High Α-fetoprotein Research Articles

The Impact of TP53-Induced Glycolysis and Apoptosis Regulator on Prognosis in Hepatocellular Carcinoma: Association with Tumor Microenvironment and Ferroptosis

<b><i>Introduction:</i></b> <i>TP53</i>-induced glycolysis and apoptosis regulator (TIGAR) is a p53 target protein that has critical roles in glycolysis and redox balance. The reports about the effect of TIGAR on prognosis and its biological role in hepatocellular carcinoma (HCC) are limited. <b><i>Methods:</i></b> A total of 386 patients with HCC who had undergone hepatic resection were enrolled. Immunohistochemical staining for TIGAR was performed. Additionally, the regulation of malignant activity and ferroptosis by TIGAR was investigated in vitro. <b><i>Results:</i></b> Patients were divided into TIGAR-positive (<i>n</i> = 80, 20.7%) and -negative (<i>n</i> = 306, 79.3%) groups. TIGAR positivity was significantly correlated with lower albumin, higher α-fetoprotein/ <i>des</i>-gamma-carboxyprothrombin, larger tumor size/number of tumors, and greater proportions of BCLC staging C/single nodular type/poor differentiation/microscopic vascular invasion/microscopic intrahepatic metastasis. In multivariate analysis, TIGAR positivity was an independent prognostic factor (<i>p</i> < 0.0001). In addition, TIGAR positivity was significantly associated with a smaller number of cluster of differentiation (CD) 8-positive T cells (<i>p</i> = 0.0450), larger number of CD68-positive macrophages (<i>p</i> = 0.0058), larger number of programmed death-ligand 1-positive cases (<i>p</i> = 0.0002), and larger number of vessels that encapsulate tumor cluster-positive cases (<i>p</i> = 0.0004). In vitro, <i>TIGAR</i> knockdown decreased cell motility and induced ferroptosis. <i>TIGAR</i> knockdown inhibited the phosphorylation of adenosine monophosphate-activated protein kinase and acetyl-CoA carboxylase. Ferroptosis induced by <i>TIGAR</i> knockdown was inhibited by liproxstatin and baicalein treatment. The combination of <i>TIGAR</i> knockdown and lenvatinib further induced ferroptosis. <b><i>Conclusion:</i></b> High expression of TIGAR impacted the clinical outcome of HCC patients and TIGAR was associated not only with tumor microenvironment but also with resistance to ferroptosis.

Impact of ACSL4 on the prognosis of hepatocellular carcinoma: Association with cancer-associated fibroblasts and the tumour immune microenvironment.

Recently, the association between hepatocellular carcinoma (HCC) and ferroptosis has been the focus of much attention. The expression of long chain fatty acyl-CoA ligase 4 (ACSL4), a marker of ferroptosis, in tumour tissue is related to better prognosis in various cancers. In HCC, ACSL4 expression indicates poor prognosis and is related to high malignancy. However, the mechanism remains to be fully understood. We retrospectively enrolled 358 patients with HCC who had undergone hepatic resection. Immunohistochemistry (IHC) for ACSL4 was performed. Factors associated with ASCL4 expression were investigated by spatial transcriptome analysis, and the relationships were investigated by IHC. The association between ACSL4 and the tumour immune microenvironment was examined in a public dataset and investigated by IHC. Patients were divided into ACSL4-positive (n = 72, 20.1%) and ACSL4-negative (n = 286, 79.9%) groups. ACSL4 positivity was significantly correlated with higher α-fetoprotein (p = .0180) and more histological liver fibrosis (p = .0014). In multivariate analysis, ACSL4 positivity was an independent prognostic factor (p < .0001). Spatial transcriptome analysis showed a positive correlation between ACSL4 and cancer-associated fibroblasts; this relationship was confirmed by IHC. Evaluation of a public dataset showed the correlation between ACSL4 and exhausted tumour immune microenvironment; this relationship was also confirmed by IHC. ACSL4 is a prognostic factor in HCC patients and its expression was associated with cancer-associated fibroblasts and anti-tumour immunity.

