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We previously showed that human hepatic intrasinusoidal (HI) natural killer (NK) T cells selectively eliminate hepatocellular carcinoma (HCC) cell lines. In this study, we investigated the underlying mechanisms on how HI γδ T cells, expanded with zoledronate, exhibit a superior cytotoxic effect on HI NK-resistant Huh7 HCC cells.γδ T cells were obtained from living liver transplant donors or from peripheral blood mononuclear cells (PBMC) of healthy volunteers and were expanded in the presence of IL-2, IL-15, and zoledronate for 2 weeks. Cytotoxicity was measured using the lactate dehydrogenase (LDH) assay in vitro and by flow cytometry using carboxyfluorescein succinimidyl ester (CFSE) in vivo.The cytotoxicity of expanded HI γδ T cells against Huh7 cells was associated with a higher pyrophosphate expression in Huh7 cells compared to SNU398 cells. In contrast, the cytotoxicity of HI γδ T cells against SNU398 cells depended on NKG2D. HI γδ T cells expressed less PD-1 than PB γδ T cells. The cytotoxicity of HI γδ T cells against Du145 and PC3 prostate cancer cells was also associated with pyrophosphate expression in these cells, as well as NKG2D and DNAM-1.The expression levels of phospho-antigen in tumor cells determined the cytotoxicity of HI γδ T cells, although the NK activating receptors, death ligands, and immune checkpoint molecules also contribute to their cytotoxicity. γδ T cells are attractive candidates for cancer immune cell therapy.

Despite remarkable advances in surgical techniques and perioperative management, left hepatic trisectionectomy (LHT) remains a challenging procedure with a somewhat high postoperative morbidity rate compared with less-extensive resections. This study aimed to analyze the short- and long-term outcomes of LHT and identify factors associated with the postoperative morbidity of this technically demanding surgical procedure.The medical records of 53 patients who underwent LHT between June 2005 and October 2019 at a single institution were retrospectively reviewed. The independent prognostic factor of postoperative morbidity was analyzed using the logistic regression model.Hepatocellular carcinoma was the most common indication for surgery (n = 21), followed by hilar cholangiocarcinoma (n = 14), intrahepatic cholangiocarcinoma (n = 10), and other pathologies (including colorectal liver metastasis, hepatolithiasis, gallbladder cancer, living donor, hemangioma, and multilocular biliary cyst; n = 8). The rates of postoperative morbidities of Clavien-Dindo grade 3 or higher and 90-day mortality were 39.6% and 1.9%, respectively. The 1-, 3-, and 5-year overall survival rates were 81.1%, 61.4%, and 44.6%, respectively. Multivariate analysis revealed that preoperative jaundice [hazard ratio (HR) = 6.15, 95% confidence interval (CI): 1.57-24.17, P = 0.009] and operative time 420 min (HR = 4.66, 95% CI: 1.27-17.17, P = 0.021) were independent predictors of postoperative morbidity.The in-hospital mortality of LHT surgery can be minimalized by a reliable preoperative evaluation of liver function and selection of the dominant anatomic features of right posterior sector, active and appropriate preoperative management for obstructive cholangitis and compensatory hypertrophy of the future remnant posterior sector, and the experience of the surgeon.

Background and aims: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) have been recommended after liver transplantation to prevent recurrence of hepatitis B virus infection. Despite its proven efficacy, the renal safety of TDF has not been established in liver transplant recipients. We aimed to compare the effects of TDF and ETV on renal function in liver transplant recipients and to evaluate risk factors for renal dysfunction after liver transplantation. Methods: This is a retrospective, observational multicenter study of data from the Korean Organ Transplantation Registry. We included adults who underwent liver transplantation for hepatitis B virus-related complications from April 2014 to December 2017 and received TDF or ETV post-transplantation. Renal dysfunction was defined as an estimated glomerular filtration rate decline by at least 20% from baseline (1 month post-transplantation). Median duration of follow-up was 29 months (interquartile range 19–42).Results: A total of 804 liver transplant patients were included. The cumulative probability of renal dysfunction was significantly higher in the TDF group than in the ETV group. Multivariable analysis confirmed that TDF was independently associated with an increased risk of renal dysfunction (hazard ratio = 1.47, 95% confidence interval 1.12-1.92; P = 0.005). Independent risk factors for renal dysfunction included older age, worse baseline renal function, and low body mass index. Renal dysfunction after liver transplantation was independently associated with increased mortality.Conclusions: In this nationwide study, use of TDF was associated with an increased risk of renal dysfunction, when compared with ETV.

Following curative liver resection (LR), resectable tumor recurrence in patients with preserved liver function leads to deciding between a repeat LR and a salvage liver transplantation (LT), if a donor's liver is available. This retrospective study compared survival outcomes and recurrence pattern following salvage living donor LT (LDLT) and repeat LR in patients with recurrent hepatocellular carcinoma (HCC). We reviewed the medical records of patients who underwent repeat LR (n = 163) or LDLT (n = 84) for recurrent HCC following curative resections, between January 2005 and December 2017 at a single institution. A 1:1 propensity score matching led to 42 patients per group. Disease-specific and recurrence-free survival were significantly better in the salvage LDLT group than in the repeat LR group (p = .042; HR = 2.40; 95% CI, 0.69-6.00 and p < .001; HR = 4.23; 95% CI, 2.05-8.71, respectively). Despite significant differences in recurrence patterns between the two groups (p = .019), the patient death rates, after recurrence, were similar for both groups (p = .760). This study indicates that salvage LDLT is superior to repeat LR for treating patients with transplantable, intrahepatic HCC recurrence, even in patients with Child-Pugh class A liver cirrhosis.

Background Simplifying immunosuppressive therapy after liver transplant may improve patient compliance, thereby preventing acute rejection and graft loss. This phase 4, open-label, single-center study was conducted to evaluate the efficacy and safety of twice-daily to once-daily tacrolimus conversion in stable liver transplant recipients. Methods Between May 2017 and January 2019, twice-daily tacrolimus was converted to once-daily tacrolimus in 101 stable recipients at least 12 months post-liver transplant in Asan Medical Center. The doses of both drugs was converted to 1:1, and the target trough level was 5 to 10 ng/mL. We prospectively analyzed graft function, drug compliance, and adverse reactions after switching regimen for 24 weeks. Results There was no acute rejection confirmed histologically within 24 weeks, which was the primary endpoint, and there was no chronic rejection, fatal deterioration of liver function, or death in any patient during this period. After conversion, the trough level of tacrolimus decreased, and the mean ± standard deviation differences between the trough level and baseline level were 1.46 (±2.41) ng/mL, 0.43 (±2.08) ng/mL, and 0.07 (±2.73) ng/mL at 3, 12, and 24 weeks after conversion, respectively. Despite transient fluctuations of the trough level, there was no evidence of rejection or graft dysfunction. There were 37 adverse reactions after conversion; most of them were mild, and thrombocytopenia developed in 1 patient as an adverse drug response. Drug compliance improved after conversion according to questionnaire responses. Conclusions The conversion to once-daily tacrolimus in stable liver transplant recipients is an effective and safe therapeutic strategy improving drug compliance.

