SOD1 inhibition enhances sorafenib efficacy in HBV-related hepatocellular carcinoma by modulating PI3K/Akt/mTOR pathway and ROS-mediated cell death.

Hepatitis B Virus (HBV) infection significantly elevates the risk of hepatocellular carcinoma (HCC), with the HBV X protein (HBx) playing a crucial role in cancer progression. Sorafenib, the primary therapy for advanced HCC, shows limited effectiveness in HBV-infected patients due to HBx-related resistance. Numerous studies have explored combination therapies to overcome this resistance. Sodium diethyldithiocarbamate (DDC), known for its anticancer effects and its inhibition of superoxide dismutase 1 (SOD1), is hypothesized to counteract sorafenib (SF) resistance in HBV-positive HCCs. Our research demonstrates that combining DDC with SF significantly reduces HBx and SOD1 expressions in HBV-positive HCC cells and human tissues. This combination therapy disrupts the PI3K/Akt/mTOR signalling pathway and promotes apoptosis by increasing reactive oxygen species (ROS) levels. These cellular changes lead to reduced tumour viability and enhanced sensitivity to SF, as evidenced by the synergistic suppression of tumour growth in xenograft models. Additionally, DDC-mediated suppression of SOD1 further enhances SF sensitivity in HBV-positive HCC cells and xenografted animals, thereby inhibiting cancer progression more effectively. These findings suggest that the DDC-SF combination could serve as a promising strategy for overcoming SF resistance in HBV-related HCC, potentially optimizing therapy outcomes.

Reconstruction of all hepatic arteries in right lobe grafts with 2 hepatic arteries and zero percent hepatic artery thrombosis.

Hepatic artery thrombosis (HAT) is a common cause of graft loss in living-donor liver transplantation, occurring in ~2.5%-8% of patients. Some right lobe grafts have 2 hepatic arteries (HAs), and the optimal reconstruction technique remains controversial. This study aimed to identify risk factors for HAT and to evaluate the efficacy of reconstructing 2 HAs in right lobe grafts. This retrospective, single-center study analyzed 1601 living-donor liver transplantation recipients with a right liver graft and divided them into 1 HA (n = 1524) and 2 HA (n = 77) groups. The reconstruction of all HAs was performed using a microscope with an interrupted suture. The primary outcome was any HAT event. Of the 1601 patients, 37.8% had a history of transcatheter arterial chemoembolization, and 130 underwent pretransplant hepatectomy. Extra-anatomical arterial reconstruction was performed in 38 cases (2.4%). HAT occurred in 1.2% of patients (20/1601) who underwent surgical revascularization. In the multivariate analysis, undergoing pretransplant hepatectomy ( p = 0.008), having a female donor ( p = 0.02), having a smaller graft-to-recipient weight ratio ( p = 0.002), and undergoing extra-anatomical reconstruction ( p = 0.001) were identified as risk factors for HAT. However, having 2 HA openings in right liver grafts was not a risk factor for HAT in our series. Kaplan-Meier survival analysis showed no significant difference in graft survival and patient survival rates between the 1 HA and 2 HA groups ( p = 0.09, p = 0.97). In our series, although the smaller HA in the 2 HA group should increase the risk of HAT, HAT did not occur in this group. Therefore, reconstructing both HAs when possible may be a reasonable approach in living-donor liver transplantation using a right liver graft with 2 HA openings.

Recipient blood group does not affect hepatocellular carcinoma recurrence after living donor liver transplantation in Korea.

