Effect of Biliary Drainage on the Prognosis of Patients with Hepatocellular Carcinoma and Bile Duct Invasion.

Background/Aims: Bile duct invasion (BDI) is rarely observed in patients with advanced hepatocellular carcinoma (HCC), leading to hyperbilirubinemia. However, the efficacy of pretreatment biliary drainage for HCC patients with BDI and obstructive jaundice is currently unclear. Thus, the aim of this study was to assess the effect of biliary drainage on the prognosis of these patients. Methods: We retrospectively enrolled a total of 200 HCC patients with BDI from multicenter cohorts. Patients without obstructive jaundice (n=99) and those who did not undergo HCC treatment (n=37) were excluded from further analysis. Finally, 64 patients with obstructive jaundice (43 subjected to drainage and 21 not subjected to drainage) were included. Propensity score matching was then conducted. Results: The biliary drainage group showed longer overall survival (median 10.13 months vs 4.43 months, p=0.004) and progression-free survival durations (median 7.00 months vs 1.97 months, p<0.001) than the non-drainage group. Multivariate analysis showed that biliary drainage was a significantly favorable prognostic factor for overall survival (hazard ratio, 0.42; p=0.006) and progression-free survival (hazard ratio, 0.30; p<0.001). Furthermore, in the evaluation of first response after HCC treatment, biliary drainage was beneficial (p=0.005). Remarkably, the durations of overall survival (p=0.032) and progression-free survival (p=0.004) were similar after propensity score matching. Conclusions: Biliary drainage is an independent favorable prognostic factor for HCC patients with BDI and obstructive jaundice. Therefore, biliary drainage should be contemplated in the treatment of advanced HCC with BDI to improve survival outcomes.

Reassessing the Impact of Coffee Consumption on Liver Disease: Insights from a Large-Scale Cohort Study with IPTW Adjustment.

Coffee consumption is globally widespread and has become a lifestyle habit. This study investigated coffee consumption and liver-related survival in a large cohort of 455,870 individuals with UK biobank, categorized into without steatosis, metabolic dysfunction-associated steatotic liver disease (MASLD), and MASLD and increased alcohol intake (MetALD). Inverse probability of treatment weighting (IPTW) adjusted for confounding variables was used, followed by Kaplan-Meier analysis. Moderate coffee consumption (1-2 cups per day) was associated with lower all-cause mortality across the entire cohort, without the steatosis, MASLD (p < 0.0001), and MetALD cohorts (p = 0.0047 for pre-IPTW, p = 0.027 for post-IPTW). Before IPTW adjustment, consuming one or more cups of coffee per day appeared to significantly reduce liver-related mortality in the overall (p = 0.015) and MASLD cohorts (p = 0.011). However, post-IPTW application, no significant differences in liver-related mortality were observed between the coffee intake groups (p = 0.778, 0.319, 0.564, 0.238 for each group). While increased coffee consumption initially seemed to reduce liver-related mortality, after IPTW adjustment, only all-cause mortality significantly decreased (p < 0.0001 and p = 0.027). These findings suggest that previous studies might have overestimated the favorable effect of coffee intake on chronic liver disease due to confounding factors.

Psyllium fiber improves hangovers and inflammatory liver injury by inhibiting intestinal drinking.

