Novel mouse model for cholestasis-induced liver fibrosis resolution by cholecystojejunostomy.

BACKGROUND AND AIM: Studies on the resolution of liver fibrosis are becoming more important in this era of etiologic eradication. In contrast to the extensive research on the recovery of liver fibrosis induced by hepatotoxic injuries, regression of cholestatic liver fibrosis has been insufficiently examined owing to the limited availability of animal models. METHODS: We examined our novel recanalization mice model of biliary obstruction, involving anastomosis between the gallbladder and jejunum (G-J anastomosis) by invagination. Transgenic mice expressing green fluorescent protein (GFP) under the collagen 1(α)1 promoter underwent G-J anastomosis 14 days after bile duct ligation (BDL) and were sacrificed 14 days later. RESULTS: Transaminase and total bilirubin levels decreased to almost normal values on day 14 after G-J anastomosis. G-J anastomosis resulted in dramatic reversal of liver fibrosis induced by BDL. Activated portal fibroblasts (PFs) double-positive for GFP and Thy-1 on immunofluorescence in the liver of BDL-injured mice became less noticeable following G-J anastomosis. Messenger RNA expression of markers for activated PFs in the liver was downregulated after anastomosis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were induced by BDL. After anastomosis, expressions of MMP-3, 8 as well as hepatocyte growth factor were further upregulated, whereas those of TIMP-1 and TIMP-3 were markedly downregulated. CONCLUSIONS: Our established G-J anastomosis model is associated with fibrosis resolution and reduced PF activation through reopening of bile duct obstruction and will be valuable for studying the recovery process of cholestatic liver fibrosis.

Utility of Mac-2 Binding Protein Glycosylation Isomer to Evaluate Graft Status After Liver Transplantation.

Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel liver fibrosis biomarker, but there are few studies on M2BPGi in liver transplantation (LT) recipients. This study aimed to evaluate the utility of M2BPGi measurement in LT recipients. We collected the clinicopathological data of 233 patients who underwent a liver biopsy at Kyoto University Hospital after LT between August 2015 and June 2019. The median values of M2BPGi in patients with METAVIR fibrosis stages F0, F1, F2, and ≥F3 were 0.61, 0.76, 1.16, and 1.47, respectively, whereas those in patients with METAVIR necroinflammatory indexes A0, A1, and ≥A2 were 0.53, 1.145, and 2.24, respectively. Spearman rank correlation test suggested that the necroinflammatory index had a stronger correlation to the M2BPGi value than the fibrosis stage. The area under the receiver operating characteristic curve of M2BPGi to predict ≥A1 was 0.75, which was significantly higher than that of any other liver fibrosis and inflammation marker. Patients with a rejection activity index (RAI) of ≥3 had a higher M2BPGi value than those with RAI ≤ 2 (P = 0.001). Patients with hepatitis C virus viremia had a higher M2BPGi value than sustained virological responders or those with other etiologies. In conclusion, the present study demonstrated that M2BPGi values are more strongly influenced by necroinflammatory activity and revealed M2BPGi, which has been thought to be a so-called fibrosis marker, as a disease activity marker in transplant recipients. M2BPGi measurement may be useful to detect early stage liver inflammation that cannot be detected by routine blood examination of LT recipients.

Foxp3+ Regulatory T Cells Inhibit CCl4-Induced Liver Inflammation and Fibrosis by Regulating Tissue Cellular Immunity.

