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The purpose of this study was to determine whether statins can enhance anticancer effects in head and neck squamous cell carcinoma (HNSCC) when used with cisplatin and act as immunogenic cell death (ICD) inducers that can be used in cancer immunotherapy. Statins alone showed both in vitro and in vivo inhibitory effects against HNSCC, and synergistic antitumor effects were observed when combined with cisplatin in a syngeneic murine HNSCC model. Statins increased calreticulin exposure and endoplasmic reticulum stress-related signals in HNSCC cells. In addition, it was confirmed that statins could activate antigen-presenting cells and tumor-specific CD8+ T cells with an increase in their numbers in the tumor tissues and draining lymph nodes, with this effect showing significant improvement following the combination therapy with cisplatin. Moreover, in triple combination with both cisplatin and anti-programmed cell death 1 receptor (anti-PD-1) antibody, statins dramatically induced further tumor eradication and improved the survival of tumor-bearing mice. Taken together, these results demonstrate that statins, administered in combination with anti-PD-1 antibody, could enhance the anticancer effect of cisplatin and potentiate the efficacy of immunotherapy for HNSCC and present a rationale for repurposing statins as an adjuvant immunotherapeutic option for HNSCC.

Cancer-associated fibroblasts (CAFs) contribute to tumor progression, and microRNAs (miRs) play an important role in regulating the tumor-promoting properties of CAFs. The objectives of this study were to clarify the specific miR expression profile in CAFs of hepatocellular carcinoma (HCC) and identify its target gene signatures. Small-RNA-sequencing data were generated from nine pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues, respectively. Bioinformatic analyses were performed to identify the HCC-CAF-specific miR expression profile and the target gene signatures of the deregulated miRs in CAFs. Clinical and immunological implications of the target gene signatures were evaluated in The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA_LIHC) database using Cox regression and TIMER analysis. The expressions of hsa-miR-101-3p and hsa-miR-490-3p were significantly downregulated in HCC-CAFs. Their expression in HCC tissue gradually decreased as HCC stage progressed in the clinical staging analysis. Bioinformatic network analysis using miRWalks, miRDB, and miRTarBase databases pointed to TGFBR1 as a common target gene of hsa-miR-101-3p and hsa-miR-490-3p. TGFBR1 expression was negatively correlated with miR-101-3p and miR-490-3p expression in HCC tissues and was also decreased by ectopic miR-101-3p and miR-490-3p expression. HCC patients with TGFBR1 overexpression and downregulated hsa-miR-101-3p and hsa-miR-490-3p demonstrated a significantly poorer prognosis in TCGA_LIHC. TGFBR1 expression was positively correlated with the infiltration of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages in a TIMER analysis. In conclusion, hsa-miR-101-3p and hsa-miR-490-3p were substantially downregulated miRs in CAFs of HCC, and their common target gene was TGFBR1. The downregulation of hsa-miR-101-3p and hsa-miR-490-3p, as well as high TGFBR1 expression, was associated with poor clinical outcome in HCC patients. In addition, TGFBR1 expression was correlated with the infiltration of immunosuppressive immune cells.

Hepatic surface nodularity quantified on CT images has shown promising results in staging hepatic fibrosis in chronic hepatitis C. The aim of this study was to evaluate hepatic surface nodularity, serum fibrosis indices, and a linear combination of them for staging fibrosis in chronic liver disease, mainly chronic hepatitis B. We developed a semiautomated software quantifying hepatic surface nodularity on CT images. Hepatic surface nodularity and serum fibrosis indices were assessed in the development group of 125 patients to generate 3 linear models combining hepatic surface nodularity with the aspartate aminotransferase to platelet ratio index, fibrosis-4 index, or platelet count in reference to the METAVIR scoring system. The models were validated in 183 patients. Hepatic surface nodularity and serum fibrosis indices all significantly correlated with fibrosis stages. For binary classifications into cirrhosis (F4), advanced fibrosis (≥ F3), and significant fibrosis (≥ F2), hepatic surface nodularity was significantly different across categories. The areas under the curve (AUCs) of the best model were 0.901, 0.872, and 0.794 for cirrhosis, advanced fibrosis, and significant fibrosis, respectively, higher than serum fibrosis indices alone (0.797–0.802, 0.799–0.818, and 0.761–0.773). In the validation group, the same model likewise showed higher AUCs (0.872, 0.831, and 0.850) compared to serum fibrosis indices (0.722–0.776, 0.692–0.768, and 0.695–0.769; p