Added value of CE-CT radiomics to predict high Ki-67 expression in hepatocellular carcinoma

BackgroundThis study aimed to develop a computed tomography (CT) model to predict Ki-67 expression in hepatocellular carcinoma (HCC) and to examine the added value of radiomics to clinico-radiological features.MethodsA total of 208 patients (training set, n = 120; internal test set, n = 51; external validation set, n = 37) with pathologically confirmed HCC who underwent contrast-enhanced CT (CE-CT) within 1 month before surgery were retrospectively included from January 2014 to September 2021. Radiomics features were extracted and selected from three phases of CE-CT images, least absolute shrinkage and selection operator regression (LASSO) was used to select features, and the rad-score was calculated. CE-CT imaging and clinical features were selected using univariate and multivariate analyses, respectively. Three prediction models, including clinic-radiologic (CR) model, rad-score (R) model, and clinic-radiologic-radiomic (CRR) model, were developed and validated using logistic regression analysis. The performance of different models for predicting Ki-67 expression was evaluated using the area under the receiver operating characteristic curve (AUROC) and decision curve analysis (DCA).ResultsHCCs with high Ki-67 expression were more likely to have high serum α-fetoprotein levels (P = 0.041, odds ratio [OR] 2.54, 95% confidence interval [CI]: 1.04–6.21), non-rim arterial phase hyperenhancement (P = 0.001, OR 15.13, 95% CI 2.87–79.76), portal vein tumor thrombus (P = 0.035, OR 3.19, 95% CI: 1.08–9.37), and two-trait predictor of venous invasion (P = 0.026, OR 14.04, 95% CI: 1.39–144.32). The CR model achieved relatively good and stable performance compared with the R model (AUC, 0.805 [95% CI: 0.683–0.926] vs. 0.678 [95% CI: 0.536–0.839], P = 0.211; and 0.805 [95% CI: 0.657–0.953] vs. 0.667 [95% CI: 0.495–0.839], P = 0.135) in the internal and external validation sets. After combining the CR model with the R model, the AUC of the CRR model increased to 0.903 (95% CI: 0.849–0.956) in the training set, which was significantly higher than that of the CR model (P = 0.0148). However, no significant differences were found between the CRR and CR models in the internal and external validation sets (P = 0.264 and P = 0.084, respectively).ConclusionsPreoperative models based on clinical and CE-CT imaging features can be used to predict HCC with high Ki-67 expression accurately. However, radiomics cannot provide added value.

Transferrin Receptor is Associated with Sensitivity to Ferroptosis Inducers in Hepatocellular Carcinoma.

Transferrin receptor (TFR), a membrane protein that has a critical role in the transport of iron into cells, is known to be a ferroptosis-related marker. Although TFR is reported to be abundantly expressed in tumor cells, its relationship with ferroptosis inducers in hepatocellular carcinoma (HCC) remains unclear. The authors performed immunohistochemical staining of TFR and divided 350 HCC patients into two groups according to its expression. They analyzed the association between TFR expression and prognosis or clinicopathologic factors. In addition, the regulation of malignant activity and its effect on the efficacy of ferroptosis inducers were investigated in vitro. For this study, 350 patients were divided into TFR-positive (n =180, 51.4%) and TFR-negative (n = 170, 48.6%) groups. The TFR-positive group had more hepatitis B surface antigen (HBs-Ag) (p = 0.0230), higher α-fetoprotein (AFP) levels (p = 0.0023), higher des-gamma-carboxyprothrombin (DCP) levels (p = 0.0327), a larger tumor size (p = 0.0090), greater proportions of Barcelona Clinic Liver Cancer (BCLC) stage B or C (p = 0.0005), poor differentiation (p < 0.0001), and microscopic intrahepatic metastasis (p = 0.0066). In the multivariate analyses, TFR expression was an independent prognostic factor in disease-free survival (p = 0.0315). In vitro, TFRC knockdown decreased cell motility. In addition, TFRC knockdown abolished artesunate (AS)-, lenvatinib-, and sorafenib-induced ferroptosis in HCC cell lines. The study demonstrated that simultaneous treatment of AS with multi-kinase inhibitor augmented the ferroptosis-inducing effects of AS in HCC cell lines. TFR expression is a poor prognostic factor in HCC, but its expression increases sensitivity to ferroptosis-inducing agents.

Surgical Outcomes for Hepatocellular Carcinoma in Patients with Child–Pugh Class B: a Retrospective Multicenter Study