Foxp3+ regulatory T (Treg) cells are pivotal in maintaining immunological self-tolerance and tissue homeostasis; however, it remains unclear how tissue Treg cells respond to liver injury and regulate chronic inflammation, which can cause liver fibrosis. We report here that hepatic Treg cells play a critical role in preventing liver pathology by suppressing inflammatory cellular immunity that can promote liver damage and fibrosis. Chronic liver inflammation induced by injections of carbon tetrachloride (CCl4) led to preferential expansion of hepatic Treg cells that prevented liver fibrosis. In contrast, depletion of Treg cells in the CCl4-induced liver fibrosis model exacerbated the severity of liver pathology. Treg depletion unleashed tissue cellular immunity and drove the activation and expansion of the pro-fibrotic IL-4-producing T helper 2 cells, as well as CCR2high Ly-6Chigh inflammatory monocytes/macrophages in the inflamed liver. Although Treg expression of amphiregulin plays a key role in tissue remodeling and repair in various inflammation models, amphiregulin from hepatic Treg cells, the largest producer among liver immune cells, was dispensable for maintaining liver homeostasis and preventing liver fibrosis during CCl4-induced chronic inflammation. Our results indicate that Treg cells control chronic liver inflammation and fibrosis by regulating the aberrant activation and functions of immune effector cells. Harnessing Treg functions, which effectively regulate tissue cellular immunity, may be a therapeutic strategy for preventing and treating liver fibrosis.

Long-term impact and clinical significance of living donor liver transplantation with respect to donor liver restoration and spleen size: A prospective study.

This study aimed to evaluate postoperative long-term liver restoration and splenic enlargement and their clinical significance in living donor liver transplantation. One hundred and sixteen donors who had donated livers more than 5 years previously accepted the invitation to participate in this study. The liver restoration rate and the splenic enlargement rate were calculated as the rate with respect to the original volume. The mean liver restoration rate was 0.99 ± 0.12 and older age was associated with a higher incidence for liver restoration rate <0.95 (P = .005), whereas type of donor operation was not. The donors with liver restoration rate <0.95 showed lower serum albumin levels than those with liver restoration rate ≥0.95. The mean splenic enlargement rate was 1.10 ± 0.16. Right lobe donors demonstrated higher splenic enlargement rate (1.14 ± 0.18) than left lobe/lateral segment donors (1.06 ± 0.13). In the donors with splenic enlargement rate ≥1.10, platelet count was not fully restored to the preoperative level. In conclusion, older age increases the risk for incomplete postoperative liver restoration, which may be associated with a decrease in albumin more than 5 years after donation. Right lobe donation poses a risk of splenic enlargement, which is associated with incomplete restoration of platelet count.

ALPlat criterion for the resection of hepatocellular carcinoma based on a predictive model of posthepatectomy liver failure.

BACKGROUND: The indocyanine green test is used widely to evaluate the risk of posthepatectomy liver failure for hepatocellular carcinoma. A more convenient and reliable scoring system is desired owing to limited accuracy and availability of the indocyanine green test. This study aimed to establish a new selection criterion for liver resection in HCC. METHODS: We reviewed retrospectively 876 patients undergoing a partial hepatectomy for hepatocellular carcinoma between 2007 and 2015 in 8 affiliated hospitals. Posthepatectomy liver failure grades B and C were regarded as posthepatectomy liver failure. We identified the risk factors for posthepatectomy liver failure and established a predictive model based on a formula for the probability of posthepatectomy liver failure. External validation was performed in an additional cohort of 250 patients. RESULTS: Posthepatectomy liver failure occurred in 92 patients (11%). The area under the receiver operating characteristic curve for the prediction of posthepatectomy liver failure was 0.646 for the platelet count, 0.641 for albumin, 0.623 for the percentage of liver remnant, and 0.607 for the plasma disappearance rate of indocyanine green. Logistic regression analysis provided a formula for the probability of posthepatectomy liver failure consisting of platelet count, albumin, and liver remnant. We defined platelet count + 90 × albumin as the ALPlat index and established an ALPlat-based criterion for operative resection that secured the same risk assumed by the indocyanine green-based criterion (Makuuchi's criterion). This criterion exhibited a greater sensitivity and specificity than the indocyanine green-based criterion in the validation cohort. CONCLUSION: The ALPlat criterion is a simple and useful method to assess liver function and to make therapeutic decisions in patients with hepatocellular carcinoma.

Reappraisal of Prognostic Impact of Tumor SUVmax by 18F-FDG-PET/CT in Intrahepatic Cholangiocarcinoma.