Purpose Alpha-fetoprotein (AFP) is a prognostic marker for hepatocellular carcinoma (HCC). We investigated the prognostic value of AFP levels in patients who achieved complete response (CR) to transarterial chemoembolization (TACE) for HCC. Materials and methods Between 2005 and 2018, 890 patients with HCC who achieved a CR to TACE were recruited. An AFP responder was defined as a patient who showed elevated levels of AFP (>10 ng/mL) during TACE, but showed normalization or a >50% reduction in AFP levels after achieving a CR. Results Among the recruited patients, 569 (63.9%) with naive HCC and 321 (36.1%) with recurrent HCC after complete resection were treated. Before TACE, 305 (34.3%) patients had multiple tumors, 219 (24.6%) had a maximal tumor size >3 cm, and 22 (2.5%) had portal vein tumor thrombosis. The median AFP level after achieving a CR was 6.36 ng/mL. After a CR, 473 (53.1%) patients experienced recurrence, and 417 (46.9%) died [median progression-free survival (PFS) and overall survival (OS) of 16.3 and 62.8 months, respectively]. High AFP levels at CR (>20 ng/mL) were independently associated with a shorter PFS [hazard ratio (HR)=1.403] and OS (HR=1.284), together with tumor multiplicity at TACE (HR=1.518 and 1.666, respectively). AFP non-responders at CR (76.2%, n=359 of 471) showed a shorter PFS (median 10.5 months vs. 15.5 months, HR=1.375) and OS (median 41.4 months vs. 61.8 months, HR=1.424) than AFP responders (all p=0.001). Conclusion High AFP levels and AFP non-responders were independently associated with poor outcomes after TACE. AFP holds clinical implications for detailed risk stratification upon achieving a CR after TACE.

We investigated whether liver stiffness (LS) quantified using magnetic resonance elastography (MRE) could predict the prognosis of advanced hepatocellular carcinoma (HCC) patients treated with sorafenib. We selected 50 sorafenib-treated advanced HCC patients who underwent MRE within 3 months before drug administration from a prospectively maintained cohort of chronic liver disease patients, according to the inclusion and exclusion criteria. Univariate and multivariate analyses were performed to evaluate the prognostic role of laboratory data, tumor characteristics, and MRE-assessed LS for overall survival (OS), progression-free survival (PFS), and significant liver injury (grade ≥ 3) after sorafenib administration. High MRE-assessed LS either as continuous (per kPa, hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.23–1.92, p 7.5 kPa, HR 4.06, 95% CI 1.40–11.79, p 7.5 kPa, HR 10.11, 95% CI 2.41–42.46, p = 0.002). PFS analysis identified higher serum AFP (≥ 400 ng/mL) and advanced tumor stage (mUICC IVb) as significant risk factors for early disease progression, whereas LS was not associated with PFS Higher MRE-assessed LS is a potential biomarker for predicting poor OS and significant liver injury in advanced HCC patients treated with sorafenib. • Higher pretreatment LS by MRE (> 7.5 kPa), higher AFP (≥ 400 ng/mL), and advanced tumor stage (mUICC IVb) were associated with poor OS in advanced HCC patients treated with sorafenib. • Higher pretreatment LS by MRE was associated with developing significant (grade ≥ 3) liver injury during sorafenib treatment, which required termination of the therapy. • Patients with high pretreatment LS by MRE should be monitored carefully for potential liver injury during sorafenib treatment.

Currently, a reliable serum biomarker for hepatocellular carcinoma (HCC) has not been established, particularly for early‐stage HCC (single tumor 0.8. In our validation study, serum exo‐miR‐4661‐5p could diagnose HCC in all stages (AUROC = 0.917), even in early stage (AUROC = 0.923), with a greater accuracy than other candidate serum exo‐miRs and serum AFP. The panel composed of exo‐miR‐4661‐5p and exo‐miR‐4746‐5p was identified as the most accurate biomarker for early‐stage HCC (AUROC = 0.947, 95% confidence interval = 0.889‐0.980, sensitivity = 81.8%, and specificity = 91.7%). In conclusion, exo‐miR‐4661‐5p–based serum panel is a promising diagnostic marker for early‐stage HCC., The present study derived potential serum exosomal microRNA panels for hepatocellular carcinoma (HCC) using a systematic, genome‐wide biomarker discovery approach. Serum exosomal microRNA‐4661‐5p–based panel is a potent diagnostic biomarker for early stage HCC and could also be used as a prognostic indicator in patients with HCC.

