Suppression of silent information regulator 1 activity in noncancerous tissues of hepatocellular carcinoma: Possible association with non-B non-C hepatitis pathogenesis.

Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD(+) )-dependent protein deacetylase. In mice, mSirt1 deficiency causes the onset of fatty liver via regulation of the hepatic nutrient metabolism pathway. In this study, we demonstrate SIRT1 expression, activity and NAD(+) regulation using noncancerous liver tissue specimens from hepatocellular carcinoma patients with non-B non-C (NBNC) hepatitis. SIRT1 expression levels were higher in NBNC patients than in healthy donors, while SIRT1 histone H3K9 deacetylation activity was suppressed in NBNC patients. In the liver of hepatitis patients, decreased NAD(+) amounts and its regulatory enzyme nicotinamide phosphoribosyltransferase expression levels were observed, and this led to inhibition of SIRT1 activity. SIRT1 expression was associated with HIF1 protein accumulation in both the NBNC liver and liver cancer cell lines. These results may indicate that the NBNC hepatitis liver is exposed to hypoxic conditions. In HepG2 cells, hypoxia induced inflammatory chemokines, such as CXCL10 and MCP-1. These inductions were suppressed in rich NAD(+) condition, and by SIRT1 activator treatment. In conclusion, hepatic SIRT1 activity was repressed in NBNC patients, and normalization of NAD(+) amounts and activation of SIRT1 could improve the inflammatory condition in the liver of NBNC hepatitis patients.

Surgical Outcomes of Hepatic Resection for Hepatitis B Virus Surface Antigen-Negative and Hepatitis C Virus Antibody-Negative Hepatocellular Carcinoma.

BACKGROUND: The incidence of hepatitis B virus surface antigen-negative and hepatitis C virus antibody-negative hepatocellular carcinoma (NBNC-HCC) is gradually increasing. METHODS: A retrospective cohort study was performed in 694 patients who underwent curative hepatic resection for primary HCC from January 1990 to December 2011. RESULTS: In the NBNC-HCC group (n = 110), the complication rate of diabetic mellitus (38 %) was significantly higher than that of the B-HCC group (n = 110; 17 %), and their rate of alcohol abuse (38 %) was significantly higher than that of both the B-HCC (26 %) and C-HCC groups (n = 474; 22 %). In the NBNC-HCC group, the tumor diameter (4.5 ± 3.6 cm) was significantly larger than that of the C-HCC group (2.9 ± 1.8 cm), but the rate of histological cirrhosis (37 %) was significantly lower than those of both the B-HCC (67 %) and C-HCC (53 %) groups. There were no significant differences regarding overall and disease-free survival among the three groups. In the NBNC-HCC group, multiple intrahepatic or distant recurrences (25 %) were significantly higher than in the C-HCC group (17 %), and the rate of recurrence more than 2 years after hepatic resection (24 %) was significantly higher than that of the B-HCC group (12 %). CONCLUSIONS: The surgical outcomes of patients with NBNC-HCC were not significantly different compared with those of the patients with B-HCC or C-HCC. There was a substantial population with late recurrence among the patients with NBNC-HCC after curative hepatic resection, and thus not only long-term follow-up but also the early establishment of preventive methods for HCC recurrence from NBNC-hepatitis are necessary.

Skeletal muscle area correlates with body surface area in healthy adults.

AIM: Depletion of skeletal muscle mass (sarcopenia) predicts survival in patients with cancer or liver cirrhosis. Recently, many reports have used computed tomography (CT) to measure muscle area to define sarcopenia. However, the definition of sarcopenia using CT has not been fully determined. The aim of this study was to establish formulae to calculate the standard area of skeletal muscle. METHODS: Forty-five healthy adults (24 men and 21 women, aged 21-66 years) who wished to donate part of their liver for transplantation underwent CT. Cross-sectional areas (cm(2) ) of skeletal muscle were measured at the caudal end of the third lumbar vertebra. Regression analysis was performed to establish formulae to calculate the standard area of skeletal muscle. A validation conducted on 30 other healthy adults was performed to check the accuracy of formulae. RESULTS: Men had a median skeletal muscle area of 155.0 cm(2) (range, 114.0-203.0), compared with 111.7 cm(2) (range, 89.8-139.3) in women (P < 0.001). Furthermore, skeletal muscle area significantly correlated with body surface area (BSA) in men (P < 0.0001, r(2) = 0.60) and women (P < 0.0001, r(2) = 0.78). The formulae to calculate skeletal muscle area were 126.9 × BSA - 66.2 in men and 125.6 × BSA - 81.1 in women. The estimated muscle area significantly correlated with actual muscle area in men (P = 0.003, r(2) = 0.64) and women (P = 0.0001, r(2) = 0.70). CONCLUSION: Sarcopenia can be defined by the difference between measured data and calculated data using our new formulae.