BACKGROUND: We previously reported that tumor standardized uptake value (SUVmax) by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) was a potential predictor in patients undergoing surgery for intrahepatic cholangiocarcinoma (ICC). However, the prognostic value of SUVmax in the era of multidisciplinary strategy has remained unclear. The aim of this study was to reappraise the prognostic value of tumor SUVmax in patients undergoing surgery for ICC. METHODS: Data from 82 consecutive ICC patients, who underwent 18F-FDG-PET/CT and subsequent surgery between 2006 and 2017, were retrieved from a prospectively maintained institutional database. Adjuvant strategy was administrated during this study period in our center. RESULTS: Tumor SUVmax was associated with tumor size (p = 0.002) and tumor number (p = 0.005), but not associated with T and N stage classified by American Joint Committee on Cancer-classification system, and other tumor factors. According to the tumor SUVmax cut-off values of 8.0 based on the minimum p value approach, actuarial 5-year overall survival (OS) rates in patients undergoing upfront surgery for ICC were significantly stratified at 54.7% versus 26.0% (low vs. high tumor SUVmax group, p = 0.008). The actuarial 3-year disease-free survival (DFS) rates were also significantly stratified at 41.0% versus 18.3% (p < 0.001). Multivariate Cox regression analyses revealed that tumor SUVmax retained its significance on OS (p = 0.039) as well as DFS (p < 0.001). CONCLUSION: Even in the era of multidisciplinary strategy, high tumor SUVmax still represents poor prognosis in patients undergoing surgery for ICC. These patients, therefore, would probably be required more effective strategies.

Optimal introduction of laparoscopic liver resection for Child-Pugh B.

INTRODUCTION: Surgery for Child-Pugh B liver function is considered risky because of its high morbidity rate and the acceptable indication criteria for laparoscopic liver resection (LLR) for Child-Pugh B patients have not been identified. We conducted a retrospective cohort study to determine the optimal introduction of LLR for Child-Pugh B patients based on our single-institute experience. METHODS: A total of 17 Child-Pugh B patients underwent LLR between 2005 and 2017. Their clinical outcomes were compared to those of LLR for Child-Pugh A patients (103 cases), conventional open liver resection for Child-Pugh B patients (19 cases), and radiofrequency ablation (RFA) for Child-Pugh B patients (20 cases) during the same period. RESULTS: LLR for Child-Pugh B patients had a significantly higher conversion rate than LLR for Child-Pugh A patients (Child-Pugh A vs B: 3.9% vs 35.3%, P < 0.01). However, patients who successfully underwent laparoscopic resection (11 cases) had fewer postoperative ascites and shorter postoperative hospital stays compared to patients who underwent conventional open liver resection. In comparison to the RFA group, the LLR group more frequently had lesions in the left lateral segment (LLR vs RFA: 50.0% vs 10.0%, P = 0.02) and exophytic tumor (21.4% vs 0%, P = 0.02) than did the RFA group. Also, compared to the RFA group, the LLR group had a lower local recurrence rate (0% vs 15%, P = 0.25) and a longer recurrence-free survival (P = 0.049), but the overall survival was similar between the two groups. CONCLUSIONS: In the treatment of Child-Pugh B liver malignancy, the minimal invasiveness of LLR was revealed. Our results suggest that lesions in the left lateral segment and exophytic tumors are good indications for LLR for Child-Pugh B.

Efficiency of acoustic radiation force impulse imaging for the staging of graft fibrosis after liver transplantation.