Objective After thyroidectomy, many patients suffer from voice problems and vague neck discomfort. The Thyroidectomy-related Voice and Symptom Questionnaire (TVSQ) is a self-administered questionnaire used to evaluate pre- and post-operative vocal status as well as throat and neck discomfort. We investigated voice conditions in thyroidectomy patients using the TVSQ as well as correlations between TVSQ responses and objective voice parameters. Also, we examined whether any clinicopathologic or surgical factors affect phonetic change after thyroidectomy. Methods We retrospectively reviewed the records of 242 patients who underwent total thyroidectomy to treat papillary carcinoma between January to December of 2019. Of these, we enrolled 232 who exhibited normal vocal cord mobility after surgery. TVSQ responses and acoustic voice analysis results were examined preoperatively and at 1, 3, and 6 months postoperatively. We subclassified patients into favorable and unfavorable TVSQ groups based on the increase in TVSQ score (△TVSQ ≥20) at 1 month postoperatively. We then investigated the difference of acoustic characteristics between two groups and analyzed the correlations between acoustic parameters and various clinical and surgical factors including pathologic results and lymph node status by subgroup. Result All acoustic voice parameters except for the noise-to-harmonics ratio were significantly worse at 1 month postoperatively and recovered over time, but the TVSQ score did not recover from the 1-month value until 6 months postoperatively. In the subgroups, among the many clinicopathologic factors examined, advanced N stage (p = 0.002) and high positive total and central-and-lateral-neck lymph node ratios were significantly associated with an increased risk of an unfavorable TVSQ (p = 0.049, 0.027, Among the acoustic parameters, only the changes in TVSQ total score and voice score were correlated with deterioration in jitter and shimmer at 1 month postoperatively. However, the correlations was not statistically significant and had disappeared at 6 months postoperatively. Conclusion We figured out that TVSQ was able to capture the negative effects of lymph node status and lymph node dissection on vocal outcomes after thyroidectomy. Although there was a weak correlation between worsened perturbation value and TVSQ changes, no other acoustic analysis parameters were statistically significant correlated with the TVSQ score.

BACKGROUND This retrospective study from a single center aimed to evaluate the long-term patency of all-in-one sleeve venoplasty (ASV) in 16 patients who underwent living donor liver transplantation (LDLT) with a right liver graft (RLG) between 2009 and 2019. ASV unifies the right hepatic vein (RHV), short hepatic vein (SHV), and middle hepatic vein (MHV) of an RLG. ASV enables wide side-to-side anastomosis to the recipient inferior vena cava (IVC). MATERIAL AND METHODS Of 2875 patients who underwent LDLT with an RLG from August 2009 to July 2019, 16 (0.5%) patients underwent ASV. We analyzed the ASV techniques applied to these patients, as well as patient long-term outcomes. RESULTS Type 1 ASV unified 1 RHV, 1 IRHV, and 1 MHV conduit (n=12 [75.0%]). Type 2 ASV unified 1 RHV, multiple IRHVs, and 1 MHV conduit (n=4 [25.0%]). All patients are currently alive, with a mean follow-up period of 70.1±41.9 months. No patient underwent retransplantation. Follow-up computed tomography showed SHV occlusion in 1 (6.3%) patient at 4 months, resulting in 1-, 3-, and 5-year SHV patency rates of 93.8% each. MHV occlusion was identified in 6 (37.5%) patients, with 1-, 3-, and 5-year MHV patency rates of 81.3%, 68.8%, and 68.8%, respectively (P=0.037). No patient underwent endovascular stenting of the SHV or MHV. Patency rates were significantly higher for SHV than MHV (P=0.037). CONCLUSIONS ASV using various vascular patches is a useful technique enabling secure reconstruction of an RLG in grafts with complex hepatic vein anatomy or recipients with poor IVC condition.

BACKGROUND This study analyzed pretransplant alpha-fetoprotein (AFP) and proteins induced by vitamin K absence or antagonist-II (PIVKA-II) in liver transplantation (LT) candidates. MATERIAL AND METHODS A total of 3,273 LT recipients enrolled at the Korean Organ Transplantation Registry were divided according to hepatocellular carcinoma (HCC) status and background liver disease, and AFP and PIVKA-II were compared. RESULTS In all patients, the median AFP and PIVKA-II were 6.3 ng/mL and 29 mAU/mL in the viable-HCC group and 3.3 ng/mL and 35 mAU/mL, respectively, in the no-HCC group (P0.001 for AFP and p=0.037 for PIVKA-II). In patients with hepatitis B virus infection, they were 6.0 ng/mL and 26 mAU/mL in the HCC group and 3.2 ng/mL and 21 mAU/mL in the no-HCC group, respectively (P0.001 and P0.001). In patients with hepatitis C virus infection, they were 10.7 ng/mL and 37 mAU/mL in the HCC group and 2.6 ng/mL and 21 mAU/mL in the no-HCC group, respectively (P0.001 and P=0.117). In alcoholic liver disease patients, they were 5.2 ng/mL and 61 mAU/mL in the HCC group and 6.4 ng/mL and 75 mAU/mL in the no-HCC group, respectively (P0.001 and P=0.419). In patients with other diseases, they were 7.1 ng/mL and 32 mAU/mL in the HCC group and 3.3 ng/mL and 28 mAU/mL in the no-HCC group, respectively (P0.001 and P=0.822). CONCLUSIONS The results of the present study indicate that pretransplant serum AFP and PIVKA-II were highly variably expressed in LT candidates with end-stage liver diseases; therefore, their values should be cautiously interpreted because their role in HCC diagnosis is limited.