Portal vein thrombosis after hepatectomy.

BACKGROUND: Although various complications after hepatectomy have been reported, there have been no large studies on postoperative portal vein thrombosis (PVT) as a complication. This study evaluated the incidence, risk factors, and clinical outcomes of PVT after hepatectomy. METHODS: The preoperative and postoperative clinical characteristics of patients who underwent hepatectomy were retrospectively analyzed. RESULTS: A total of 208 patients were reviewed. The incidence of PVT after hepatectomy was 9.1 % (n = 19), including main portal vein (MPV) thrombosis (n = 7) and peripheral portal vein (PPV) thrombosis (n = 12). Patients with MPV thrombosis had a significantly higher incidence of right hepatectomy (p < 0.001), larger resection volume (p = 0.003), and longer operation time (p = 0.021) than patients without PVT (n = 189). Multivariate analysis identified right hepatectomy as a significant independent risk factor for MPV thrombosis (odds ratio 108.9; p < 0.001). Patients with PPV thrombosis had a significantly longer duration of Pringle maneuver than patients without PVT (p = 0.002). Among patients who underwent right hepatectomy, those with PVT (n = 6) had a significantly lower early liver regeneration rate than those without PVT (n = 13; p = 0.040), and those with PVT had deterioration of liver function on postoperative day 7. In all patients with MPV thrombosis who received anticoagulation therapy, PVT subsequently resolved. CONCLUSIONS: Postoperative PVT after hepatectomy is not rare. It is closely related to delayed recovery of liver function and delayed liver regeneration.

Fas-deficient fully allogeneic dendritic cells administered via an intratumoral injection route show efficient antitumor effects in murine models.

Dendritic cell (DC)-based immunotherapy is a potent, active and specific cancer immunotherapy, as DCs are preferable professional APCs (pAPCs) that prime the tumor-associated antigen (TAA) -specific CD8+ T-cell response. In DC-based immunotherapy, allogeneic DCs may be an alternative source of DCs for patients in whom it is difficult to obtain a sufficient number of quality-guaranteed, autologous DCs. However, the usefulness of fully allogeneic DCs in DC-based immunotherapy is controversial, and many investigators have failed to demonstrate that fully allogeneic DCs can induce an efficient antitumor effect in various experimental settings. In this study, we found that the injection of Fas-deficient fully allogeneic DCs via an intratumoral injection route exerted efficient antitumor effects, as did syngeneic DCs, but wild-type fully allogeneic DCs did not. Intratumoral injection therapy using Fas-deficient syngeneic DCs does not show superior tumor growth suppression compared to that using wild-type syngeneic DCs, suggesting that the inhibition of functional Fas may be critical for overcoming the unfavorable factor related to allogeneic DCs, especially overcoming the rejection response to alloantigens, in therapy using fully allogeneic DCs. In addition, the intratumoral injection therapy using Fas-deficient fully allogeneic DCs induced the generation of a significant tumor-specific CD8+ T-cell response, which is restricted by a host-derived major histocompatibility antigen. Therefore, intratumoral injection therapy using fully allogeneic DCs of which functional Fas is inhibited may be an alternative in clinical DC-based immunotherapy, under circumstances that do not allow the use of autologous DCs.