AIM: Liver biopsy is the gold standard for assessing liver fibrosis (LF) after liver transplantation (LT), but its invasiveness limits its utility. This study aimed to evaluate the usefulness of liver stiffness measurement (LSM) using acoustic radiation force impulse (ARFI) imaging to assess LF after LT. METHODS: Between September 2013 and January 2017, 278 patients who underwent liver biopsy after LT in Kyoto University Hospital (Kyoto, Japan) were prospectively enrolled. Liver stiffness measurement was carried out using ARFI imaging; its value was expressed as shear wave velocity (Vs) [m/s]. The LF was evaluated according to METAVIR score (F0-F4). The diagnostic performance of Vs for F2≤ and F3≤ was assessed and compared with that of laboratory tests using receiver operating characteristic (ROC) analysis. RESULTS: The median Vs values increased according to the progression of LF (F0, 1.18 (0.78-1.92); F1, 1.35 (0.72-3.54); F2, 1.55 (1.05-3.37); F3, 1.84 (1.41-2.97)). The Vs had the highest area under the ROC curve (AUROC) for the prediction of both F2 ≤ and F3 ≤ fibrosis (F2, 0.77; and F3, 0.85). With the cut-off value of Vs >1.31, sensitivity, specificity, positive predictive value, and negative predictive value were 89.4%, 53.3%, 37.3%, and 94.2% in predicting F2≤, respectively. Shear wave velocity diagnosed LF better than any laboratory tests regardless of the type of primary disease. CONCLUSIONS: Acoustic radiation force impulse helps to assess graft LF after LT. The high sensitivity suggested that ARFI might reduce the frequency of liver biopsies by detecting patients who are unlikely to have significant fibrosis after LT. (Unique trial no. UMIN R000028296.).

Usefulness of Preoperative 18F-FDG-PET in Detecting Invasive Intraductal Papillary Neoplasm of the Bile Duct.

BACKGROUND/AIM: Preoperative identification of the invasive component remains challenging in intraductal papillary neoplasm of the bile duct (IPNB). We evaluated the ability of preoperative 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) to differentiate between non-invasive IPNB, invasive IPNB, and papillary cholangiocarcinoma (CCA). PATIENTS AND METHODS: The maximum standardized uptake values (SUVmax) of 11 patients with IPNB (6 non-invasive and 5 invasive) and 20 with papillary CCA who underwent pre-surgical 18F-FDG-PET were assessed. The SUVmax cut-off that predicts an invasive component was determined using receiver operating characteristic (ROC) curve analysis. RESULTS: The SUVmax in patients with invasive IPNB and papillary CCA were significantly higher than in patients with non-invasive IPNB (p=0.035 and 0.0025, respectively). ROC curve analysis revealed an optimal SUVmax cut-off of 4.5, which had 94.5% accuracy, 76.0% sensitivity, and 100% specificity. CONCLUSION: Our data suggest that the preoperative 18F-FDG-PET SUVmax can differentiate non-invasive IPNB from invasive IPNB and papillary CCA.

Low Preoperative Platelet Count Predicts Risk of Subclinical Posthepatectomy Liver Failure in Right Lobe Donors for Liver Transplantation.

Living donor right hepatectomy (LDRH) is a common procedure in adult-to-adult living donor liver transplantation, but it is associated with a higher risk of posthepatectomy liver failure (PHLF) compared with left hepatectomy because of a smaller remnant. We identified risk factors for PHLF and other complications in LDRH, verified the appropriateness of the criteria, and explored the possibility of adjusting the minimum remnant liver volume (RLV) based on individual risk. Between October 2005 and November 2017, 254 donors undergoing LDRH at Kyoto University Hospital were enrolled. Clinical data were collected retrospectively. All complications were graded according to the Clavien-Dindo classification. No donors had grade 4 or 5 complications or clinically significant grade B or C PHLF. Grade A PHLF occurred in 30 donors (11.8%). Male sex (P = 0.01), lower preoperative platelet count (PLT; P = 0.01), higher prothrombin time-international normalized ratio (P = 0.03), higher total bilirubin (P = 0.01), smaller RLV (P = 0.03), and greater blood loss (P = 0.04) were associated with increased risk of PHLF in the univariate analysis, whereas PLT, RLV, and blood loss remained significant in the multivariate analysis. Grade 2 or 3 complications were observed in 32 (12.6%) donors. Higher body mass index (BMI; P = 0.002) and larger blood loss (P = 0.02) were identified as risk factors for complications (Clavien-Dindo grade ≥ 2) in univariate analysis. Only BMI remained significant in the multivariate analysis. In conclusion, LDRH is performed safely with acceptable morbidity under the current criteria. Minimum RLV may be marginally adjusted by PLT and reducing intraoperative blood loss minimizes PHLF risk. Liver Transplantation 00 000-000 2018 AASLD.