PURPOSE: This study assessed whether or not the ABO blood type affects the incidence of HCC recurrence after living donor liver transplantation (LDLT). METHODS: This retrospective observational study included 856 patients with hepatocellular carcinoma (HCC) who underwent LDLT between January 2006 and December 2016 at the Asan Medical Center. RESULTS: This study included 324 patients (37.9%) with blood type A, 215 (25.1%) with blood type B, 210 (24.5%) with blood type O, and 107 (12.5%) with blood type AB. ABO-incompatible LT was performed in 136 (15.9%) patients. The independent risk factors for the disease-free survival (DFS) were maximal tumor diameter, microvascular invasion, and Milan criteria. The only independent risk factor for the overall survival (OS) was microvascular invasion. The ABO blood group did not affect the DFS (P = 0.978) or OS (P = 0.261). The DFS according to the ABO blood group did not differ significantly between the ABO-compatible (p = 0.701) and ABO-incompatible LDLT recipients (p = 0.147). The DFS according to the ABO blood group did not differ significantly between patients within the Milan criteria (p = 0.934) and beyond the Milan criteria (p = 0.525). The DFS did not differ significantly between recipients with and without type A blood (p = 0.941). CONCLUSIONS: This study demonstrated that the ABO blood group system had no prognostic impact on the oncological outcomes of patients undergoing LT for HCC.

Efficacy and safety of adhesion barrier in living-donor liver transplantation with right liver graft to prevent delayed gastric emptying.

Delayed gastric emptying (DGE) is a common complication of liver transplantation. This study aimed to clarify the efficacy and safety of the application of an adhesion barrier for preventing DGE in living-donor liver transplantation. This retrospective study included 453 patients who underwent living-donor liver transplantation using a right lobe graft between January 2018 and August 2019, and the incidence of postoperative DGE and complications was compared between patients in whom adhesion barrier was used (n=179 patients) and those in whom adhesion barrier was not used (n=274 patients). We performed 1:1 propensity score matching between the 2 groups, and 179 patients were included in each group. DGE was defined according to the International Study Group for Pancreatic Surgery classification. The use of adhesion barrier was significantly associated with a lower overall incidence of postoperative DGE in liver transplantation (30.7 vs. 17.9%; p =0.002), including grades A (16.8 vs. 9.5%; p =0.03), B (7.3 vs. 3.4%; p =0.08), and C (6.6 vs. 5.5%; p =0.50). After propensity score matching, similar results were observed for the overall incidence of DGE (29.6 vs. 17.9%; p =0.009), including grades A (16.8 vs. 9.5%; p =0.04), B (6.7 vs. 3.4%; p =0.15), and C (6.1 vs. 5.0%; p =0.65). Univariate and multivariate analyses showed a significant correlation between the use of adhesion barrier and a low incidence of DGE. There were no statistically significant differences in postoperative complications between the 2 groups. The application of an adhesion barrier could be a safe and feasible method to reduce the incidence of postoperative DGE in living-donor liver transplantation.

Favorable Prognostic Factors for Survival Outcomes of Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis After Hepatectomy.

BACKGROUND: This study aimed to investigate prognostic factors of recurrence and survival associated with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). PATIENTS AND METHODS: This retrospective study included 161 patients with HCC with PVTT who underwent hepatectomy between January 2003 and January 2014 at the Asan Medical Center. Regression analyses were conducted to identify favorable predictive factors for overall survival (OS) and recurrence-free survival (RFS). RESULTS: The median follow-up was 15.9 months, while 1-, 3-, and 5-year OS was 65.0%, 38.4%, and 36.0%, respectively, and 1-year RFS was 25.5%. There were no significant differences in OS and RFS between the patients with portal vein invasion (Vp) 1-2 and Vp3-4 PVTT. Patients with intrahepatic recurrence had significantly better overall survival than patients with extrahepatic recurrence. Transcatheter arterial chemoembolization and radiofrequency ablation were the most effective treatments for intrahepatic metastasis, and surgery was the most effective treatment for extrahepatic metastasis. On multivariate analysis, absence of esophageal varices, maximal tumor size < 5 cm, tumor location in single lobe, and anatomical resection were favorable prognostic factors for OS and R0 resection, and absence of microvascular invasion was a favorable prognostic factor for RFS. CONCLUSION: The long-term outcome of patients with HCC with PVTT can be improved under consideration of favorable prognostic factors including absence of esophageal varices, maximal tumor size < 5 cm, tumor location in single lobe, and anatomical resection, R0 resection, and absence of microvascular invasion. In addition, recurrent HCC required aggressive management to prolong overall survival.

Incidence of superficial left hepatic vein and its usability for graft hepatic vein venoplasty in pediatric liver transplantation.

