Course Of Hepatocellular Carcinoma Research Articles

UCHL5 promotes hepatocellular carcinoma progression by promoting glycolysis through activating Wnt/β-catenin pathway.

Hepatocellular carcinoma (HCC) is highly malignant with a dismal prognosis, although the available therapies are insufficient. No efficient ubiquitinase has been identified as a therapeutic target for HCC despite the complicating role that of proteins ubiquitination plays in the malignant development of HCC. The expression of ubiquitin carboxyl terminal hydrolase L5 (UCHL5) in HCC tumor tissue and adjacent normal tissue was determined using the cancer genome atlas (TCGA) database and was validated using real-time quantitative polymerase chain reaction (RT-qRCR), Western blot and immunohistochemistry (IHC), and the relation of UCHL5 with patient clinical prognosis was explored. The expression of UCHL5 was knocked down and validated, and the effect of UCHL5 on the biological course of HCC was explored using cellular assays. To clarify the molecular mechanism of action of UCHL5 affecting HCC, expression studies of Adenosine triphosphate adenosine triphosphate (ATP), extracellular acidification (ECAR), and glycolysis-related enzymes were performed. The effects of UCHL5 on β-catenin ubiquitination and Wnt signaling pathways were explored in depth and validated using cellular functionalities. Validation was also performed in vivo. In the course of this investigation, we discovered that UCHL5 was strongly expressed in HCC at both cellular and tissue levels. The prognosis of patients with high UCHL5 expression is considerably worse than that of those with low UCHL5 expression. UCHL5 has been shown to increase the degree of glycolysis in HCC cells with the impact of stimulating the proliferation and metastasis of HCC cells in both in vivo and in vitro. UCHL5 downregulates its degree of ubiquitination by binding to β-catenin, which activates the Wnt/β-catenin pathway and accelerates HCC cell glycolysis. Thereby promoting the growth of the HCC. In summary, we have demonstrated for the first time that UCHL5 is a target of HCC and promotes the progression of hepatocellular carcinoma by promoting glycolysis through the activation of the Wnt/β-catenin pathway. UCHL5 may thus serve as a novel prognostic marker and therapeutic target for the treatment of HCC.

The Diagnostic Value of Alpha-fetoprotein and Lens Culinaris Agglutinin-reactive Alpha-fetoprotein in Liver Cirrhosis and Hepatocellular Carcinoma patients in Pakistan

Background: Hepatocellular carcinoma (HCC) is the most commonly encountered liver cancer and it accounts for 7% of all cancers and is accountable for a million deaths yearly.
 Because of latent HCV infections in our general population, there is projected rise in new HCC cases in Pakistan; with the onset of HCC several decades after initial infection has occurred. The poor predicted outcome of HCC is because of the fact that in the disease course of HCC, it is diagnosed at a very late stage. This results in effective medical intervention difficult.
 The purpose of this study is to establish a serum marker and/or panels of serum markers, that can detect the at risk patients with chronic liver disease, not only before but also after early development of HCC.
 Methodology: This study was conducted for ten months in Lahore General Hospital, Lahore, Punjab, Pakistan after taking the approval from the ethical board. A total of eighty patients (40 patients of HCC and 40 patients of LC) were included using non-probability, consecutive sampling. AFP and AFP-L3 levels of these patients were measured. The data was analyzed using SPSS Ver. 25. A p-value of ≤0.05 was considered as statistically significant.
 Results: In group 1, the mean age of patients was 60.02 ± 11.5 years and in group 2, it was 60.80 ± 7.42 years. In group 1, the mean of AFP was 64.93 ± 171.76 (ng/mL) and AFP-L3 was 0.56 ± 0.51(ng/mL). On the other hand, in group 2, the mean of AFP was 329.88 ± 231.55 (ng/mL) and AFP-L3 was 177.59 ± 104.10 (ng/mL). Significant association was found between AFP and AFP-L3 in both groups. Receiver operating characteristic (ROC) curve for AFP and AFP-L3 in relation to both groups obtained. The sensitivity of AFP was 85% and specificity was 80%. The sensitivity and specificity of AFP-L3 was 90 and 100%, respectively.
 Conclusion: AFP-L3 has a better diagnostic value for hepatocellular carcinoma than AFP.

