STAT3 Decoy Oligodeoxynucleotides Suppress Liver Inflammation and Fibrosis in Liver Cancer Cells and a DDC-Induced Liver Injury Mouse Model.

Liver damage caused by various factors results in fibrosis and inflammation, leading to cirrhosis and cancer. Fibrosis results in the accumulation of extracellular matrix components. The role of STAT proteins in mediating liver inflammation and fibrosis has been well documented; however, approved therapies targeting STAT3 inhibition against liver disease are lacking. This study investigated the anti-fibrotic and anti-inflammatory effects of STAT3 decoy oligodeoxynucleotides (ODN) in hepatocytes and liver fibrosis mouse models. STAT3 decoy ODN were delivered into cells using liposomes and hydrodynamic tail vein injection into 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice in which liver injury was induced. STAT3 target gene expression changes were verified using qPCR and Western blotting. Liver tissue fibrosis and bile duct proliferation were assessed in animal experiments using staining techniques, and macrophage and inflammatory cytokine distribution was verified using immunohistochemistry. STAT3 decoy ODN reduced fibrosis and inflammatory factors in liver cancer cell lines and DDC-induced liver injury mouse model. These results suggest that STAT3 decoy ODN may effectively treat liver fibrosis and must be clinically investigated.

Multiple Graft Bile Ducts Do Not Affect the Postoperative Outcomes of Right Lobe Living Donor Liver Transplantation.

Multiple graft duct openings are associated with a high incidence of biliary complications (BCs), and biliary reconstruction for multiple graft bile ducts (BDs) remains a surgical challenge during living donor liver transplantation (LDLT). In particular, biliary reconstruction using "high biliary radicals (HBR)" of recipients for multiple graft BDs has a high probability of BCs. Herein, we analyzed outcomes by retrospectively reviewing 283 patients who underwent right lobe LDLT from January 2013 to September 2019. In total, 112 LDLT procedures using grafts with multiple BDs have been performed under our policies. In recent cases with 2 orifices located on the same hilar plate, we did dunking with a mucosal eversion technique instead of ductoplasty. When 2 orifices are located far apart on different hilar plates, we attempted to perform separate duct-to-duct anastomosis (DDA) using HBR of the recipient instead of hepaticojejunostomy. Among patients with multiple graft BDs, 20 underwent ductoplasty, 50 were treated using dunking with mucosal eversion technique, and 40 underwent separate DDA using HBR (HBR group). The incidence rates of biliary leakage and stricture were 8.9% and 10.7% in the multiple BD group, respectively, congruent with the outcomes of the single BD group. In subgroup analysis, we compared clinical outcomes between the HBR and single BD groups; the incidence of BCs in the HBR group was 15.0%, comparable to that of the single BD group. In conclusion, multiple graft BDs do not negatively impact the BC rate compared with single-graft BD when applying our technique to prevent BCs.

Technical Refinement to Prevent Hepatic Outflow Disturbance in Right Lobe Living Donor Liver Transplantation: The New Simplified One-Orifice Venoplasty Technique.

Middle hepatic vein (MHV) reconstruction is often essential to avoid hepatic congestion and serious graft dysfunction in living donor liver transplantation (LDLT). This article introduces the evolution of our MHV reconstruction technique and the excellent outcomes of a new simplified one-orifice venoplasty. We compared clinical outcomes among 3 types of one-orifice techniques through a retrospective review of 378 recipients who underwent LDLT using a modified right lobe graft at our institution from January 2008 to December 2018; group I (n = 34) received separate outflow reconstruction, group II (n = 166) received the one-orifice technique to create a wider single outflow with patchwork, and group III (n = 178) received the more simplified one-orifice technique in which neo-MHV was reconstructed into the right hepatic vein without patch venoplasty. Patient demographic characteristics did not differ significantly among the 3 groups, but cold ischemic time and operative time in groups II and III were significantly shorter than those in group I. Moreover, the early patency rates of MHV in groups II and III were higher than those in group I. In particular, group I received an MHV or right hepatic vein stenting more frequently than group II or III during the early posttransplant period. In conclusion, this new simplified one-orifice technique could be an effective method to overcome technical difficulties and the outflow disturbance during right lobe LDLT without complex benchwork to create a large outflow.