BackgroundsLiver resection for hepatocellular carcinoma (HCC) in patients with Child–Pugh class (CPC) B increases the incidence of postoperative complication and in-hospital death and decreases the disease-free survival (DFS) and overall survival (OS) compared with those with CPC A. Conversely, some selected patients possibly gained benefits for liver resection. MethodsClinical records of 114 patients with CPC B who underwent liver resection for HCC were retrospectively reviewed. The risk of postoperative complications (Clavien–Dindo classification grade of ≥ II), postoperative recurrence, and death was analyzed. ResultsPostoperative complications occurred in 36 patients (31.6%), and 2 died within 90 days postoperatively due to the liver and respiratory failure, respectively. Multivariate analysis indicated that albumin-bilirubin (ALB) grade III and extended operation time were found as independent risk factors for postoperative complications. The DFS and OS rates at 3/5 years after liver resection were 30.8%/25.3% and 68.4%/48.9%, respectively. Multivariate analysis indicated that the extended blood loss, high α-fetoprotein (AFP) level (≥ 200 ng/mL), and Barcelona Clinic Liver Cancer stage C were found to be independent risk factors for postoperative recurrence. The high AFP level was also an independent prognostic factor for OS. Patients with high AFP levels had postoperative recurrence within 2 years and a higher number of extrahepatic recurrences than those with low AFP levels (< 200 ng/mL). ConclusionFor patients with HCC with CPC B who were scheduled for liver resection, ALBI grade III and high AFP level should be considered as unfavorable outcomes after liver resection.

Role of Tri-Phasic Computed Tomography in Evaluation of Hepatocellular Carcinoma Patients with Liver Cirrhosis

OBJECTIVESTo assess the usefulness of Tri-phasic computed tomography in the evaluation of hepatocellular carcinoma in cirrhotic patients.METHODOLOGYThis cross-sectional study was carried out in the Radiology and Imaging Department of Hayatabad Medical Complex Peshawar from October 2020 to September 2021 (01 year). Tri-phasic CT was done in all patients. Patients with suspected hepatocellular carcinoma diagnosed by clinical and ultrasonography and having high serum α-fetoprotein levels were enrolled in the study.RESULTSMalignant cases on tri-phasic CT were 120(82.8%) while benign cases were 25 (17.2%) Fig -I. In malignant tumor cases, 99(82.5%) patients had hepatocellular carcinoma (HCC), 13(10.8%) had metastases and 8(6.7%) had dysplastic nodule respectively. In benign tumour cases, 15(60%) had regenerative nodules, 6(24%) had hepatic adenoma and 4 (16%) had haemangioma. Tri -phasic CT as a tool in the diagnosis of hepatocellular carcinoma in cirrhotic patients showed a sensitivity of 96.8%, specificity of 79.7%, the accuracy of 95%, positive predictive values of 96.2% and negative predictive values of 88.1%.CONCLUSIONTri-Phasic CT can be an ideal diagnostic tool for detecting as well as characterizing hepatocellular carcinoma in cirrhotic patients.

Older Age and High α-Fetoprotein Predict Higher Risk of Hepatocellular Carcinoma in Chronic Hepatitis-B-Related Cirrhotic Patients Receiving Long-Term Nucleos(t)ide Analogue Therapy.

Background: Nucleos(t)ide analogues (NUCs) were proved to reduce hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients, but data were limited on their efficacy in cirrhotic CHB patients. Methods: A total of 447 cirrhotic CHB patients treated with tenofovir/entecavir were retrospectively analyzed and divided into HCC (n = 48) and non-HCC (n = 399) groups. The median follow-up period was 62.1 months. Results: A total of 48 patients (10.7%) developed HCC during surveillance. The annual incidence rate of HCC was 2.04 per 100 person-years. The cumulative incidence of HCC was 0.9%, 9.8%, and 22.1% at 1, 5, and 10 years, respectively. Significant predictors for HCC identified using a multiple Cox regression analysis were age ≥50 years (hazard ratio (HR): 2.34) and α-fetoprotein (AFP) ≥8 ng/mL (HR: 2.05). The incidence rate of HCC was 8.67-fold higher in patients with age ≥50 years and AFP ≥8 ng/mL (3.14 per 100 person-years) than those with age <50 years and AFP <8 ng/mL (0.36 per 100 person-years). Conclusions: Cirrhotic CHB patients with age <50 years and AFP <8 ng/mL had the lowest annual incidence of HCC. However, those with age ≥50 years or/and AFP ≥8 ng/mL had a significantly higher risk for HCC development and warrant a careful surveillance schedule.

Epidemiological Characteristics of Primary Liver Cancer in Mainland China From 2003 to 2020: A Representative Multicenter Study.