Preoperative metabolic tumor volume of intrahepatic cholangiocarcinoma measured by 18F-FDG-PET is associated with the KRAS mutation status and prognosis.

BACKGROUND: Surgical resection remains the mainstay of curative treatment for intrahepatic cholangiocarcinoma (ICC). Prognosis after surgery is unsatisfactory despite improvements in treatment and post-operative clinical management. Despite developments in the molecular profiling of ICC, the preoperative prediction of prognosis remains a challenge. This study aimed to identify clinical prognostic indicators by investigating the molecular profiles of ICC and evaluating the preoperative imaging data of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET). METHODS: A retrospective analysis was performed on 50 consecutive patients with ICC who underwent curative hepatectomy after 18F-FDG-PET examination. To evaluate the molecular profiles of ICC, KRAS mutation status was assessed in resected specimens. For the assessment of glucose uptake, we observed the expression of glucose transporter-1 (GLUT-1) by immunohistochemistry. The data of 18F-FDG-PET were re-evaluated as follows: maximum standardized uptake value, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Cut-off values were determined using receiver operating characteristic (ROC) curve analysis. Cumulative overall survival (OS) was analyzed using the Kaplan-Meier analysis. RESULTS: Overall, 16 (32.0%) patients had mutations in KRAS. Patients with mutated KRAS exhibited shorter OS than those with wild-type KRAS (5-year OS, 0% vs. 35.1%, P < 0.001). GLUT-1 expression was significantly higher in tumors with mutated KRAS than in tumors with wild-type KRAS (median, 4.0 vs. 1.0, P < 0.001). Survival was significantly different when stratified by expression of GLUT-1 (5-year OS, 0% vs. 46.5%, P <0.001). Among the 18F-FDG-PET parameters, the MTV and TLG were significantly higher in the mutated KRAS group than in the wild-type KRAS group (P = 0.013 and P = 0.026, respectively). ROC curve analysis revealed a cut-off value of 38 for the MTV, with the highest accuracy (area under the curve = 0.789; 95% confidence interval, 0.581-0.902) for predicting KRAS mutation. This cut-off value permitted stratification of OS (high vs. low: 5-year OS, 13.1% vs. 36.7%, P = 0.008). CONCLUSIONS: High MTV is associated with KRAS mutation and poor postoperative outcomes in patients with ICC, suggesting that the MTV of ICC measured by 18F-FDG-PET may provide useful information for tumor molecular profiles and prognosis.

Long-Term Survival of Recurrent Intrahepatic Cholangiocarcinoma: The Impact and Selection of Repeat Surgery.

BACKGROUND: Definitive guidelines for recurrent intrahepatic cholangiocarcinoma (ICC) do not exist. This study has focused on the repeat surgery when analyzing the survival outcomes of recurrent ICC. We evaluated the relationship between clinicopathological features of the primary tumor and implementation of the repeat surgery to identify its potential selection criteria. METHODS: A total of 108 patients with recurrent ICC between 1993 and 2015 were analyzed. Of these, 15 patients underwent repeat surgery and 93 did not. RESULTS: Seven out of 29 patients with intrahepatic recurrence and eight out of 44 patients with extrahepatic recurrence were amenable to the repeat surgery. Thirty-five patients with simultaneous or consequent intrahepatic recurrence and extrahepatic recurrence were not amenable to the repeat surgery. Patients who underwent repeat surgery had a lower proportion of lymph node metastases (n = 0 [0%] vs. n = 47 [50.5%], p < 0.001), multiple tumors in the primary tumor (n = 1 [6.7%] vs. n = 31 [33.3%], p = 0.037), or early recurrence (≤ 1 year; n = 4 [26.7%] vs. n = 62 [66.7%], p = 0.003). Survival after recurrence (SAR) was better in patients who underwent repeat surgery than in those who did not (median SAR time: 91.6 vs. 10.4 months, and 3-year survival: 86.7 vs. 8.7%, respectively, p < 0.001). CONCLUSIONS: Repeat surgery for recurrent ICC with an appropriate selection can be associated with prolonged survival. Regarding the feasibility, nodal status, number of tumors on the primary tumor, and time to recurrence may be considered as selection criteria.