Predicting the Recurrence of Hepatocellular Carcinoma after Primary Living Donor Liver Transplantation Using Metabolic Parameters Obtained from 18F-FDG PET/CT.

This study evaluated the prognostic value of metabolic parameters based on the standardized uptake value (SUV) normalized by total body weight (bwSUV) and by lean body mass (SUL) measured on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for predicting tumor recurrence after primary living donor liver transplantation (LDLT) in patients with hepatocellular carcinoma (HCC) without transplantation locoregional therapy. This retrospective study enrolled 49 patients with HCC. The maximum tumor bwSUV (T-bwSUVmax) and SUL (T-SULmax) were measured on PET. The maximum bwSUV (L-bwSUVmax), mean bwSUV (L-bwSUVmean), maximum SUL (L-SULmax), and mean SUL (L-SULmean) were measured in the liver. All metabolic parameters were evaluated using survival analyses and compared to clinicopathological factors. Tumor recurrence occurred in 16/49 patients. Kaplan-Meier analysis revealed that all metabolic parameters were significant (p < 0.05). Univariate analysis revealed that prothrombin-induced by vitamin K absence or antagonist-II; T-stage; tumor number; tumor size; microvascular invasion; the Milan criteria, University of California, San Francisco (UCSF), and up-to-seven criteria; T-bwSUVmax/L-bwSUVmean; T-SULmax; T-SULmax/L-SULmax; and T-SULmax/L-SULmean were significant predictors. Multivariate analysis revealed that the T-SULmax/L-SULmean (hazard ratio = 115.6; p = 0.001; cut-off, 1.81) and UCSF criteria (hazard ratio = 172.1; p = 0.010) were independent predictors of tumor recurrence. SUL-based metabolic parameters, especially T-SULmax/L-SULmean, were significant, independent predictors of HCC recurrence post-LDLT.

Upper Midline Incision Could Become Standard Practice for Living Donor Right Hepatectomy.

BACKGROUND: Laparoscopic approaches have not been performed in living right donor hepatectomy (LDRH) because these are more technically demanding and are associated with increased donor morbidity. Instead, several studies have described LDRH using an upper midline incision (UMI) to reduce donor morbidity. Herein, we describe our experience with small UMI as a standard procedure for LDRH. METHODS: We retrospectively reviewed the outcomes of 444 LDRH at our institution from January 2010 to June 2019; 124 donors received LDRH using UMI (UMI group) and 320 donors underwent LDRH using a J-shaped incision (J-shaped group). This incision has been performed regardless of graft type, body mass index, graft weight, or vascular variations. Patient demographic characteristics, intraoperative parameters, laboratory data, and postoperative complications were compared between the 2 groups. RESULTS: The mean size of the UMIs was 12.4 cm (range, 11-16 cm) and the overall complication rates did not differ significantly between the 2 groups. Most postoperative outcomes were not different between the 2 groups, but the length of hospital stay and operation time in the UMI group were significantly lower than those in the J-shaped group. In multivariate logistic regression analyses, only large grafts (>900 g) and significant hepatic steatosis (≥15%) were significant risk factors for difficult operation but not related to type of incision. CONCLUSION: LDRH could be safely performed with a small UMI and could be considered as standard practice during LDRH.

Safety and Efficacy of Living Donor Hepatectomy Without Systemic Heparinization: Short- and Long-Term Outcomes.

