Abstract

Aim

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that has two different tumor phenotypes in a single tumor nodule. The relationship between genetic mutations and clinicopathological features of cHCC-CCA remains to be elucidated.

Methods

Whole-exome sequencing analyses were carried out in 13 primary and 2 recurrent cHCC-CCAs. The whole-exome analyses and clinicopathological information were integrated.

Results

TP53 was the most frequently mutated gene in this cohort, followed by BAP1, IDH1/2, and NFE2L2 mutations in multiple cases. All tumors with diameters <3 cm had TP53 mutations. In contrast, six of seven tumors with diameters ≥3 cm did not have TP53 mutations, but all seven tumors had mutations in genes associated with various pathways, including Wnt, RAS/PI3K, and epigenetic modulators. In the signature analysis, the pattern of mutations shown in the TP53 mutation group tended to be more similar to HCC than the TP53 nonmutation group. Mutations in recurrent cHCC-CCA tumors were frequently identical to those in the primary tumor, suggesting that those tumors originated from identical clones of the primary cHCC-CCA tumors. Recurrent and co-occurrent HCC tumors in the same patients with cHCC-CCA had either common or different mutation patterns from the primary cHCC-CCA tumors in each case.

Conclusions

The study suggested that there were two subtypes of cHCC-CCA, one involving TP53 mutations in the early stage of the carcinogenic process and the other not involving such mutations. The comparison of the variants between primary and recurrent tumors suggested that cHCC-CCA was derived from an identical clone.

Abstract

Aim

Microvascular invasion (MVI) is an independent risk factor for postoperative recurrence and metastasis in hepatocellular carcinoma (HCC). However, the specific protein expression profiles that differentiate HCC with MVI from those without MVI remain unclear.

Methods

The profiles of proteins in early-stage HCC tissues and normal liver tissues were characterized by quantitative proteomics techniques. Immunohistochemical (IHC) staining was performed on tissue microarrays from 80 HCC patients to assess the expression of MSH2 and MSH6. Cell counting and colony formation, migration and invasion assays were performed in vitro.

Results

We identified 5164 proteins in both HCC tissues and adjacent normal liver tissues. As compared to HCC without MVI, 148 upregulated proteins and 97 downregulated proteins were found in HCC with MVI. Particularly noteworthy was the remarkable upregulation of MSH6/MSH2 among these dysregulated proteins in HCC with MVI. Further validation through bioinformatics prediction and IHC confirmed the elevated expression of MSH6/MSH2, which correlated with aggressive disease characteristics and poor prognosis. Receiver operating characteristic curve analyses demonstrated a substantial area under curve of 0.761 (specificity: 71.79%, sensitivity: 73.17%) for the combined use of MSH6/MSH2. Knockdown of MSH6/MSH2 significantly inhibited HCC cell proliferation and invasion in vitro.

Conclusions

Our study establishes MSH6 or MSH2 as an oncogene that is prominently overexpressed during HCC progression which provides new targets for HCC with MVI.

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Present study firstly identified TSH was a promising predictor for HBV-ACLF outcome, and then developed a novel prognostic score (mCLIF-OFs) by weighting TSH. Thirdly, we estimated and validated the high performance of the novel mCLIF-OFs from aspects of calibration, discrimination, and clinical net benefit. Those findings would facilitate early assessment of prognosis of HBV-ACLF and provide a novel tool to manage the life-threatening disease.

Abstract

Background

To weighted the prognostic value of thyroid hormones in catastrophic ACLF.

Methods

A retrospective cohort (n=635) and two prospective cohorts (n=353, and 198) were enrolled in this study. The performance of novel developed prognostic score was assessed from aspects of reliability, discrimination, and clinical net benefit.

Results

Thyroid-stimulating hormone (TSH) was identified as most potential prognostic predictor for HBV-ACLF among thyroid hormones. The novel score (mCLIF-OFs) was developed with weighted TSH and other scored organs in CLIF-OFs using the retrospective cohort (n=635). The predicted risk and observed probabilities of death were comparable across the deciles of mCLIF-OFs (Hosmer-Lemeshow χ² =4.28, p=0.83; Brier scaled=11.9). The C-index of mCLIF-OFs (0.885 [0.883-0.887]) for 30-day mortality was significantly higher than that of the CLIF-OFs, CLIF-SOFAs, CLIF-C ACLFs, MELD, and Child-Pugh (all p<0.001). The absolute improvements of prediction error rates of the mCLIF-OFs comparing to the above five scores were from 19.0% to 61.1%. After the analysis of probability density function (PDF), the mCLIF-OFs showed the least overlapping coefficients (27.9%) among above prognostic scores. Additionally, the mCLIF-OFs also show greater net benefit than above five prognostic scores over a wide range of risk threshold of death. Similar results were validated in two prospective ACLF cohorts with HBV and non-HBV etiologies.