Magnetic resonance elastography (MRE) is a non-invasive tool for measuring liver stiffness (LS) with high diagnostic accuracy. This study investigated whether quantified LS by MRE could predict early recurrence of patients with hepatocellular carcinoma (HCC) within the Milan criteria. A prospectively collected cohort, which included the HCC patients who underwent MRE before treatment (an HCC-MRE cohort), was analyzed. In the HCC-MRE cohort, only patients under the Milan criteria, who underwent hepatic resection, radiofrequency ablation (RFA), or transarterial chemoembolization (TACE), were reviewed. We investigated whether LS assessed by MRE was an independent predictor of early recurrence using Cox regressions and Kaplan-Meier analyses. A total of 192 HCC patients under the Milan criteria who underwent hepatic resection (n = 96), RFA (n = 23), or TACE (n = 73) were included. Higher LS ratings (kPa; hazard ratio [HR] = 1.12; 95% confidence interval [CI] = 1.01–1.25; p = 0.040) emerged as an independent risk factor for early tumor recurrence. In the subgroup analysis, higher LS ratings were associated with higher risks of early HCC recurrence in both the resection/RFA group (> 4.5 kPa; HR = 2.95; 95% CI = 1.26–6.94; p = 0.013) and the TACE group (> 6 kPa; HR = 2.94; 95% CI = 1.27–6.83; p = 0.012). LS assessed by MRE was an independent predictor of early recurrence among HCC patients under the Milan criteria after achieving a complete response. • Liver parenchymal stiffness measured by MRE predicts early recurrence of treated HCC under Milan criteria. • A liver stiffness > 5.5 kPa was associated with worse recurrence-free survival. • Patients with high pre-treatment LS may benefit from stringent follow-up.

Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Wiskott-Aldrich syndrome protein family member 2 (WASF2) is an integral member of the actin cytoskeleton pathway that plays a crucial role in cell motility. In this study, we aimed to explore the role of WASF2 in HCC carcinogenesis and its regulatory mechanism. Methods: WASF2 expression in HCC was analyzed using six public RNA-seq datasets and 66 paired tissues from patients with HCC. Role of WASF2 in HCC cell phenotypes was evaluated using small interfering RNA (siRNA) in vitro and in vivo. Epigenetic regulatory mechanism of WASF2 was assessed in the Cancer Genome Atlas liver hepatocellular carcinoma project (TCGA_LIHC) dataset and also validated in 38 paired HCC tissues. Results: WASF2 is overexpressed in HCC and is clinically correlated with prognosis. WASF2 inactivation decreased the viability, growth, proliferation, migration, and invasion of Huh-7 and SNU475 HCC cells by restoring G2/M checkpoint function, inducing cell death, and inhibiting epithelial-mesenchymal transition, and hindering actin polymerization. In addition, WASF2 knockdown using siWASF2 in a xenograft mouse model exerted tumor suppressive effect. Furthermore, we observed a negative correlation between WASF2 methylation status and mRNA expression. The cg24162579 CpG island in the WASF2 5′ promoter region was hypomethylated in HCC compared to matched non-tumor samples. Patients with high WASF2 methylation and low WASF2 expression displayed the highest overall survival.Conclusions: WASF2 is overexpressed and hypomethylated in HCC and correlates with patient prognosis. Moreover, WASF2 inactivation exerts anti-tumorigenic effects on HCC cells in vitro and in vivo, suggesting that WASF2 could be a potential therapeutic target for HCC.

