The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) was recently shown to be a liver fibrosis glycobiomarker with a unique fibrosis-related glycoalteration. We evaluated the ability of WFA+-M2BP to predict the development of hepatocellular carcinoma (HCC) in patients who were infected with the hepatitis C virus (HCV). A total of 707 patients who had been admitted to our hospital with chronic HCV infection without other potential risk factors were evaluated to determine the ability of WFA+-M2BP to predict the development of HCC; factors evaluated included age, sex, viral load, genotypes, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, alpha-fetoprotein (AFP), WFA+-M2BP, and the response to interferon (IFN) therapy. Serum WFA+-M2BP levels were significantly increased according to the progression of liver fibrosis stage (P < 0.001). In each distinctive stage of fibrosis (F0-F1, F2, F3, and F4), the risk of development of HCC was increased according to the elevation of WFA+-M2BP. Multivariate analysis identified age >57 years, F4, AFP >20 ng/mL, WFA+-M2BP ≥4, and WFA+-M2BP 1-4 as well as the response to IFN (no therapy vs. sustained virological response) as independent risk factors for the development of HCC. The time-dependent areas under the receiver operating characteristic curve demonstrated that the WFA+-M2BP assay predicted the development of HCC with higher diagnostic accuracy than AFP. Conclusion: WFA+-M2BP can be applied as a useful surrogate marker for the risk of HCC development, in addition to liver biopsy. (Hepatology 2014;60:1563–1570)

Since the discovery of the senescence-associated secretory phenotype, the role of senescent hepatic stellate cells (HSCs) in hepatocellular carcinoma (HCC) development has gained increasing attention. Similar to cytokines, extracellular vesicles (EVs) are essential for intercellular communication. However, the function of EVs derived from senescent HSCs in HCC progression has not been extensively studied. The aims of the present study were to characterize the EVs derived from senescent HSCs and determine their role in the tumor microenvironment. Cellular senescence was induced in human hepatic stellate cells (HHSteCs) with various concentrations of etoposide. Induction was confirmed using EdU staining and 53BP1 and p21 immunostaining. EVs were isolated by ultracentrifugation and analyzed by nanoparticle tracking analysis. Multiplex immunoassays were used to compare the levels of growth factors secreted from hepatoma cell lines and macrophage cells pretreated with EVs derived from senescent HHSteCs (senescent EVs) with those pretreated with EVs derived from normal cultured HHSteCs (normal EVs). Treatment with 25 µM etoposide for 3 days was the most effective at inducing senescence in HHSteCs. This finding was confirmed by induction of irreversible cell-cycle arrest, upregulation of 53BP1 and p21 expression, and increased SA-β-gal staining. Senescent HHSteCs released increased quantities of EV particles compared with normally cultured HHSteCs. Multiplex analysis revealed that there was no difference between hepatoma cell lines treated with normal EVs and those treated with senescent EVs in growth factor secretion. In contrast, the secretion of epidermal growth factor (EGF) was increased by macrophage cells treated with senescent EVs compared with those treated with normal EVs. Furthermore, senescent EVs did not affect the viability of hepatoma cells but increased the viability of hepatoma cells co-cultured with macrophage cells. In conclusion, the release of EVs from senescent HSCs was higher compared with normal HSCs. Furthermore, senescent EVs promoted HCC development by upregulating EGF secretion from macrophages.

The changes in the venous ketone body were associated with the muscle status and predicted the prognosis of patients with HCC who underwent TACE. The venous ketone bodies could be a new predictor of the prognosis of HCC patients after TACE.

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Background: Some patients with liver cirrhosis have sleep-wake disturbance and reduced quality of life (QOL). However, the effects of L-carnitine on QOL and sleep-wake disturbance have not been extensively studied. Thus, we aimed to examine the effects of L-carnitine on the sleep quality and QOL in cirrhotic patients.Methods: We investigated 19 cirrhotic patients (age: 65.0±10.2 years, male:female=10:9, Child-Pugh score: 6.5±1.8) treated with 1500-mg L-carnitine at Nagasaki University Hospital and its associated hospitals. We used questionnaires to evaluate the patients’ sleep-wake disturbance and QOL at the time of entry and 8 weeks. Results: Cirrhosis-related symptom scores (CSSs), Pittsburgh Sleep Quality Index (PSQI) and General Health (GH) of QOL score improved with L-carnitine treatment (CSS: from 11.5±9.4 to 9.4±3.7, p=0.015; PSQI: from 9.6±5.8 to 7.4±3.3, p=0.035; GH: from 33.5±8.2 to 38.3±9.8, p=0.05). L-carnitine treatment reduced PSQI in 12 out of 14 patients with sleep disturbance (PSQI>5). CSS was improved in 12 cases (63%), and PSQI was improved in 13 cases (68%). However, L-carnitine treatment did not improve daytime hypersomnolence, as evaluated by the Epworth Sleepiness Scale. None of patients had any adverse events related to the L-carnitine treatment.Conclusions: L-carnitine is a safe and useful treatment for cirrhotic patients with reduced sleep quality and QOL.