patients with unresectable HCC who underwent TACE (HCC-TACE). The correlation between serum GR levels and clinical pathological factors, tumor reactivity, and prognosis was investigated. The modified Response Evaluation Criteria in Solid Tumors (mRECIST) was utilized for assessing the treatment response to TACE. A nomogram for predicting the response to TACE treatment efficacy was developed. ResultsSerum GR demonstrated superior diagnostic performance in HCC patients. The baseline levels of serum GR were associated with the patient's age, tumor size, BCLC staging, and tumor thrombi of the portal vein (TTPV) (p < 0.05). Elevated baseline levels of serum GR were also identified as independent prognostic factors for predicting lower overall survival (OS) and shorter time to radiological progression (TTP) (p < 0.001). Moreover, it is worth noting that non-responders group exhibited a substantial increase in median GR level in the fourth week following TACE treatment (p < 0.0001), whereas the median GR level of responders group did not display a significant augmentation (p > 0.05). Lastly, the changes in serum GRt1-t3 were negatively correlated with TTP (p < 0.001). The nomogram developed to predict the risk of mRECIST responsiveness in patients with HCC-TACE demonstrated excellent discriminatory ability. ConclusionSerum GR can serve as a valuable biomarker for the diagnosis of HCC and for predicting the therapeutic efficacy and prognosis of TACE treatment.

Diagnostic value of serum STIP1 in HCC and AFP-negative HCC.

This study aimed to investigate the diagnostic value of stress-induced phosphoprotein 1 (STIP1) in serum for hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP)-negative HCC (ANHC). In this study, serum samples were collected from 158 HCC patients and 63 non-HCC patients. Logistic regression analysis was performed to identify independent risk factors associated with HCC and ANHC. The diagnostic values of each index for HCC and ANHC were analyzed using receiver operating characteristic (ROC) curve analysis. The STIP1, des-γ-carboxy prothrombin (DCP), and AFP levels were higher in the HCC groups than in the non-HCC groups (P < .05). Age, DCP, STIP1, and hepatitis B virus infection were independent predictors of HCC (P < .05). The diagnostic value of STIP1 for HCC was higher than that of DCP. Additionally, age, STIP1, and hepatitis B virus infection were independent predictors for ANHC patients. The ROC curve exhibited an area under the curve value of 0.919 for STIP1, with a diagnostic cutoff value of 68.5 U/mL. Moreover, 36 ANHC patients and 19 AFP-negative non-HCC patients were included to validate the diagnostic model. A total of 20 patients had STIP1 levels greater than 68.5 U/mL, resulting in diagnostic accuracy of 67.3%, sensitivity of 55.6%, and specificity of 89.5%. STIP1 demonstrates excellent diagnostic value for HCC and ANHC.

MRI radiomics based on deep learning automated segmentation to predict early recurrence of hepatocellular carcinoma.

To investigate the utility of deep learning (DL) automated segmentation-based MRI radiomic features and clinical-radiological characteristics in predicting early recurrence after curative resection of single hepatocellular carcinoma (HCC). This single-center, retrospective study included consecutive patients with surgically proven HCC who underwent contrast-enhanced MRI before curative hepatectomy from December 2009 to December 2021. Using 3D U-net-based DL algorithms, automated segmentation of the liver and HCC was performed on six MRI sequences. Radiomic features were extracted from the tumor, tumor border extensions (5 mm, 10 mm, and 20 mm), and the liver. A hybrid model incorporating the optimal radiomic signature and preoperative clinical-radiological characteristics was constructed via Cox regression analyses for early recurrence. Model discrimination was characterized with C-index and time-dependent area under the receiver operating curve (tdAUC) and compared with the widely-adopted BCLC and CNLC staging systems. Four hundred and thirty-four patients (median age, 52.0 years; 376 men) were included. Among all radiomic signatures, HCC with 5 mm tumor border extension and liver showed the optimal predictive performance (training set C-index, 0.696). By incorporating this radiomic signature, rim arterial phase hyperenhancement (APHE), and incomplete tumor "capsule," a hybrid model demonstrated a validation set C-index of 0.706 and superior 2-year tdAUC (0.743) than both the BCLC (0.550; p < 0.001) and CNLC (0.635; p = 0.032) systems. This model stratified patients into two prognostically distinct risk strata (both datasets p < 0.001). A preoperative imaging model incorporating the DL automated segmentation-based radiomic signature with rim APHE and incomplete tumor "capsule" accurately predicted early postsurgical recurrence of a single HCC. The DL automated segmentation-based MRI radiomic model with rim APHE and incomplete tumor "capsule" hold the potential to facilitate individualized risk estimation of postsurgical early recurrence in a single HCC. A hybrid model integrating MRI radiomic signature was constructed for early recurrence prediction of HCC. The hybrid model demonstrated superior 2-year AUC than the BCLC and CNLC systems. The model categorized the low-risk HCC group carried longer RFS.