Prognostic impact of programmed cell death 1 ligand 1 expression in human leukocyte antigen class I-positive hepatocellular carcinoma after curative hepatectomy.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common solid tumors worldwide. Surgery is potentially curative, but high recurrence rates worsen patient prognosis. The interaction between the proteins programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) is an important immune checkpoint. The significance of PD-L1 expression and human leukocyte antigen class I (HLA class I), recognized by CD8 T cells, in the prognosis of patients with HCC remains to be determined. METHODS: We assessed the levels of PD-L1 and HLA class I expression on HCC samples from 80 patients who had undergone hepatectomy at our institution, and evaluated the correlations between PD-L1 and HLA class I expression and patient prognosis. RESULTS: High HLA class I expression was correlated with significantly better recurrence-free survival (RFS), but not overall survival (OS). Multivariate analysis showed that high HLA class I expression was an independent predictor of improved RFS. Low expression of PD-L1 on HCC tended to predict better OS, but the difference was not statistically significant. PD-L1 expression on HCC correlated with the number of CD163-positive macrophages and HLA class I expression with CD3-positive cell infiltration. Univariable and multivariable analyses showed that combined PD-L1 low/HLA class I high expression on HCCs was prognostic for improved OS and RFS. CONCLUSIONS: PD-L1 status may be a good predictor of prognosis in HCC patients with high HLA class I expression. Novel therapies targeting the PD-L1/PD-1 pathway may improve the prognosis of patients with HCC.

Prognostic factors affecting survival at recurrence of hepatocellular carcinoma after living-donor liver transplantation: with special reference to neutrophil/lymphocyte ratio.

BACKGROUND: In living-donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC), it is important to predict not only who may be susceptible to recurrence but also who may survive longer. The neutrophil/lymphocyte ratio (NLR) is useful to properly assess the patient without decreasing the long-term survival after LDLT. In this study, we investigated the relationship between NLR and prognosis of patients with recurrent HCC after LDLT. METHODS: In total, 167 LDLTs for HCC were enrolled in this study. Clinicopathologic factors for HCC recurrence after LDLT were investigated and prognostic factors were examined with respect to survival. RESULTS: The following factors were found to be significant in patients with HCC recurrence compared with the controls: α-fetoprotein ≧300 ng/mL, des-γ-carboxyprothrombin ≧300 mAU/mL, NLR ≧4, tumor number >3, tumor size ≧5 cm, duration of last treatment of HCC to LDLT <3 months, Milan criteria exceeded, histologic tumor number ≧10, histologic tumor size >5 cm, poor differentiation, presence of histologic vascular invasion, adjuvant chemotherapy, and interferon therapy against patients with hepatitis C virus. Male sex, interferon therapy against patients with hepatitis C virus, α-fetoprotein ≧300 ng/mL at recurrence, NLR ≧4 at recurrence, and nonsurgical resection for recurrent HCC were significantly related to poor prognosis. The 3-year survival rate after recurrence was 0% in patients with NLR ≧4 and 43.6% in patients with NLR <4. NLR was reelevated after LDLT in patients who later died; however, NLR gradually decreased in surviving patients. CONCLUSION: NLR at recurrence is a prognostic factor affecting survival after recurrence in LDLT for HCC.

Obstructing spontaneous major shunt vessels is mandatory to keep adequate portal inflow in living-donor liver transplantation.

BACKGROUND: It has not been addressed whether the major spontaneous portosystemic shunt vessels should be ligated in living-donor liver transplantation (LDLT). METHODS: We performed a retrospective analysis of 324 cases of adult-to-adult LDLT. RESULTS: Factors associated with the presence of major (>10 mm) shunt vessels (n=130) included portal vein (PV) thrombosis (27.7%), lower PV pressure at laparotomy, Child-Pugh class C, and transplantation of right-side grafts. The types of major portosystemic shunt vessels included splenorenal shunts (46.2%), gastroesophageal shunts (26.9%), mesocaval shunts (13.8%), and others (13.1%). Ligation of the major shunt vessels increased PV pressure (mean [SD], from 16.8 [3.9] mm Hg to 18.6 [4.3] mm Hg; P<0.001) and PV flow (mean [SD], from 1.35 [0.67] L/min to 1.67 [0.67] L/min; P<0.001) into the grafts. Post-LDLT computed tomography showed patent major shunts in 14 patients. Nine of such patients (64.3%) with unligated major shunt vessels (undetected shunt vessels, n=5; incomplete ligation, n=2; and the shunt was newly created or left open to maintain high PV pressure after reperfusion, n=3) required secondary interventions. Two of these patients died because of graft dysfunction. PV flow was significantly lower in the nine patients who underwent secondary ligation of the major shunt vessels compared with patients with successful primary ligation (mean [SD], 0.96 [0.34] L/min vs. 1.65 [0.63] L/min; P=0.001). CONCLUSIONS: It is an appropriate option to obstruct the major portosystemic shunt vessels to ensure adequate graft inflow in LDLT.