Association of Tumor Cell Metabolic Subtype and Immune Response With the Clinical Course of Hepatocellular Carcinoma.

Tumor metabolism plays an important role in tumorigenesis and tumor progression. This study evaluated the potential association of tumor cell metabolism and immune cell tumor infiltration with the clinical course of hepatocellular carcinoma (HCC). Gene-wise normalization and principal component analysis were performed to evaluate the metabolic system. A tumor microenvironment score system of tumor immune cell infiltration was constructed to evaluate its association with metabolic subtypes. Finally, we analyzed the impact of metabolism and immune cell infiltration on the clinical course of HCC. A total of 673 HCC patients were categorized into cholesterogenic (25.3%), glycolytic (14.6%), mixed (10.4%), and quiescent (49.8%) types based on glycolysis and cholesterol biosynthesis gene expression. The subgroups including the glycolytic genotyping expression (glycolytic and mixed types) showed a higher mortality rate. The glycolytic, cholesterogenic, and mixed types were positively correlated with M0 macrophage, resting mast cell, and naïve B-cell infiltration (P = .013, P = .019, and P = .006, respectively). In TCGA database, high CD8+ T cell and low M0 macrophage infiltration were associated with prolonged overall survival (OS, P = .0017 and P < .0001, respectively). Furthermore, in glycolytic and mixed types, patients with high M0 macrophage infiltration had a shorter OS (P = .03 and P = .013, respectively), and in quiescent type, patients with low naïve B-cell infiltration had a longer OS (P = .007). Tumor metabolism plays a prognostic role and correlates with immune cell infiltration in HCC. M0 macrophage and CD8+ T cell appear to be promising prognostic biomarker for HCC. Finally, M0 macrophages may represent a useful immunotherapeutic target in patients with HCC.

Human Epidermal Growth Factor Receptor 2 (HER2) Expression by Immunohistochemistry and Its Clinical Significance in Hepatocellular Carcinoma: A Single-Center Analysis.

Human epidermal growth factor receptor 2 (HER2) is a member of the tyrosine kinase receptor family. It has been identified as an oncogene and is associated with poor outcomes in multiple tumortypes. In hepatocellular carcinoma (HCC), there are contradictory data regarding the HER2 expression and its role in tumor development and progression. Some studies have identified HER2 expression as an early event during tumorigenesis, which decreases with progression and metastasis. Additional data provided evidence that treatment with anti-HER2 therapy resulted in local response and reduction in the metastasis rate in HCC micemodels. Patients with histological diagnoses of HCC between 2010 and 2020 were included. HER2 staining was performed by immunohistochemistry (IHC), and scoring was done in accordance with the gastric cancer guidelines as 0, 1+, 2+, and 3+. Clinicopathological features were accessed by medical records. This study aims to evaluate HER2 expression by IHC in HCCand to correlate this expression with some clinicopathological features such as Barcelona Clinic Liver Cancer (BCLC) staging,number of hepatic lesions,alpha-fetoprotein level, underlying liver disease, presence of livercirrhosis, Child-Pugh score, and tumor recurrence. A total of 57 specimens from 54 patients were included. Of the patients, 85% were men, and the median age at diagnosis was 71 years (interquartile range: 59-75 years). Regarding stage, 61% were at stage 0-A of BCLC. Of the patients,57% had a solitary HCC nodule. Concerning treatment, surgery was performed in 50% of the patients.HER2 expression was identified in seven patients: five in the membrane and two in the cytoplasm. Concerning the membrane staining, HER2 expression was scored as 1+/2+ in 7.4% (n = 4 patients). Of the patients with HER2 expression, fourhad a BCLC stage of 0-A and a single HCC nodule; alpha-fetoprotein was <400 ng/mL in all cases. There was no correlation to clinicopathological features. In one patient with HER2 2+ expressionat diagnosis, this expression was not identified at tumor progression. Median disease-free survival in HER2 with IHC scores 1+/2+ and cytoplasmatic was 38 months versus 22 months in HER2 with a score of 0 (p = 0.604). HER2 expression is a rare event in HCC. It was not possible to identify any relation to clinicopathological features. However, when we relate our data to previous trials, HER2 appears to be an early event in the course of HCC.