Introduction: Excessive alcohol intake often results in hangovers and inflammatory liver damage, posing a significant health concern. Current treatment options for hangovers are still insufficient, highlighting the urgent need for new therapeutic approaches. Psyllium fiber (PF) is well-known for its gastrointestinal benefits, but its effect on hangovers is less explored. Methods: We utilized a mouse model with a single binge drinking (4 g/kg) to induce hangover and inflammatory liver injury. Intestine and liver injury were serologically and histologically estimated. Hangover symptoms were assessed using cylinder and footprint tests to objectively quantify hangover symptoms in mice. Results: Binge drinking significantly activated alcohol-metabolizing enzymes in the small intestine and liver, leading to inflammatory damage. Concurrently, there was a rise in alcohol metabolites such as acetaldehyde and acetone, which exhibited a positive correlation with hangover symptoms in mice. Interestingly, the oral administration of PF (100 mg/kg) alongside alcohol consumption significantly reduced the activity of these enzymes and lowered the levels of alcohol metabolites. Mice treated with PF exhibited a considerable improvement in hangover symptoms and a reduction in hepatic inflammation, compared to control groups. Furthermore, in vitro experiments using HepG2 cell lines and semipermeable membranes demonstrated that PF effectively inhibits alcohol absorption into the body. Discussion: In conclusion, PF demonstrates a potential protective effect against alcohol-induced hangover and liver injury by inhibiting the absorption of alcohol and lowering hangover-related alcohol metabolites. This study suggests that PF could serve as an effective therapeutic option for mitigating the adverse effects of excessive alcohol consumption.

CX3CR1+ macrophages interact with hepatic stellate cells to promote hepatocellular carcinoma through CD8+ T cell suppression.

BACKGROUND AND AIMS: Hepatic stellate cells (HSCs) contribute to hepatocellular carcinoma (HCC) progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX3CR1+ macrophages to pro-tumorigenic properties in the peritumoral area. APPROACH AND RESULTS: In single cell RNA-sequencing analysis of HCC patients, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area, and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14+CD11b+HLA-DR‒ macrophages with CX3CR1 in the HCC adjacent region where α-SMA-expressing activated HSCs (aHSCs) showed co-localized expression of CX3CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX3CR1+Ly6C+ macrophages was mostly observed with decreased CD8+ T cells. In adoptive transfer and in vitro co-culture of myeloid cells, we demonstrated that CX3CR1+Ly6C+ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or co-culturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX3CR1+Ly6C+ macrophages and human blood CD14+ cells, leading to the suppression of CD8+ T cell proliferation. Moreover, genetic deficiency of CX3CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development. CONCLUSION: We showed that CX3CR1+Ly6C+ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX3CR1+Ly6C+ macrophages, subsequently depriving CD8+ T cells of arginine and promoting HCC.

Defecation alleviates hangover by terminating intestinal drinking.

Introduction: The concept of "intestinal drinking" in this study refers to the continued absorption of alcohol in the gastrointestinal tract until adequate defecation occurs. Methods: A longitudinal observation of hangover symptoms and alcohol metabolites in healthy humans following binge drinking was conducted. Results: The hangover symptoms resulting from binge alcohol consumption were relieved by defecation. Following the defecation process, not only the blood ethanol levels, but also the concentrations of blood acetaldehyde, methanol, and iso-propanol, exhibited significant reductions. Conclusions: This pilot study provides a different perspective for addressing hangovers and potentially mitigating the risks of alcoholic liver diseases.

A temperature-responsive intravenous needle that irreversibly softens on insertion.

The high stiffness of intravenous needles can cause tissue injury and increase the risk of transmission of blood-borne pathogens through accidental needlesticks. Here we describe the development and performance of an intravenous needle whose stiffness and shape depend on body temperature. The needle is sufficiently stiff for insertion into soft tissue yet becomes irreversibly flexible after insertion, adapting to the shape of the blood vessel and reducing the risk of needlestick injury on removal, as we show in vein phantoms and ex vivo porcine tissue. In mice, the needles had similar fluid-delivery performance and caused substantially less inflammation than commercial devices for intravenous access of similar size. We also show that an intravenous needle integrated with a thin-film temperature sensor can monitor core body temperature in mice and detect fluid leakage in porcine tissue ex vivo. Temperature-responsive intravenous needles may improve patient care.

New Insights into the Pathogenesis of Metabolic-Associated Fatty Liver Disease (MAFLD): Gut-Liver-Heart Crosstalk.