Conclusions

Weighted TSH portended the outcome of ACLF patients, which may be treated as “damaged organ” of the hypothalamic-pituitary-thyroid axis. The novel mCLIF-OFs is a reliable prognostic score with better discrimination power and clinical net benefit than CLIF-OFs, CLIF-SOFAs, CLIF-C ACLFs, MELD, and Child-Pugh.

This article is protected by copyright. All rights reserved.

Abstract

Aims

Ursodeoxycholic acid is the first-line treatment for primary biliary cholangitis, and treatment response is one of the factors predicting the outcome. To prescribe alternative therapies, clinicians might need additional information before deciphering the treatment response to ursodeoxycholic acid, contributing to a better patient prognosis. In this study, we developed and validated machine learning (ML) algorithms to predict treatment responses using pretreatment data.

Methods

This multicenter cohort study included collecting datasets from two data samples. Data 1 included 245 patients from 18 hospitals for ML development, and was divided into (i) training and (ii) development sets. Data 2 (iii: test set) included 51 patients from our hospital for validation. An extreme gradient boosted tree predicted the treatment response in the ML model. The area under the curve was used to evaluate the efficacy of the algorithm.

Results

Data 1 showed that patients complying with the Paris II treatment response had significantly lower serum alkaline phosphatase and total bilirubin levels than those who did not respond. Three factors, total bilirubin, total protein, and alanine aminotransferase levels were selected as essential variables for prediction. Data 2 showed that patients complying with the Paris II criteria had significantly high prothrombin time and low total bilirubin levels. The area under the curve of extreme gradient boosted tree was good for (ii) (0.811) and (iii) (0.856).

Conclusions

We demonstrated the efficacy of ML in predicting the treatment response for patients with primary biliary cholangitis. Early identification of cases requiring additional treatment with our novel ML model may improve prognosis.

The cost-effectiveness of hepatitis E vaccination for patients with chronic hepatitis B (CHB) is unclear. We developed a decision tree–Markov model to assess the cost-effectiveness of three hepatitis E vaccination strategies among these patients. We found that the disease burden in CHB patients superinfected with hepatitis E virus is relatively heavy in China, and the screening-based hepatitis E vaccination strategy for CHB patients is the most cost-effective option.

Abstract

Aim

This study aimed to evaluate the cost-effectiveness of hepatitis E vaccination strategies in chronic hepatitis B (CHB) patients.

Methods

Based on the societal perspective, the cost-effectiveness of three hepatitis E vaccination strategies—vaccination without screening, screening-based vaccination, and no vaccination—among CHB patients was evaluated using a decision tree–Markov model, and incremental cost-effectiveness ratios (ICERs) were calculated. Values for treatment costs and health utilities were estimated from a prior investigation on disease burden, and values for transition probabilities and vaccination-related costs were obtained from previous studies and government agencies. Sensitivity analyses were undertaken for assessing model uncertainties.

Results

It was estimated that CHB patients superinfected with hepatitis E virus (HEV) incurred significantly longer disease course, higher economic burden, and more health loss compared to those with HEV infection alone (all p < 0.05). The ICERs of vaccination without screening and screening-based vaccination compared to no vaccination were 41,843.01 yuan/quality-adjusted life year (QALY) and 29,147.32 yuan/QALY, respectively, both lower than China's per-capita gross domestic product (GDP) in 2018. The screening-based vaccination reduced the cost and gained more QALYs than vaccination without screening. One-way sensitivity analyses revealed that vaccine price, vaccine protection rate, and decay rate of vaccine protection had the greatest impact on the cost-effectiveness analysis. Probabilistic sensitivity analyses confirmed the base-case results, and if the willingness-to-pay value reached per-capita GDP, the probability that screening-based vaccination would be cost-effective was approaching 100%.

Conclusions

The disease burden in CHB patients superinfected with HEV is relatively heavy in China, and the screening-based hepatitis E vaccination strategy for CHB patients is the most cost-effective option.

This single-center cohort study has demonstrated the significance of virtual portal pressure gradient (vPPG) response in disease prognosis of cirrhotic patients who require carvedilol to prevent first VH. The computation of vPPG includes the reconstruction of 3D portal vein and application of fluid dynamics analysis. Monocyte chemoattractant protein-1 makes a contribution to vPPG-reducing effects by carvedilol in cirrhotic patients.