Barriers to palliative care in hepatocellular carcinoma: A review of the literature.

Hepatocellular carcinoma (HCC) is a deadly and burdensome form of liver cancer with an increasing global prevalence. Its course is unpredictable as it frequently occurs in the context of underlying end-stage liver disease, and the associated symptoms and adverse effects of treatment cause severe suffering for patients. Palliative care (PC) is a medical specialty that addresses the physical, emotional, and spiritual needs of patients and their carers in the context of life-limiting illness. In other cancers, a growing body of evidence has demonstrated that the early introduction of PC at diagnosis improves patient and carer outcomes. Despite this, the integration of palliative care at the diagnosis of HCC remains suboptimal, as patients usually receive PC only at the very terminal phase of their disease, even when diagnosed early. Significant barriers to the uptake of palliative care in the treatment algorithm of hepatocellular carcinoma fall under four main themes: data limitations, disease, clinician, and patient factors. Barriers relating to data limitations mainly encapsulated the risk of bias inherent in published work in the field of PC. Clinician-reported barriers related to negative attitudes towards PC and a lack of time for PC discussions. Barriers related to the disease align with prognostic uncertainty due to the unpredictable course of HCC. Significantly, there exists a paucity of evidence exploring patient-perceived barriers to timely PC implementation in HCC. Given that patients are often the underrepresented stakeholder in the delivery of PC, future research should explore the patient perspective in adequately designed qualitative studies as the first step.

Evaluation of Amino Acids Profile as Non-Invasive Biomarkers of Hepatocellular Carcinoma in Egyptians.

Hepatocellular carcinoma (HCC) is the most dangerous complication of chronic liver disease. It is a multifactorial complicated disease. Hepatitis C and hepatitis B viruses (HCV and HBV, respectively) represent the main causes of HCC in Egypt. Early diagnosis is very important to aid in early intervention. The goal of this research is to evaluate the metabolic role of different amino acids as non-invasive biomarkers over the course of HCC. This study included 302 participants with 97 diagnosed, untreated HCC patients, 81 chronic HCV patients, 56 chronic HBV patients, 18 co-infected patients, and a control group of 50 normal age and gender-matched individuals. All participants provided complete medical histories and underwent complete clinical examinations, abdominal ultrasonography and/or computed tomography, routine laboratory investigations, estimation of serum α-fetoprotein, and determination of amino acid levels using ultra-performance liquid chromatography (UPLC MS/MS). This work revealed a decline in branched chain amino acids (BCAA) and increase in aromatic amino acids (AAA) among infected groups (HCC, HBV, HCV, and co-infected patients) compared to control subjects and a marked change in Fisher's and the BCAAs/tyrosine molar concentration ratios (BTR) between controls and infected groups. Different amino acids could be used as non-invasive markers to discriminate and follow chronic hepatitis patients to predict the course of HCC.

The efficacy of contrast-enhanced computed tomography on the management of gastroesophageal varices in patients with hepatocellular carcinoma

The screening of gastroesophageal varices (GEV) is critical in hepatocellular carcinoma (HCC) management. Contrast-enhanced computed tomography (CECT) is often performed in patients with HCC. Therefore, this study aimed to examine the use of CECT in screening for GEV and predicting GEV bleeding. This retrospective study enrolled 312 consecutive patients who are initially diagnosed with HCC, measured the lower esophageal (EIV) and fundal intramural vessel (FIV) diameter on CECT, examined the changes after 1, 2, and 3 years, and verified the relationship with GEV bleeding. The EIV and FIV diameter on CECT correlates well with endoscopic variceal classification. EIV significantly worsened after 2 and 3 years. FIV showed worsening at both 1, 2, and 3 years. Cumulative GEV bleeding rates were 3.7% at 1 year and 6.2% at 3 years. The multivariate analysis revealed that EIV, FIV, and portal vein tumor thrombus were associated with GEV bleeding. Furthermore, EIV deterioration at 1, 2, and 3 years correlated with GEV bleeding. In conclusion, CECT is useful in variceal management during the longitudinal clinical course of HCC, and has the potential to decrease screening endoscopy. With deterioration in EIV, treatments should be considered due to a high-risk GEV bleeding.