Metabolism-associated fatty liver disease (MAFLD) is a multifaceted disease that involves complex interactions between various organs, including the gut and heart. It is defined by hepatic lipid accumulation and is related to metabolic dysfunction, obesity, and diabetes. Understanding the intricate interplay of the gut-liver-heart crosstalk is crucial for unraveling the complexities of MAFLD and developing effective treatment and prevention strategies. The gut-liver crosstalk participates in the regulation of the metabolic and inflammatory processes through host-microbiome interactions. Gut microbiota have been associated with the development and progression of MAFLD, and its dysbiosis contributes to insulin resistance, inflammation, and oxidative stress. Metabolites derived from the gut microbiota enter the systemic circulation and influence both the liver and heart, resulting in the gut-liver-heart axis playing an important role in MAFLD. Furthermore, growing evidence suggests that insulin resistance, endothelial dysfunction, and systemic inflammation in MAFLD may contribute to an increased risk of cardiovascular disease (CVD). Additionally, the dysregulation of lipid metabolism in MAFLD may also lead to cardiac dysfunction and heart failure. Overall, the crosstalk between the liver and heart involves a complex interplay of molecular pathways that contribute to the development of CVD in patients with MAFLD. This review emphasizes the current understanding of the gut-liver-heart crosstalk as a foundation for optimizing patient outcomes with MAFLD.

xCT-mediated glutamate excretion in white adipocytes stimulates interferon-γ production by natural killer cells in obesity.

Obesity-mediated hypoxic stress underlies inflammation, including interferon (IFN)-γ production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-γ production remain obscure. Here, we show that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in white adipocytes, resulting in CXCR4+ NK cell recruitment. Interestingly, this spatial proximity between adipocytes and NK cells induces IFN-γ production in NK cells by stimulating metabotropic glutamate receptor 5 (mGluR5). IFN-γ then triggers inflammatory activation of macrophages and augments xCT and CXCL12 expression in adipocytes, forming a bidirectional pathway. Genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells alleviates obesity-related metabolic disorders in mice. Consistently, patients with obesity showed elevated levels of glutamate/mGluR5 and CXCL12/CXCR4 axes, suggesting that a bidirectional pathway between adipocytes and NK cells could be a viable therapeutic target in obesity-related metabolic disorders.

Comprehensive transcriptomic analysis and meta-analysis identify therapeutic effects of N-acetylcysteine in nonalcoholic fatty liver disease.

Introduction: The continuous rise in the prevalence of nonalcoholic fatty liver disease (NAFLD) is emerging as a global health issue. Although the protective effects of N-acetylcysteine (NAC), an antioxidant, against various diseases have been reported, it is still unclear whether NAC has therapeutic potential in NAFLD. Thus, the present meta-analysis aimed to investigate the efficacy of NAC on NAFLD in preclinical studies. Methods: By searching PubMed, Web of Science, and Cochrane Library, 13 studies were included. The methodological quality was assessed based on the SYstematic Review Centre for Laboratory animal Experimentation guideline, and heterogeneity was evaluated with I 2 and p values. Publication bias was assessed by Egger's test and sensitivity analysis was performed. Results: The results showed that NAC treatment significantly improved systemic and hepatic lipid metabolism (p < 0.01), inflammation-related liver injury (p < 0.01), glucose intolerance (p < 0.05), and hepatic steatosis (p < 0.01) by restoring hepatic glutathione (GSH) (p < 0.05) and GSH reductase (p < 0.05) levels compared to controls in NAFLD-induced animals. Consistently, in bulk, single-cell, and spatial transcriptomics data, the abovementioned target pathways of NAC were strongly associated with NAFLD development in mice and patients. Conclusion: Our study suggests that NAC has therapeutic potential for NAFLD and should be considered for future clinical trials.

A Meta-Analysis of Preclinical Studies to Investigate the Effect of Panax ginseng on Alcohol-Associated Liver Disease.