Background/Aims: To analyze the incidence and risk factors of outcomes after liver transplantation (LT) in the Korean population. Methods: This study analyzed data from the liver cohort of Korean Organ Transplantation Registry (KOTRY) who had LT between May 2014 and December 2017. Study measures included the incidence of post-LT outcomes in recipients of living donor LT (LDLT) and deceased donor LT (DDLT). Cox multivariate proportional hazards model was used to determine the potential risk factors predicting the outcomes. Results: A total of 2,563 adult recipients with LT (LDLT, n=1,956; DDLT, n=607) were included, with mean±standard deviation age of 53.9±8.9 years, and 72.2% were male. The post-LT outcomes observed in each LDLT and DDLT recipients were death (4.0% and 14.7%), graft loss (5.0% and 16.1%), rejection (7.0% and 12.0%), renal failure (2.7% and 13.8%), new onset of diabetes (12.5% and 15.4%), and hepatocellular carcinoma (HCC) recurrence (both 6.7%). In both LDLT and DDLT recipients, the most common post-LT complications were renal dysfunction (33.6% and 51.4%), infection (26.7% and 48.4%), and surgical complication (22.5% and 23.9%). Incidence of these outcomes were generally higher among recipients of DDLT than LDLT. Multivariate analysis indicated recipient age and DDLT as significant risk factors associated with death and graft loss. DDLT and ABO incompatible transplant were prognostic factors for rejection, and HCC beyond Milan criteria at pre-transplant was a strong predictor of HCC recurrence. Conclusions: This study is a good indicator of the post-LT prognosis in the Korean population and suggests a significant burden of post-LT complications. (Clin Mol Hepatol 2021;27:451-462)

Background This study evaluated the safety and effectiveness of minimally invasive living donor hepatectomy in comparison with the open procedure, using Korean Organ Transplantation Registry data. Methods We reviewed the prospectively collected data of all 1,694 living liver donors (1,071 men, 623 women) who underwent donor hepatectomy between April 2014 and December 2017. The donors were grouped on the basis of procedure type to the minimally invasive procedure group (n = 304) or to the open procedure group (n = 1,390) and analyzed the relationships between clinical data and complications. Results No donors died after the procedure. The overall complication rates after operation in the minimally invasive procedure group and the open procedure group were 6.2% and 3.5%, respectively. Biliary complications were the most frequent events in both groups (minimally invasive procedure group, 2.4%; open procedure group, 1.6%). The majority of complications occurred within 7 days after surgery in both groups. The duration of hospitalization was shorter in the minimally invasive procedure group than in the open procedure group (9.04 ± 3.78 days versus 10.29 ± 4.01 days; P Conclusion Based on its similar outcomes in our study, minimally invasive donor hepatectomy cannot be an alternative option compared with the open procedure method. To overcome this, we need to ensure better surgical safety, such as lower complication rate and shorter duration of hospitalization.

Background Most guidelines recommend simultaneous liver-kidney transplantation (SLKT) in patients with liver cirrhosis (LC) and severe chronic kidney disease (CKD) over liver transplantation alone (LTA). CKD, however, is not irreversible. This study evaluates the reversibility of kidney disease after LTA based on kidney size. Materials and methods In this single-center retrospective study, we classified 90 patients with LC and severe CKD into 3 groups: the normal kidney (NK)-LTA group (n=39), small kidney (SK)-LTA group (both kidneys Results The NK-LTA group had a lower percentage of hepatocellular carcinoma and a higher pre-liver transplantation (LT) estimated glomerular filtration rate. This group, however, was older, received livers from a higher percentage of deceased donors, and had a higher Child-Pugh score. Renal recovery, defined as the return of creatinine to their baseline, or a persistent change from baseline but not persistent (≥3 months) need for renal replacement therapy after LT, was found in 79% in the NK-LTA group, which was higher than 7.5% in the SK-LTA group. Renal and patient survival was found in 56% of the NK-LTA group, which was higher than 2.5% of the SK-LTA group. Conclusions There is a high percentage of renal recovery in the NK-LTA group, and accordingly, this does not justify SLKT, since this would result in a "waste" of kidneys. Therefore, KT after LT is recommended over SLKT for the LC patients with NK size.

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

We assessed the prognostic impact of the ADV score (α-fetoprotein [AFP]–des-γ-carboxyprothrombin [DCP]–tumor volume [TV] score) for predicting hepatocellular carcinoma (HCC) recurrence and patient survival after living donor liver transplantation (LDLT). This study included 843 HCC patients who underwent LDLT between January 2006 and December 2015 at Asan Medical Center. These cases were divided into treatment-naive (TN, n = 256]) and pretransplant-treated (PT, n = 587 [69.6%]) groups. There were weak or nearly no correlations among AFP, DCP, and TV. There existed high correlations between the pretransplant and explant findings regarding tumor number, size, and ADV score. Right lobe grafts were implanted in 760 (90.2%) patients. HCC recurrence and all-cause patient death occurred in 182 (15.9%) and 126 (15.0%) respectively during the follow-up period for 75.6 ± 35.5 months. The 5-year tumor recurrence (TR) and overall patient survival (OS) rates were 21.5% and 86.2%, respectively. The PT group showed higher TR (p < 0.001) and lower OS rates (p < 0.001). TR and OS were closely correlated with both pretransplant and explant ADV scores in the TN and PT groups. The ADV score enabled further prognostic stratification of the patients within and beyond the Milan, UCSF, and Asan Medical Center criteria. Compared with the 7 pre-existing selection criteria, ADV score with a cutoff of 5log showed the highest prognostic contrast regarding TR and OS. Our prognostic prediction model using ADV scores is an integrated quantitative surrogate biomarker for posttransplant prognosis in HCC patients and can provide reliable information that assists the decision-making for LDLT.