Ficolin-2: A potential immune-related therapeutic target with low expression in liver cancer

This study aimed to investigate the role of ficolin-2 (FCN2) in the development and course of hepatocellular carcinoma (HCC) and to contribute to the evolution of innovative HCC therapeutics. Oncomine, GEPIA (Gene Expression Profiling Interactive Analysis), TISIDB (Tumor Immune System Interactions and Drug Bank database), UALCAN (University of Alabama at Birmingham Cancer data analysis portal), UCSC (University of California, Santa Cruz), R package, the Kaplan-Meier technique, Cox regression analysis, LinkedOmics, Pearson's correlation, and a nomogram were used to investigate the prognostic value of FCN2 in HCC. Co-expressed genes were screened. A protein-protein interaction network was created using the STRING database. Finally, immunohistochemistry was performed to establish the expression of FCN2 in HCC tissues. A pan-cancer study centered on HCC-related molecular analysis was also conducted to look for a link between FCN2 and immune infiltration, immune modulators, and chemokine receptors. In HCC tissues, the expression of FCN2 was observed to be lower than that in normal tissues. This was connected to the HCC marker alpha-fetoprotein, showing that FCN2 is involved in the development and progression of cancer. FCN2 may act through Staphylococcus aureus infection, lectins, and other pathways. Furthermore, at the immune level, the expression of FCN2 in HCC was associated with some immune cell infiltration, immunomodulators, and chemokine receptors. FCN2 may be an immune checkpoint inhibitor for HCC, creating a breakthrough in the treatment of HCC.

Potential Role of Tumor Cell Metabolic Subtype in the Clinical Course of Hepatocellular Carcinoma

INTRODUCTION: Tumor metabolism is critical in tumorigenesis and development. This study aims to evaluate the potential role and the prognostic value of tumor cell metabolism in the progression of hepatocellular carcinoma (HCC). METHODS: Systematic analyses were performed using genome, transcriptome, and clinical characteristics to evaluate the metabolic system in 673 HCC patients. We analyzed the impact of metabolism on the clinical course of HCC. Univariate and multivariate Cox proportional-hazards regression methods were used to screen overall survival (OS). RESULTS: Included HCC patients were categorized into cholesterogenic (25.3%), glycolytic (14.6%), mixed (10.4%), and quiescent (49.8%) types based on the glycolysis and cholesterol biosynthesis gene expression. The distribution of α-fetoprotein (AFP; <300 μg/L or ≥300 μg/L) but not TMN stages among the 4 metabolic subtypes showed significant differences (p < 0.05). The quiescent subtype was associated with a low AFP expression level (p < 0.05) and the glycolytic subtype was associated with a higher AFP level (p < 0.01). The mixed type and glycolytic type had a shorter median OS (p < 0.0001). And the metabolic subtype emerged as an independent predictor of HCC patients’ survival in multivariate analyses. CONCLUSION: These results suggest that the metabolic subtypes were consistent with AFP expression and may play a prognostic role in HCC patients. And the glycolytic metabolism-related genes may induce tumor progression in HCC.

Integrative analysis of the characteristic of lipid metabolism-related genes for the prognostic prediction of hepatocellular carcinoma.

Background:Dysregulation of lipid metabolism is implicated in the progression of hepatocellular carcinoma (HCC). We therefore investigated the molecular characteristics of lipid-metabolism-related genes in HCC.Methods:Multi-dimensional bioinformatics analysis was conducted to comprehensively identify the lipid metabolism-related genes (LMRGs) from public databases, as well as the clinical information, immune features, and biological characteristics of HCC. The IMGR were then used to classify HCC into molecular phenotypes. Six lipid metabolism-related genes sets with the potential to predict the prognosis of HCC patients were identified.Results:A total of 770 HCC patients with complete clinical information and corresponding 776 LMRGs were downloaded from 3 databases. Univariate cox and non-negative matrix factorization analyses were used to classify HCC patients into 2 clusters. This molecular classification was associated with overall survival, clinical characteristics, and immune cells. The biological function of the differentially expressed LMRGs in the 2 clusters showed the genes associated with tumor-related metabolism pathways. A combination of multivariate/univariate cox regression and least absolute shrinkage and selection operator analyses were conducted to build a 6 LMRGs signature (6-IS) to predict the prognosis of HCC. The 6-IS signature was found to be an independent prognostic factor. Performance of the 6-IS prognostic signature was verified in a validation set and compared with an external data set. Results revealed the 6-IS signature could effectively predict the prognosis of patients with HCC.Conclusions:This study provides new insights into the role of LMRG in the pathogenesis of HCC and presents a novel prognostic signature 6-IS monitoring the clinical course of HCC.