Background/Aims: Phosphatase and tensin homolog (PTEN) is a known tumor suppressor gene that is downregulated in hepatocellular carcinoma (HCC). Here, we investigated the association between single nucleotide polymorphisms (SNPs) of PTEN and HCC development in patients with hepatitis B virus (HBV) infection. Methods: Six SNPs of PTEN at positions rs1234221, rs1903860, rs1234220, rs1903858, rs2299941, and rs17431184 were analyzed in a development population (417 chronic HBV carriers without HCC and 281 chronic HBV carriers with HCC). PTEN rs1903858, rs1903860, and rs2299941 SNPs were further assessed for the development of HCC in a validation population of 200 patients with HBV-related liver cirrhosis. Results: In the development population, PTEN rs1903860 C allele, rs1903858 G allele, and rs2299941 G allele were associated with a low risk of HCC. The haplotype A-T-A-A-A was associated with an increased risk of HCC (recessive model; odds ratio=2.277, 95% confidence interval [CI] =1.144-4.532, P=0.019). In the validation population, PTEN rs2299941 G allele was the only significant protective genetic polymorphism related to HCC development after adjustment for age and sex (hazard ratio=0.582, 95% CI =0.353-0.962, P=0.035). Conclusions: These findings suggest that genetic polymorphisms in PTEN may affect HCC development in patients with chronic HBV infection. (J Liver Cancer 2019;19:46-54)

Protein markers of hepatocellular carcinoma (HCC)-derived exosomes (HEX) have not yet been fully evaluated. Here, we identified novel protein contents of HEX and their clinical significance as biomarkers. Exosomes were isolated from human HCC cell lines and an immortalized normal hepatocyte cell line. Proteomic analyses revealed 15 markedly overexpressed proteins in HEX. The clinical relevance of the 15 proteins was analyzed in public RNA-sequencing datasets, and 6 proteins were selected as candidate of potential biomarkers. Serum CCT8 and CFL1 were markedly overexpressed in test cohort (n = 8). In the validation cohort (n = 224), the area under the curve (AUC) of serum CCT8 and CFL1 for HCC diagnosis was calculated as 0.698 and 0.677, respectively, whereas that of serum alpha-fetoprotein (AFP) was 0.628. The combination of three serum markers (CCT8, CFL1, and AFP) demonstrated the highest AUC for HCC diagnosis. (AUC = 0.838, 95% confidence interval = 0.773–0.876) Furthermore, higher serum CCT8 and CFL1 concentrations were significantly associated with the presence of vascular invasion, advanced tumor stage, poor disease-free survival, and poor overall survival. Cofilin-1 and CCT8, enriched proteins in HEX, were identified as potential diagnostic and prognostic serum biomarkers for HCC patients.

Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC.

OBJECTIVE. The goal of this study was to evaluate radiologic and clinical factors associated with overall survival of advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy (HAIC). MATERIALS AND METHODS. This single-center retrospective study included 180 patients with advanced hepatocellular carcinoma who underwent HAIC with a 5-fluorouracil (250-500 mg/m2 for 5 hours) plus cisplatin (10-20 mg/m2 for 1-2 hours) regimen via an implantable port system. Survival curves were generated by the Kaplan-Meier method and compared by log-rank tests. Factors associated with overall survival were evaluated with Cox proportional hazard models. RESULTS. The median overall survival time was 7.6 months (95% CI, 6.1-9.1), and the objective response rate was 15%. In multivariate analysis, infiltrative tumor growth (hazard ratio [HR], 1.002; p = .03) and rimlike arterial enhancement (HR, 3.040; p < .001) were pretreatment radiologic factors associated with reduced overall survival. No early response to treatment (HR, 2.064-6.491) and higher Child-Pugh class (HR, 2.010-2.815) were strong prognostic factors of poor outcome. Treatment with three or more HAIC cycles (HR, 0.371; p = .001) and high-dose HAIC (HR, 0.447; p < .001) were favorable for increased overall survival. CONCLUSION. Infiltrative tumor growth and rimlike arterial enhancement in pre-treatment imaging studies were associated with poor prognosis, and better early radiologic response and preserved liver function reserve were strong indicators of prolonged survival. Recognizing these radiologic and clinical predictors may help optimize care of patients with hepatocellular carcinoma.