Background More than 400 liver transplants were performed at Asan Medical Center (AMC) in 2011, and over 500 liver transplants including 420 living-donor liver transplants (LDLTs) were performed in 2019. Herein, we report the methodology of these procedures. Methods Since the first adult LDLTs at AMC using the left and right lobes were successfully performed, various innovative techniques and approaches have been developed: modified right lobe, dual graft, donor exchange for ABO incompatibility, expansion of indications and no-touch techniques for hepatocellular carcinoma, intraoperative cine-portogram and additional intervention for large collaterals, management of portal vein thrombosis (PVT) and stenosis, salvage LDLT after major hepatectomy, and timely LDLT for patients with acute-on-chronic liver failure. Results Four hundred twenty LDLTs in 403 adult and 17 pediatric patients and 85 deceased-donor liver transplants in 74 adult and 11 pediatric patients were performed. The number of deceased-donor liver transplants remained constant since 2011, but the number of LDLTs increased steadily. One hundred thirty patients (25.7%) required urgent liver transplantations and 24 patients with acute-on-chronic liver failure underwent LDLT. PVT including grade 1,2,3, and 4 was reported in 91 patients (18.0%), and Yerdel’s grade 2, 3, and 4 PVT was reported in 47 patients (51.6%); all patients with PVT were successfully treated. Adult LDLTs for hepatocellular carcinoma and ABO incompatibility accounted for 52.6% and 24.3% of the cases, respectively. In-hospital mortality in 2019 was 2.97%. Conclusion Continual efforts to overcome challenging problems in LDLT with various innovations and dedication of the team members during the perioperative period to improve patient outcomes were crucial in increasing the number of liver transplantations at Asan Medical Center.

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.

There is much controversy regarding enhanced recovery for recipients of liver transplants from deceased and living donors. The objectives of this Review were to summarise current knowledge on individual enhanced recovery elements on short-term outcomes, identify key components for comprehensive pathways, and create internationally accepted guidelines on enhanced recovery for liver-transplant recipients. The ERAS4OLT.org collaborative partnered by the International Liver Transplantation Society performed systematic literature reviews on the effect of 32 relevant enhanced perioperative recovery elements on short-term outcomes, and global specialists prepared expert statements on deceased and living donor liver transplantation. The Grading Recommendations, Assessment, Development and Evaluations approach was used for rating of quality of evidence and grading of recommendations. A virtual international consensus conference was held in January, 2022, in which results were presented, voted on by the audience, and discussed by an independent international jury of eight members, applying the Danish model of consensus. 273 liver transplantation specialists from 30 countries prepared expert statements on elements of enhanced recovery for liver transplantation based on the systematic literature reviews. The consensus conference yielded 80 final recommendations, covering aspects of enhanced recovery for preoperative assessment and optimisation, intraoperative surgical and anaesthetic conduct, and postoperative management for the recipients of liver transplants from both deceased and living donors, and for the living donor. The recommendations represent a comprehensive overview of the relevant elements and areas of enhanced recovery for liver transplantation. These internationally established guidelines could direct the development of enhanced recovery programmes worldwide, allowing adjustments according to local resources and practices.

Background IPNB is very rare disease and most previous studies on IPNB were case series with a small number due to low incidence. The aim of this study is to validate previously known clinicopathologic features of intraductal papillary neoplasm of bile duct (IPNB) based on the first largest multicenter cohort. Methods Among 587 patients previously diagnosed with IPNB and similar diseases from each center in Korea, 387 were included in this study after central pathologic review. We also reviewed all preoperative image data. Results Of 387 patients, 176 (45.5%) had invasive carcinoma and 21 (6.0%) lymph node metastasis. The 5-year overall survival was 80.9% for all patients, 88.8% for IPNB with mucosal dysplasia, and 70.5% for IPNB with invasive carcinoma. According to the “Jang & Kim's modified anatomical classification,” 265 (68.5%) were intrahepatic, 103 (26.6%) extrahepatic, and 16 (4.1%) diffuse type. Multivariate analysis revealed that tumor invasiveness was a unique predictor for survival analysis. (p = 0.047 [hazard ratio = 2.116, 95% confidence interval 1.010–4.433]). Conclusions This is the first Korean multicenter study on IPNB through central pathologic and radiologic review process. Although IPNB showed good long-term prognosis, relatively aggressive features were also found in invasive carcinoma and extrahepatic/diffuse type.

BACKGROUND The prevalent location and incidence of intraductal papillary neoplasm of the bile duct (IPNB) and invasive carcinoma associated with them have varied markedly among studies due to differences in diagnostic criteria and tumor location. METHODS IPNBs were classified into two types: Type 1 IPNB, being histologically similar to intraductal papillary mucinous neoplasm of the pancreas, and Type 2 IPNB, having a more complex histological architecture with irregular papillary branching or foci of solid-tubular components. Medical data were evaluated. RESULTS Among 694 IPNB patients, 520 and 174 had Type 1 and Type 2, respectively. The levels of AST, ALT, ALP, T. Bil, and CEA were significantly higher in patients with Type 2 than in those with Type 1. Type 1 IPNB was more frequently located in the intrahepatic bile duct than Type 2, whereas Type 2 was more frequently located in the distal bile duct than Type 1 IPNB (P

No study has investigated the short-term effect of acute insulin resistance on liver steatosis in critically ill condition. We analyzed the effects of critically ill conditions of brain-dead donors (BDDs) on the development and progression of liver steatosis to investigate the influencing factors.This study was conducted retrospectively between January 2003 and December 2017. BDDs were for organ procurement. BDDs with body mass indexes (BMIs) 18.5 kg/mOf the 179 BDDs, 87 (48.6%) had liver steatosis. BMI (r = 0.176, P = .019) and SGL (r = 0.267, P .001) were correlated with steatosis. The length of the predonation period (LPDP) was negatively correlated with steatosis (r = -0.379, P .001). BMI (odds ratio 1.266, P = .002), SGL ≥180 mg/dL (odds ratio 2.825, P = .003), and LPDP (odds ratio 0.885, P = .001) were independent risk factors for liver steatosis.Liver steatosis is related to the SGL and BMI. Liver steatosis develops acutely in the early phase of critical illness and patients recover gradually.

Purpose The current standard chemotherapy for advanced biliary tract cancer (BTC) has limited benefit, and novel therapies need to be investigated. Materials and MethodsIn this prospective cohort study, programmed death ligand-1 (PD-L1)–positive BTC patients who progressed on first-line gemcitabine plus cisplatin were enrolled. Pembrolizumab 200 mg was administered intravenously every 3 weeks. ResultsBetween May 2018 and February 2019, 40 patients were enrolled. Pembrolizumab was given as second-line (47.5%) or ≥ third-line therapy (52.5%). The objective response rate was 10% and 12.5% by Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 and immune- modified RECIST (imRECIST) and median duration of response was 6.3 months. Among patients with progressive disease as best response, one patient (1/20, 5.0%) achieved complete response subsequently. The median progression-free survival (PFS) and overall survival (OS) were 1.5 months (95% confidence interval [CI], 0.0 to 3.0) and 4.3 months (95% CI, 3.5 to 5.1), respectively, and objective response per imRECIST was significantly associated with PFS (p < 0.001) and OS (p=0.001). Tumor proportion score ≥ 50% was significantly associated with higher response rates including the response after pseudoprogression (vs. < 50%; 37.5% vs. 6.5%; p=0.049). Conclusion Pembrolizumab showed modest anti-tumor activity in heavily pretreated PD-L1–positive BTC patients. In patients who showed objective response, durable response could be achieved.