A convenient and efficient 4-(diethylamino)-butylamine-labeled polarity-response-homodispersed strategy for absolute quantification of carboxyl submetabolome: Monitoring the whole progressive course of hepatocellular carcinoma

Recent studies have shown that dysregulation of carboxyl submetabolome homeostasis is closely related to the occurrence and development of hepatocellular carcinoma (HCC). However, it is still a challenge to quantify carboxyl metabolites with high efficiency by conventional methods due to their species diversity and nature differences. Moreover, there are few studies on carboxyl submetabolome profiling during the whole progression of HCC. In this study, a convenient and efficient workflow for absolute quantification of carboxyl submetabolome was established based on the 4-(diethylamino)-butylamine (DEABA)-labeled polarity-response-homodispersed strategy. After optimizing derivation conditions with response surface methodology (RSM), the reaction only needed 1 min at room temperature, which radically simplified the labeling process. Compared with nonderivatization, the gaps of polarities and responses of the analytes were narrowed by DEABA labeling, realizing the polarity-response-homodispersion. Then resolution and sensitivity in HPLC-MS/MS were improved significantly. Ultimately, the workflow was applied to monitor carboxyl metabolic profile in human plasma of the whole progressive course of hepatocellular carcinoma. Combined with analysis of variance (ANOVA), orthogonal partial least squares discrimination analysis (OPLS-DA), Bayesian linear discriminant analysis (BLDA) and other data mining methods, the biomarkers of “health-hepatitis-cirrhosis-HCC” were screened out, and the diagnostic model was established. Furthermore, the relevancy between carboxyl submetabolome disorders and the pathogenesis of HCC was investigated. The developed method has the characteristics of high sensitivity, high coverage and high practicability, which is suitable for the study of biomarkers of carboxyl submetabolome in the whole progression of HCC.

Chemokines in Primary Liver Cancer.

The liver is responsible for extremely important functions in the human body. In the liver’s structure, we distinguish between connective tissue (stroma) and parenchyma, the latter of which is formed from the basic structural and functional units of the liver—hepatocytes. There are many factors, that negatively affect the liver cells, contributing to their damage. This may lead to fibrosis, liver failure and, in consequence, primary liver cancer, which is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Chemokines are a large family of secreted proteins. Their main role is to direct the recruitment and migration of cells to sites of inflammation or injury. Some authors suggest that these proteins might play a potential role in the development of many malignancies, including primary liver cancer. The aim of this study was to evaluate and summarize the knowledge regarding liver diseases, especially primary liver cancer (HCC) and the participation of chemokines in the development of this malignancy. Chemokines involved in the initiation of this type of tumor belong mainly to the CC and CXC chemokines. Their significant role in the course of hepatocellular carcinoma proves their usefulness in detecting and monitoring the course and treatment in patients with this disease.

Direct-acting antivirals for hepatitis C virus-infected patients with hepatocellular carcinoma.

BACKGROUNDHepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients has a high risk of recurrence. Although eradication of HCV is expected to reduce this risk, the risk in patients with a history of HCC may be high after treatment with direct-acting antivirals (DAAs).AIMTo determine the risk factors for HCC recurrence in patients with HCV and a history of HCC.METHODSThe risk of HCC recurrence in patients with a history of HCC and/or of HCC occurrence in patients without a history of HCC after DAA therapy was retrospectively analyzed in 311 HCV patients treated at our institution and several neighboring hospitals. The frequency and predictors of HCC recurrence/ occurrence after DAA treatment were included in these analyses. The clinical course of HCC before and after DAA treatment was also evaluated.RESULTSHCV patients with a history of HCC were older and had greater progression of liver fibrosis and diabetes than patients without a history of HCC. Median recurrence-free survival (RFS) was 1092 d in patients with a history of HCC, and post-DAA HCC recurrence/occurrence was observed in 29 patients (53.7%) with and 5 (1.9%) without a history of HCC over 6 years (P < 0.001). RFS in patients with a history of HCC did not differ significantly before and after DAA treatment. The frequency of HCC recurrence/occurrence in patients with a history of HCC was lower after than before DAA treatment. Multivariate analysis showed that the incidence rate of HCC recurrence/occurrence before DAA treatment was the only independent predictor of HCC recurrence/occurrence after DAA treatment. Liver function was well preserved and clinical course was good in patients with HCC recurrence/occurrence after DAA therapy.CONCLUSIONDAA therapy in patients infected with HCV is also effective in patients with a history of HCC. Curative treatment for HCC is desirable before DAA therapy. The frequency of HCC recurrence/occurrence before DAA therapy was associated with a significantly increased risk of HCC recurrence after DAA therapy. Careful observation after DAA therapy is required in patients with a history of HCC.

Impact of acute decompensation on the prognosis of patients with hepatocellular carcinoma.

Organ failure in patients with acute decompensation (AD) is a defining characteristic of acute-on-chronic liver failure (ACLF). However, the clinical features of AD during the long-term clinical course of hepatocellular carcinoma (HCC) are still poorly understood. This study aimed to clarify features and impact of AD/ACLF on the prognosis of patients after treatment for HCC. This retrospective study enrolled 556 consecutive patients who were initially diagnosed with HCC, and analyses were conducted taking into account HCC treatment type, HCC stage, and presence or absence of cirrhosis. During follow-up, 299 patients with AD were hospitalized. AD occurrence is closely related to prognosis, regardless of the presence or absence of cirrhosis and HCC stage, and early-onset AD (within 90 days after HCC treatment) has negative impact on prognosis. In the intermediate-advanced-stage group, surgical resection had a positive impact on AD incidence post-treatment. After systemic therapy for HCC, renal impairment was the predictive factors for AD development. The 28/90-day mortality rate was higher among 41 cases (13.7%) with AD who exhibited ACLF as compared with cases without ACLF. AD without cirrhosis had similar ACLF incidence and short-term mortality, compared to AD with cirrhosis. The prognostic model using a decision-tree-based approach, which includes ACLF, bilirubin level, HCC progression, and MELD score is useful for predicting 90- or 28-day mortality after AD diagnosis. Careful management of patients with HCC who are hospitalized with AD is necessary, considering ACLF, HCC progression, and liver function.

Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: Immunohistochemical Assessment of Markers of Cancer Cell Metabolism

Introduction: Hepatocellular carcinoma (HCC) has been associated to non-alcoholic fatty liver disease (NAFLD). We sought to investigate the immunoexpression of several glycolytic metabolism-associated markers in patients with HCC associated to NAFLD and associate these factors to their clinical-pathological characteristics. Methods: We evaluated 35 HCC specimens from 21 patients diagnosed with non-alcoholic steatohepatitis (NASH) undergoing liver resection (12 patients), liver transplantation (8 patients), or both (1 patient). Histological features, clinical aspects, demographic and biochemical data, as well as the immunohistochemical reactivity for monocarboxylate transporters 1, 2, and 4; their chaperone CD147; carbonic anhydrase IX; and glucose transporter-1 (GLUT1) were assessed. Results: Metabolic-associated cirrhosis was present in 12 of the 21 patients (8 child A and 4 child B scores). From 9 patients without cirrhosis, 3 presented NASH F3 and 6 NASH F2. Sixteen (76%) had diabetes mellitus, 17 (81%) arterial hypertension, and 19 (90%) body mass index above 25 kg/m²; 8 (38%) had dyslipidemia. From 35 nodules, steatosis was found in 26, ballooning in 31 nodules, 25 of them diagnosed as steatohepatitic subtype of HCC. MCT4 immunoexpression was associated with extensive intratumoral fibrosis, advanced clinical stages, and shorter overall survival. GLUT1 was noticeable in nodules with extensive intratumoral steatosis, higher intratumoral fibrosis, and advanced clinical stages. Immunohistochemical expression of the metabolic biomarkers MCT4 and GLUT1 was higher in patients with Barcelona-clinic liver cancer B or C. GLUT1 correlated with higher degree of steatosis, marked ballooning, intratumoral fibrosis, and higher parenchymal necroinflammatory activity. Conclusion: Our data indicate that the expression of the glycolytic phenotype of metabolic markers, especially GLUT1 and MCT4, correlates with a more severe course of HCC occurring in NASH patients.