Background/aims Posthepatectomy liver failure (PHLF) is a major complication that increases mortality in patients with hepatocellular carcinoma after surgical resection. The aim of this retrospective study was to evaluate the utility of magnetic resonance elastography-assessed liver stiffness (MRE-LS) for the prediction of PHLF and to develop an MRE-LS-based risk prediction model. Methods A total of 160 hepatocellular carcinoma patients who underwent surgical resection with available preoperative MRE-LS data were enrolled. Clinical and laboratory parameters were collected from medical records. Logistic regression analyses were conducted to identify the risk factors for PHLF and develop a risk prediction model. Results PHLF was present in 24 patients (15%). In the multivariate logistic analysis, high MRE-LS (kPa; odds ratio [OR] 1.49, 95% confidence interval [CI] 1.12 to 1.98, p=0.006), low serum albumin (≤3.8 g/dL; OR 15.89, 95% CI 2.41 to 104.82, p=0.004), major hepatic resection (OR 4.16, 95% CI 1.40 to 12.38, p=0.014), higher albumin-bilirubin score (>-0.55; OR 3.72, 95% CI 1.15 to 12.04, p=0.028), and higher serum α-fetoprotein (>100 ng/mL; OR 3.53, 95% CI 1.20 to 10.40, p=0.022) were identified as independent risk factors for PHLF. A risk prediction model for PHLF was established using the multivariate logistic regression equation. The area under the receiver operating characteristic curve (AUC) of the risk prediction model was 0.877 for predicting PHLF and 0.923 for predicting grade B and C PHLF. In leave-one-out cross-validation, the risk model showed good performance, with AUCs of 0.807 for all-grade PHLF and 0. 871 for grade B and C PHLF. Conclusions Our novel MRE-LS-based risk model had excellent performance in predicting PHLF, especially grade B and C PHLF.

Hepatic surface nodularity quantified on CT images has shown promising results in staging hepatic fibrosis in chronic hepatitis C. The aim of this study was to evaluate hepatic surface nodularity, serum fibrosis indices, and a linear combination of them for staging fibrosis in chronic liver disease, mainly chronic hepatitis B.We developed a semiautomated software quantifying hepatic surface nodularity on CT images. Hepatic surface nodularity and serum fibrosis indices were assessed in the development group of 125 patients to generate 3 linear models combining hepatic surface nodularity with the aspartate aminotransferase to platelet ratio index, fibrosis-4 index, or platelet count in reference to the METAVIR scoring system. The models were validated in 183 patients.Hepatic surface nodularity and serum fibrosis indices all significantly correlated with fibrosis stages. For binary classifications into cirrhosis (F4), advanced fibrosis (≥ F3), and significant fibrosis (≥ F2), hepatic surface nodularity was significantly different across categories. The areas under the curve (AUCs) of the best model were 0.901, 0.872, and 0.794 for cirrhosis, advanced fibrosis, and significant fibrosis, respectively, higher than serum fibrosis indices alone (0.797-0.802, 0.799-0.818, and 0.761-0.773). In the validation group, the same model likewise showed higher AUCs (0.872, 0.831, and 0.850) compared to serum fibrosis indices (0.722-0.776, 0.692-0.768, and 0.695-0.769; p 0.001 for F4).Hepatic surface nodularity combined with serum blood test could be a practical method to predict cirrhosis, advanced fibrosis, and significant fibrosis in chronic liver disease patients, providing higher accuracy than using serum fibrosis indices alone.

Exosomal microRNAs (exo-miRs) contribute to cancer metastasis. To identify pro-metastatic circulating exo-miRs in hepatocellular carcinoma (HCC), next-generation sequencing-based plasma exo-miR profiles of 14 patients with HCC (eight non-metastatic and six with metastasis within 1 year of follow-up) were analyzed. Sixty-one miRs were significantly overexpressed among patients with metastatic HCC. Candidate miRs were selected through integrative analyses of two different public expression datasets, GSE67140 and The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA_LIHC). Integrative analyses revealed 3 of 61 miRs (miR-106b-5p, miR-1307-5p, and miR-340-5p) commonly overexpressed both in metastasis and vascular invasion groups, with prognostic implications. Validation was performed using stored blood samples of 150 patients with HCC. Validation analysis showed that circulating exo-miR-1307-5p was significantly overexpressed in the metastasis group (p = 0.04), as well as in the vascular invasion and tumor recurrence groups. Circulating exo-miR-1307-5p expression was significantly correlated with tumor stage progression (p &lt, 0.0001). Downstream signaling pathways of miR-1307 were predicted using TargetScan and Ingenuity Pathway Analysis. On comprehensive bioinformatics analysis, the downstream pathway of miR-1307-5p, promoting epithelial&ndash, mesenchymal transition (EMT), showed SEC14L2 and ENG downregulation. Our results show that circulating exo-miR-1307-5p promotes metastasis and helps predict metastasis in HCC, and SEC14L2 and ENG are target tumor suppressor genes of miR-1307 that promote EMT.