Surgical and oncological outcomes in ruptured hepatocellular carcinoma (HCC) are not well known. The objective of this study was to review and compare survival outcomes and recurrence rates between ruptured and unruptured HCC. Data of patients with ruptured HCC who underwent curative surgical resection between January 2000 and December 2016 were retrospectively reviewed. To compare survival outcomes between ruptured and unruptured HCC, 1:2 individual matching was conducted. The 1-, 3-, and 5-year overall survival (OS) rates were 88.8%, 67.0%, and 51.9%, respectively. The 1-, 3-, and 5-year disease-free survival (DFS) rates were 51.7%, 32.8%, and 25.0%, respectively. OS and DFS rates were significantly lower in the ruptured HCC group than the matched unruptured HCC group. HCC recurred in 63 patients (70.8%), 33 (52.4%) of whom presented with both intrahepatic and extrahepatic recurrences. Mean recurrence interval was 12.6 ± 13.8 months. The 1-, 3-, and 5-year survival rates after recurrence were 61.6%, 40.2%, and 33.6%, respectively. Mean survival time after recurrence was 26.4 ± 29.5 months. Incidence of peritoneal seeding (PS) was 18.0%, and eight of them demonstrated solitary lesion. Mean recurrence interval was 5.9 ± 8.2 months. The 1-, 3-, and 5-year OS rates after recurrence were significantly lower in patients with PS (49.7%, 18.7%, and 9.3%, respectively) than in patients without PS. Hepatectomy in ruptured HCC did show worse survival outcome compared with unruptured HCC and bear a high risk of PS. However, surgical resection combined with transcatheter arterial chemoembolization could help in achieving acceptable oncological outcomes.

Background This study analyzed treatment and outcomes in patients with primary extrahepatic malignancy (EHM) incidentally diagnosed during pretransplant evaluation for living donor liver transplantation (LDLT). Methods Of 4621 adult patients undergoing LDLT over 19 years, 41 were diagnosed with EHM shortly before LDLT (incidental malignancy group), and 92 had been treated for EHM more than 6 months before LDLT (treated malignancy group). Results Most common EHMs were colorectal, thyroid, and stomach cancers in the incidental malignancy group; and stomach, breast, thyroid, colorectal, and renal cell cancers and lymphoma in the treated malignancy group. Mean interval between EHM diagnosis and LDLT in the incidental malignancy group was 1.5 ± 1.6 months. Of the 41 patients in this group, 15 (35.6%), seven (17.1%), and 16 (39.0%) underwent EHM treatment before, during, and after LDLT, respectively, whereas three (7.3%) underwent observation alone. During a mean follow-up of 70.1 ± 50.8 months, six (14.6%) patients showed tumor recurrence, and three (7.3%) died of tumor progression. All recurrences developed in patients with tumor stages higher than the earliest stage. The mean interval between EHM diagnosis and LDLT in treated malignancy group was 79.8 ± 79.6 months. During a mean follow-up of 63.2 ± 54.1 months, three (3.3%) patients showed tumor recurrence and one (1.1%) died of tumor progression. The incidence of EHM recurrence was significantly higher (P = .025), and the overall post-transplant patient survival rate was significantly lower (P = .046), in the incidental malignancy than in the treated malignancy group. Conclusions Only patients with earliest-stage EHM detected shortly before LDLT are indicated for upfront LDLT combined with peritransplant EHM treatment.

Objectives Histopathologic characteristics of choledochal cysts and their clinical implications have not been previously comprehensively studied. Methods Smooth muscle distribution patterns and other histologic findings (inflammation, metaplasia, dysplasia, and heterotopia) in 233 surgically resected choledochal cysts were evaluated. Results Mean patient age was 23.3 ± 19.8 years, with male:female ratio of 0.3. Most cases were Todani type I (175 cases, 75.1%) or IVa (56 cases, 24.1%). Choledochal cysts with thin scattered/no muscle fiber (175 cases, 75.1%) were the predominant pattern and were associated with more frequent postoperative biliary stricture (P = .031), less frequent pyloric metaplasia (P = .016), and mucosal smooth muscle aggregates (P 20 years vs ≤20 years), suggesting that chronic irritation in association with developmental anomalies involves tumorigenesis from choledochal cysts. Conclusion Smooth muscle distribution pattern of choledochal cyst may predict postoperative complication, raising clinical implications of smooth muscle patterns in postoperative management of choledochal cysts.

BACKGROUND Because of the supply shortage for homologous vein allografts, we previously used ringed Gore-Tex vascular grafts for middle hepatic vein (MHV) reconstruction in living donor liver transplantation. However, owing to the subsequent unavailability of ringed Gore-Tex grafts, we replaced them with Hemashield vascular grafts. This study aimed to compare the patency of Hemashield grafts with that of ringed Gore-Tex grafts. MATERIAL AND METHODS This was a retrospective double-arm study between the study group that used Hemashield grafts (n=63) and the historical control group that used ringed Gore-Tex grafts (n=126). RESULTS In the Gore-Tex and Hemashield groups, mean age was 53.1±6.2 and 54.3±10.4 years; model for end-stage liver disease score was 16.5±8.3 and 17.5±9.9; and graft-recipient weight ratio was 1.11±0.23 and 1.12±0.25, respectively. In the Gore-Tex graft group, V5 reconstruction was done in single (n=107, 84.9%), double (n=17, 13.5%), and none (n=2, 1.6%). V8 reconstruction was done in single (n=95, 75.4%), double (n=1, 0.8%), and none (n=30, 23.8%). In the Hemashield group, V5 reconstruction was done in single (n=43, 68.3%), double (n=19, 30.2%), and triple (n=1, 1.6%). V8 reconstruction was done in single (n=45, 71.4%), double (n=9, 14.3%), and none (n=9, 14.3%). One-year conduit patency rates in the Gore-Tex and Hemashield groups were 54.8% and 71.6%, respectively (p=0.048). CONCLUSIONS MHV reconstruction using Hemashield vascular grafts demonstrated higher short-term patency rates than those associated with ringed Gore-Tex vascular grafts. We suggest that the Hemashield vascular graft is one of the best prosthetic materials for MHV reconstruction.