Alcohol-associated liver disease (ALD) has become a major global concern, but the development of effective drugs remains a challenge despite numerous preclinical and clinical pieces of research on the effects of natural compounds. To address this, a meta-analysis was conducted on the efficacy of Panax ginseng for ALD based on preclinical studies. We identified 18 relevant studies from PubMed, Web of Science, and Cochrane Library database and evaluated their methodological quality using the Systematic Review Centre for Laboratory animal Experimentation tool. We analyzed the data using I2, p-values, and fixed effects models to assess overall efficacy and heterogeneity. The results of the meta-analysis suggested that Panax ginseng treatment is effective in reducing the levels of inflammatory markers associated with hepatic injury caused by ALD in animal experiments. Additionally, the administration of Panax ginseng was found to down-regulate inflammatory cytokines and attenuate lipid metabolism in ALD. Moreover, Panax ginseng markedly improved the antioxidant systems in ALD. Therefore, we concluded that Panax ginseng has the potential to be a promising therapeutic agent for ALD. Further research is needed to confirm these findings and to determine the optimal dosage and duration of treatment for patients with ALD.

The Efficacy of Panax ginseng for the Treatment of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Preclinical Studies.

Although tremendous research has reported the protective effects of natural compounds in nonalcoholic fatty liver disease (NAFLD), there is still no approved drug. This study aimed to examine the efficacy of Panax ginseng in NAFLD in preclinical studies. A total of 41 studies were identified by searching the PubMed, Web of Science, and Cochrane Library databases. The methodological quality was assessed by the risk of bias tool from the Systematic Review Center for Laboratory Animal Experimentation. The standardized mean difference (SMD) with a 95% confidence interval was calculated, and the random effects model was used to examine overall efficacy or heterogeneity. The publication bias was analyzed by Egger's test. The results showed that Panax ginseng treatment significantly reduced the systemic levels of alanine aminotransferase (SMD: -2.15 IU/L; p < 0.0001), aspartate aminotransferase (SMD: -2.86 IU/L; p < 0.0001), triglyceride (SMD: -2.86 mg/dL; p < 0.0001), total cholesterol (SMD: -1.69 mg/dL; p < 0.0001), low-density lipoprotein (SMD: -1.46 mg/dL; p < 0.0001), and fasting glucose (SMD: -1.45 mg/dL; p < 0.0001) while increasing high-density lipoprotein (SMD: 1.22 mg/dL; p = 0.0002) in NAFLD regardless of animal models or species. These findings may suggest that Panax ginseng is a promising therapeutic agent for NAFLD treatment.

Catecholamine induces Kupffer cell apoptosis via growth differentiation factor 15 in alcohol-associated liver disease.

Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the ß2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.

Hepatic Cannabinoid Signaling in the Regulation of Alcohol-Associated Liver Disease.

PURPOSE: The endocannabinoid system has emerged as a key regulatory signaling pathway in the pathophysiology of alcohol-associated liver disease (ALD). More than 30 years of research have established different roles of endocannabinoids and their receptors in various aspects of liver diseases, such as steatosis, inflammation, and fibrosis. However, pharmacological applications of the endocannabinoid system for the treatment of ALD have not been successful because of psychoactive side effects, despite some beneficial effects. Thus, a more delicate and detailed elucidation of the mechanism linking the endocannabinoid system and ALD may be of paramount significance in efforts to apply the system to the treatment of ALD. SEARCH METHODS: Three electronic databases (PubMed, MEDLINE, and Cochrane Library) were used for literature search from November 1988 to April 2021. Major keywords used for literature searches were "cannabinoid," "cannabinoid receptor," "ALD," "steatosis," and "fibrosis." SEARCH RESULTS: According to the inclusion and exclusion criteria, the authors selected 47 eligible full-text articles out of 2,691 searched initially. Studies in the past 3 decades revealed the opposite effects of cannabinoid receptors CB1R and CB2R on steatosis, inflammation, and fibrosis in ALD. DISCUSSION AND CONCLUSIONS: This review summarizes the endocannabinoid signaling in the general physiology of the liver, the pathogenesis of ALD, and some of the potential therapeutic implications of cannabinoid-based treatments for ALD.