There is no consensus regarding the use of systemic heparin, and long-term outcomes of living donor hepatectomy (LDH) without systemic heparinization have not yet been determined. This study was performed to determine whether systemic heparinization can be omitted during LDH, with a focus on donor safety and long-term outcomes. We retrospectively analyzed the outcomes of 175 cases of LDH performed in our institution between January 2011 and December 2014: group I (n = 79) received systemic heparinization, whereas group II (n = 96) did not, but liver graft was flushed with a heparinized perfusate. Postoperative bleeding requiring blood transfusion or intervention was more frequent in group I than in group II (P = .028). The decreases in donor hemoglobin and hematocrit levels, and platelet count during the early postoperative period, were greater in group I than in group II. In multivariate analysis, systemic heparin was the only independent risk factor for blood transfusion (odds ratio [OR] = 5.114; 95% confidence interval [CI]: 1.201-21.775; P = .027) and significant postoperative bleeding (OR = 7.731; 95% CI: 1.345-44.429; P = .022) after LDH. Most postoperative complications including graft vascular thrombosis were similar between the 2 groups, as was the survival rate, and neither graft loss due to vascular thrombosis nor non-anastomotic biliary stricture was evident. In conclusion, omission of systemic heparinization during LDH is a feasible and safe option without adverse effects.

Feasibility of Dual Living Donor Liver Transplantation From Donors With Complex Portal Vein Variations.

Living donor liver transplantation (LDLT) from donors with complex portal vein anomalies has been considered a challenging procedure because vasculobiliary variations of the donor's liver may lead to significant increases in donor and recipient complications. The use of donors with anatomic variations may be considered under the accurate preoperative planning if a more suitable donor is not available. We report a successful dual LDLT for 2 donors with portal vein anomaly to overcome the small-for-size graft syndrome and secure donor safety. A 62-year-old man was referred to our institution for liver transplant because of hepatitis B-related liver cirrhosis with hepatocellular carcinoma. The only available donors were his son and his daughter-in-law, one with type IV portal venous anatomic variation and the other with type III variation. Neither of the 2 available donors were suitable as a single donor because of the complexity of the portal vein reconstruction and the donor's safety. Therefore, the decision was made to perform LDLT using dual graft, and we planned to harvest the right posterior sector graph from the first donor together with the left lobe graft of the second donor. Donor hepatectomy and recipient total hepatectomy were performed in the usual manner. He has recovered well with normal graft function, and there has been no tumor recurrence after dual LDLT. Dual graft LDLT using right posterior sector and left lobe graft could be undertaken successfully to overcome the small-for-size graft syndrome and secure the safety of donors in cases with the complex portal vein anomalies.

Novel Method for Reconstructing Multiple Graft Bile Ducts During Right Lobe Living Donor Liver Transplant: Dunking With Mucosal Eversion Technique.

BACKGROUND: Multiple graft bile ducts (BDs) and anastomoses have been considered as risk factors for biliary complications after living donor liver transplant (LDLT). Various surgical techniques have been introduced, and most surgeons perform unification ductoplasty for multiple adjacent BDs during LDLT. However, this could cause hemobilia and is difficult to perform when 2 ductal orifices are far apart or show a size discrepancy. METHODS: Here, we introduce our novel reconstruction technique for multiple adjacent graft BDs and discuss its effects on postoperative outcomes compared with ductoplasty. We compared the clinical outcomes of 2 biliary reconstruction techniques by retrospectively reviewing 58 recipients who underwent LDLT with right lobe grafts using these 2 techniques at our institution between January 2013 and September 2018: group 1 (n = 20) received ductoplasty, and group 2 (n = 38) was treated with dunking with mucosal eversion technique. RESULTS: Overall biliary complication rates were 20.0% in group 1 and 10.5% in group 2 (P = .32). Biliary stricture in group 2 was not frequent compared with that in group 1 (7.9% vs 15.0%, P = .398). Moreover, incidence of biliary stricture in group 2 was not different than that in the group using graft with single BD during the same period (P > .624). CONCLUSIONS: Our novel technique could be a useful method for reconstructing adjacent BDs in LDLT and the best alternative to ductoplasty. Moreover, it seems to be a reasonable option when 2 orifices are far apart or show a size discrepancy.

A Multicenter, Randomized, Open-Label Study to Compare Micafungin with Fluconazole in the Prophylaxis of Invasive Fungal Infections in Living-Donor Liver Transplant Recipients.