BackgroundThe contribution of hepatitis B virus (HBV) and hepatitis C virus (HCV) to primary liver cancer (PLC) and their association with cancer aggressiveness remains uncertain in China, a country with half of global PLC. We aimed to characterize this using data from four representative medical centers.MethodsIn total, 15,801 PLC patients were enrolled from the centers distributed in Easter5n, Southern, Northern, and Western China from 2003 to 2020. Of those, 7585 with curative surgery were involved in survival analysis. A nomogram was constructed using preoperative parameters to predict postoperative survival.ResultsHepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma accounted for 93.0%, 4.3%, and 1.6% in PLC, respectively. The seropositivities of HBV and HCV were 84.4% and 3.2% in HCC, respectively. The seropositivity of anti-HCV antibody was significantly higher in HBV-negative than in HBV-positive HCC patients (13.2% vs. 1.1%). Compared to HCV-positive HCC (HCV-HCC), HBV-positive HCC (HBV-HCC) was associated with 12-year earlier onset, higher proportions of males, high α-fetoprotein, large tumor size, advanced Barcelona Clinic Liver Cancer (BCLC) stage, and vascular tumor thrombus. The proportions of HCC and HBV seropositivity increased, whereas that of anti-HCV decreased, from 2003 to 2020. Postoperative five-year survival rate was 73.5%, 64.1%, 34.9%, and 19.7% in HCC at BCLC stage 0, A, B, and C, respectively. The multivariate Cox regression analysis showed that HBV seropositivity, incomplete tumor capsule, vascular tumor thrombus, tumor diameter (≥3 cm), advanced BCLC stage (B+C), α-fetoprotein (≥20ng/ml), and direct bilirubin (>8µmol/L) contributed independently to shorter overall survival (OS); whereas post-operative radiofrequency ablation and second resection independently improved OS in HCC. HCV-HCC had a more favorable prognosis than did HBV-HCC (Log-rank test, P<0.001). A nomogram composed of age, gender, and the preoperative independent risk factors was accurate in predicting postoperative survival in HCC (C-index: 0.735; 95% confidence interval: 0.727–0.743).ConclusionHBV contributes to 84.4% of HCC in China, and actively promotes hepatocarcinogenesis and HCC progression. A favorable postoperative survival obtained in patients at the early BCLC stage highlights the importance of screening for early HCC in high-risk populations. Our preoperative prognosis prediction model is important in clinical decision-making.

Nomogram based on inflammation-related markers for predicting survival of patients undergoing hepatectomy for hepatocellular carcinoma.

BACKGROUNDPrevious nomograms for hepatocellular carcinoma (HCC) did not include the neutrophil-to-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio (PLR). This study aimed to establish an effective nomogram capable of estimating the association between preoperative inflammatory factors and overall survival (OS) of HCC patients after hepatectomy.AIMTo analyse the factors affecting the prognosis of HCC and establish a nomogram.METHODSA total of 626 HCC patients (410 training set patients from the First Affiliated Hospital of Anhui Medical University and 216 validation set patients from the First Affiliated Hospital of University of Science and Technology of China) underwent hepatectomy from January 2014 to December 2017 and were followed up every 3–6 mo. The nomogram was based on OS-related independent risk factors identified by Cox regression analysis. The C-index, calibration curve, and area under the curve (AUC) were used to evaluate the nomogram’s accuracy.RESULTSThe 1-, 2- and 3-year OS rates were 79.0%, 68.0% and 45.4% in the training cohort (median OS = 34 mo) and 92.1%, 73.9% and 51.2% in the validation cohort (median OS = 38 mo). Higher α-fetoprotein [hazard ratio (HR) = 1.812, 95% confidence interval (CI): 1.343–2.444], NLR (HR = 2.480, 95%CI: 1.856–3.312) and PLR (HR = 1.974, 95%CI: 1.490–2.616), tumour size ≥ 5 cm (HR = 1.323, 95%CI: 1.002–1.747), and poor differentiation (HR = 3.207, 95%CI: 1.944–5.290) were significantly associated with shortened OS. The developed nomogram integrating these variables showed good reliability in both the training (C-index = 0.71) and validation cohorts (C-index = 0.75). For predicting 1-, 2- and 3-year OS, the nomogram had AUCs of 0.781, 0.743 and 0.706 in the training cohort and 0.789, 0.815 and 0.813 in the validation cohort. The nomogram was more accurate in predicting prognosis than the AJCC TNM staging system.CONCLUSIONThe prognostic nomogram combining pathological characteristics and inflammation indicators could provide a more accurate individualized risk estimate for the OS of HCC patients with hepatectomy.

Gadoxetate-enhanced MRI Features of Proliferative Hepatocellular Carcinoma Are Prognostic after Surgery.

