Association between the early high level of serum tacrolimus and recurrence of hepatocellular carcinoma in ABO-incompatible liver transplantation

BACKGROUND Clinical factors predicting graft survival(GS)after ABO-incompatible(ABOi)liver transplantation(LT),and differences between recipients with and without hepatocellular carcinoma(HCC)are unclear.AIM To analyze the impact of serial serum tacrolimus trough concentration in recipients with or without(HCC)in ABOi living-donor liver transplantation(LDLT).METHODS We analyzed a historical cohort of 89 recipients who underwent ABOi LDLT,including 47 patients with HCC.RESULTS The 1-,3-,5-,and 10-year GS rates were 85.9%,73.3%,71.4%,and 71.4%,respectively,and there were no significant differences between HCC and non-HCC recipients.In multivariate Coxregression analyses,tacrolimus trough concentrations below 5.4 ng/mL at 24 wk post-LT,in addition to the antibody-mediated rejection(AMR)were associated with poor-graft outcomes.In HCC patients,AMR[hazard ratio(HR)=63.20,P<0.01]and HCC recurrence(HR=20.72,P=0.01)were significantly associated with poor graft outcomes.HCCs outside Milan criteria,and tacrolimus concentrations at 4 wk post-LT>7.3 ng/mL were significant predictive factors for HCC recurrence.After propensity score matching,patients with high tacrolimus concentrations at 4 wk had significantly poor recurrence-free survival.CONCLUSION Elevated tacrolimus levels at 4 wk after ABOi LDLT have been found to correlate with HCC recurrence.Therefore,careful monitoring and control of tacrolimus levels are imperative in ABOi LT recipients with HCC.

Clinical advantages of single port laparoscopic hepatectomy

AIM To evaluate the clinical advantages of single-port laparoscopic hepatectomy(SPLH) compare to multiport laparoscopic hepatectomy(MPLH).METHODS We retrospectively reviewed the medical records of 246 patients who underwent laparoscopic liver resection between January 2008 and December 2015 at our hospital. We divided the surgical technique into two groups; SPLH and MPLH. We performed laparoscopic liver resection for both benign and malignant disease. Major hepatectomy such as right and left hepatectomy was also done with sufficient disease-free margin. The operative time, the volume of blood loss, transfusion rate, and the conversion rate to MPLH or open surgery was evaluated. The post-operative parameters included the meal start date after operation, the number of postoperative days spent in the hospital, and surgical complications was also evaluated.RESULTS Of the 246 patients, 155 patients underwent SPLH and 91 patients underwent MPLH. Conversion rate was 22.6% in SPLH and 19.8% in MPLH(P = 0.358). We performed major hepatectomy, which was defined as resection of more than 2 sections, in 13.5% of patients in the SPLH group and in 13.3% of patients in the MPLH group(P = 0.962). Mean operative timewas 136.9 ± 89.2 min in the SPLH group and 231.2 ± 149.7 min in the MPLH group(P < 0.001). The amount of blood loss was 385.1 ± 409.3 m L in the SPLH group and 559.9 ± 624.9 m L in the MPLH group(P = 0.016). The safety resection margin did not show a significant difference(0.84 ± 0.84 cm in SPLH vs 1.04 ± 1.22 cm in MPLH, P = 0.704). Enteral feeding was started earlier in the SPLH group(1.06 ± 0.27 d after operation) than in the MPLH group(1.63 ± 1.27 d)(P < 0.001). The mean hospital stay after operation was non-significantly shorter in the SPLH group than in the MPLH group(7.82 ± 2.79 d vs 7.97 ± 3.69 d, P = 0.744). The complication rate was not significantly different(P = 0.397) and there was no major perioperative complication or mortality case in both groups. CONCLUSION Single-port laparoscopic liver surgery seems to be a feasible approach for various kinds of liver diseases.

Ameliorating liver fibrosis in an animal model using the secretome released from miR-122-transfected adipose-derived stem cells

BACKGROUND Recently,the exclusive use of mesenchymal stem cell(MSC)-secreted molecules,called secretome,rather than cells,has been evaluated for overcoming the limitations of cell-based therapy,while maintaining its advantages.However,the use of na?ve secretome may not fully satisfy the specificity of each disease.Therefore,it appears to be more advantageous to use the functionally reinforced secretome through a series of processes involving physico-chemical adjustments or genetic manipulation rather than to the use na?ve secretome.AIM To determine the therapeutic potential of the secretome released from miR-122-transfected adipose-derived stromal cells(ASCs).METHODS We collected secretory materials released from ASCs that had been transfected with antifibrotic miR-122(MCM)and compared their antifibrotic effects with those of the na?ve secretome(CM).MCM and CM were intravenously administered to the mouse model of thioacetamide-induced liver fibrosis,and their therapeutic potentials were compared.RESULTS MCM infusion provided higher therapeutic potential in terms of:(A)Reducing collagen content in the liver;(B)Inhibiting proinflammatory cytokines;and(C)Reducing abnormally elevated liver enzymes than the infusion of the na?ve secretome.The proteomic analysis of MCM also indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the na?ve secretome.CONCLUSION We could,thus,conclude that the secretome released from miR-122-transfected ASCs has higher antifibrotic and anti-inflammatory properties than the na?ve secretome.Because miR-122 transfection into ASCs provides a specific way of potentiating the antifibrotic properties of ASC secretome,it could be considered as an enhanced method for reinforcing secretome effectiveness.