Abstract

Aim

This study aimed to assess the prognostic significance of virtual portal pressure gradient (vPPG) response to carvedilol in patients with compensated cirrhosis (CC).

Methods

Compensated cirrhosis patients with high-risk varices were prospectively enrolled to receive carvedilol for prevention of first variceal hemorrhage (VH) and followed up for 1 year. The vPPG response was defined as a reduction of vPPG >10% from baseline after 1-month therapy. Logistic and Cox regression analyses were performed to identify independent predictors for vPPG response and first decompensation, respectively. Competitive risk models were constructed to predict disease progression, and validated using the C-index, Kaplan–Meier analysis, competitive risk analysis, and calibration curves.

Results

A total of 129 patients completed this study, of whom 56 (43.4%) achieved vPPG response and were referred as vPPG responders. Baseline vPPG, red color sign, Model for End-stage Liver Disease score, serum monocyte chemoattractant protein-1 (MCP-1), and laminin levels significantly correlated with vPPG response, which itself was further documented as an independent predictor of VH, ascites, and overall decompensation events in CC. Moreover, the red color sign or Child–Turcotte–Pugh score effectively predicted VH, while ascites correlated well with portal flow velocity or MCP-1. The predictive models for VH and ascites showed a good discrimination with C-index values of 0.747 and 0.689 respectively, and the high consistency on calibration curves.

Conclusion

The vPPG response could be used as a noninvasive tool for prediction of disease progression in patients with CC.

According to the multivariate analysis, age, male sex, history of hepatocellular carcinoma, and hepatobiliary phase hypointense nodule without arterial phase hyperenhancement were independent risk factors significantly associated with the development of hypervascular hepatocellular carcinoma (p < 0.001–0.04). The incidence rate of hypervascular hepatocellular carcinoma was significantly higher among patients with a history of hepatocellular carcinoma than in those without a history of hepatocellular carcinoma (p < 0.001). The 1-, 3-, and 5-year cumulative hypervascular hepatocellular carcinoma development rates were 11.7%, 46.9%, and 71.9%, respectively, among patients with a history of hepatocellular carcinoma, whereas the rates were 2.0%, 8.0%, and 9.7%, respectively, in the patients without a history of hepatocellular carcinoma. The incidence rate of hypervascular hepatocellular carcinoma was significantly higher among patients with hepatobiliary phase hypointense nodule without arterial phase hyperenhancement than in those without that nodule (p < 0.001). The 1-, 3-, and 5-year cumulative hypervascular hepatocellular carcinoma development rates were 10.9%, 44.2%, and 61.6%, respectively, in the patients with hepatobiliary phase hypointense nodule without arterial phase hyperenhancement, whereas the rates were 2.5%, 9.9%, and 15.9%, respectively, in the patients without that nodule.

Abstract

Aim

To determine risk factors associated with hepatocellular carcinoma (HCC) development following direct-acting antiviral (DAA) therapy.

Methods

We enrolled patients with chronic hepatitis C who underwent direct-acting antiviral therapy and achieved sustained virologic response at 12 weeks between 2012 and 2018. Subsequently, patients were followed up. The primary endpoint was the development of HCC or the date of the last follow up when the absence of HCC was confirmed. Uni- and multivariate Cox proportional hazards models were used to identify factors contributing to HCC development, including gadoxetic acid-enhanced magnetic resonance imaging findings. The cumulative incidence rates of HCC development were calculated using the Kaplan–Meier method, and differences between groups were assessed using the log-rank test.

Results

The final study cohort comprised 482 patients (median age 70.5 years; 242 men). The median follow-up period was 36.8 months. Among 482 patients, 96 developed HCC (19.9%). The 1-, 3-, and 5-year cumulative rates of HCC development were 4.9%, 18.6%, and 30.5%, respectively. Multivariate analysis revealed that age, male sex, history of HCC, and hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were independent risk factors significantly associated with HCC development (p < 0.001–0.04). The highest risk group included patients with both a history of HCC and the presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement (the 1- and 3-year cumulative HCC development rates were 14.2% and 62.2%, respectively).

Conclusion

History of HCC and presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were strong risk factors for HCC development following direct-acting antiviral therapy.

Structure of HCC-Scope (with gray zone) for training and validation: artificial intelligence systems used for the identification of NASH-HCC.

Abstract

Background and Aim

The aim of this study was to develop a novel noninvasive test using an artificial intelligence/neural network system (called HCC-Scope) to diagnose early-stage hepatocellular carcinoma (HCC) on the background of nonalcoholic steatohepatitis (NASH).

