High Α-fetoprotein Level Research Articles

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.

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.

Prognostic significance of combined α-fetoprotein and CA19-9 for hepatocellular carcinoma after hepatectomy

BackgroundThe prognosis of hepatocellular carcinoma (HCC) varies considerably among patients with the same disease stage and characteristics, and only about two thirds show high levels of α-fetoprotein (AFP), a common prognostic indicator for HCC. Here, we assessed whether the combination of presurgical serum levels of AFP and carbohydrate antigen 19-9 (CA19-9) can predict the prognosis of HCC patients after hepatectomy.MethodsThe clinicopathological characteristics and post-hepatectomy outcomes of 711 HCC patients were retrospectively reviewed. The patients were classified into three groups based on whether their preoperative serum levels of both AFP and CA19-9 were higher than the respective cut-offs of 400 ng/ml and 37 U/ml [double positive (DP)], the level of only one marker was higher than the cut-off [single positive (SP)], or neither level was higher than the cut-off [negative (N)]. The overall survival (OS) and recurrence-free survival (RFS) rates were estimated using Kaplan–Meier curves. Univariate and multivariate survival analyses were performed to identify the clinicopathological factors significantly associated with HCC prognosis.ResultsThe 1-year, 3-year, and 5-year RFS and OS rates in the N group were significantly higher than those in the SP group, while the DP group showed the lowest rates. Multivariate Cox regression analysis showed that large tumor size (> 5 cm), multiple tumors (≥ 2), incomplete tumor capsule, positive microvascular invasion, Barcelona Clinic Liver Cancer C stage, and CA19-9 level > 37 U/mL were independent risk factors for RFS and OS in HCC patients. Moreover, aspartate aminotransferase levels > 40 U/L proved to be an independent prognostic factor for OS.ConclusionThe combination of serum AFP and CA19-9 levels may be a useful prognostic marker for HCC patients after hepatectomy.

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.

SLAMF6/Ly108 promotes the development of hepatocellular carcinoma via facilitating macrophage M2 polarization.

Tumor-associated macrophages (TAMs) are capable of worsening hepatocellular carcinoma (HCC) prognosis by accelerating tumor growth and progression. Signaling lymphocyte activation molecule family member 6 (SLAMF6; Ly108 in mice) is an immune regulator that is involved in numerous diseases. However, whether SLAMF6 might affect macrophage function in HCC has not yet been reported. Therefore, the present study aimed to determine the relationship between SLAMF6 expression on macrophages and HCC progression. In the present study, the expression of SLAMF6 in human blood samples and mice was analyzed by flow cytometry. Furthermore, macrophage-related polarization markers were detected via reverse transcription quantitative PCR. Clonogenic formation and Transwell assay were performed to determine the proliferation, migration and invasion of HCC cells. In addition, a murine HCC model was established to detect the function of SLAMF6 in vivo. The results demonstrated that SLAMF6 expression was increased in CD14+ cells obtained from patients with HCC. It was also determined that this increase was associated with a positive hepatitis B virus DNA status and high levels of α-fetoprotein. Polarized TAMs from THP-1 cells, murine peritoneal macrophages and murine bone marrow-derived macrophages all exhibited higher levels of SLAMF6 compared with M1 cells. Furthermore, an increased expression of Ly108 was detected in macrophages obtained from mice tumor tissues, indicating that the tumor microenvironment may promote Ly108 expression and macrophage M2 polarization. Ly108 small interfering RNA was applied to macrophages, which resulted in the suppression of M2 polarization. Ly108-silenced macrophages attenuated HCC cell migration and invasion and prevented tumor growth by inhibiting the nuclear factor-κB pathway. Altogether, the results from the present study suggested that SLAMF6/Ly108 was upregulated in TAMs, which may in turn accelerate the development of HCC.