Superior gallstone dissolubility and safety of tert-amyl ethyl ether over methyl-tertiary butyl ether

BACKGROUND The use of methyl-tertiary butyl ether(MTBE)to dissolve gallstones has been limited due to concerns over its toxicity and the widespread recognition of the safety of laparoscopic cholecystectomy.The adverse effects of MTBE are largely attributed to its low boiling point,resulting in a tendency to evaporate.Therefore,if there is a material with a higher boiling point and similar or higher dissolubility than MTBE,it is expected to be an attractive alternative to MTBE.AIM To determine whether tert-amyl ethyl ether(TAEE),an MTBE analogue with a relatively higher boiling point(102°C),could be used as an alternative to MTBE in terms of gallstone dissolubility and toxicity.METHODS The in vitro dissolubility of MTBE and TAEE was determined by measuring the dry weights of human gallstones at predetermined time intervals after placing them in glass containers with either of the two solvents.The in vivo dissolubility was determined by comparing the weights of solvent-treated gallstones and control(dimethyl sulfoxide)-treated gallstones,after the direct infusion of each solvent into the gallbladder in both hamster models with cholesterol and pigmented gallstones.RESULTS The in vitro results demonstrated a 24 h TAEE-dissolubility of 76.7%,56.5%and 38.75%for cholesterol,mixed,and pigmented gallstones,respectively,which represented a 1.2-,1.4-,and 1.3-fold increase in dissolubility compared to that of MTBE.In the in vitro experiment,the 24 h-dissolubility of TAEE was 71.7%and 63.0%for cholesterol and pigmented gallstones,respectively,which represented a 1.4-and 1.9-fold increase in dissolubility compared to that of MTBE.In addition,the results of the cell viability assay and western blot analysis indicated that TAEE had a lower toxicity towards gallbladder epithelial cells than MTBE.CONCLUSION We demonstrated that TAEE has higher gallstone dissolubility properties and safety than those of MTBE.As such,TAEE could present an attractive alternative to MTBE if our findings regarding its efficacy and safety can be consistently reproduced in further subclinical and clinical studies.

Generation of induced secretome from adipose-derived stem cells specialized for disease-specific treatment:An experimental mouse model

BACKGROUND Recently,the exclusive use of mesenchymal stem cell(MSC)-secreted molecules,named as the secretome,have been evaluated for overcoming the limitations of cell-based therapy while maintaining its advantages.AIM To improve cell-free therapy by adding disease-specificity through stimulation of MSCs using disease-causing materials.METHODS We collected the secretory materials(named as inducers)released from AML12 hepatocytes that had been pretreated with thioacetamide(TAA)and generated the TAA-induced secretome(TAA-isecretome)after stimulating adipose-derived stem cells with the inducers.The TAA-isecretome was intravenously administered to mice with TAA-induced hepatic failure and those with partial hepatectomy.RESULTS TAA-isecretome infusion showed higher therapeutic potential in terms of(1)restoring disorganized hepatic tissue to normal tissue;(2)inhibiting proinflammatory cytokines(interleukin-6 and tumor necrosis factor-α);and(3)reducing abnormally elevated liver enzymes(aspartate aminotransferase and alanine aminotransferase)compared to the naïve secretome infusion in mice with TAA-induced hepatic failure.However,the TAA-isecretome showed inferior therapeutic potential for restoring hepatic function in partially hepatectomized mice.Proteomic analysis of TAA-isecretome identified that antioxidant processes were the most predominant enriched biological networks of the proteins exclusively identified in the TAA-isecretome.In addition,peroxiredoxin-1,a potent antioxidant protein,was found to be one of representative components of TAA-isecretome and played a central role in the protection of TAA-induced hepatic injury.CONCLUSION Appropriate stimulation of adipose-derived stem cells with TAA led to the production of a secretome enriched with proteins,especially peroxiredoxin-1,with higher antioxidant activity.Our results suggest that appropriate stimulation of MSCs with pathogenic agents can lead to the production of a secretome specialized for protecting against the pathogen.This approach is expected to open a new way of developing various specific therapeutics based on the high plasticity and responsiveness of MSCs.