Pediatric patients with biliary atresia (BA) often present liver cirrhosis-associated portal hypertension and portal vein (PV) hypoplasia. For successful liver transplantation (LT), it is essential to maintain sufficient PV inflow through stenosis-free PV reconstruction with effective ligation of collateral veins. The aim of this study was to assess the clinical usability of intraoperative cine-portogram (IOCP) in young pediatric patients who underwent LT for BA.Medical records of pediatric patients younger than 10 years who underwent primary LT for BA from 2018 to 2020 were reviewed.A total of 31 patients had undergone Kasai portoenterostomy soon after birth. Their median ages at Kasai portoenterostomy and LT were 1 and 11 months, respectively. Types of LT were living-donor LT in 13, deceased-donor split LT in 15, and deceased-donor whole LT in three patients. PV interposition using an iliac vein homograft was performed in 28 patients receiving partial liver grafts. Side-to-side PV unification venoplasty was performed in three patients undergoing whole LT. All patients underwent ligation of collateral veins. IOCP was performed in 6 (19.4%) patients. Four showed no or faint residual venous collaterals. Collateral vein embolization and endovascular stenting were performed in one patient each. PV insufficiency-free survival rate was 100% at 1 year and 93.8% at 3 years. All patients are currently alive with a median follow-up period of 23 months.Intraoperative cine-portogram can be a useful method for identification and embolization of residual portosystemic collateral veins in young pediatric patients who undergo LT for biliary atresia.

Bloodstream infection (BSI) is one of the most significantly adverse events that can occur after liver transplantation (LT) in children.To analyze the profile of BSI according to the postoperative periods and assess the risk factors after pediatric LT.Clinical data, collected from medical charts of children (Of the examined patients, 106 (28%) experienced 162 episodes of pathogen-confirmed BSI during the first year after LT. There were 1.53 ± 0.95 episodesBSI was frequently observed in patients after pediatric LT, affecting survival outcomes. The profile of BSI may inform clinical treatment and management in high-risk children after LT.

Background 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 LT is to achieve complete donor safety and zero recipient mortality. Methods 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 conducted between 1994 and 2020. A Cox's proportional hazards model was used for multivariate analysis. The trends for independent prognostic factors were analyzed according to the treatment era, i.e. I (1994~2002), II (2003~2011), and III (2012~2020). Result Primary LDLTs were conducted on 287 children during the study period. Biliary atresia (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 I (n=81), the cumulative survival rates at one and five years after LDLT were 90.1% and 81.5% for patients, and 86.4% and 77.8% for grafts, respectively. During era II (n=113), the corresponding rates were 92.9% and 92% for patients, and 89.4% and 86.7% for grafts. During era III (n=93), the corresponding rates were 100% and 98.6% for patients, and 98.9% and 95.4% for grafts. By multivariate analysis, primary diagnosis ALF, bloodstream infection, posttransplant lymphoproliferative disease, and chronic rejection were found to be negative prognostic indicators for patient survival. Conclusion Based on generalized care guidelines and our 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.

Purpose In biliary tract cancer (BTC), standard chemotherapy has limited benefit and no molecular targeted agents have been approved. This study investigated the genetic profile of BTC to identify potential new therapeutic targets and predictive biomarkers. Methods Targeted exome sequencing was performed for 124 patients with BTC [gallbladder cancer (GBC), 25; intrahepatic cholangiocarcinoma (ICC), 55; extrahepatic cholangiocarcinoma (ECC), 44]. Survival analysis was performed in 112 patients who received palliative chemotherapy for locally unresectable or metastatic disease. Results Genetic alterations were observed in 104 patients (83.8%); the most commonly mutated genes were TP53 (44.4%), KRAS (29.0%), ARID1A (12.1%) and IDH1 (9.7%). IDH1/2 mutations appeared more frequently in ICC (23.6%, P = 0.0002) than in GBC (4.0%) or ECC (2.3%), while ERBB2/3 mutations were found only in GBC (20.0%) and ECC (11.4%). Patients harbouring TP53 mutations had shorter overall survival (OS; median 15.2 vs. 37.8 months, P = 0.018), while IDH1 mutations showed a tendency for longer progression-free survival (PFS; 10.6 vs. 6.1 months, P = 0.124). Potentially actionable genetic alterations were found in 54.8%, and 7.1% received appropriate molecular targeted therapy in the clinical trial setting. Germline or somatic mutations in DNA damage repair (DDR) genes were found in 63.5% of patients and were significantly associated with longer PFS (6.9 vs. 5.7 months, P = 0.013) and OS (21.0 vs. 13.3 months, P = 0.009) in patients who received first-line platinum-containing chemotherapies (n = 88). Conclusions A subgroup of patients with BTC may benefit from targeted therapy by the aid of genetic information. In particular, DDR alterations may be a predictive biomarker for response to platinum-containing chemotherapy in patients with BTC.

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/mWe reviewed 521 patients with high BMI ( 25.0 kg/mLMR 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/mObesity 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/m

BACKGROUND AND AIMS Chromophobe hepatocellular carcinoma (HCC) is a newly included subtype of HCC in the 5th edition of the WHO classification with distinctive histological features (chromophobic cytoplasm with anaplastic nuclei and pseudocyst formation) and is strongly associated with the alternative lengthening of telomeres (ALT) phenotype. However, the clinicopathologic characterization and molecular features of chromophobe HCC are unknown. METHODS To comprehensively characterize chromophobe HCC, whole exome sequencing, copy number variation, and transcriptomic analyses were performed in 224 surgically resected HCC cases. Additionally, telomere-specific fluorescence in situ hybridization was used to assess ALT. These genomic profiles and ALT status were compared with clinicopathological features among subtypes of HCC, particularly chromophobe HCC and conventional HCC. RESULTS Chromophobe HCC was observed in 10.3% (23/224) cases and, compared to conventional HCC, was more frequent in females (P = .023). The overall and recurrence-free survival outcomes were similar between patients with chromophobe HCC and conventional HCC. However, chromophobe HCC displayed significantly more upregulated genes involving cell cycle progression and DNA repair. Additionally, ALT was significantly enriched in chromophobe HCC (87%; 20/23) compared to conventional HCC (2.2%, 4/178; P

Background Multiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8+ tumor-infiltrating lymphocytes (TILs) remain unclear. Methods To determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8+ TILs in Il17a −/− mice, Il17a Cre R26 DTA mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4+ T cells or CD11b+Gr-1hi myeloid cells in vivo, respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset. Results Depletion of CD4+ T cells promotes the exhaustion of CD8+ T cells with a concomitant increase in IL-17-producing CD8+ T (Tc17) cells in the tumor. Unlike IFN-γ-producing CD8+ T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103+KLRG1−IL-7Rαhi tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1hiTim3+TOX+ terminally exhausted CD8+ T cells in the tumor. Blockade of IL-17 or RORγt pathway inhibits exhaustion of CD8+ T cells and also delays tumor growth in vivo. Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8+ T cell exhaustion signature gene sets in multiple cancers. Conclusion IL-17-producing cells promote terminal exhaustion of CD8+ T cells and tumor progression in vivo, which can be reversed by blockade of IL-17 or RORγt pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8+ T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.