Background Hepatocellular carcinomas (HCCs) are heterogeneous neoplasms, and the prognosis varies based on the subtype. Two broad molecular classes of HCC have been proposed: a proliferative and a nonproliferative class. Purpose To evaluate the gadoxetate-enhanced MRI findings of the proliferative class HCC and its prognostic significance after surgery. Materials and Methods This retrospective cohort study evaluated patients with surgically resected treatment-naive single HCC (≤5 cm) who underwent hepatic resection from January 2010 through February 2013 and preoperative gadoxetate-enhanced MRI. A Cox proportional hazards model was used to determine the predictive factors for overall survival (OS), intrahepatic distant recurrence, and extrahepatic metastasis (EM). The mean follow-up period was 75.5 months ± 30.2 (standard deviation). Multivariable logistic regression was performed to determine factors associated with proliferative class HCC. Results A total of 158 patients (mean age, 57 years ± 11; 128 men and 30 women) were evaluated. Forty-two of the 158 HCCs (26.6%) were proliferative class HCCs (17 macrotrabecular-massive HCCs, 14 keratin 19-positive HCCs, 10 scirrhous HCCs, and one sarcomatoid HCC). The proliferative class was associated with worse OS (hazard ratio [HR], 3.1; 95% CI: 1.5, 6.0; P = .01) and higher rates of intrahepatic distant recurrence (HR, 1.83; 95% CI: 1.1, 2.9; P = .01) and EM (HR, 9.97; 95% CI: 3.2, 31.4; P < .001). Rim arterial phase hyperenhancement (APHE) at gadoxetate-enhanced MRI (odds ratio [OR], 6.35; 95% CI: 1.9, 21.7; P = .01) and high serum α-fetoprotein (>100 ng/mL) (OR, 4.18; 95% CI: 1.64, 10.7; P = .01) were independent predictors for proliferative HCC. The presence of rim APHE was associated with poor OS (HR, 2.4; 95% CI: 1.2, 4.9; P = .02) and higher rates of EM (HR, 7.4; 95% CI: 2.5, 21.7; P < .01). Conclusion The proliferative class of hepatocellular carcinoma (HCC) is an independent factor for poor overall survival with increased rates of intrahepatic and extrahepatic metastasis. Rim arterial phase hyperenhancement at gadoxetate-enhanced MRI may help to identify proliferative class HCC and predict poor overall survival and an increased incidence of extrahepatic metastasis. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Krinsky and Shanbhogue in this issue.

Long non-coding RNA00844 inhibits MAPK signaling to suppress the progression of hepatocellular carcinoma by targeting AZGP1.

BackgroundPrevious data have confirmed that disordered long non-coding ribonucleic acid (lncRNA) expression is evident in many cancers and is correlated with tumor progression. The present study aimed to investigate the function of long non-coding RNA00844 (LINC00844) in hepatocellular carcinoma (HCC).MethodsThe expression levels of target genes were detected with real-time polymerase chain reaction (PCR) and western blotting. The biologic function of HCC cells was determined with cell viability assay, colony formation assay, cell cycle analysis, apoptosis detection, and Transwell migration assay in vitro. Tumorigenesis was performed with cell injection in vivo. The relationship between LINC00844 and survival outcomes was determined with the Cox proportional hazards model. A RNA precipitation assay was conducted to reveal the types of LINC00844 that potentially bind with proteins.ResultsLINC00844 was found to be significantly decreased in HCC tissue and was correlated with poor tumor characteristics, such as portal vein invasion, high α-fetoprotein (AFP), and a high rate of tumor recurrence. Exotic LINC00844 expression in HCC cell lines significantly suppressed proliferation and migration, as well as invasiveness, whereas LINC00844 deletion had the opposite effect. LINC00844 overexpression significantly inhibited HCC tumorigenesis in vivo. Mechanistic analyses indicated that the mitogen-activated protein kinase (MAPK) signaling pathway was remarkably inactivated by LINC00844. Furthermore, the immunoprecipitation assay verified that LINC00844 can bind to zinc-alpha-2-glycoprotein (AZGP1) and interfere with its translocation. LINC00844 can also promote AZGP1 expression, leading to the suppression of the transforming growth factor-β1 (TGF-β1)-extracellular signal-regulated kinase (ERK) pathway.ConclusionsLINC00844 is a novel anti-oncogene in the development of HCC and a potentially promising therapeutic target in HCC.

Diagnostic and prognostic value of MCM3 and its interacting proteins in hepatocellular carcinoma.

