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Background: Early recurrence (ER) of hepatocellular carcinoma (HCC) (within 1 year after resection) is known to be a poor prognostic factor. The aim was to identify the risk factors associated with ER after HCC resection. Methods: Data were analyzed retrospectively from patients who underwent primary resection for HCC from two hospitals. For cross‐validation, HCC resection cases were divided into the training and testing cohort. The clinicopathological factors between the ER and non‐ER groups and factors for predicting ER and prognosis after HCC resection were compared. Results: Out of 173 patients in the training dataset, 33 patients had ER and the ER group showed larger tumor size, more intrahepatic metastasis (IM), and a higher ratio of serum des‐gamma‐carboxy prothrombin (DCP) to tumor volume (TV) (DCP/TV) than the non‐ER group. Out of 203 patients in the testing dataset, 30 patients had ER and the ER group demonstrated larger tumor size, more IM, and higher serum alpha‐fetoprotein, AFP/TV, DCP/TV, AFP/tumor maximum diameter (TMD), and DCP/TMD than the non‐ER group. The patients were divided into high and low DCP/TV groups and high serum DCP/TV was associated with unfavorable overall survival in the training and testing dataset. Multivariate analysis confirmed that high serum DCP/TV and IM were independently associated with ER. Conclusion: Preoperative high serum DCP/TV may be useful for stratifying patients at risk of early HCC recurrence after curative resection. [ABSTRACT FROM AUTHOR]

Aim: In patients with liver cirrhosis, high levels of serum myostatin are associated with poor prognosis. We aimed to clarify the influence of myostatin on the prognosis of patients with non‐alcoholic fatty liver disease–hepatocellular carcinoma (NAFLD‐HCC) without cirrhosis and on the progression of liver fibrosis. Methods: Serum myostatin levels were evaluated in 234 patients who underwent primary surgical resection for single HCC. To clarify the impact of myostatin on liver fibrosis, we established human primary liver fibroblasts from resected livers, and cultured them in the presence of myostatin. Results: The median age was 67.4 years, the median L3 skeletal muscle mass index was 44.4 cm2/m2, and the median body mass index was 23.4 kg/m2. Eighty‐two (35.0%) patients had sarcopenia (L3 skeletal muscle mass index: men <42, women <38 cm2/m2). The etiologies of liver disease were hepatitis B virus (n = 61), hepatitis C virus (n = 86), and non‐B non‐C hepatitis (n = 87) including NAFLD (n = 74). High preoperative serum myostatin and vascular invasion were independent predictors of poor overall survival (OS). High serum myostatin was associated with poor OS in patients with no sarcopenia (n = 152). In patients without advanced liver fibrosis (Fibrosis stage, 0–2; n = 58), high levels of serum myostatin were also associated with poor OS, regardless of sarcopenia. Serum myostatin levels were increased with the progression of liver fibrosis. Liver fibroblasts were activated and produced collagen following stimulation with myostatin. Conclusions: In patients with NAFLD‐HCC without advanced liver fibrosis, high levels of serum myostatin were associated with poor OS. Myostatin activated primary fibroblasts and stimulated collagen production. [ABSTRACT FROM AUTHOR]

Aim: Early hepatocellular carcinoma (HCC) recurrence after curative resection is a known poor prognostic factor. We aimed to identify microRNAs associated with recurrence after curative HCC resection. Methods: To identify risk factors for early recurrence and metastasis, 694 patients who underwent primary curative HCC resection were analyzed. We evaluated microRNA expression in cancerous and non‐cancerous tissues by microarray and quantitative PCR analyses using 16 HCC samples. We defined patients who had a recurrence within 1 year of resection as the early recurrence (ER) group, patients who had a recurrence within 1–5 years as the late recurrence (LR) group, and patients who did not recur during the 5‐year observation period as the no recurrence (NR) group. We examined the relationship between microRNA expression and clinical features. Results: Multivariate analysis revealed that α‐fetoprotein >31 ng/mL, tumor size >4 cm, and intrahepatic metastasis (IM) were significant factors. Afterwards, microarray analyses revealed that microRNA (miR)‐125b‐5p and miR‐148a‐3p were significantly downregulated in recurrent cases. The ratio of miR‐125b‐5p expression in cancerous versus non‐cancerous tissue (miR‐125b ratio), but not miR‐148a‐3p, was significantly lower in the ER group. Early recurrence was associated with reduced overall survival compared with the LR and NR group. The miR‐125b ratio was significantly lower in the ER group than in the LR and NR groups. Multivariate analysis showed that a low miR‐125b ratio and IM were independently associated with ER and disease‐free survival. Conclusions: Assessing tissue miR‐125b‐5p expression and IM is useful for stratifying patients at risk of early HCC recurrence after curative resection. [ABSTRACT FROM AUTHOR]