Prognostic Impact of Vessels that Encapsulate Tumor Cluster (VETC) in Patients who Underwent Liver Transplantation for Hepatocellular Carcinoma

Background: There is limited published information about prognostic value of vessels that encapsulate tumor cluster (VETC) based on their involvement with immune cells in hepatocellular carcinoma (HCC). Our aim was to evaluate prognostic impact of VETC in patients who underwent living-donor liver transplantation (LDLT) for HCC, focusing on the involvement of VETC with immune status in tumor microenvironment (TME). Methods: Using a database of 150 patients who underwent LDLT for HCC, immunohistochemical staining of CD34 for VETC, angiopoietin-2 (Ang-2), CD3, and CD68, was reviewed with patients’ clinicopathological factors. Results: A strong correlation between VETC pattern and malignant potential in HCC was observed; larger tumor size (P<0.001), more numbers of tumors (P=0.003), higher α-fetoprotein levels (P=0.001), higher des-γ-carboxy prothrombin levels (P=0.022), microvascular invasion (P<0.001), and poor differentiation (P=0.010). Overall survival (OS) of patients with VETC(+) was significantly lower than those with VETC(-) (P=0.021; 5-year OS rates, 72.0% vs. 87.1%). Further, the ratio of CD3(+) cells was significantly lower in VETC(+) group (P =0.001), indicating that VETC activity may be strongly correlated with lymphocyte activity. Moreover, combination status of VETC(+)/CD3low was an independent risk factor for mortality [hazard ratio 2.760, 95% CI 1.183 - 6.439, P=0.019]. Additionally, the combination of VETC expression with immune status (low CD3 levels) enabled further classification of patients based on their clinical outcome. Conclusions: Our results show the prognostic impact of VETC expression, tumor-infiltrating lymphocytes (TILs), and their combination in the setting of LDLT for HCC, which can be a novel prognostic biomarker for mortality after LDLT.

Comparative long-term outcomes of laparoscopic hepatectomy and radiofrequency ablation for hepatocellular carcinoma located in the anterolateral segments of the liver.

Laparoscopic liver resection (LLR) is considered the standard surgical approach for resecting small hepatocellular carcinomas (HCC) located in the anterolateral segments of the liver. However, few studies have compared LLR and radiofrequency ablation (RFA) in such cases. We retrospectively compared the short- and long-term outcomes of 101 patients who underwent LLR and 264 patients who underwent RFA because of a newly diagnosed single, small (≤4cm) HCC located in the anterolateral segments of the liver. By applying 1:1 propensity score matching, we matched 61 patients in both groups. Although the 5-year overall survival rates were similar (83.6% vs 84.5%; P=.913), the 5-year disease-free survival rate was greater in the LLR group (56.4% vs 41.8%; P=.009). In patients with an α-fetoprotein level of ≥100ng/mL, the 5-year overall (100% vs 80.0%; P=.022) and disease-free survival (76.6% vs 45.5%; P=.006) rates were greater in the LCC group. For patients with a single, small HCC located in the anterolateral segments of the liver, LLR was associated with similar complication and overall survival rates, but better disease-free survival compared with RFA. LLR may be recommended for patients with higher α-fetoprotein levels.

National Trends and Waitlist Outcomes of Locoregional Therapy Among Liver Transplant Candidates With Hepatocellular Carcinoma in the United States

Policy changes in the United States have lengthened overall waiting times for patients with hepatocellular carcinoma (HCC). We investigated temporal trends in utilization of locoregional therapy (LRT) and associated waitlist outcomes among liver transplant (LT) candidates in the United States. Data for primary adult LT candidates listed from 2003 to 2018 who received HCC exception were extracted from the Organ Procurement and Transplantation Network database. Explant histology was examined, and multivariable competing risk analysis was used to evaluate the association between LRT type and waitlist dropout. There were 31,609 eligible patients with at least 1 approved HCC exception, and 34,610 treatments among 24,145 LT candidates. The proportion with at least 1 LRT recorded increased from 42.3% in 2003 to 92.4% in 2018. Chemoembolization remains the most frequent type, followed by thermal ablation, with a notable increase in radioembolization from 3% in 2013 to 19% in 2018. An increased incidence of LRT was observed among patients with tumor burden beyond Milan criteria, higher α-fetoprotein level, and more compensated liver disease. Receipt of any type of LRT was associated with a lower risk of waitlist dropout; there was no significant difference by number of LRTs. In inverse probability of treatment weighting-adjusted analysis, radioembolization or ablation as the first LRT was associated with a reduced risk of waitlist dropout compared with chemoembolization. In a large nationwide cohort of LT candidates with HCC, LRT, and in particular radioembolization, increasingly was used to bridge to LT. Patients with greater tumor burden and those with more compensated liver disease received more treatments while awaiting LT. Bridging LRT was associated with a lower risk of waitlist dropout.

Prognostic Impact of Vessels that Encapsulate Tumor Cluster (VETC) in Patients who Underwent Liver Transplantation for Hepatocellular Carcinoma.