Aberrant DNA replication is one of the driving forces behind oncogenesis. Furthermore, minichromosome maintenance complex component 3 (MCM3) serves an essential role in DNA replication. Therefore, in the present study, the diagnostic and prognostic value of MCM3 and its interacting proteins in hepatocellular carcinoma (HCC) were investigated. By utilizing The Cancer Genome Atlas (TCGA) database, global MCM3 mRNA levels were assessed in HCC and normal liver tissues. Its effects were further analyzed by reverse transcription-quantitative PCR (RT-qPCR), western blotting and immunohistochemistry in 78 paired HCC and adjacent tissues. Functional and pathway enrichment analyses were performed using the Search Tool for the Retrieval of Interacting Genes database. The expression levels of proteins that interact with MCM3 were also analyzed using the TCGA database and RT-qPCR. Finally, algorithms combining receiver operating characteristic (ROC) curves were constructed using binary logistic regression using the TCGA results. Increased MCM3 mRNA expression with high α-fetoprotein levels and advanced Edmondson-Steiner grade were found to be characteristic of HCC. Survival analysis revealed that high MCM3 expression was associated with poor outcomes in patients with HCC. In addition, MCM3 protein expression was associated with increased tumor invasion in HCC tissues. MCM3 and its interacting proteins were found to be primarily involved in DNA replication, cell cycle and a number of binding processes. Algorithms combining ROCs of MCM3 and its interacting proteins were found to have improved HCC diagnosis ability compared with MCM3 and other individual diagnostic markers. In conclusion, MCM3 appears to be a promising diagnostic biomarker for HCC. Additionally, the present study provides a basis for the multi-gene diagnosis of HCC using MCM3.

Radiologic-Pathologic Correlation of Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement at Gadoxetic Acid-enhanced MRI: A Multicenter Study.

Background Hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) at gadoxetic acid-enhanced MRI may indicate hepatocellular carcinoma (HCC) or nonmalignant cirrhosis-associated nodules. Purpose To assess the distribution of pathologic diagnoses of HBP hypointense nodules without APHE at gadoxetic acid-enhanced MRI and to evaluate clinical and imaging features in differentiating their histologic grades. Materials and Methods This retrospective multicenter study included pathologic analysis-confirmed HBP hypointense nodules without APHE (≤30 mm) in patients with chronic liver disease or cirrhosis screened between January 2008 and June 2016. Central pathologic review by 10 pathologists determined final histologic grades as progressed HCC, early HCC, high-grade dysplastic nodule (DN), and low-grade DN or regenerative nodule. Gadoxetic acid-enhanced MRI features were analyzed by three radiologists. Multivariable logistic regression analyses with elastic net regularization were performed to identify clinical and imaging features for differentiating histologic grades. Results There were 298 patients (mean age, 59 years ± 10; 226 men) with 334 nodules evaluated, and progressed HCCs were diagnosed in 44.0% (147 of 334), early HCCs in 20.4% (68 of 334), high-grade DNs in 27.5% (92 of 334), and low-grade DNs or regenerative nodules in 8.1% (27 of 334). Serum α-fetoprotein level 100 ng/mL or greater (odds ratio, 2.7; P = .01) and MRI features including well-defined margin (odds ratio, 5.5; P = .003), hypointensity at precontrast T1-weighted imaging (odds ratio, 3.2; P < .001), intermediate hyperintensity at T2-weighted imaging (odds ratio, 3.4; P < .001), and restricted diffusion (odds ratio, 1.9; P = .04) were independent predictors for progressed HCC at multivariable analysis. Conclusion In patients at high risk for hepatocellular carcinoma (HCC), hepatobiliary phase hypointense nodules without arterial phase hyperenhancement at gadoxetic acid-enhanced MRI corresponded mainly to progressed HCCs, early HCCs, and high-grade dysplastic nodules. High α-fetoprotein level and some imaging features at MRI helped to differentiate progressed HCC from lower grade nodules. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Motosugi in this issue.

Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment Predictive Factors and Role of Epigenetics.

Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of hepatocellular carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short–medium term but reduces the risk of HCC in the medium–long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects’ post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management.

Hepatoblastoma-An Unusual Presentation: A Case Report

Hepatoblastoma (HB) is the most common primary hepatic malignancy in children and accounts for 43% of the pediatric liver tumors. The usual presentation is the presence of an abdominal mass, vomiting, elevated αfetoprotein levels and thrombocytosis and it occurs in infants and children under 3 years of age. A 6-year-old male child presented to the outpatient department with complaints of mild to moderate grade fever, vomiting and loose stools for 3 days. The child was otherwise active and there was no palpable abdominal mass. USG abdomen and CT scan revealed the presence of an encapsulated solid hepatic tumor suggestive of HB. Complete blood count showed an elevated WBC count, high ESR and high α-fetoprotein levels (958 ng/ml) but no thrombocytosis. A nonanatomical excisional biopsy of the tumor confirmed it to be hepatoblastoma. The unusual features noticed in this case was presentation at a slightly later age (6 years), absence of abdominal mass and absence of thrombocytosis.

Multiphase Liver MRI for Identifying the Macrotrabecular-Massive Subtype of Hepatocellular Carcinoma.