Liquid biopsy can provide a strong basis for precision medicine. We aimed to identify novel single-nucleotide variants (SNVs) in circulating tumor DNA (ctDNA) in patients with hepatocellular carcinoma (HCC). Deep sequencing of plasma-derived ctDNA from 59 patients with HCC was performed using a panel of 2924 SNVs in 69 genes. In 55.9% of the patients, at least one somatic mutation was detected. Among 25 SNVs in 12 genes, four frequently observed SNVs, MLH1 (13%), STK11 (13%), PTEN (9%), and CTNNB1 (4%), were validated using droplet digital polymerase chain reaction with ctDNA from 62 patients with HCC. Three candidate SNVs were detected in 35.5% of the patients, with a frequency of 19% for MLH1 chr3:37025749T>A, 11% for STK11 chr19:1223126C>G, and 8% for PTEN chr10:87864461C>G. The MLH1 and STK11 SNVs were also confirmed in HCC tissues. The presence of the MLH1 SNV, in combination with an increased ctDNA level, predicted poor overall survival among 107 patients. MLH1 chr3:37025749T>A SNV detection in ctDNA is feasible, and thus, ctDNA can be used to detect somatic mutations in HCC. Furthermore, the presence or absence of the MLH1 SNV in ctDNA, combined with the ctDNA level, can predict the prognosis of patients with HCC.

Severe alcoholic hepatitis (AH) is the most aggressive form of alcohol-related liver disease with high mortality. The microbiome is an emerging therapeutic target in alcohol-related liver disease.To investigate the microbiome composition in patients with severe AH, and to determine microbiome recovery after rifaximin treatment in gut bacteria and bacteria derived-extracellular vesicles.We enrolled 24 patients with severe AH and 24 healthy controls. Additional faecal samples were collected after 4 weeks in 8 patients with severe AH who completed rifaximin treatment. Treatment response was defined based on Lille score model after 7 days of treatment. Metagenomic profiling was performed using 16S ribosomal RNA amplicon sequencing.Faecal microbiomes of patients with severe AH had lower alpha diversity and higher beta diversity than those of healthy controls in both gut bacteria and extracellular vesicles. Bacilli, Lactobacillales and Veillonella were significantly increased in the gut bacteria of patients with severe AH, and Veillonella, Veillonella parvula group and Lactobacillales were significantly increased in the extracellular vesicles of patients with severe AH. Eubacterium_g23, Oscillibacter and Clostridiales decreased in the gut bacteria of patients with severe AH, and Eubacterium_g23, Oscillibacter and Christensenellaceae decreased in the extracellular vesicles of patients with severe AH. After rifaximin treatment, 17 taxa in the gut bacteria and 23 taxa in extracellular vesicles were significantly restored in patients with severe AH. In common, Veillonella and Veillonella parvula group increased in patients with severe AH and decreased after rifaximin treatment, and Prevotella and Prevotellaceae decreased in patients with severe AH and increased after rifaximin treatment. Treatment non-responders showed a significantly lower abundance of Prevotella at baseline than did treatment responders.Dysbiosis was confirmed in severe AH but was alleviated by rifaximin treatment. Taxa associated with severe AH can be candidate biomarkers or therapeutic targets.