BACKGROUNDS: The anatomy of the left hepatic vein (LHV) is variable; thus, it should be considered for graft hepatic vein (GHV) venoplasty for left lateral section (LLS) and left liver grafts. This study assessed the incidence of superficial LHV (sLHV) branches according to LHV anatomy and its usability for GHV venoplasty in pediatric liver transplantation (LT). METHODS: This study consisted of three parts: (1) anatomical classification of LHV variations and the incidence of sLHV branches; (2) morphometric simulative analysis of GHV reconstruction and (3) clinical application based on LHV anatomy. RESULTS: The LHV anatomy of 248 potential LLS graft donors was classified into four types according to the number and location of GHV openings: one single opening (type 1; n = 186 [75.0%]), two large openings (type 2; n = 35 [14.1%]), one large and one small adjacent opening (type 3; n = 14 [5.6%]), and two large widely-separated openings (type 4; n = 13 [5.2%]). An sLHV branch was identified in 87 of 248 (35.1%) donor livers. Morphometric analysis of simulative GHV venoplasty with an sLHV branch increased GHV diameters by 30% in type 1 LLS grafts and 20% in type 2/3 LLS grafts. An analysis of 50 consecutive patients who underwent pediatric LT showed that the 2-year rates of GHV obstruction were 2.0% with LLS grafts and 0% with left liver grafts. CONCLUSIONS: The GHV orifice can be enlarged through LHV anatomy-based unification venoplasty. Unification venoplasty with an sLHV branch provided sufficient enlargement of the GHV orifice.

Analysis of outcomes and renal recovery after adult living-donor liver transplantation among recipients with hepatorenal syndrome.

When timely access to deceased-donor livers is not feasible, living-donor liver transplantation (LDLT) is an attractive option for patients with hepatorenal syndrome (HRS). This study's primary objective was to describe outcomes after LDLT among HRS recipients, and the secondary objective was to determine predictors of poor renal recovery after LDLT. This single-center, retrospective study included 2185 LDLT recipients divided into HRS (n = 126, 5.8%) and non-HRS (n = 2059, 94.2%) groups. The study outcomes were survival and post-LT renal recovery. The HRS group had a higher death rate than the non-HRS group (17.5% vs. 8.6%, p < 0.001). In the HRS group, post-LT renal recovery occurred in 69.0%, and the death rate was significantly lower in association with HRS recovery compared with non-recovery (5.7% vs. 43.6%, p < 0.001). Multivariable analysis indicated that post-LT sepsis (p < 0.001) and non-recovery of HRS (p < 0.001) were independent negative prognostic factors for survival. Diabetes mellitus (p = 0.01), pre-LT peak serum creatinine ≥3.2 mg/dl (p = 0.002), time interval from HRS diagnosis to LDLT ≥38 days (p = 0.01), and post-LT sepsis (p = 0.03) were important negative prognostic factors for renal recovery after LDLT. In conclusion, post-LT renal recovery was important for survival, and the interval from HRS to LDLT was significantly associated with post-LT renal recovery.

Recent Improvement in Survival Outcomes and Reappraisal of Prognostic Factors in Pediatric Living Donor Liver Transplantation.

Living donor liver transplantation (LDLT) is a significant advancement for the treatment of children with end-stage liver disease given the shortage of deceased donors. The ultimate goal of pediatric LDLT is to achieve complete donor safety and zero recipient mortality. We conducted a retrospective, single-center assessment of the outcomes as well as the clinical factors that may influence graft and patient survival after primary LDLTs performed between 1994 and 2020. A Cox proportional hazards model was used for multivariate analyses. The trends for independent prognostic factors were analyzed according to the following treatment eras: 1, 1994 to 2002; 2, 2003 to 2011; and 3, 2012 to 2020. Primary LDLTs were performed on 287 children during the study period. Biliary atresia (BA; 52%), acute liver failure (ALF; 26%), and monogenic liver disease (11%) were the leading indications. There were 45 graft losses (16%) and 27 patient deaths (7%) in this population during the study period. During era 1 (n = 81), the cumulative survival rates at 1 and 5 years after LDLT were 90.1% and 81.5% for patients and 86.4% and 77.8% for grafts, respectively. During era 2 (n = 113), the corresponding rates were 92.9% and 92% for patients and 89.4% and 86.7% for grafts, respectively. During era 3 (n = 93), the corresponding rates were 100% and 98.6% for patients and 98.9% and 95.4% for grafts, respectively. In the multivariate analyses, primary diagnosis ALF, bloodstream infection, posttransplant lymphoproliferative disease, and chronic rejection were found to be negative prognostic indicators for patient survival. Based on generalized care guidelines and center-oriented experiences, comprehensive advances in appropriate donor selection, refinement of surgical techniques, and meticulous medical management may eventually realize a zero-mortality rate in pediatric LDLT.