Background The recently described "macrotrabecular-massive" (MTM) histologic subtype of hepatocellular carcinoma (HCC) (MTM-HCC) represents an aggressive form of HCC and is associated with poor survival. Purpose To investigate whether preoperative MRI can help identify MTM-HCCs in patients with HCC. Materials and Methods This retrospective study included patients with HCC treated with surgical resection between January 2008 and February 2018 and who underwent preoperative multiphase contrast material-enhanced MRI. Least absolute shrinkage and selection operator (LASSO)-penalized and multivariable logistic regression analyses were performed to identify clinical, biologic, and imaging features associated with the MTM-HCC subtype. Early recurrence (within 2 years) and overall recurrence were evaluated by using Kaplan-Meier analysis. Multivariable Cox regression analysis was performed to determine predictors of early and overall recurrence. Results One hundred fifty-two patients (median age, 64 years; interquartile range, 56-72 years; 126 men) with 152 HCCs were evaluated. Twenty-six of the 152 HCCs (17%) were MTM-HCCs. LASSO-penalized logistic regression analysis identified substantial necrosis, high serum α-fetoprotein (AFP) level (>100 ng/mL), and Barcelona Clinic Liver Cancer (BCLC) stage B or C as independent features associated with MTM-HCCs. At multivariable analysis, substantial necrosis (odds ratio = 32; 95% confidence interval [CI] = 8.9, 114; P < .001), high serum AFP level (odds ratio = 4.4; 95% CI = 1.3, 16; P = .02), and BCLC stage B or C (odds ratio = 4.2; 95% CI = 1.2, 15; P = .03) were independent predictors of MTM-HCC subtype. Substantial necrosis helped identify 65% (17 of 26; 95% CI: 44%, 83%) of MTM-HCCs (sensitivity) with a specificity of 93% (117 of 126; 95% CI: 87%, 97%). In adjusted models, only the presence of satellite nodules was independently associated with both early (hazard ratio = 3.7; 95% CI: 1.5, 9.4; P = .006) and overall (hazard ratio = 3.0; 95% CI: 1.3, 7.2; P = .01) tumor recurrence. Conclusion At multiphase contrast-enhanced MRI, substantial necrosis helped identify macrotrabecular-massive hepatocellular carcinoma subtype with high specificity. © RSNA, 2020.

Integrative analysis of DNA methylation and gene expression reveals distinct hepatocellular carcinoma subtypes with therapeutic implications.

We aimed to develop an HCC classification model based on the integrated gene expression and methylation data of methylation-driven genes. Genome, methylome, transcriptome, proteomics and clinical data of 369 HCC patients from The Cancer Genome Atlas Network were retrieved and analyzed. Consensus clustering of the integrated gene expression and methylation data from methylation-driven genes identified 4 HCC subclasses with significant prognosis difference. HS1 was well differentiated with a favorable prognosis. HS2 had high serum α-fetoprotein level that was correlated with its poor outcome. High percentage of CTNNB1 mutations corresponded with its activation in WNT signaling pathway. HS3 was well differentiated with low serum α-fetoprotein level and enriched in metabolism signatures, but was barely involved in immune signatures. HS3 also had high percentage of CTNNB1 mutations and therefore enriched in WNT activation signature. HS4 was poorly differentiated with the worst prognosis and enriched in immune-related signatures, but was barely involved in metabolism signatures. Subsequently, a prediction model was developed. The prediction model had high sensitivity and specificity in distributing potential HCC samples into groups identical with the training cohort. In conclusion, this work sheds light on HCC patient prognostication and prediction of response to targeted therapy.

Modulation of Nqo1 activity intercepts anoikis resistance and reduces metastatic potential of hepatocellular carcinoma.

The processing of intracellular reactive oxygen species (ROS) by nuclear factor erythroid‐derived 2‐like 2 (Nrf2) and NADPH quinone oxidoreductase 1 (Nqo1) is important for tumor metastasis. However, the clinical and biological significance of Nrf2/Nqo1 expression in hepatocellular carcinoma (HCC) remains unclear. We aimed to clarify the clinical importance of Nrf2/Nqo1 expression in HCC and evaluate the association of Nrf2/Nqo1 expression with HCC metastasis. We also evaluated the impact of Nqo1 modulation on HCC metastatic potential. We used spheroids derived from HCC cell lines. In anchorage‐independent culture, HCC cells showed increased ROS, leading to the upregulation of Nrf2/Nqo1. Futile stimulation of Nqo1 by β‐lapachone induces excessive oxidative stress and dramatically increased anoikis sensitivity, finally diminishing the spheroid formation ability, which was far stronger than depletion of Nqo1. We analyzed 117 cases of primary HCC who underwent curative resection. Overexpression of Nrf2/Nqo1 in primary HCC was associated with tumor size, high α‐fetoprotein, and des‐γ‐carboxy‐prothrombin levels. Overexpression of Nrf2/Nqo1 was also associated with multiple intrahepatic recurrences (P = .0073) and was an independent risk factor for poor prognosis (P = .0031). NADPH quinone oxidoreductase 1 plays an important role in anchorage‐independent survival, which is essential for survival for circulation and distant metastasis of HCC cells. These results suggest that targeting Nqo1 activity could be a potential strategy for HCC adjuvant therapy.