BACKGROUND: Although invasive fungal infections (IFIs) contribute to substantial morbidity and mortality in liver transplant recipients, only a few randomized studies analyzed the results of antifungal prophylaxis with echinocandins. The aim of this open-label, non-inferiority study was to evaluate the efficacy and safety of micafungin in the prophylaxis of IFIs in living-donor liver transplantation recipients (LDLTRs), with fluconazole as the comparator. METHODS: LDLTRs (N = 172) from five centers were randomized 1:1 to receive intravenous micafungin 100 mg/day or fluconazole 100~200 mg/day (intravenous or oral). A non-inferiority of micafungin was tested against fluconazole. RESULTS: The per-protocol set included 144 patients without major clinical trial protocol violations: 69 from the micafungin group and 75 from the fluconazole group. Mean age of the study patients was 54.2 years and mean model for end-stage liver disease (MELD) score amounted to 16.5. Clinical success rates in the micafungin and fluconazole groups were 95.65% and 96.10%, respectively (difference: - 0.45%; 90% confidence interval [CI]: - 6.93%, 5.59%), which demonstrated micafungin's non-inferiority (the lower bound for the 90% CI exceeded - 10%). The study groups did not differ significantly in terms of the secondary efficacy endpoints: absence of IFIs at the end of the prophylaxis and the end of the study, time to proven IFI, fungal-free survival, and adverse reactions. A total of 17 drug-related adverse events were observed in both groups; none of them was serious and all resolved. CONCLUSION: Micafungin can be used as an alternative to fluconazole in the prevention of IFIs in LDLTRs. CLINICAL TRIALS REGISTRATION: NCT01974375.

Comparison of hepatic artery reconstruction using surgical loupe and operating microscope during living donor liver transplantation focusing on the beginner's point.

BACKGROUNDS/AIMS: Hepatic artery (HA) reconstruction during living donor liver transplantation (LDLT) has been performed by experienced microsurgeons with operative microscope in most centers. However, it takes long time to learn the skills and so, to simplify this procedure, transplant surgeons recently performed this procedure using surgical loupe. METHODS: This study retrospectively reviewed outcomes of 237 LDLTs at our institution from January 2012 to October 2016. In group I, HA reconstruction was performed under operative microscope by an experienced microsurgeon and in group II, it was performed using surgical loupe by a transplant surgeon with little experience for arterial anastomosis. RESULTS: There was no difference in most perioperative outcomes between two groups except mean time required for HA reconstruction (24.2±4.3 vs. 20.9±6.9 minutes, p=0.001). Multivariable regression modeling to adjust for baseline differences showed that the use of surgical loupe was not associated with either HA thrombosis or intraoperative HA revision rate. CONCLUSIONS: HA reconstruction under surgical loupe can be performed simply and yields results as good as with operative microscopy, even when the transplant surgeon has less experience with HA anastomosis.

Effects of µ-Opioid Receptor Gene Polymorphism on Postoperative Nausea and Vomiting in Patients Undergoing General Anesthesia with Remifentanil: Double Blinded Randomized Trial.

Association between postoperative nausea and vomiting (PONV) and µ-opioid receptor A118G single nucleotide polymorphism (SNP) is undefined and might underlie inconsistent results of studies on PONV occurrence in patients undergoing general anesthesia with the opioid, remifentanil. Four hundred and sixteen Korean women undergoing breast surgery with general anesthesia were randomized to receive remifentanil 10 ng/mL (plasma-site, Minto model) using a target-controlled infusion device and either propofol for total intravenous anesthesia (T group) or sevoflurane for inhalation anesthesia (I group) with bispectral index values maintained between 40 and 60. Blood specimens were collected after anesthesia induction for A118G SNP analysis. PONV and postoperative pain were evaluated. A118G SNP type distribution among Korean female adults studied was AG (n=195)>AA (n=158)>GG (n=63). Regardless of anesthetic technique, patients with GG types had lower PONV scale on arrival at postoperative care unit (PACU) (P=0.002), while T group showed lower PONV scale than I group up to 6 hr after PACU discharge in AA and AG types. No differences were apparent for postoperative pain among opioid receptor polymorphism. PONV occurrence differs according to opioid receptor polymorphism and anesthetic technique in patients undergoing general anesthesia with remifentanil.