There is limited published information about prognostic value of vessels that encapsulate tumor cluster (VETC) based on their involvement with immune cells in hepatocellular carcinoma (HCC). Our goal was to evaluate prognostic impact of VETC in patients who underwent living-donor liver transplantation (LDLT) for HCC, focusing on the involvement of VETC with immune status in tumor microenvironment (TME). Using a database of 150 patients who underwent LDLT for HCC, immunohistochemical staining of CD34 for VETC, angiopoietin-2 (Ang-2), CD3, and CD68, was reviewed with patients' clinicopathological factors. A strong correlation between VETC pattern and malignant potential in HCC was observed; larger tumor size (P < 0.001), more numbers of tumors (P = 0.003), higher α-fetoprotein levels (P = 0.001), higher des-γ-carboxy prothrombin levels (P = 0.022), microvascular invasion (P < 0.001), and poor differentiation (P = 0.010). Overall survival (OS) of patients with VETC(+) was significantly lower than those with VETC(-) (P = 0.021; 5-year OS rates, 72.0% vs. 87.1%). Furthermore, the ratio of CD3(+) cells was significantly lower in VETC(+) group (P = 0.001), indicating that VETC activity may be strongly correlated with lymphocyte activity. Moreover, combination status of VETC(+)/CD3low was an independent risk factor for mortality (hazard ratio 2.760, 95% confidence interval 1.183-6.439, P = 0.019). Additionally, the combination of VETC expression with immune status (low CD3 levels) enabled further classification of patients based on their clinical outcome. Our results show the prognostic impact of VETC expression, tumor-infiltrating lymphocytes (TILs), and their combination in the setting of LDLT for HCC, which can be a novel prognostic biomarker for mortality after LDLT.

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.

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.

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.

Genomic Profiles of a Patient of Pulmonary Hepatoid Adenocarcinoma With High AFP Level: A Case Report

Hepatoid adenocarcinoma of lung (HAL) is a rare and aggressive tumor. The current study reported a new HAL case in the right lower lung with high serum α-fetoprotein (AFP) level in a 71-year-old male patient. After the confirmation of morphology and immunohistochemistry, the patient was diagnosed clinically with HAL and treated with radio-frequency ablation. However, the patient whose disease progressed eventually died 4 months after diagnosis. Whole genome sequencing analysis identified a driver gene mutation in the FAT atypical cadherin 1 gene (FAT1) and the copy number loss. The tumor was microsatellite-stable and tumor mutation burden (TMB) was 1.69 mutations/Mb. PD-L1 expression was negative by IHC. Our finding provide further clues for the molecular basis of HAL and the efficacy of immunotherapy needs to be explored.

Prognostic predictors for patients with hepatocellular carcinoma receiving adjuvant transcatheter arterial chemoembolization.

We aimed to confirm the clinical effectiveness of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in patients with hepatocellular carcinoma after liver resection, and further identify the patients who could benefit most from PA-TACE. Propensity score matching at a ratio of 1 : 2 was used between hepatectomy patients with and without receiving PA-TACE. Kaplan-Meier analysis was performed to compare overall survival and recurrence-free survival between two groups. Univariate COX regression and stratified analyses were performed to screen and identify survival predictors for PA-TACE patients. The identified predictive markers were validated in an external cohort. The propensity analysis matched 116 patients in PA-TACE group to 232 in the control group. Visible protective effect of PA-TACE was shown by survival curves in matched series (log-rank P=0.009 and 0.008), with hazard ratio of being 0.599 (95% confidence interval: 0.420-0.855) and 0.623 (95% confidence interval: 0.449-0.866), respectively, for overall survival and recurrence-free survival. The identified prognostic predictors for PA-TACE included TNM stage, tumor size and number, hepatitis B infection, spleen diameter, preoperative serum α-fetoprotein, alkaline phosphatase, γ-glutamyl transpeptidase and monocyte, and three risk signatures (aspartate aminotransferase-to-alanine aminotransferase ratio, neutrophil-to-lymphocyte ratio, and systemic immune-inflammation index). The treatment effectiveness of adjuvant transcatheter arterial chemoembolization for patients with hepatocellular carcinoma after surgery was validated in this study, and the best candidates for PA-TACE were identified as well, including patients with late-stage tumor, portal hypertension, and high preoperative serum levels of α-fetoprotein, alkaline phosphatase, γ-glutamyl transpeptidase, and monocytes.