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.

The heterogeneous immune landscapes of intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Here we aimed to investigate the implications of tissue-resident memory (TRM)-related features of tumour-infiltrating CD8From ICC patients, we obtained blood samples and ICC surgical specimens (n = 33). We performed multicolour flow cytometry, multiplexed immunohistochemistry and RNA sequencing.When compared to peripheral CD8CD69

Background Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA) has wide histologic diversity. This study investigated the prognostic impacts of cHCC-CCA histology according to the 2019 World Health Organization (WHO) classification. Methods This retrospective observational study included 153 patients who underwent surgical resection for cHCC-CCA at Asan Medical Center between August 2012 and July 2019. Results During the study period, 153 patients, 112 (73.2%) men and 41 (26.8%) women with a mean age of 56.4 ± 10.8 years, underwent R0 resection for cHCC-CCA. Mean tumor diameter was 4.2 ± 2.6 cm, and 147 (96.1%) patients had solitary tumors. According to 2019 WHO classification, 111 (72.5%) patients had cHCC-CCA alone, and 29 of them (26.1%) showed stem cell features. cHCC-CCA-intermediate cell carcinoma and cHCC-CCA-cholangiolocellular carcinoma were identified in 27 (17.6%) and 15 (9.8%), respectively. The 1-, 3-, and 5-year tumor recurrence and patient survival rates were 31.8% and 92.1%, 49.8% and 70.9%, and 59.0% and 61.7%, respectively. Univariate analyses revealed that significant prognostic factors were tumor size >5 cm, microscopic and macroscopic vascular invasion, lymph node metastasis, 8th American Joint Committee on Cancer (AJCC) tumor stage, and status of stem cell features. Multivariate analysis revealed 8th AJCC tumor stage and status of stem cell features as independent prognostic factors. 2019 WHO classification was not associated with post-resection prognosis. Conclusions 2019 WHO classification was not associated with post-resection prognosis, thus was considered as simplified histologic classification requiring prognostic validation. We suggest that stem cell features should be included as an essential component of the pathology report for cHCC-CCA.

BACKGROUND Salvage liver transplantation is a definite treatment for recurrent hepatocellular carcinoma (HCC) after hepatectomy. ADV score is calculated by multiplying α-fetoprotein and des-γ-carboxyprothrombin concentrations and tumor volume. Prognostic accuracy of ADV score was assessed in patients undergoing salvage living donor liver transplantation (LDLT) and their outcomes were compared with patients undergoing primary LDLT. METHODS This study was a retrospective, single-center, case-controlled study. Outcomes were compared in 125 patients undergoing salvage LDLT from 2007 to 2018 and in 500 propensity score-matched patients undergoing primary LDLT. RESULTS In patients undergoing salvage LDLT, median intervals between hepatectomy and tumor recurrence, between first HCC diagnosis and salvage LDLT, and between hepatectomy and salvage LDLT were 12.0, 37.2, and 29.3 months, respectively. Disease-free survival (DFS, P = .98) and overall survival (OS, P = .44) rates did not differ significantly in patients undergoing salvage and primary LDLT. Pretransplant and explant ADV scores were significantly predictive of DFS and OS in patients undergoing salvage and primary LDLT (P

Laparoscopic living donor hepatectomy for transplantation has been well established over the past decade. This study aimed to assess its safety and feasibility in pediatric living donor liver transplantation (LDLT) by comparing the surgical and long-term survival outcomes on both the donor and recipient sides between open and laparoscopic groups. The medical records of 100 patients (≤17 years old) who underwent ABO-compatible LDLT using a left lateral liver graft between May 2008 and June 2016 were analyzed. A total of 31 donors who underwent pure laparoscopic hepatectomy and their corresponding recipients were included in the study; 69 patients who underwent open living donor hepatectomy during the same period were included as a comparison group. To overcome bias from the different distributions of covariables among the patients in the 2 study groups, a 1:1 propensity score matching analysis was performed. The mean follow-up periods were 92.9 and 92.7 months in the open and laparoscopic groups, respectively. The mean postoperative hospital stay of the donors was significantly shorter in the laparoscopic group (8.1 days) than in the open group (10.6 days; P < 0.001). Overall, the surgical complications in the donors and overall survival rate of recipients did not differ between the groups. Our data suggest that the laparoscopic environment was not associated with long-term graft survival during pediatric LDLT. In addition, the laparoscopic approach for the donors did not adversely affect the corresponding recipient's outcome. Laparoscopic left lateral sectionectomy for living donors is a safe, feasible, and reproducible procedure for pediatric liver transplantation.

Human liver-derived stem cells (hLD-SCs) have been proposed as a possible resource for stem cell therapy in patients with irreversible liver diseases. However, it is not known whether liver resident hLD-SCs can differentiate toward a hepatic fate better than mesenchymal stem cells (MSCs) obtained from other origins. In this study, we compared the differentiation ability and regeneration potency of hLD-SCs with those of human umbilical cord matrix-derived stem cells (hUC-MSCs) by inducing hepatic differentiation. Undifferentiated hLD-SCs expressed relatively high levels of endoderm-related markers (GATA4 and FOXA1). During directed hepatic differentiation supported by two small molecules (Fasudil and 5-azacytidine), hLD-SCs presented more advanced mitochondrial respiration compared to hUC-MSCs. Moreover, hLD-SCs featured higher numbers of hepatic progenitor cell markers on day 14 of differentiation (CPM and CD133) and matured into hepatocyte-like cells by day 7 through 21 with increased hepatocyte markers (ALB, HNF4A, and AFP). During in vivo cell transplantation, hLD-SCs migrated into the liver of ischemia-reperfusion injury-induced mice within 2 h and relieved liver injury. In the thioacetamide (TAA)-induced liver injury mouse model, transplanted hLD-SCs trafficked into the liver and spontaneously matured into hepatocyte-like cells within 14 days. These results collectively suggest that hLD-SCs hold greater hepatogenic potential, and hepatic differentiation-induced hLD-SCs may be a promising source of stem cells for liver regeneration.