We investigated whether liver stiffness (LS) quantified using magnetic resonance elastography (MRE) could predict the prognosis of advanced hepatocellular carcinoma (HCC) patients treated with sorafenib.We selected 50 sorafenib-treated advanced HCC patients who underwent MRE within 3 months before drug administration from a prospectively maintained cohort of chronic liver disease patients, according to the inclusion and exclusion criteria. Univariate and multivariate analyses were performed to evaluate the prognostic role of laboratory data, tumor characteristics, and MRE-assessed LS for overall survival (OS), progression-free survival (PFS), and significant liver injury (grade ≥ 3) after sorafenib administration.High MRE-assessed LS either as continuous (per kPa, hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.23-1.92, p0.001) or categorical ( 7.5 kPa, HR 4.06, 95% CI 1.40-11.79, p0.01) variable was significantly associated with poor OS along with higher serum alpha-fetoprotein (AFP, ≥ 400 ng/mL) and advanced tumor stage (modified Union for International Cancer Control (mUICC) IVb). Higher MRE-assessed LS was also significantly associated with the development of significant liver injury after sorafenib administration (per kPa, HR 1.62, 95% CI 1.21-2.17, p = 0.001; 7.5 kPa, HR 10.11, 95% CI 2.41-42.46, p = 0.002). PFS analysis identified higher serum AFP (≥ 400 ng/mL) and advanced tumor stage (mUICC IVb) as significant risk factors for early disease progression, whereas LS was not associated with PFS CONCLUSION: Higher MRE-assessed LS is a potential biomarker for predicting poor OS and significant liver injury in advanced HCC patients treated with sorafenib.• Higher pretreatment LS by MRE ( 7.5 kPa), higher AFP (≥ 400 ng/mL), and advanced tumor stage (mUICC IVb) were associated with poor OS in advanced HCC patients treated with sorafenib. • Higher pretreatment LS by MRE was associated with developing significant (grade ≥ 3) liver injury during sorafenib treatment, which required termination of the therapy. • Patients with high pretreatment LS by MRE should be monitored carefully for potential liver injury during sorafenib treatment.

Background and aim The histologic discrepancies between preoperative endoscopic forceps biopsy (EFB) and endoscopic submucosal dissection (ESD) specimens sometimes confuse the endoscope operator. This study aimed to analyze the limitation of the biopsy-based diagnosis before ESD and to evaluate which factors affect the discordant pathologic results between EFB and ESD. Methods A total of 1427 patients, who were diagnosed with gastric adenoma by EFB, were enrolled. Cancer confirmed on EFB was excluded (n = 513). We retrospectively reviewed cases and compared histologic diagnoses in the biopsy sample with the final diagnosis in the endoscopically resected specimen. Results The diagnosis was upgraded (from low-grade dysplasia to high-grade dysplasia or adenocarcinoma, or from high-grade dysplasia to adenocarcinoma) in 328 cases (23.0%), concordant in 944 (66.1%), and downgraded (from high-grade dysplasia to low-grade dysplasia or non-neoplasia, or from low-grade dysplasia to non-neoplasia) in 155 (10.9%). Multivariate logistic regression analysis showed that surface ulceration and depressed lesions were associated with significant risk factors for upgrading. Age younger than 60 years and size Conclusions Careful endoscopic observation should consider size, ulceration, and depression to ensure accurate diagnosis when a gastric neoplasm is suspected.

Background/Aims: The mucosal healing process after endoscopic submucosal dissection (ESD) is mostly scarring change (flat type), but a protruded lesion is occasionally found. We investigated the factors influencing the mucosal healing process, such as the flat and protruded types. Methods: A total of 2,096 ESD cases were performed from February 2005 to December 2013, and 1,757 underwent follow-up endoscopy after 3 months to check the healing type of the ulceration. We retrospectively reviewed the medical charts to analyze demographic, endoscopic, and pathological findings between the 2 groups. Results: Forty-eight cases were of the protruded type and 1,709 were of the flat type. In univariate analysis, the protruded type was found more in the antrum, anterior wall, and greater curvature (p < 0.001). In protruded types, the Helicobacter pylori (H. pylori) infection rate was lower (p < 0.017), the mean length of ESD specimen was shorter (p < 0.012), the fibrosis rate was lower (p < 0.033), and the mean number of hot biopsy and clips during ESD were less (p < 0.008 and p < 0.001 respectively). Conclusions: The healing type of mucosal ulceration after ESD seemed to be influenced by location, specimen size, and the presence of an H. pylori infection.