Pancreatic Stellate Cells Have Distinct Characteristics From Hepatic Stellate Cells and Are Not the Unique Origin of Collagen-Producing Cells in the Pancreas.

OBJECTIVES: The origin of collagen-producing myofibroblasts in pancreatic fibrosis is still controversial. Pancreatic stellate cells (PSCs), which have been recognized as the pancreatic counterparts of hepatic stellate cells (HSCs), are thought to play an important role in the development of pancreatic fibrosis. However, sources of myofibroblasts other than PSCs may exist because extensive studies of liver fibrosis have uncovered myofibroblasts that did not originate from HSCs. This study aimed to characterize myofibroblasts in an experimental pancreatic fibrosis model in mice. METHODS: We used transgenic mice expressing green fluorescent protein via the collagen type I α1 promoter and induced pancreatic fibrosis with repetitive injections of cerulein. RESULTS: Collagen-producing cells that are negative for glial fibrillary acidic protein (ie, not derived from PSCs) exist in the pancreas. Pancreatic stellate cells had different characteristics from those of HSCs in a very small possession of vitamin A using mass spectrometry and a low expression of lecithin retinol acyltransferase. The microstructure of PSCs was entirely different from that of HSCs using flow cytometry and electron microscopy. CONCLUSIONS: Our study showed that characteristics of PSCs are different from those of HSCs, and myofibroblasts in the pancreas might be derived not only from PSCs but also from other fibrogenic cells.

A Novel Biomarker-Based Preoperative Prognostic Grading System for Predicting Survival After Surgery for Intrahepatic Cholangiocarcinoma.

BACKGROUND: Although treatment strategies for intrahepatic cholangiocarcinoma (ICC) are shifting towards multidisciplinary approaches, preoperative radiographic methods for identifying patients requiring further therapy are unclear. This study was designed to establish a prognostic grading system using preoperatively available objective biomarkers. METHODS: A novel preoperative prognostic grading system for predicting survival after surgery for ICC was developed from multivariate analysis of 134 ICC patients who underwent surgery between 1996 and 2015 using preoperatively available biomarkers. RESULTS: The median overall survival time and 3- and 5 year survival rates were 33.3 months, 48, and 38%, respectively. Of the preoperative biomarkers, the neutrophil-to-lymphocyte ratio (≥5), and C-reactive protein (≥5 mg/L) and carbohydrate antigen 19-9 (≥500 IU/mL) levels were independently associated with poor overall survival. Based on the presence of these factors, the preoperative prognostic grades were defined as follows: grade 1, no factor; grade 2, one factor; and grade 3, two or three factors. The median overall survival time and 3- and 5 year survival rates of patients with grade 1 (70.3 months, 66, and 53%, respectively) were higher than those of patients with grade 2 (23.4 months, 37, and 30%, respectively; P = 0.004) and grade 3 (8.8 months, 5% both; 2 vs. 3, P < 0.001). Multivariable analysis revealed that the preoperative prognostic grading system independently predicted survival after adjusting for known prognostic factors. CONCLUSIONS: A novel biomarker-based preoperative prognostic grading system for ICC significantly stratifies survival after surgery and may identify patients requiring further treatment.

Hepatic vagus nerve regulates Kupffer cell activation via α7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis.