Metabotropic Glutamate Receptor 5 in Natural Killer Cells Attenuates Liver Fibrosis by Exerting Cytotoxicity to Activated Stellate Cells.

BACKGROUND AND AIMS: The important roles of glutamate and metabotropic glutamate receptor 5 (mGluR5) in HSCs have recently been reported in various liver diseases; however, the mechanism linking the glutamine/glutamate metabolism and mGluR5 in liver fibrosis remains unclear. Here, we report that mGluR5 activation in natural killer (NK) cells attenuates liver fibrosis through increased cytotoxicity and interferon-γ (IFN-γ) production in both mice and humans. APPROACH AND RESULTS: Following 2-week injection of carbon tetrachloride (CCl4 ) or 5-week methionine-deficient and choline-deficient diet, liver fibrosis was more aggravated in mGluR5 knockout mice with significantly decreased frequency of NK cells compared with wild-type mice. Consistently, NK cell-specific mGluR5 knockout mice had aggravated CCl4 -induced liver fibrosis with decreased production of IFN-γ. Conversely, in vitro activation of mGluR5 in NK cells significantly increased the expression of anti-fibrosis-related genes including Ifng, Prf1 (perforin), and Klrk1 (killer cell lectin like receptor K1) and the production of IFN-γ through the mitogen-activated extracellular signal-regulated kinase/extracellular signal-related kinase pathway, contributing to the increased cytotoxicity against activated HSCs. However, we found that the uptake of glutamate was increased in activated HSCs, resulting in shortage of extracellular glutamate and reduced stimulation of mGluR5 in NK cells. Consequently, this could enable HSCs to evade NK cell cytotoxicity in advanced liver fibrosis. In vivo, pharmacologic activation of mGluR5 accelerated CCl4 -induced liver fibrosis regression by restoring NK cell cytotoxicity. In humans, mGluR5 activation enhanced the cytotoxicity of NK cells isolated from healthy donors, but not from patients with cirrhosis with significantly reduced mGluR5 expression in NK cells. CONCLUSIONS: mGluR5 plays important roles in attenuating liver fibrosis by augmenting NK cell cytotoxicity, which could be used as a potential therapeutic target for liver fibrosis.

Ginsenoside F2 attenuates chronic-binge ethanol-induced liver injury by increasing regulatory T cells and decreasing Th17 cells.

BACKGROUND: Recently, beneficial roles of ginsenoside F2 (GF2), a minor constituent of Panax ginseng, have been demonstrated in diverse inflammatory diseases. However, its roles in alcoholic liver inflammation and injury have not been clearly understood. Here, we investigated the underlying mechanism by which GF2 ameliorated alcoholic liver injury. METHODS: To induce alcoholic liver injury, C57BL/6J wild type (WT) or interleukin (IL)-10 knockout (KO) mice were orally administered with ethanol (3 g/kg) or ethanol-containing GF2 (50 mg/kg) for 2 wk. Liver injury and infiltration of macrophages and neutrophils were evaluated by serum biochemistry and immunohistochemistry, respectively. The changes of hepatic immune cells were assessed by flow cytometry and polymerase chain reaction analysis. In vitro differentiation of naïve T cells was performed. RESULTS: GF2 treatment significantly attenuated alcoholic liver injury, in which infiltrations of inflammatory macrophages and neutrophils were decreased. Moreover, the frequencies of Foxp3+ regulatory T cells (Tregs) increased but IL-17-producing T (Th17) cells decreased in GF2-treated mice compared to controls. Furthermore, the mRNA expression of IL-10 and Foxp3 was significantly increased, whereas IL-17 mRNA expression was suppressed in GF2-treated mice. However, these beneficial roles of GF2 were not observed in GF2-treated IL-10 KO mice, suggesting a critical role of IL-10. Similarly, GF2 treatment suppressed differentiation of naïve T cells into Th17 cells by inhibiting RORγt expression and stimulating Foxp3 expression. CONCLUSION: The present study suggests that GF2 treatment attenuates alcoholic liver injury by increasing IL-10 expression and Tregs and decreasing IL-17 expression and Th17 cells.