Clinical outcome in patients with hepatocellular carcinoma after living-donor liver transplantation

AIM: To investigate risk factors for hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT) and efficacy of various criteria. METHODS: From October 2000 to November 2011, 233 adult patients underwent LDLT for HCC at our institution. After excluding nine postoperative mortality cases, we analyzed retrospectively 224 patients. To identify risk factors for recurrence, we evaluated recurrence, disease-free survival (DFS) rate, survival rate, and various other factors which are based on the characteristics of both the patient and tumor. Additionally, we developed our own criteria based on our data. Next, we compared our selection criteria with various tumor-grading scales, such as the Milan criteria, University of California, San Francisco (UCSF) criteria, TNM stage, Barcelona Clinic Liver Cancer (BCLC) stage and Cancer of the Liver Italian Program (CLIP) scoring system. The median follow up was 68 (6-139) mo.RESULTS: In 224 patients who received LDLT for HCC, 37 (16.5%) experienced tumor recurrence during the follow-up period. The 5-year DFS and overall survival rates after LDLT in all patients with HCC were 80.9% and 76.4%, respectively. On multivariate analysis, the tumor diameter {5 cm; P < 0.001; exponentiation of the B coefficient [Exp(B)], 11.89; 95%CI: 3.784-37.368} and alpha fetoprotein level [AFP, 100 ng/mL; P = 0.021; Exp(B), 2.892; 95%CI: 1.172-7.132] had significant influences on HCC recurrence after LDLT. Therefore, these two factors were included in our criteria. Based on these data, we set our selection criteria as a tumor diameter ≤ 5 cm and AFP ≤ 100 ng/mL. Within our new criteria (140/214, 65.4%), the 5-year DFS and overall survival rates were 88.6% and 81.8%, respectively. Our criteria (P = 0.001), Milan criteria (P = 0.009), and UCSF criteria (P = 0.001) showed a significant difference in DFS rate. And our criteria (P = 0.006) and UCSF criteria (P = 0.009) showed a significant difference in overall survival rate. But Milan criteria did not show significant difference in overall survival rate (P = 0.137). Among stages 0, A, B and C of BCLC, stage C had a significantly higher recurrence rate (P = 0.001), lower DFS (P = 0.001), and overall survival rate (P = 0.005) compared with the other stages. Using the CLIP scoring system, the group with a score of 4 to 5 showed a high recurrence rate (P = 0.023) and lower DFS (P = 0.011); however, the overall survival rate did not differ from that of the lower scoring group. The TNM system showed a trend of increased recurrence rate, decreased DFS, or survival rate according to T stage, albeit without statistical significance. CONCLUSION: LDLT is considered the preferred therapeutic option in patients with an AFP level less than 100 ng/mL and a tumor diameter of less than 5 cm.

Comparative long-term outcomes for pancreatic volume change, nutritional status, and incidence of new-onset diabetes between pancreatogastrostomy and pancreatojejunostomy after pancreaticoduodenectomy

Background:The difference in volume change in a pancreatic remnant according to the type of pancreaticoenterostomy after pancreaticoduodenectomy(PD)for long-term follow-up is unknown.Also,there are few studies that evaluate the difference in general nutritional status and pancreatic endocrine function,including new-onset diabetes mellitus(NODM)depending on the type of pancreaticoenterostomy.This study aimed to compare serial pancreatic volume changes in pancreatic remnants between pancreatogastrostomy(PG)and pancreatojejunostomy(PJ)after PD and to evaluate the difference in general nutritional status and incidence of NODM between PG and PJ.Methods:This study enrolled 115 patients who had survived for more than 3 years after PD.They were divided into the PG group and the PJ group.Their clinicopathologic factors were collected and analyzed.We calculated serial pancreas volume and pancreatic duct size precisely from preoperative stage to 5 years after surgery by image-processing software specifically designed for navigation and visualization of multimodality and multidimensional images.Consecutive changes of albumin and body mass index(BMI)as related to general nutritional status were compared between the PG and PJ groups.To evaluate the incidence and risk factors of NODM following PD,subgroup analysis was performed in 88 patients who did not have diabetes preoperatively.Results:Most patient demographics were not significantly different between the PG group(n=45)and PJ group(n=70).There was no significant difference in volume reduction between the groups from postoperative 1 month to 5 years(PG group?18.21±14.66 mL versus PJ group?14.43±13.05 mL,P=0.209).But there was a significant difference in increased pancreatic duct size between the groups from postoperative 1 month to 5 years(PG group 1.66±2.20 mm versus PJ group 0.54±1.54 mm,P=0.007).There was no significant difference in the increase of total serum albumin between the groups for 5 years after surgery(PG group 0.51±0.47 g/dL,14.3%versus PJ group 0.42±0.60 g/dL,11.3%,P=0.437).There was also no significant difference in BMI decrease between the groups(PG group?1.13±3.12,?4.9%versus PJ group?1.97±2.01,?8.7%,P=0.206).On the whole,NODM was diagnosed in 19 patients out of the 88 patients(21.6%)who did not have DM preoperatively.The incidence of NODM was not significantly different between the groups(PG group 21.6%versus PJ group 21.5%,P=0.995).In addition,pancreaticoenterostomy was not an independent risk factor for NODM by logistic regression analysis(odds ratio,0.997,95%CI:0.356–0.2.788,P=0.995).No other risk factors for NODM were found.Conclusions:PG and PJ following PD induced similar pancreatic volume reduction during long-term follow-up.There was no difference in general nutritional status or incidence of NODM between the groups after PD.