Salvage dual graft living donor liver transplantation after major hepatectomy.

Salvage living donor liver transplantation (LDLT) after major hepatectomy has been considered a challenging procedure due to operative complexity. We report a successful case of salvage dual graft LDLT after right hepatectomy. A 48-year-old male was transferred to Daegu Catholic University Medical Center because of duodenal variceal bleeding. He underwent right hepatectomy due to hepatocellular carcinoma four years prior. We performed LDLT with dual graft from his wife and sister. During operation, portal vein anastomosis of the right lobe graft was performed using an interposing cadaveric iliac vein graft and the right gastroepiploic artery was anastomosed to the hepatic artery of the left lobe graft. Adequate graft inflow was demonstrated by postoperative imaging studies. He has been doing well with normal graft function for 31 months. Salvage dual graft LDLT could be undertaken successfully in patients with prior major hepatectomy under accurate preoperative planning and proper surgical techniques.

The paracholedochal vein: a feasible option as portal inflow in living donor liver transplantation.

Extensive thrombosis of the portal and splenomesenteric veins combined with cavernous transformation of the portal vein (CTPV) has been considered to be a contraindication for living donor liver transplantation (LDLT) due to technical difficulties and perioperative risks. In recent years, several surgical innovations including cavoportal hemitransposition, renoportal anastomosis, and portal arterialization have been introduced to overcome diffuse portal vein thrombosis (PVT) and CTPV, but their outcomes were unsatisfactory with significant morbidity and mortality. Herein, we report two successful cases of adult LDLT in diffuse PVT with CTPV managed using the paracholedochal vein as portal inflow to the graft.

Simplified one-orifice venoplasty for middle hepatic vein reconstruction in adult living donor liver transplantation using right lobe grafts.

Middle hepatic vein (MHV) reconstruction is often essential to avoid hepatic congestion and serious graft dysfunction in living donor liver transplantation (LDLT). The aim of this report was to introduce evolution of our MHV reconstruction technique and excellent outcomes of simplified one-orifice venoplasty. We compared clinical outcomes with two reconstruction techniques through retrospective review of 95 recipients who underwent LDLT using right lobe grafts at our institution from January 2008 to April 2012; group 1 received separate outflow reconstruction and group 2 received new one-orifice technique. The early patency rates of MHV in group 2 were higher than those in group 1; 98.4% vs. 88.2% on postoperative day 7 (p = 0.054) and 96.7% vs. 82.4% on postoperative day 14, respectively (p = 0.023). Right hepatic vein (RHV) stenosis developed in three cases in group 1, but no RHV stenosis developed because we adopted one-orifice technique (p = 0.043). The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in group 2 were significantly lower than those in group 1 during the early post-transplant period. In conclusion, our simplified one-orifice venoplasty technique could secure venous outflow and improve graft function during right lobe LDLT.

Characteristic clinical and pathologic features for preoperative diagnosed groove pancreatitis.

PURPOSE: Groove pancreatitis is a rare specific form of chronic pancreatitis that extends into the anatomical area between the pancreatic head, the duodenum, and the common bile duct, which are referred to as the groove areas. We present the diagnostic modalities, pathological features and clinical outcomes of a series of symptomatic patients with groove pancreatitis who underwent pancreaticoduodenectomy. METHODS: Six patients undergoing pancreaticoduodenectomy between May 2006 and May 2009 due to a clinical diagnosis of symptomatic groove pancreatitis were retrospectively included in the study. RESULTS: Five cases were male and one case was female, with a median age at diagnosis of 50 years. Their chief complaints were abdominal pain and vomiting. Abdominal computed tomography, endoscopic ultrasound and endoscopic retrograde cholangiopancreatography were performed. Preoperative diagnosis of all patients was groove pancreatitis. Histological finding was compatible with clinically diagnosed groove pancreatitis in five patients and the pathologic diagnosis of the remaining patient was adenocarcinoma of distal common bile duct. Following pancreaticoduodenectomy, four living patients experienced significant pain alleviation. CONCLUSION: The diagnostic imaging modalities of choice for groove pancreatitis are computed tomography and endoscopic ultrasonography. If symptomatic groove pancreatitis is suspected, careful follow-up of patients is necessary and pancreaticoduodenectomy seems to be a reasonable treatment option.