Mitochondrial Double-Stranded RNA in Exosome Promotes Interleukin-17 Production Through Toll-Like Receptor 3 in Alcohol-associated Liver Injury.

BACKGROUND AND AIMS: Mitochondrial double-stranded RNA (mtdsRNA) and its innate immune responses have been reported previously; however, mtdsRNA generation and its effects on alcohol-associated liver disease (ALD) remain unclear. Here, we report that hepatic mtdsRNA stimulates toll-like receptor 3 (TLR3) in Kupffer cells through the exosome (Exo) to enhance interleukin (IL)-17A (IL-17A) production in ALD. APPROACH AND RESULTS: Following binge ethanol (EtOH) drinking, IL-17A production primarily increased in γδ T cells of wild-type (WT) mice, whereas the production of IL-17A was mainly facilitated by CD4+ T cells in acute-on-chronic EtOH consumption. These were not observed in TLR3 knockout (KO) or Kupffer cell-depleted WT mice. The expression of polynucleotide phosphorylase, an mtdsRNA-restricting enzyme, was significantly decreased in EtOH-exposed livers and hepatocytes of WT mice. Immunostaining revealed that mtdsRNA colocalized with the mitochondria in EtOH-treated hepatocytes from WT mice and healthy humans. Bioanalyzer analysis revealed that small-sized RNAs were enriched in EtOH-treated Exos (EtOH-Exos) rather than EtOH-treated microvesicles in hepatocytes of WT mice and humans. Quantitative real-time PCR and RNA sequencing analyses indicated that mRNA expression of mitochondrial genes encoded by heavy and light strands was robustly increased in EtOH-Exos from mice and humans. After direct treatment with EtOH-Exos, IL-1ß expression was significantly increased in WT Kupffer cells but not in TLR3 KO Kupffer cells, augmenting IL-17A production of γδ T cells in mice and humans. CONCLUSIONS: EtOH-mediated generation of mtdsRNA contributes to TLR3 activation in Kupffer cells through exosomal delivery. Consequently, increased IL-1ß expression in Kupffer cells triggers IL-17A production in γδ T cells at the early stage that may accelerate IL-17A expression in CD4+ T cells in the later stage of ALD. Therefore, mtdsRNA and TLR3 may function as therapeutic targets in ALD.

Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis.

Activation of hepatocyte cannabinoid receptor-1 (CB1R) by hepatic stellate cell (HSC)-derived 2-arachidonoylglycerol (2-AG) drives de novo lipogenesis in alcoholic liver disease (ALD). How alcohol stimulates 2-AG production in HSCs is unknown. Here, we report that chronic alcohol consumption induced hepatic cysteine deficiency and subsequent glutathione depletion by impaired transsulfuration pathway. A compensatory increase in hepatic cystine-glutamate anti-porter xCT boosted extracellular glutamate levels coupled to cystine uptake both in mice and in patients with ALD. Alcohol also induced the selective expression of metabotropic glutamate receptor-5 (mGluR5) in HSCs where mGluR5 activation stimulated 2-AG production. Consistently, genetic or pharmacologic inhibition of mGluR5 or xCT attenuated alcoholic steatosis in mice via the suppression of 2-AG production and subsequent CB1R-mediated de novo lipogenesis. We conclude that a bidirectional signaling operates at a metabolic synapse between hepatocytes and HSCs through xCT-mediated glutamate-mGluR5 signaling to produce 2-AG, which induces CB1R-mediated alcoholic steatosis.

Reduction of Intrahepatic Tumour by Hepatic Arterial Infusion Chemotherapy Prolongs Survival in Hepatocellular Carcinoma.