Incidence and risk factors of hepatocellular carcinoma change over time in patients with hepatitis C virus infection who achieved sustained virologic response.

In patients with chronic hepatitis C, hepatocellular carcinoma (HCC) occurs at a certain frequency, even if a sustained virologic response (SVR) is achieved by antiviral treatment. Old age, liver fibrosis, and high post-treatment α-fetoprotein (AFP) level are typical risk factors of post-SVR HCC. We examined whether the frequencies and factors of HCC in patients with an SVR achieved from interferon treatment changed. Methods Among patients prospectively registered for pegylated interferon and ribavirin treatment, 2021 with an SVR without HCC development during the treatment period were followed up. The mean observation period was 49.5 ± 26.2months. The multivariable Cox regression analysis showed that older age, diabetes mellitus, advanced liver disease, and higher post-treatment AFP level were the independent risk factors throughout the observation period. The annual occurrence rate of HCC was 0.74% in the third year, 0.54% in the fourth year, and 0.40% in the fifth year; it gradually decreased from the third year. Because the time course hazards for HCC changed at 48months, we separately analyzed its risk factors before and after this change point. The multivariable Cox regression analysis showed that the four above-mentioned factors were significantly related to HCC development within 4years. Conversely, the univariable Cox regression analysis only identified diabetes mellitus as a significant factor for HCC development after 4years. The frequency of HCC in hepatitis C patients who achieved an SVR from interferon treatment decreased during the observation period, and its risk factors changed between the early and late periods.

Diffuse and canalicular patterns of glypican-3 expression reflect malignancy of hepatocellular carcinoma.

Glypican-3 (GPC3) is expressed in most hepatocellular carcinomas (HCCs). To investigate the significance of various GPC3 staining patterns in HCC, we classified 134 HCC patients into three groups: those with diffuse GPC3 staining, canalicular GPC3 staining, and others (including negative staining). HCCs with diffuse staining were correlated with poor differentiation, high Ki-67 indices, high serum α-fetoprotein (AFP) levels, and early recurrence. In contrast, HCCs with canalicular staining were well differentiated with lower AFP levels. Overall survival in this group was better than that of the other two groups. Comparative analysis of GPC3 staining patterns with markers for HCC subclassification showed that diffuse staining was correlated with the expression of biliary/stem cell markers, whereas canalicular staining was correlated with expression of the markers of WNT-activated HCCs. Induction of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), known as a target of the WNT signaling pathway, in HCC cells resulted in reduced GPC3 expression in vitro. The LGR5-induced cells formed tumors with canaliculus-like structures in mice and showed canalicular GPC3 staining. The current findings showed the significance of recognizing distinct GPC3 staining patterns, i.e., diffuse and canalicular, which may reflect different carcinogenetic mechanisms and indicate the level of malignancy of HCC.

A 6-Year-Old Child With Citrin Deficiency and Advanced Hepatocellular Carcinoma

We report the case of a 6-year-old boy with citrin deficiency and advanced hepatocellular carcinoma diagnosed by using imaging. He exhibited intrahepatic cholestasis 2 days after his birth and was misdiagnosed with inspissated bile syndrome at that time. The symptoms of jaundice spontaneously resolved when he was 5 months old. However, his transaminase levels remained elevated for ∼6 years, for which he received no treatment. He preferred a high-protein, high-fat, low-carbohydrate diet, which has been observed in many patients with citrin deficiency, but no clinical features of adult-onset type II citrullinemia were observed. At the age of 6 years, he was admitted to our hospital with a nonviral infection and high α-fetoprotein level; results from an abdominal MRI and computed tomography revealed multiple tumors in the liver. Because of his history of intrahepatic cholestasis in the neonatal period, he was suspected to have citrin deficiency. A genetic analysis of solute carrier family 25, member 13 revealed the presence of a homozygous 851del4 mutation, and a diagnosis of citrin deficiency was made. The patient did not qualify for liver transplantation and died 2 months later, after discharge from our hospital. Thus, this case reveals that not all patients with neonatal intrahepatic cholestasis spontaneously and totally improve, and this case is used to emphasize that patients with neonatal intrahepatic cholestasis should be managed carefully, especially in the stage of failure to thrive and dyslipidemia caused by citrin deficiency, which may lead to advanced hepatocellular carcinoma.