Aim: Congestive hepatopathy often leads to liver fibrosis and hepatocellular carcinoma. Imaging modalities provided clinical evidence that elevation of liver stiffness and tumor occurrence are mainly induced in the periphery of the liver in patients with congestive hepatopathy. However, clinical relevance of liver stiffness and liver fibrosis is unclear because liver congestion itself increases liver stiffness in congestive hepatopathy. It also unclear which factors configure such regional disparity of tumor development in patients with congestive hepatopathy. To answer these questions, we evaluated the macroscopic spatial distribution of liver fibrosis and tumors in the murine model of congestive hepatopathy. Methods: Chronic liver congestion was induced by partial ligation of the suprahepatic inferior vena cava. Distribution of liver congestion, fibrosis, and tumors in partial ligation of the suprahepatic inferior vena cava mice were assessed by histological findings, laser microdissection (LMD)‐based qPCR and enhanced computed tomography. LMD‐based RNA‐sequencing was performed to identify causal factors that promote tumor development in congestive hepatopathy. Results: Liver fibrosis was mainly induced in the periphery of the liver and co‐localized with distribution of liver congestion. Liver tumors were also induced in the periphery of the liver where liver congestion and fibrosis occurred. LMD‐based RNA‐sequencing revealed the upregulation of extracellular matrix/collagen fibril‐, wound healing‐, angiogenesis‐, morphogenesis‐, and cell motility‐related signaling pathways in periphery of liver compared with liver center. Conclusions: Our findings showed the experimental relevance of liver congestion, fibrosis, and tumor development in congestive hepatopathy, and may provide important locational information. Macroscopic regional disparity observed in this murine model should be considered to manage patients with congestive hepatopathy. [ABSTRACT FROM AUTHOR]

Aim: Although the survival rate after living‐donor liver transplantation (LDLT) is improving, sepsis still limits the prognosis. Immune dysfunction and sarcopenia are often observed in LDLT patients, and increase susceptibility to infection. Brain‐derived neurotrophic factor (BDNF) is a myokine produced by immune cells and skeletal muscle. We aimed to determine whether serum BDNF could be a feasible biomarker for sepsis of LDLT patients. Methods: We measured serum samples from 124 patients who underwent LDLT and 9 healthy volunteers for BDNF. We examined its correlation with incidence rate of sepsis. To clarify the source of BDNF, we examined its expression in lymphocytes, skeletal muscle cells, and hepatocytes. Results: Patients who experienced sepsis showed worse short‐term survival. Preoperative serum BDNF was lower in LDLT patients compared with healthy volunteers, and was also lower in Child–Pugh C compared with Child–Pugh A or B. Serum BDNF was inversely correlated with Model for End‐Stage Liver Disease and controlling nutritional status (CONUT) scores, but had a weak positive correlation with skeletal muscle mass index (SMI). Multivariate analysis revealed that serum BDNF was independently associated with sepsis. Preoperative serum BDNF was a better predictor of sepsis in LDLT patients than CONUT score or SMI. Serum BDNF was positively correlated with lymphocyte counts, especially T cells. In vitro, T cells and skeletal muscle cells produced BDNF. Conclusions: Preoperative serum BDNF could be a predictive biomarker for sepsis after LDLT, by reflecting the systemic condition including hepatic function, nutritional status, and immune status. [ABSTRACT FROM AUTHOR]

Aim: Non‐alcoholic fatty liver disease (NAFLD) is a leading cause of liver disease worldwide. Because liver fibrosis is associated with the long‐term prognosis of patients with NAFLD, there is an urgent need for non‐invasive markers of liver fibrosis. Sialic acid‐binding immunoglobulin‐like lectin‐7 (Siglec‐7) is an immunomodulatory molecule expressed on various immune cells, including macrophages, which plays a key role in liver inflammation and fibrosis in NAFLD. We aimed to determine whether serum levels of soluble Siglec‐7 (sSiglec‐7) could have utility at a marker of fibrosis in this patient population. Methods: We examined serum samples from 93 NAFLD patients and 19 healthy donors for macrophage‐associated protein, including sSiglec‐7, soluble CD163, and YKL‐40, and examined their correlation with liver fibrosis scores, tissue elastography, and histological findings. Independent factors associated with advanced fibrosis were analyzed using a logistic regression model and a decision tree. To clarify the source of sSiglec‐7, we examined its expression in liver tissue‐derived macrophages and cultured monocyte‐derived macrophages. Results: Serum sSiglec‐7 levels were significantly higher in NAFLD patients compared with healthy donors, and correlated positively with sCD163 and YKL‐40 levels. Serum sSiglec‐7 was an independent diagnostic marker with high specificity (96.3%) for advanced fibrosis (F3 and F4) in NAFLD patients. Siglec‐7 was mainly expressed on CCR2+ macrophages in the liver, and sSiglec‐7 production by monocyte‐derived macrophages in vitro was increased after stimulation by pro‐inflammatory factors. Conclusions: Elevated serum sSiglec‐7 could serve as an independent marker with high specificity for advanced liver fibrosis in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Although it has been recognized that those who are positive for anti-hepatitis B core antibody (anti-HBcAb) and negative for hepatitis B surface antigen (HBsAg) with normal liver function could be donors for living donor liver transplantation under appropriate prophylaxis, the negative impact of positive HBcAb on such donors themselves has not been reported. We present a case of a living donor with positive HBcAb, who donated his left lobe for his sister with unresectable giant hepatic hemangioma, and the donor himself developed a de novo hepatocellular carcinoma (HCC) 10 years after donation. He had been lost from the follow-up program since 1 year after donation. Imaging studies showed a heterogeneously enhanced mass compatible with HCC, which was 9 cm in size with portal invasion into the anterior portal vein of the remnant liver. Re-laparotomy for hepatectomy with the removal of the tumor thrombus in the anterior portal vein of the remnant liver was carried out, and he is free from recurrence 6 months after surgery on prophylactic sorafenib. At our institute, 58 (9.6%) donors among the 603 living donors were anti-HBcAb positive and anti-HBsAg negative, and we started regular HCC surveillance using sonogram every 6 months for these patients. [ABSTRACT FROM AUTHOR]