Operative and long-term oncologic outcomes of laparoscopic versus open major liver resection in patients with a high body mass index (> 25 kg/m2): a propensity score matching analysis.

BACKGROUND: With the recent rapid increase in the prevalence of obesity, the number of obese patients requiring liver resection, including laparoscopy, has increased. Accordingly, evaluating the outcome of laparoscopic liver resection in obese patients is increasingly important. This study aimed to compare the safety and feasibility of laparoscopic major liver resection (LMR) and open major liver resection (OMR) in patients with a high body mass index (BMI > 25.0 kg/m2). METHODS: We reviewed 521 patients with high BMI (> 25.0 kg/m2) who underwent major liver resection for various indications between January 2009 and November 2018 at Asan Medical Center. We performed 1:1 propensity score matching of the LMR and OMR groups, with 120 patients subsequently included in each group. RESULTS: LMR was associated with lower blood loss and shorter postoperative hospital stays (p < 0.001). Although there was no significant difference in overall complications (p = 0.080), non-liver-specific complications were observed less frequently after LMR (p = 0.025). American Society of Anesthesiologists class > II, BMI > 30 kg/m2, and malignancy were independent predictors of morbidity. In a subgroup analysis of patients with hepatocellular carcinoma, there was no significant difference between the two groups in overall survival (hazard ratio 0.225; 95% confidence interval 0.049-1.047; p = 0.057) and recurrence-free survival (hazard ratio 0.761; 95% confidence interval 0.394-1.417; p = 0.417). CONCLUSIONS: Obesity should not be considered a contraindication for major liver resection using a laparoscopic approach; however, when applying this approach for resecting malignancies in patients with a BMI > 30 kg/m2 and comorbid diseases, special attention should be paid to the possibility of complications.

Safe use of right lobe living donor livers with moderate steatosis in adult-to-adult living donor liver transplantation: a retrospective study.

Hepatic steatosis (HS) beyond a certain degree can jeopardize living donor (LD) safety, particularly in right lobe (RL) donors, making it a major obstacle for donor pool expansion in adult-to-adult living donor liver transplantation (ALDLT). From July 2004 to June 2016, 58 LDs donated their RLs despite having moderate HS (30%-50% steatosis) determined by intraoperative biopsy at a single center. We performed greedy matching to compare the outcomes of the donors and recipients of this group with those of LDs with no HS. The mean left lobe (LL) HS value in the 58 cases was 20.9 ± 12.4%, which was significantly lower than the mean RL HS value (38.8 ± 6.7%, P < 0.001). The mean ratio of the remnant LL to the total liver volume was 37.8 ± 2.2. No differences were observed in the postoperative liver function and donor and recipient morbidity and mortality rates. The liver regeneration rates in recipients and donors at 1 month, 6 months, and 1 year postoperatively did not differ significantly. The patient and graft survival rates of the recipients showed no differences. The use of well-selected RL grafts with moderate steatosis does not impair graft function, recipient outcomes, or donor safety.

Outflow vein venoplasty of left lateral section graft for living donor liver transplantation in infant recipients.