The role of complement in the clinical course of hepatocellular carcinoma.

BackgroundThe complement system, an innate immune system, may either play an antitumor role, or promote tumorigenesis and cancer progression in different kinds of cancer. The function of complement in hepatocellular carcinoma (HCC) is unclear.MethodsThe gene expressions of the complement system were based on data obtained from TCGA and GEO. We explored gene expressions, mutation, enrichment analysis, clinicopathology, patients' outcome, and immune infiltration via Gepia2, cBioPortal, Metascape, UALCAN, Kaplan–Meier Plotter, and TIMER 2.ResultsFive complement genes, including C1R, C6, C7, CFP, and CFHR3, were not only found to be significantly downregulated in HCC samples compared with normal liver samples, but also found to be significantly associated with overall survival, disease‐free survival, and progress‐free survival in HCC patients. In addition, lower mRNA expression of C1R, C6, C7, and CFHR3 were found correlated with advanced cancer stages and higher tumor grades in HCC patients. Also, the expression levels of CFP were correlated with many sets of immune markers of tumor immune cells, such as those of CD8+ T cells, CD4+ T cells, B cells, M2 macrophages, neutrophils, DCs, Th1 cells, Th2 cells, and T cell exhaustion in HCC. Based on that, we developed a prognostic model for HCC patients—Riskscore = (−0.0053)*C6+(−0.0498)*C7+(−0.1045)*CFHR3.ConclusionC1R, C6, C7, CFP, and CFHR3 could be prognostic biomarkers for patients with HCC.

The role of CpG island methylator phenotype in the clinical course of hepatocellular carcinoma.

Aberrant DNA methylation is strongly associated with heterogeneity in tumors. This study investigated the prognostic value of CpG island methylator phenotype in hepatocellular carcinoma (HCC). A total of 319 HCC samples with 21 121 CpG sites were included in this study and 215 disease-free survival (DFS) and overall survival (OS)-related CpG sites were identified. These CpG sites were divided into seven clusters by using consensus clustering method. Cluster 4, which constructed the prognostic prediction model as the seed cluster to evaluate survival risk for DFS and OS of HCC patients, had the lowest methylation level with the worse prognosis. The low-risk group patients had a significantly prolonged DFS and OS than the patients in the high-risk group (P = 0.008 and P < 0.001, respectively). A receiver operating characteristic curve results for predicting DFS and OS were 0.691 and 0.695, respectively. These results suggested that the CpG site methylation appears to be an informative prognostic biomarker in HCC. The CpG site methylation-related prognostic model may be an innovative insight to evaluate clinical outcomes for HCC patients. The code of the analysis is available at https://www.bioconductor.org. Supplementary data are available at Bioinformatics online.

SOX4 as biomarker in hepatitis B virus-associated hepatocellular carcinoma.

