Clinical impact of lymphocyte/C-reactive protein ratio on postoperative outcomes in patients with rectal cancer who underwent curative resection.

Cancer-related systemic inflammation influences postoperative outcomes in cancer patients. Although the relationship between inflammation-related markers and postoperative outcomes have been investigated in many studies, their clinical significance remains to be elucidated in rectal cancer patients. We focused on the lymphocyte count/C-reactive protein ratio (LCR) and its usefulness in predicting short- and long-term outcomes after rectal cancer surgery. Patients with rectal cancer who underwent curative resection at our institution between 2010 and 2018 were enrolled in this study. We comprehensively compared the effectiveness of 11 inflammation-related markers, including LCR and other clinicopathological characteristics, in predicting postoperative complications and survival. Receiver operating characteristic curve analysis indicated that LCR had the highest area under the curve value for predicting the occurrence of postoperative complications. In the multivariate analysis, male sex (odds ratio [OR]: 2.21, 95% confidence interval [CI] 1.07-4.57, P = 0.031), low tumor location (OR: 2.44, 95% CI 1.23-4.88, P = 0.011), and low LCR (OR: 3.51, 95% CI 1.63-7.58, P = 0.001) were significantly and independently associated with the occurrence of postoperative complications. In addition, multivariate analysis using Cox's proportional hazard regression model for the prediction of survival showed that low LCR (≤ 12,600) was significantly associated with both poor overall survival (hazard ratio [HR]: 2.07, 95% CI 1.03-4.15, P = 0.041) and recurrence-free survival (HR: 2.21, 95% CI 1.22-4.01, P = 0.009). LCR is a useful marker for predicting both short- and long-term postoperative outcomes in rectal cancer patients who underwent curative surgery.

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.

A systematic review and meta-analysis comparing the short- and long-term outcomes for laparoscopic and open liver resections for liver metastases from colorectal cancer.

BACKGROUND: The laparoscopic approach to liver resection has experienced exponential growth in recent years. However, evidence-based guidelines are needed for its safe future progression. The main aim of our study was to perform a systematic review and meta-analysis comparing the short- and long-term outcomes of laparoscopic and open liver resections for colorectal liver metastases (CRLM). METHODS: To identify all the comparative manuscripts between laparoscopic and open liver resections for CRLM, all published English language studies with more than ten cases were screened. In addition to the primary meta-analysis, 3 specific subgroup analyses were performed on patients undergoing minor-only, major-only and synchronous resections. The quality of the studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) methodology and Newcastle-Ottawa Score. RESULTS: From the initial 194 manuscripts identified, 21 were meta-analysed, including results from the first randomized trial comparing open and laparoscopic resections of CRLM. Five of these were specific to patients undergoing a synchronous resection (399 cases), while six focused on minor (3 series including 226 cases) and major (3 series including 135 cases) resections, respectively. Thirteen manuscripts compared 2543 cases but could not be assigned to any of the above sub-analyses, so were analysed independently. The majority of short-term outcomes were favourable to the laparoscopic approach with equivalent rates of negative resection margins. No differences were observed between the approaches in overall or disease-free survival at 1, 3 or 5 years. CONCLUSION: Laparoscopic liver resection for CRLM offers improved short-term outcomes with comparable long-term outcomes when compared to open approach.

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.

Elevated levels of circulating ITIH4 are associated with hepatocellular carcinoma with nonalcoholic fatty liver disease: from pig model to human study.