The orifice size of the LHV trunk in LLS grafts is often too small for direct anastomosis. Several methods were developed to enlarge the graft and recipient hepatic vein orifices. This study described our surgical techniques to secure hepatic vein reconstruction in infant recipients and analyzed the patency outcomes. Twelve infants undergoing pediatric LDLT were selected during 2-year study period between January 2018 and December 2019. Surgical techniques and vascular complications of graft hepatic vein outflow were analyzed. The mean recipient age was 12.5 ± 4.5 months; mean body weight was 9.4 ± 1.0 Kg; and mean graft-recipient weight ratio was 2.8 ± 0.6%. Primary diseases were biliary atresia in six patients, metabolic diseases in two, hepatoblastoma in two, and acute liver failure in two. Eight LLS grafts were recovered through an open method, and four LLS grafts were recovered through a laparoscopic method. A small superficial LHV branch was present in five of 12 LLS grafts, which was opened to widen the graft hepatic vein orifice. Incision-and-patch venoplasty was performed in 10, unification venoplasty in 1 and no venoplasty in 1. All four LLS grafts recovered through a laparoscopic approach required circumferential vein patch because of very short hepatic vein stump. No patient experienced graft hepatic vein-associated vascular complications during the follow-up period of 19.3 ± 9.3 months. Our surgical techniques with incision-and-patch venoplasty for LLS grafts is beneficial to reduce the risk of hepatic vein outflow obstruction in recipients receiving LLS grafts.

Long-term perioperative outcomes of pure laparoscopic liver resection versus open liver resection for hepatocellular carcinoma: a retrospective study.

BACKGROUND: Laparoscopic treatment for hepatocellular carcinoma (HCC) has increased. We retrospectively compared the perioperative and long-term oncological outcomes of laparoscopic liver resection (LLR) with those of open liver resection (OLR) for hepatocellular carcinoma (HCC) in well-matched patient groups using propensity score matching (PSM). METHODS: We reviewed medical records of patients with HCC who underwent liver resection between July 2007 and April 2016 at our center. In total, 2335 patients were included in this study and divided into LLR (n = 264) and OLR (n = 2071) groups. For group comparisons, 1:2 PSM was used with covariates of baseline characteristics, including tumor characteristics and surgical liver resection procedures. RESULTS: After PSM, there were 217 and 434 patients in the LLR and OLR groups, respectively. The LLR group had shorter hospital stays (8.9 vs. 14.8 days; P < 0.001) and lower postoperative morbidity (6.5% vs. 12.0%; P = 0.022). The 1-, 3-, and 5-year overall survival rates were 98.1%, 87.0%, and 78.6%, respectively, for the LLR group, and 98.3%, 90.8%, and 84.3%, respectively, for the OLR group (P = 0.570). The 1-, 3-, and 5-year disease-free survival rates were 81.0%, 62.0%, and 49.1%, respectively, for the LLR group, and 85.3%, 64.7%, and 56.2%, respectively, for the OLR group (P = 0.563). CONCLUSIONS: Long-term oncological outcomes were comparable between LLR and OLR for selected patients. LLR was associated with multiple benefits, even for selected patients with cirrhosis who underwent major hepatectomy. LLR for HCC performed by an experienced surgeon could be considered a safe and feasible alternative to OLR for selected patients.

Prognosis of Split Liver Transplantation Compared with Whole Liver Transplantation in Adult Patients: Single-center Results under the Korean MELD Score-based Allocation Policy.

BACKGROUND: Split liver transplantation (SLT) has been occasionally performed in Korea. This study compared the incidence and prognosis of SLT with whole liver transplantation (WLT) in adult patients. METHODS: Between June 2016 and November 2019, 242 adult patients underwent a total of 256 deceased donor liver transplantation operations. SLT was performed in 7 patients (2.9%). RESULTS: The mean age of SLT donors was 29.7 ± 7.4 years, and the mean age of recipients was 55.7 ± 10.6 years, with the latter having a mean model for end-stage liver disease score of 34.6 ± 3.1. Mean split right liver graft weight was 1,228.6 ± 149.7 g and mean graft-recipient weight ratio was 1.97 ± 0.39. Of the seven SLT recipients, Korean Network for Organ Sharing (KONOS) status was one in status 1, one in status 2 and five in status 3. The graft (P = 0.72) and patient (P = 0.84) survival rates were comparable in the SLT and WLT groups. Following propensity score matching, graft (P = 0.61) and patient (P = 0.91) survival rates remained comparable in the two groups. Univariate analysis showed that pretransplant ventilator support and renal replacement therapy were significantly associated with patient survival, whereas KONOS status category and primary liver diseases were not. Multivariate analysis showed that pretransplant ventilator support was an independent risk factor for patient survival. CONCLUSION: Survival outcomes were similar in adult SLT and WLT recipients, probably due to selection of high-quality grafts and low-risk recipients. Prudent selection of donors and adult recipients for SLT may expand the liver graft pool for pediatric patients without affecting outcomes in adults undergoing SLT.