BACKGROUND: Nonalcoholic fatty liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Kupffer cells play a central role in promoting hepatic inflammation, which leads to the development of NASH. We investigated the anti-inflammatory effect of hepatic vagus-mediated stimulation of the α7 nicotinic acetylcholine receptor (α7nAChR) on Kupffer cells in NASH pathogenesis. METHODS: Wild-type (WT) mice undergoing hepatic vagotomy (HV) were fed a methionine- and choline-deficient (MCD) diet for 1 week. α7nAChR knockout (α7KO) chimeric mice were generated by transplanting α7KO bone marrow cells into irradiated and Kupffer cell-deleted WT recipients. Kupffer cells were isolated from WT mice and treated with α7nAChR agonist under stimulation by lipopolysaccharide and/or palmitic acid. RESULTS: HV aggravated MCD diet-induced NASH in both steatosis and inflammation. The hepatic inflammatory response, including the upregulation of tumor necrosis factor alpha (TNFα), interleukin (IL)-12, and monocyte chemoattractant protein 1 (MCP-1), was accelerated in HV mice, accompanied by the downregulation of PPARα pathway genes. Kupffer cells were highly activated via the phosphorylation and nuclear translocation of nuclear factor-kappa B (NF-κB) in MCD diet-fed HV mice. The α7nAchR agonist suppressed the inflammatory response of primary Kupffer cells induced by lipopolysaccharide and palmitic acid by attenuating the NF-κB cascade. α7KO chimeric mice fed an MCD diet for 1 week developed advanced NASH with highly activated Kupffer cells. The hepatic expression of TNFα, IL-12, and MCP-1 was upregulated in α7KO chimeric mice, accompanied by abnormal lipid metabolism. CONCLUSIONS: Hepatic vagus activity regulates the inflammatory response of Kupffer cells via α7nAChR in NASH development.

Usefulness of Mac-2 Binding Protein Glycosylation Isomer for Prediction of Posthepatectomy Liver Failure in Patients With Hepatocellular Carcinoma.

OBJECTIVE: The aim of this study was to evaluate the usefulness of the Mac-2 binding protein glycosylation isomer (M2BPGi) for the prediction of posthepatectomy liver failure (PHLF) in hepatocellular carcinoma (HCC) patients. SUMMARY BACKGROUND DATA: M2BPGi is a novel serum marker of liver fibrosis. The usefulness of M2BPGi for the prediction of PHLF has not been evaluated. METHODS: Clinicopathological data were analyzed in 138 HCC patients who underwent liver resection between August 2011 and November 2014. PHLF was evaluated according to the definition of the International Study Group of Liver Surgery. Performance of preoperative parameters in predicting PHLF was determined using receiver operating characteristic (ROC) analysis. RESULTS: Serum M2BPGi level correlated with the METAVIR fibrosis score. M2BPGi levels of hepatitis C virus (HCV)-positive patients were significantly higher than those of HCV-negative patients, even in the same fibrosis stage. PHLF ≥ Grade B developed in 19 patients (13.8%). The area under the ROC curve (AUROC) of M2BPGi for the prediction of PHLF ≥ Grade B was 0.71. In multivariate analysis, M2BPGi [odds ratio (OR): 2.08, 95% confidence interval (CI) 1.28-3.55], platelet count (OR: 0.39, 95% CI 0.18-0.80), and resection rate (OR: 2.71, 95% CI 1.46-5.40) were the significant factors associated with PHLF ≥ Grade B. The AUROC of the PHLF index defined by these factors was 0.81. Notably, in patients with HCV infection, the predictive ability of M2BPGi for PHLF (AUROC 0.85) was the best among the preoperative parameters. CONCLUSIONS: M2BPGi is a useful predictor of PHLF, especially in patients with HCV infection.

Phase I clinical trial of olprinone in liver surgery.