Methods

In total, 175 patients with histologically proven nonalcoholic fatty liver disease and 55 patients with NASH-HCC were enrolled for training and validation studies. Of the 55 patients with NASH-HCC, 27 (49.1%) had very early-stage HCC, and six (10.9%) had early-stage HCC based on the Barcelona Clinic Liver Cancer staging system. Diagnosis with HCC-Scope was performed based on 12 items: age, sex, height, weight, AST level, ALT level, gamma-glutamyl transferase level, cholesterol level, triglyceride level, platelet count, diabetes status, and IgM-free apoptosis inhibitor of macrophage level. The FMVWG2U47 hardware (Fujitsu Co. Ltd, Tokyo, Japan) and the originally developed software were used.

Results

HCC-Scope had sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 100% for the differential diagnosis between non-HCC and HCC in a training study with gray zone analysis. It was also excellent in the validation study (95.0% sensitivity, 100% specificity, 100% PPV, and 97.1% NPV with gray zone analysis and 95.2% sensitivity, 100% specificity, 100% PPV, and 97.1% NPV without gray zone analysis). HCC-Scope had a significantly higher sensitivity (85.3%) and specificity (85.1%) than alpha-fetoprotein (AFP) level, AFP-L3 level, des-gamma-carboxy prothrombin (DCP) level, and the gender–age–AFP-L3–AFP–DCP (GALAD) score.

Conclusions

HCC-Scope can accurately differentially diagnose between non-HCC NASH and NASH-HCC, including very early-stage NASH-HCC.

Abstract

Aim

Hepatitis E virus (HEV) causes subclinical or acute self-limiting hepatitis. We surveyed the current seroprevalence and incidence of HEV infection among the general population in Iwate Prefecture, Japan, where the endemic infection is presumed to be low.

Methods

Between 2014 and 2016, we recruited individuals from Iwate Prefecture, Japan, who visited a general medical work-up program. Serum anti-HEV antibody and HEV RNA were measured twice, with an interval of 2 years. Anti-HEV antibody was measured with enzyme-linked immunosorbent assay and HEV RNA with reverse transcription-polymerase chain reaction.

Results

Study participants comprised 1284 Japanese (650 men and 634 women) with age ranging 20–89 years. A total of 90 participants were found to be positive for anti-HEV immunoglobulin G on the first visit, with a prevalence of 7.0% (95% confidence interval [CI] 5.6%–8.4%). Seroprevalence was higher in men than in women (10.1% vs. 3.7%, p < 0.001), and in those aged in their 50s–80s than in those aged in their 20s–40s (p = 0.006). Positive seroconversion indicating new HEV infection was found in seven of 1194 seronegative participants (0.59%; 95% CI 0.15%–1.0%), indicating the incidence of HEV infection to be 272 per 100 000 person-years (95% CI 109–561).

Conclusions

Our observations suggest that the incidence of HEV infection is high and that it is a leading cause of hepatitis virus infection in Iwate Prefecture, Japan.

Abstract

Aim

To investigate the prognostic value of the preoperative albumin–lymphocyte–platelet–C-reactive protein (ALPC) index in patients with hepatocellular carcinoma (HCC) undergoing curative hepatectomy. We also evaluated the relationship between the ALPC index and the phosphorylated nuclear factor erythroid 2-related factor 2 (p-Nrf2) levels.

Methods

Data were analyzed retrospectively from 256 patients who underwent resection for HCC. For cross-validation, patients were divided into the training and testing cohort. We assessed eight combinations of inflammatory markers for predictive value for recurrence. We examined the associations of the ALPC index with recurrence-free survival and overall survival in univariate and multivariate analyses (Cox proportional hazards model). Immunohistochemical staining of p-Nrf2 was performed on tumor samples of 317 patients who underwent hepatic resection for HCC.

Results

A high preoperative ALPC index correlated with a high serum albumin concentration, small tumor size, low rate of poor differentiation, solitary tumor, early Barcelona Clinic Liver Cancer stage, and low rate of microscopic intrahepatic metastasis in the training dataset. A high preoperative ALPC index correlated with a high serum albumin concentration, high serum alpha-fetoprotein concentration, small tumor size, a low rate of poor differentiation and a low rate of microscopic intrahepatic metastasis in the testing dataset. A higher preoperative ALPC index was an independent predictor of longer recurrence-free survival and overall survival in the training and testing datasets. A high ALPC index was associated with negative p-Nrf2 expression in HCC tumor cells.

Conclusions

We showed that a high ALPC index was an independent prognostic factor for patients with HCC undergoing curative hepatic resection.