Pretransplant Hepatic Malignancy Increases Risk of De Novo Malignancy after Liver Transplantation.

BACKGROUND: Hepatocellular carcinoma (HCC) recurrence and development of de novo malignancy (DNM) after liver transplantation (LT) are the major causes of late recipient death. METHODS: We analyzed the incidence of extrahepatic DNM following living donor LT according to the status of pretransplant hepatic malignancy. We selected 2,076 adult patients who underwent primary LDLT during 7 years from January 2010 to December 2016. RESULTS: The pretransplant hepatic malignancy group (n = 1,012) showed 45 cases (4.4%) of the following extrahepatic DNMs: posttransplant lymphoproliferative disease (PTLD) in 10; lung cancer in 10; stomach cancer in 6; colorectal cancer in 5; urinary bladder cancer in 3; and other cancers in 11. The pretransplant no hepatic malignancy group (n = 1,064) showed 25 cases (2.3%) of the following extrahepatic DNMs: colorectal cancer in 3; stomach cancer in 3; leukemia in 3; lung cancer in 3; PTLD in 2; prostate cancer in 2; and other cancers in 9. Incidences of extrahepatic DNM in the pretransplant hepatic malignancy and no hepatic malignancy groups were as follows: 1.1% and 0.5% at 1 year, 3.2% and 2.0% at 3 years, 4.6% and 2.5% at 5 years, and 5.4% and 2.8% at 8 years, respectively (P = 0.006). Their overall patient survival rates were as follows: 97.3% and 97.2% at 1 year, 91.6% and 95.9% at 3 years, 89.8% and 95.4% at 5 years, and 89.2% and 95.4% at 8 years, respectively (P < 0.001). Pretransplant hepatic malignancy was the only significant risk factor for posttransplant extrahepatic DNM. CONCLUSION: Our results suggest that patients who had pretransplant hepatic malignancy be followed up more strictly because they have a potential risk of primary hepatic malignancy recurrence as well as a higher risk of extrahepatic DNM than patients without pretransplant hepatic malignancy.

Hepatitis B Prophylaxis after Liver Transplantation in Korea: Analysis of the KOTRY Database.

BACKGROUND: Prophylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. We conducted real-world analysis of HBV prophylaxis after LT in the Korean population. METHODS: Korean Organ Transplantation Registry (KOTRY) database and additionally collected data (n = 326) were analyzed with special reference to types of HBV prophylaxis. RESULTS: The study cohort comprised 267 cases of living-donor LT and 59 cases of deceased-donor LT. Hepatocellular carcinoma (HCC) was diagnosed in 232 (71.2%) of these subjects. Antiviral agents were used in 255 patients (78.2%) prior to LT. HBV DNA was undetectable in 69 cases (21.2%) and detectable over wide concentrations in the other 257 patients (78.8%) prior to LT. Polymerase chain reaction analysis of the store blood samples detected HBV DNA in all patients, with 159 patients (48.9%) showing concentrations > 100 IU/mL. Post-transplant HBV regimens during the first year included combination therapy in 196 (60.1%), hepatitis B immunoglobulin (HBIG) monotherapy in 121 (37.1%), and antiviral monotherapy in 9 (2.8%). In the second post-transplant year, these regimens had changed to combination therapy in 187 (57.4%), HBIG monotherapy in 112 (34.4%), and antiviral monotherapy in 27 (8.3%). Trough antibody to hepatitis B surface antigen titers > 500 IU/mL and >1,000 IU/mL were observed in 61.7% and 25.2%, respectively. The mean simulative half-life of HBIG was 21.6 ± 4.3 days with a median 17.7 days. Up to 2-year follow-up period, HCC recurrence and HBV recurrence developed in 18 (5.5%) and 6 (1.8%), respectively. HCC recurrence developed in 3 of 6 patients with HBV recurrence. CONCLUSION: Combination therapy is the mainstay of HBV prophylaxis protocols in a majority of Korean LT centers, but HBIG was often administered excessively. Individualized optimization of HBIG treatments using SHL is necessary to adjust the HBIG infusion interval.