BACKGROUND/AIM: This study aimed to identify the survival benefit of intrahepatic tumour control by hepatic arterial infusion chemotherapy (HAIC) in hepatocellular carcinoma (HCC) patients with portal vein tumour thrombus (PVTT) or extrahepatic metastasis. PATIENTS AND METHODS: Between 2010 and 2017, a total of 187 consecutive patients with advanced HCC were treated with HAIC. The survival outcomes and response rates to HAIC were analysed. RESULTS: The intrahepatic objective response (OR) rate of all enrolled patients was 18.7%. The survival outcome of patients with OR was significantly better from those without OR, irrespective of initial distant metastasis. Achievement of intrahepatic OR by HAIC and favourable liver function at the time of best response evaluation were two independent factors associated with better OS. CONCLUSION: HAIC-induced intrahepatic tumour reduction significantly prolonged patient survival, irrespective of PVTT or initial distant metastasis.

Pathologic complete response to chemoembolization improves survival outcomes after curative surgery for hepatocellular carcinoma: predictive factors of response.

BACKGROUND: We identified the predictive factors and prognostic significance of transarterial chemoembolization (TACE) for achieving pathologic complete response (pCR) before curative surgery for hepatocellular carcinoma (HCC) in hepatitis B-endemic areas. METHODS: Among 753 HCC patients treated with surgery, 124 patients underwent preoperative TACE before liver resection (LR), and 166 before liver transplantation (LT) between 2005 and 2016. Overall survival (OS) and recurrence-free survival (RFS) were analyzed. Pathologic response (PR) was defined as the mean percentage of necrotic area, and pCR was defined as the absence of viable tumor. RESULTS: A total of 34 (27%) and 38 (23%) patients had pCR before LR and LT, respectively. Alpha-fetoprotein (AFP) < 100 ng/mL and single tumor were significant preoperative predictors of pCR. OS and RFS were significantly improved in patients with pCR or a PR ≥ 90%, but not in patients with PR ≥ 50% after LR and LT. On multivariate analyses, PR ≥ 90% remained an independent predictor of better OS and RFS in LR and LT groups. CONCLUSION: Overall, our data clearly demonstrate that pCR predicts favorable prognosis after curative surgery for HCC, and predictors of pCR are AFP <100 ng/mL and single tumor.

18F-fluorodeoxyglucose uptake of hepatocellular carcinoma as a prognostic predictor in patients with sorafenib treatment.

PURPOSE: Sorafenib, an oral multikinase inhibitor, is a recommended treatment option available for patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). This study aimed to evaluate the performance of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) for predicting tumour progression during sorafenib treatment. METHODS: We formed a retrospective cohort comprising patients treated with sorafenib for at least 30 days and undergoing 18F-FDG PET/CT within 1 month before treatment. For statistical analyses, the tumour-to-liver standardised uptake value (SUV) ratio (TLR) of the most hypermetabolic lesion was measured. RESULTS: Among a total of 35 patients, two obtained partial remission, and 11 showed stable disease after the first response evaluation. Patients with a TLR ≥ 2.9 (n = 17) had a median overall survival (OS) of 3.7 months after sorafenib treatment, whereas patients with a TLR < 2.9 (n = 18) had median OS of 12.2 months (P < 0.001), although the disease control rate was not significantly different between the two groups. Pretreatment TLR ≥ 2.9 (hazard ratio [HR] = 6.318, P = 0.002) and Child-Pugh class B (HR = 4.316, P = 0.044) were poor prognostic factors for OS, and a TLR ≥ 2.9 (HR = 2.911, P = 0.024) was the only poor prognostic factor for progression-free survival in a multivariate analysis. CONCLUSION: Pretreatment tumour metabolic activity assessed by 18F-FDG PET is an independent prognostic factor for survival in patients with BCLC-C stage HCC receiving sorafenib monotherapy, although it may not predict tumour response to the treatment.