BACKGROUND: Noninvasive biomarkers are urgently needed for optimal management of nonalcoholic fatty liver disease (NAFLD) for the prevention of disease progression into nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). In order to identify the biomarkers, we generated the swine hepatocellular carcinoma (HCC) model associated with NAFLD and performed serum proteomics on the model. METHODS: Microminipigs were fed a high-fat diet to induce NAFLD and a normal diet as the control. To induce HCC, diethylnitrosamine was intraperitoneally administered. Biopsied liver samples were histopathologically analyzed every 12 weeks. Serum proteins were separated by blue native two-dimensional gel electrophoresis and proteins of interest were subsequently identified by MALDI-TOF MS/MS. Human serum samples were analyzed to validate the candidate protein using antibody-mediated characterization. RESULTS: In the NAFLD pigs, hepatic histology of nonalcoholic steatohepatitis (NASH) was observed at 36 weeks, and HCC developed at 60 weeks. Among serum proteins identified with MALDI-TOF MS/MS, serum inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), an acute response protein which is secreted primarily by liver, was identified as the most characteristic protein corresponding with NAFLD progression and HCC development in the NAFLD pigs. With immunoassay, serum ITIH4 levels in the NAFLD pigs were chronologically increased in comparison with those in control animal. Furthermore, immunohistochemistry showed ITIH4 expression in hepatocytes also increased in both the cancer lesions and parenchyma as NAFLD progressed. Human study is also consistent with this observation because serum ITIH4 levels were significantly higher in HCC-NAFLD patients than in the simple steatosis, NASH, and virus-related HCC patients. Of note, HCC-NAFLD patients who had higher serum ITIH4 levels exhibited poorer prognosis after hepatectomy. CONCLUSIONS: We established an HCC pig model associated with NAFLD. Serum proteomics on the swine HCC with NAFLD model implicated ITIH4 as a non-invasive biomarker reflecting NAFLD progression as well as subsequent HCC development. Most importantly, the results in the swine study have been validated in human cohort studies. Dissecting speciation of serum ITIH4 promises to have clinical utility in monitoring the disease.

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.).

A Systematic Review and Meta-Analysis Comparing the Short- and Long-Term Outcomes for Laparoscopic and Open Liver Resections for Hepatocellular Carcinoma: Updated Results from the European Guidelines Meeting on Laparoscopic Liver Surgery, Southampton, UK, 2017.

BACKGROUND: The laparoscopic approach to liver resection has experienced exponential growth in recent years; however, its application is still under debate and objective, evidence-based guidelines for its safe future progression are needed. OBJECTIVE: The aim of this study was to perform a systematic review and meta-analysis comparing the short- and long-term outcomes of laparoscopic and open liver resections for hepatocellular carcinoma (HCC). METHODS: To identify all the comparative manuscripts reporting on laparoscopic and open liver resection for HCC, all published English-language studies with more than 10 cases were screened. In addition to the primary meta-analysis, four specific subgroup analyses were performed on patients with Child-Pugh A cirrhosis, resections for solitary tumors, and those undergoing minor and major resections. The quality of the studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) methodology and the Newcastle-Ottawa Scale. RESULTS: From the initial 361 manuscripts, 28 were included in the meta-analysis. Five of these 28 manuscripts were specific to patients with Child-Pugh A cirrhosis (321 cases), 11 focused on solitary tumors (1003 cases), 16 focused on minor resections (1286 cases), and 3 focused on major resections (164 cases). Three manuscripts compared 1079 cases but could not be assigned to any of the above subanalyses. In general terms, short-term outcomes were favorable when using a laparoscopic approach, especially in minor resections. The only advantage seen with an open approach was reduced operative time during major liver resections. No differences in long-term outcomes were observed between the approaches. CONCLUSIONS: Laparoscopic liver resection for HCC is feasible and offers improved short-term outcomes, with comparable long-term outcomes as the open approach.

Effect of mapping biopsy on surgical management of cholangiocarcinoma.

BACKGROUND: The effect of endoscopic transpapillary mapping biopsy (MB) on decision-making of surgical indications, selecting surgical procedures, or operative outcomes remains unclear. METHODS: Two-hundred and thirty-four patients with cholangiocarcinoma who were evaluated for surgical resection from 2007 to 2017 were reviewed. MB was performed in 80 patients who underwent tumor resection. We examined how MB affected operative indications or modified surgical procedures. Operative curability was compared between patients with and without preoperative MB. RESULTS: MB resulted in avoidance of noncurative resections in eight patients (14%, 8/57) of abandoned laparotomies. Based on the MB, surgical procedures were modified in nine patients (11.3%, 9/80), and this was justified by pathological examinations in eight patients (88.9%, 8/9). The MB group had an improved negative margin rate (83.8% vs 67.5%, P = 0.017) and a lower incidence of carcinoma in situ (8.8% vs 20.0%, P = 0.043) at the first cut than the non-MB group. The incidence of bile leakage was significantly lower in the MB group in both anastomotic site (5.0% vs 16.3%, P = 0.018) and parenchymal surface (2.5% vs 10.0%, P = 0.043). CONCLUSION: MB is helpful for selecting optimal surgical procedure for cholangiocarcinoma and it contributes for safe surgery by securing negative bile duct margin on the first cut.