Sequential transcatheter arterial chemoembolization and portal vein embolization before right hemihepatectomy in patients with hepatocellular carcinoma.

BACKGROUND: Recent studies showed that sequential selective transcatheter arterial chemoembolization (TACE) and portal vein embolization (PVE) provided better future liver remnant (FLR) regeneration rate and disease-free survival following surgery compared with PVE alone. The present study aimed to clarify whether preoperative sequential TACE and PVE before right hemihepatectomy can reduce postoperative hepatocellular carcinoma (HCC) recurrence and improve long-term disease-free and overall survival. METHODS: Recurrence and survival outcomes were retrospectively evaluated in 205 patients with HCC who underwent right hemihepatectomy by a single surgeon from November 1993 to November 2017. Patients were divided into four groups according to the procedure performed before the surgery: sequential TACE and PVE (TACE-PVE), PVE-only, TACE-only, or naïve control groups. The baseline patient and tumor characteristics, postoperative outcomes, recurrence-free survival and overall survival were analyzed. RESULTS: Baseline patient and tumor characteristics upon diagnosis were similar in all four groups, while sequential TACE and PVE were well tolerated. The TACE-PVE group had a higher mean increase in percentage FLR volume compared with that of the PVE-only group (17.46% ± 6.63% vs. 12.14% ± 5.93%; P = 0.001). The TACE-PVE group had significantly better overall and disease-free survival rates compared with the other groups (both P < 0.001). CONCLUSIONS: Sequential TACE and PVE prior to surgery can be an effective therapeutic strategy for patients with HCC scheduled for major hepatic resection. The active application of preoperative sequential TACE and PVE for HCC would allow more patients with marginal FLR volume to become candidates for major hepatic resection by promoting compensatory FLR hypertrophy without the deterioration of basal hepatic functional reserve or tumor progression.

Surgical Techniques and Long-term Outcomes of Living-donor Liver Transplantation With Inferior Vena Cava Replacement Using Atriocaval Synthetic Interposition Graft for Budd-Chiari Syndrome.

OBJECTIVE: We aimed to describe our living-donor liver transplantation (LDLT) surgical technique and its long-term patency for patients with Budd-Chiari syndrome (BCS) and retrohepatic inferior vena cava (IVC) obstruction that extends up to the atrium. BACKGROUND: From a technical perspective, LDLT for BCS with an IVC obstruction up to the right atrium is one of the most challenging surgical procedures. Consequently, the optimal surgical technique for patients with BCS has not yet been elucidated. METHODS: A durable LDLT technique without piggy-back hepatectomy was designed using a large-caliber synthetic interposition vascular graft between the right atrium and the infrahepatic IVC for reconstructing the hepatic outflow tract in patients with BCS. RESULTS: Between May 2006 and May 2017, 5 of 17 BCS patients who underwent LDLT required the described technique. All patients with a median follow-up of 10.5 years (range, 9.2-11.5 years) demonstrated the patent IVC grafts and no recurrence of BCS. CONCLUSIONS: Our refined technique does not require unnecessary and dangerous dissection of the diseased IVC, and eliminates the residual suprahepatic vena cava with the possibility of BCS recurrence by connecting the graft to the healthy atrium.

Splenic devascularization can replace splenectomy during adult living donor liver transplantation - a historical cohort study.