An early single-center experience of portal vein thrombosis in living donor liver transplantation: clinical feature, management and outcome.

PURPOSE: Portal vein thrombosis (PVT) has been considered a relative contraindication for living donor liver transplantation (LDLT). However, it is no longer a contraindication of LDLT due to improvement in surgical techniques and approaches to PVT. The aim of this study was to assess the impact of PVT on outcomes in LDLT patients. METHODS: We retrospectively analyzed the data from 97 adult patients undergoing LDLT in our center from July 2008 to June 2010. Intraoperative findings and preoperative imaging results were reviewed for PVT grading (Yerdel grading). We analyzed the technical aspects and comparisons of risk factors, perioperative variables, and survivals between patients with and without PVT based on the grades. RESULTS: In the 97 LDLT patients, 18 patients were confirmed to have PVT (18.5%) including grade I cases (n = 8), grade II (n = 7), and grade III (n = 3). Prior treatment of portal hypertension was found to be an independent risk factor for PVT (P = 0.001). The comparisons between PVT and no PVT groups showed no significant difference in intraoperative and postoperative variables except for postoperative bleeding (P = 0.036). The short-term portal vein patency, in-hospital mortality and survival rates were not significantly different between the PVT and control groups. CONCLUSION: The outcomes are similar to non-PVT group in terms of in-hospital mortality, survival rates, and postoperative complications. Therefore, our study suggests that PVT cannot be considered to be a contraindication for LDLT and LDLT could be undertaken without increased morbidity and mortality in patients with PVT, in spite of operative complexity.

The value of gadoxetate disodium-enhanced MR imaging for predicting posthepatectomy liver failure after major hepatic resection: a preliminary study.

PURPOSE: To investigate whether preoperative gadoxetate-disodium-enhanced MR imaging predicts posthepatectomy liver failure (PHLF) in patients who underwent major hepatic resection. MATERIALS AND METHODS: Twenty nine patients who underwent preoperative gadoxetate-disodium-enhanced MR imaging and following major hepatic resection were enrolled. Hepatic parenchymal signal intensity (SI) on pre-contrast T1-weighted imaging and 20min hepatocyte phase was measured at each of the four liver segments by two observers using region of interest measurements. The mean value was calculated and used at each phase. The relative contrast enhancement index (RCEI) was calculated: (20min hepatocyte phase SI-pre-contrast SI)/pre-contrast SI. PHLF was determined by the International Study Group of Liver Surgery 2011 guidelines. Correlation analysis was performed between preoperative liver function test and RCEI. Diagnostic accuracy of RCEI for predicting PHLF was calculated with receiver operating characteristic curve analysis. The reproducibility of the RCEI measurement was evaluated. RESULTS: There was a significant correlation between preoperative albumin (r=0.496, P=0.006), T-bilirubin (r=-0.383, P=0.041), and RCEI. Seven patients (24%) experienced PHLF, and one of these patients (3%) died. The diagnostic accuracy of RCEI was 0.838 (sensitivity 85.7%, specificity 77.3%, cut-off value: 0.7508, 95% confidence interval: 0.654, 0.947). The 95% limits of agreement and ICC between repeated RCEI measurements were 18.4% of the mean and 0.94, respectively, and between RCEI measurements by the two observers were 21.7% and 0.929, respectively. CONCLUSION: Our results show that preoperative gadoxetate-disodium-enhanced MR imaging can predict PHLF in patients who underwent major hepatic resection.