Correlation of Long Noncoding RNA SEMA6A-AS1 Expression with Clinical Outcome in HBV-Related Hepatocellular Carcinoma

PurposeHepatocellular carcinoma (HCC) is the seventh most commonly diagnosed cancer and the fourth-leading cause of cancer-related death worldwide. Chronic hepatitis B virus (HBV) is the leading cause of HCC in China. Emerging evidence suggests that long noncoding (lnc)-RNAs are deregulated and are involved in the development of HCC. Our previous study found that HBV X protein can promote HCC by altering lncRNA expression profiles. The purpose of this study was to investigate the expression of the lncRNA semaphorin 6A–antisense RNA 1 (SEMA6A-AS1) and its prognostic value in HBV-related HCC. MethodsSamples of HCC tissues and adjacent nontumor tissues were collected from patients who were pathologically diagnosed with HBV-related HCC after hepatectomy. Eligible patients had not received preoperative radiotherapy, chemotherapy, or embolotherapy. Real-time quantitative reverse-transcription polymerase chain reaction was performed to evaluate the expression levels of SEMA6A-AS1 in all tissue specimens. The correlations between SEMA6A-AS1 expression and clinicopathologic characteristics were analyzed using the χ2 test and the Fisher exact test. Overall survival curves constructed by the Kaplan–Meier method and univariate analysis made by Cox proportional hazards modeling were used for determining the prognostic significance of SEMA6A-AS1. FindingsSpecimens were collected from 47 patients (45 men, 2 women; mean age, 48.4 [10.7] years). SEMA6A-AS1 expression was significantly downregulated in HBV-related HCC tissues compared with that in adjacent noncancerous hepatic tissues (P < 0.01). Low levels of SEMA6A-AS1 were correlated with high α-fetoprotein level (P = 0.002), high Edmondson-Steiner tumor grade (P = 0.047), high tumor node metastasis stage (P = 0.01), capsular invasion (P = 0.005), and poor clinical response (P = 0.002). Additionally, both Kaplan–Meier estimator and univariate Cox regression analysis revealed that low SEMA6A-AS1 expression was significantly associated with poor overall survival (P < 0.05). ImplicationsThe results show that low expression of SEMA6A-AS1 was associated with a poor prognosis in patients with HBV-related HCC. It is necessary to determine the function and mechanism of SEMA6A-AS1 in HCC in order to identify it as a prognostic biomarker and therapeutic target.

Prognostic impact of hepatitis B or C on intrahepatic cholangiocarcinoma.

Background/AimsIntrahepatic cholangiocarcinoma (ICC) is the second-most common primary liver malignancy, arising from the peripheral intrahepatic bile duct epithelium. Hepatitis B virus (HBV) or hepatitis C virus (HCV) may be involved in the development of ICC. We explored the prognostic value of hepatitis virus infection, as well as other prognostic factors affecting survival in patients with ICC.MethodsA retrospective chart review was performed for patients diagnosed with ICC between August 2005 and December 2018 at Konkuk University Medical Center. We identified a total of 131 patients with ICC. Overall survival rates of patients with and without hepatitis were determined. Univariate and multivariate analyses were used to estimate factors influencing survival outcomes.ResultsA total of 17.6% (23/131) of patients were positive for HBV or HCV. Hepatitis B positive ICC patients were significantly younger with higher albumin and higher α-fetoprotein than those without hepatitis viral infections. The median survival of hepatitis-positive and hepatitis-negative groups was 280 and 213 days, respectively. Survival rates were not significantly different between the two groups (p = 0.279). Multivariate analyses indicated that lower serum carbohydrate antigen 19-9 (CA 19-9) (p < 0.001), lower T stage (p = 0.042), the absence of lymph-node metastasis (p = 0.043), and receiving curative surgery (p = 0.033) were independent predictors of better outcomes.ConclusionsWhile hepatitis influenced a number of clinical features in ICC patients, it did not affect survival rate. Prognostic factors influencing survival outcomes with ICC were CA 19-9 level, T stage, the presence of lymph node metastasis, and curative surgery.