Background Complex-based chemical shift imaging-based magnetic resonance imaging (CSE-MRI) is emerging as a preferred method for noninvasively quantifying proton density fat fraction (PDFF), a promising quantitative imaging biomarker (QIB) for longitudinal hepatic steatosis measurement. Purpose To determine linearity, bias, repeatability, and reproducibility of the PDFF measurement using CSE-MRI (CSE-PDFF) across scan intervals, MR field strengths, and readers in phantom and nonalcoholic fatty liver disease (NAFLD) patients. Study type Institutional Review Board (IRB)-approved prospective. Subjects Fat-water phantom and 20 adult patients. Field strength/sequence 1.5 T and 3.0 T MR systems and a commercially available CSE-MRI sequence (IDEAL-IQ). Assessment Two independent readers measured CSE-PDFF of fat-water phantom and NAFLD patients across two field strengths and scan intervals (same-day and 2-week) each and in a combination of both. MR spectroscopy-based PDFF (MRS-PDFF) was used as the reference standard for phantom PDFF. Statistical tests Linearity and bias of measurement were evaluated by linear regression analysis and Bland-Altman plots, respectively. Repeatability and reproducibility were assessed by coefficient of variance and repeatability / reproducibility coefficients (RC). The intraclass correlation coefficient was used to validate intra- and interobserver agreements. Results CSE-PDFF showed high linearity and small bias (-0.6-0.4 PDFF%) with 95% limits of agreement within ±2.9 PDFF% across field strengths, 2-week interscan period, and readers in the clinical scans. CSE-PDFF was highly repeatable and reproducible both in phantom and clinical scans, with the largest observed RC across field strengths and 2-week interscan period being 3 PDFF%. Data conclusion CSE-PDFF is a robust QIB with high linearity, small bias, and excellent repeatability/reproducibility. A change of more than 3 PDFF% across field strengths within 2 weeks of scan interval likely reflects a true change, which is well within the clinically acceptable range. Level of evidence 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:305-314.

Hepatocellular carcinoma (HCC) has a high rate of cancer recurrence (up to 70%) in patients who undergo surgical resection. We investigated prognostic gene signatures for predicting HCC recurrence using in silico gene expression analysis. Recurrence-associated gene candidates were chosen by a comparative analysis of gene expression profiles from two independent whole-transcriptome datasets in patients with HCC who underwent surgical resection. Five promising candidate genes, CETN2, HMGA1, MPZL1, RACGAP1, and SNRPB were identified, and the expression of these genes was evaluated using quantitative reverse transcription PCR in the validation set (n = 57). The genes CETN2, HMGA1, RACGAP1, and SNRPB, but not MPZL1, were upregulated in patients with recurrent HCC. In addition, the combination of HMGA1 and MPZL1 demonstrated the best area under the curve (0.807, 95% confidence interval [CI] = 0.681–0.899) for predicting HCC recurrence. In terms of clinicopathological correlation, CETN2, MPZL1, RACGAP1, and SNRPB were upregulated in patients with microvascular invasion, and the expression of MPZL1 and SNRPB was increased in proportion to the Edmonson tumor differentiation grade. Additionally, overexpression of CETN2, HMGA1, and RACGAP1 correlated with poor overall survival (OS) and disease-free survival (DFS) in the validation set. Finally, Cox regression analysis showed that the expression of serum alpha-fetoprotein and RACGAP1 significantly affected OS, whereas platelet count, microvascular invasion, and HMGA1 expression significantly affected DFS. In conclusion, HMGA1 and RACGAP1 may be potential prognostic biomarkers for predicting the recurrence of HCC after surgical resection.

The simultaneous synthesis of a phytosteryl ester and enrichment of stearidonic acid (SDA) were performed via a one-step lipase-catalyzed esterification of fatty acids from Ahiflower™ seed oil with phytosterol. A commercial lipase (Lipase OF) from Candida rugosa was employed as a biocatalyst. Three solvents were screened and cyclohexane was selected as a suitable reaction medium. The effects of enzyme loading, temperature, and solvent amount were investigated. The conversion as well as the SDA content were significantly improved by adding molecular sieves after 1 h of reaction. The optimum conditions were the enzyme loading of 10% (based on the total substrate weight), the temperature of 30 °C, and the solvent amount of 4 mL (based on a substrate weight of 2 g), respectively. The maximum conversion and SDA content in the residual fatty acid were 81 mol% and 58 mol%, respectively, under the optimum conditions. The SDA content increased a 3.4-fold from 17 mol% in Ahiflower™ seed oil to 58 mol%.