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.

CAAT/enhancer binding protein-homologous protein deficiency attenuates liver ischemia/reperfusion injury in mice.

Ischemia/reperfusion injury (IRI) is one of the main causes of liver dysfunction after liver surgery. Involvement of endoplasmic reticulum (ER) stress in various diseases has been demonstrated, and CAAT/enhancer binding protein-homologous protein (CHOP) is a transcriptional regulator that is induced by ER stress. It is also a key regulator of ER stress-mediated apoptosis. The aim of this study was to investigate the role of CHOP in liver IRI. Wild type (WT) and CAAT/enhancer binding protein-homologous protein knockout (CHOP-/-) mice were subjected to 70% liver warm ischemia/reperfusion for 60 minutes. At different times after reperfusion, liver tissues and blood samples were collected for evaluation. Induction of ER stress including CHOP expression was ascertained. Liver damage was evaluated based on serum liver enzymes, liver histology, and neutrophil infiltration. Hepatocyte death including apoptosis was assessed. Liver warm IRI induced ER stress in both WT and CHOP-/- mice. In addition, CHOP expression was up-regulated in WT mice. At 6 hours after reperfusion, liver damage was attenuated in CHOP-/- mice. On the basis of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, apoptotic and necrotic cells were significantly reduced in CHOP-/- mice. CHOP deficiency also reduced the cleavage of caspase 3 and expression of the proapoptotic protein B cell lymphoma 2-associated X protein. Liver IRI induces CHOP expression, and CHOP deficiency attenuates liver IRI by inhibiting apoptosis. Elucidation of the function of CHOP in liver IRI may contribute to further investigation for a therapy against liver IRI associated with the ER stress pathway. Liver Transplantation 24 645-654 2018 AASLD.

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.

Proposal of a New Preoperative Prognostic Model for Solitary Hepatocellular Carcinoma Incorporating 18F-FDG-PET Imaging with the ALBI Grade.

BACKGROUND: Existing prognostic systems were not developed using only objective variables available preoperatively, and therefore do not provide ideal prognostication for patients undergoing hepatectomy for hepatocellular carcinoma (HCC). We aimed to develop a preoperative prognostic model using objective variables involving two parameters: 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) and the albumin-bilirubin (ALBI) grade. METHODS: This study included 207 consecutive patients with solitary HCC who underwent 18F-FDG-PET prior to hepatectomy. The tumor to non-tumor maximum standardized uptake value ratio (TNR) was used as an 18F-FDG PET imaging parameter. RESULTS: The 5-year overall survival (OS) and disease-free survival (DFS) rates were 58.6% and 28.8%, respectively. Multivariate analysis of OS identified TNR ≥ 2 (hazard ratio [HR] 1.743, 95% confidence interval [CI] 1.114-2.648, p = 0.016) and ALBI grade 2 (HR 1.966, 95% CI 1.349-2.884, p < 0.001) as the only significant prognostic factors; tumor diameter and tumor markers were not significant. Patients were divided into low- (TNR < 2 and ALBI grade 1), intermediate- (TNR < 2 and ALBI grade 2, or TNR ≥ 2 and ALBI grade 1), and high-risk (TNR ≥ 2 and ALBI grade 2) groups, which differed significantly in terms of survival (5-year OS: 75.7, 49.6, and 27.3%, respectively, p < 0.001; 5-year DFS: 37.0, 24.9, and 13.6%, respectively, p < 0.001). Compared with other staging systems, our model had the best discriminatory ability (corrected Akaike information criteria 1054.8, p < 0.001) and homogeneity (likelihood ratio Chi square value 27.6, p < 0.001). CONCLUSION: A preoperative prognostic model incorporating 18F-FDG-PET imaging with the ALBI grade may be useful for estimating the prognosis of selected patients with solitary HCC.

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.

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.

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.

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.

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.