PURPOSE: Post-hepatectomy liver failure is one of the most serious complications liver surgeons must overcome. We previously examined olprinone, a selective phosphodiesterase III inhibitor, and demonstrated its hepatoprotective effects in rats and pigs. We herein report the results of a phase I clinical trial of olprinone in liver surgery (UMIN000004975). METHODS: Twenty-three patients who underwent hepatectomy between 2011 and 2015 were prospectively registered. In the first 6 cases, olprinone (0.1 µg/kg/min) was administered for 24 h from the start of surgery. In the remaining 17 cases, olprinone (0.05 µg/kg/min) was administered from the start of surgery until just before the transection of the liver parenchyma. The primary endpoint was safety, and the secondary endpoint was efficacy. For the evaluation of efficacy, the incidence of post-hepatectomy liver failure in 20 hepatocellular carcinoma patients was externally compared with 20 propensity score-matched patients. RESULTS: No intraoperative side effects were observed, and the morbidity rates in the analyzed cohorts were acceptable. The rate of post-hepatectomy liver failure frequency tended to be lower in the olprinone group. CONCLUSIONS: The safety of olprinone in liver surgery was confirmed. The efficacy of olprinone will be re-evaluated in clinical trials.

Prediction of posthepatectomy liver failure based on liver stiffness measurement in patients with hepatocellular carcinoma.

BACKGROUND: Posthepatectomy liver failure (PHLF) is a potentially fatal complication, and the accurate prediction of PHLF is essential. Liver stiffness measurement (LSM) has been accepted widely as a noninvasive assessment for liver fibrosis. We aimed to evaluate the usefulness of LSM in predicting PHLF. METHODS: One hundred seventy-seven patients with hepatocellular carcinoma who underwent liver resection between August 2011 and October 2014 were analyzed prospectively. LSM was performed by Virtual Touch Tissue Quantification based on acoustic radiation force impulse imaging, and its value was expressed as the shear wave velocity (Vs) [m/s]. The remnant liver volume rate (Rem) was calculated by computed tomography volumetry. PHLF was diagnosed on the basis of the definition from the International Study Group of Liver Surgery. RESULTS: PHLF occurred in 38 patients (21.5%): grade A, 17 patients (9.6%); grade B, 15 patients (8.5%); and grade C, 6 patients (3.4%). The area under the receiver operating characteristic curve of the Vs for predicting PHLF was 0.67 for grade ≥A, 0.78 for grade ≥B, and 0.74 for grade C, which was greater than any other preoperative factor for each grade. Multivariate stepwise selection identified 2 significant factors associated with PHLF grade ≥B: Vs (odds ratio, 2.66; 95% confidence interval, 1.69-4.41, P < .01) and Rem (odds ratio, 0.47; 95% confidence interval, 0.27-0.79, P < .01). The logistic model that included the Vs and Rem resulted in an area under the receiver operating characteristic curve of 0.80 for predicting PHLF grade ≥B. CONCLUSION: LSM was useful for the prediction of PHLF and the estimation of the safe Rem range.

Bile duct stone formation around a nylon suture after gastrectomy: a case report.

BACKGROUND: Many cases of choledocholiths formed around sutures and clips used during cholecystectomy have been reported. We describe a case of gallstone formation around a nylon suture after non-biliary surgery. To the best of our knowledge, this is the first report of such a case. CASE PRESENTATION: A 75-year-old Japanese man, who had undergone distal gastrectomy for gastric cancer and reconstruction with the Billroth II method 8 years earlier, presented with gastric discomfort. Abdominal ultrasonography was conducted and we diagnosed cholecysto-choledocholithiasis with dilatation of the intrahepatic bile duct. He underwent cholecystectomy and cholangioduodenostomy for choledocholith removal. Gallstones, which had formed around a nylon suture used during the previous gastrectomy, were found in the bile duct. Sutures of the same material had also been placed on the duodenum. Chemical analysis revealed that the stones were composed of calcium bilirubinate. The patient was discharged on postoperative day 19, and choledocholithiasis has not recurred thus far. CONCLUSION: The findings from this case suggest that standard, non-resorbable sutures used in gastrectomy may be associated with the formation of bile duct stones; therefore, absorbable suture material may be required to avert gallstone formation even in the case of gastrectomy.