Background: Hepatitis B virus infection is associated with liver disease, including cancers. In this study, we assessed the power of sex-determining region Y (SRY)-related high-mobility group (HMG)-box 4(SOX4) gene to predict the clinical course of hepatocellular carcinoma (HCC).Methods: To evaluate the differential expression of SOX4 and its diagnostic and prognostic potential in HCC, we analyzed the GSE14520 dataset. Stratified analysis and joint-effect analysis were done using SOX4 and clinical factor. We then designed a nomogram for predicting the clinical course of HCC. Differential SOX4 expression and its correlation with tumor stage as well as its diagnostic and prognostic value were analyzed on the oncomine and GEPIA websites. Gene set enrichment analysis was explored as well as candidate gene ontology and metabolic pathways modulated by in SOX4 HCC.Results: Our analysis revealed that the level of SOX4 was significantly upregulated in tumor issue (P <0.001). This observation was validated through oncomine dataset and MERAV analysis (all P <0.05). Diagnostic receiver operating characteristic (ROC) analysis of SOX4 suggested it has diagnostic potential in HCC (GSE14520 dataset: P <0.001, area under curve (AUC) = 0.782; Oncomine: (Wurmbach dataset) P = 0.002, AUC = 0.831 and (Mas dataset) P <0.001, AUC = 0.947). In addition, SOX4 exhibited high correlation with overall survival of HBV-associated HCC (adjusted P = 0.004, hazard ratio (HR) (95% confidence interval (CI)) = 2.055 (1.261-3.349) and recurrence-free survival (adjusted P = 0.008, HR (95% CI) = 1.721 (1.151-2.574). These observations which were verified by GEPIA analysis for overall survival (P = 0.007) and recurrence-free survival (P= 0.096). Gene enrichment analysis revealed that affected processes included lymphocyte differentiation, pancreatic endocrine pathways, and insulin signaling pathway. SOX4 prognostic value was evaluated using nomogram analysis for HCC 1, 3, and 5-year, survival.Conclusion: Differential SOX4 expression presents an avenue of diagnosing and predicting clinical course of HCC. In HCC, SOX4 may affect TP53 metabolic processes, lymphocyte differentiation and the insulin signaling pathway.

Inpatient Specialty-Level Palliative Care Is Delivered Late in the Course of Hepatocellular Carcinoma and Associated With Lower Hazard of Hospital Readmission

ContextLittle is known about receipt of specialty-level palliative care by people with hepatocellular carcinoma (HCC) or its impact on health care utilization. ObjectivesIdentify patient characteristics associated with receipt of specialty-level palliative care among hospitalized HCC patients and measure association with time to readmission. MethodsWe used logistic regression to examine relationships between receipt of inpatient palliative care consultation by HCC patients at an academic center (N = 811; 2012–2016) and clinical and demographic covariates at index hospitalization. We used a survival analysis model accounting for competing risk of mortality to compare time to readmission among individuals who did or did not receive palliative care during the admission and performed a sensitivity analysis using kernel weights to account for selection bias. ResultsOverall, 16% received inpatient palliative care consults. Those who received consults had worse laboratory values than those who did not. In a multivariable model, higher Model for End-Stage Liver Disease Sodium, receipt of sorafenib, and higher pain scores were significantly associated with increased odds of palliative care, whereas liver transplantation and admission to a surgical service were associated with lower odds. For time to readmission (2076 hospitalizations for 811 individuals with 175 palliative care visits), the subhazard ratio for readmission for patients who received consults was 0.26 (95% CI = 0.18–0.38) and 0.35 (95% CI = 0.24–0.52) with a kernel-weighted sample. ConclusionInpatient palliative care consultation was received by individuals with more advanced disease and associated with lower readmission hazard. These findings support further research and the development of HCC-specific programs that increase access to specialty-level palliative care.

Contrast enhancement patterns of hepatocellular carcinoma with portal vein thrombosis

Purpose. To study contrast enhancement patterns of hepatocellular carcinoma (HCC) in cases with portal thrombosis and without it.Materials and methods. 61 consecutive patients with HCC were included in the study and divided into two groups: 41 patient with portal vein thrombosis (main group) and 20 patients without thrombosis (control group). Each patient underwent a abdominal CE MDCT for the analysis of the lesion contrast enhancement.Results. The 1st – “classic” – contrast enhancement pattern with a peak at arterial phase was observed in 2 (5%) patients with HCC complicated by portal thrombosis and in 10 (50%) patients without thrombosis (p &lt; 0.01). The 2nd – “hypervascular” pattern with a peak shifted in 60–120s after contrast agent administration and no wash out was observed in 14 (34%) patients in the main group and in 10 (50%) patients in the control group (p = 0.4). The 3rd pattern – inhomogeneous contrast enhancement of liver parenchyma in the territory of thrombosed vein without visible tumor was discovered in 17 (41%) cases (p &lt; 0.01). The 4th pattern – peripheral enhancement in arterial and portal phase with insignificant central enhancement in delayed phase was visualized in 8 cases (20%, p = 0.072).Conclusion. Portal thrombosis, which complicates the course of HCC, significantly changes the patterns of tumor’s contrast enhancement. This should be taken into account when image analysis to avoid diagnostic errors.