Simultaneous splenectomy (SSPX) in adult living donor liver transplantation (ALDLT) has definitely beneficial roles such as portal flow modulation in small-for-size graft and correction of hypersplenism-related pancytopenia, and so on, but disastrous complications after SSPX often occur. For the first time, we devised unique and innovative splenic devascularization (SDV) procedure to alleviated untoward effects of SSPX but to maintain its benefits for the indicated patients. From April 2013 to December 2014, 520 recipients underwent ALDLT, and the SSPX and SDV were simultaneously performed in 62 (11.9%) and 61 (11.7%) patients, respectively. The most common indication was hypersplenism-related pancytopenia (n = 101), small-for-size graft (n = 14), hepatitis C virus (HCV) (n = 7), and splenic artery aneurysm (n = 1). Postoperative small-for-size graft syndrome (SFSS) was absent in both SSPX and SDV, and preoperative pancytopenia was improved in both groups since postoperative 1 week, although SSPX was more substantial than SDV. Preoperative splenic volume (706.2 ± 282.9 ml) after SDV significantly decreased to 425.5 ± 204.4 ml on 1 month, respectively. In contrast to SDV, SSPX resulted in longer operation time and higher incidence of postoperative complications including mortality. In conclusion, SDV can replace SSPX during ALDLT without hampering its beneficial roles seriously, but get rid of splenectomy-related lethal complication.

Determination of Hepatitis B Immunoglobulin Infusion Interval Using Pharmacokinetic Half-life Simulation for Posttransplant Hepatitis B Prophylaxis.

BACKGROUND: Prophylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. This study established an individualized HBV prophylaxis protocol, through optimization of hepatitis B immunoglobulin (HBIG) administration, with application of simulative half-life (SHL). METHODS: This study involved five parts: Part 1 developed the SHL estimation method with 20 patients; Parts 2 and 3 assessed the SHL variability and developed a simulation model to apply SHL in 100 patients; Part 4 validated the simulation model in 114 patients, and Part 5 was a cross-sectional study on the current status of HBIG infusion intervals in 660 patients. RESULTS: In Part 1, infusion of 10,000 IU HBIG induced add-on rise hepatitis B surface antibody (anti-HBs) titer of 5,252.5 ± 873.7 IU/L, which was 4.4% lower than actual measurement. Mean SHL of 20.0 ± 3.7 days was 2.2% longer than actual measurement. In Part 2, the medians of the intra- and inter-individual coefficient of variation in SHL were 13.5% and 18.5%, respectively. Pretransplant HBV DNA load and posttransplant antiviral therapy did not affect SHL. In Part 3, a simulation model was developed to determine the interval of HBIG infusion, by using SHL. In Part 4, all 114 patients were successfully managed with regular HBIG infusion intervals of ≥ 8 weeks, and the interval was prolonged to ≥ 12 weeks in 89.4%, with a target trough anti-HBs titer ≥ 200 IU/L. In Part 5, 47.4% of our patients received HBIG excessively, at a target trough titer of 500 IU/L. CONCLUSION: SHL estimation using only clinically available parameters seems to be reliably accurate when compared with actual measurements. We believe that SHL estimation is helpful to establish a personalized HBV prophylaxis protocol for optimizing HBIG administration.

Cytotoxicity of Human Hepatic Intrasinusoidal CD56bright Natural Killer Cells against Hepatocellular Carcinoma Cells.

Hepatic intrasinusoidal (HI) natural killer (NK) cells from liver perfusate have unique features that are similar to those of liver-resident NK cells. Previously, we have reported that HI CD56bright NK cells effectively degranulate against SNU398 hepatocellular carcinoma (HCC) cells. Thus, the aim of this study was to further investigate the phenotype and function of HI NK cells. We found that HI CD56bright NK cells degranulated much less to Huh7 cells. HI CD56bright NK cells expressed NKG2D, NKp46, TNF-related apoptosis-inducing ligand (TRAIL), and FAS ligand (FASL) at higher levels than CD56dim cells. SNU398 cells expressed more NKG2D ligands and FAS and less PD-L1 than Huh7 cells. Blockade of NKG2D, TRAIL, and FASL significantly reduced the cytotoxicity of HI NK cells against SNU398 cells, but blockade of PD-L1 did not lead to any significant change. However, HI NK cells produced IFN-γ well in response to Huh7 cells. In conclusion, the cytotoxicity of HI CD56bright NK cells was attributed to the expression of NKG2D, TRAIL, and FASL. The results suggest the possible use of HI NK cells for cancer immunotherapy and prescreening of HCC cells to help identify the most effective NK cell therapy recipients.