Background Secondary biliary cirrhosis (SBC) represents a unique form of cirrhosis that develops in the liver secondary to persistent biliary obstruction. This study aimed to review the living donor liver transplants (LDLTs) performed at our center for patients with SBC and end-stage liver disease and to share the perioperative strategies undertaken to achieve satisfactory outcomes. Methods The medical records of 29 patients who underwent LDLT for SBC between December 1994 and July 2018 at the Asan Medical Center (Seoul, South Korea) were retrospectively reviewed. Their clinical data were extracted and statistically analyzed. Survival curves were computed. Results The perioperative and in-hospital morbidity rates were 72.4% and 10.3%, respectively. The overall mean recipient follow-up was 80.0 (SD, 66.4) months (range, 0.8-246.8 months). Patient survival rates after 1, 3, 5, and 10 years after transplant were 82.8%, 79.3%, 79.3%, and 79.3%, respectively. For liver grafts, the survival rates were 82.8%, 75.8%, 75.8%, and 75.8% at 1, 3, 5, and 10 years, respectively. Conclusions LDLT is potentially a final lifesaving resort for patients with SBC with portal hypertension. However, considering the difficulty of surgery and perioperative management, LDLT should be performed by experienced transplant surgeons in a center where a multidisciplinary approach is possible.

Some of patients are suffered from pitch lowering of voice after thyroidectomy. We sought to identify factors predictive of a recovery from lowered pitch voice after thyroid surgery. We retrospectively reviewed the records of 133 patients who underwent total thyroidectomy to treat papillary carcinoma between January 2012 and February 2013. Of these, we enrolled 78 who exhibited a lower-pitched voice (SFF fall > 12 Hz) at 2 weeks post-operatively than pre-operatively and investigated pitch recovery after 3 months. We subclassified patients into recovery and non-recovery groups and compared videostroboscopic findings, acoustic voice data, and thyroidectomy-related voice questionnaire scores pre-operatively and 2, 8, and 12 weeks post-operatively. Vocal cord asymmetry on videostroboscopic examination at 2 weeks post-operatively (odds ratio 19.056, p = 0.001*) was more frequent in the non-recovery group. In acoustic analysis, mean pre-operative SFF was higher in the non-recovery group than the recovery group (190.9 ± 27.5 and 180.9 ± 24.6 Hz, respectively; p = 0.030*). Also, a reduction in the SFF of > 19.6 Hz, at 2 weeks post-operatively versus pre-operatively, predicted non-recovery of pitch-lowering in patients with reduced SFF within post-operative 3 months, with 72.0% sensitivity and 71.2% specificity. After 6 months of follow-up, no patient who exhibited an SFF fall > 19.6 Hz recovered to within 10 Hz of the pre-operative value. A reduction in the speaking fundamental frequency (SFF) > 19.6 Hz at 2 weeks post-operatively predicted persisting lowering of voice pitch after thyroidectomy among those with lower-pitched voices after surgery. Pre-operative high SFF and post-operative stroboscopic findings including vocal cord asymmetry at 2 weeks post-operatively also predicted persisting lowering of voice pitch for 3 months.

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., Graphical Abstract

Some patients experience long-term voice change after thyroidectomy. One of the most common symptoms of voice change is pitch lowering, which is closely related to unfavorable voice quality. Here we observed voice outcomes for 6 months of follow-up after thyroidectomy to identify factors closely related to low-pitched voice.We retrospectively reviewed the records of 2,297 patients who underwent thyroidectomy between January 2014 and December 2017. All the patients had their vocal status examined using videostroboscopy, acoustic voice analyses, aerodynamic study, and Thyroidectomy-Related Voice Questionnaire scores. We stratified patients into 2 groups (low-pitched voice versus favorable voice) according to pitch lowering (reduction in speaking fundamental frequency ≥12 Hz 1 month after thyroidectomy compared to the preoperative value). We compared preoperative data with postoperative data collected 1, 3, and 6 months after thyroidectomy to identify factors contributing to low-pitched voice.Univariate logistic regression analyses showed that factors related to low-pitched voice were female sex, older age, low body weight, short stature, and a high positive lymph node ratio. Multivariate analyses showed that female sex and older age were significantly associated with a negative prognosis for low-pitched voice 1 month after thyroidectomy (odds ratios 0.41 and 1.04, respectively; P.001). Receiver operating characteristic curves for predicting sustained low-pitched voice during 6 months showed that speaking fundamental frequency ≥12.48 Hz 1 month after thyroidectomy was the optimal cutoff value, with 87.9% sensitivity and 95.8% specificity (P.001).Female sex and older age are strongly associated with increased risk for low-pitched voice after thyroidectomy. Speaking fundamental frequency ≥12.48 Hz 1 month after thyroidectomy can be used to predict sustained low-pitched voice after thyroidectomy.

We assessed the prognostic accuracy of ADV score (α-fetoprotein [AFP]-des-γ-carboxyprothrombin [DCP]-tumor volume [TV] score) following resection of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). This was a retrospective observational study. This study included 147 patients who underwent hepatic resection for HCC with PVTT. They were followed up for ≥ 66 months or until patient death. The grades of PVTT were Vp1 in 121 (14.3%), Vp2 in 41 (27.9%), Vp3 in 71 (48.3%), and Vp4 in14 (9.5%) cases. Preoperative HCC treatment was performed in 48 (32.7%) patients. R0 and R1 resections were performed in 119 (81.0%) and 28 (19.0%) cases, respectively. The 5-year tumor recurrence, HCC-specific survival, and post-recurrence survival rates were 79.2%, 43.5%, and 25.4%, respectively. Neither PVTT grade nor history of preoperative HCC treatment was a significant prognostic indicator. Stratification in accordance with ADV scores of 1log- and 3log-intervals resulted in high prognostic accuracy in predicting tumor recurrence and patient survival. Following cluster analysis, the cutoff for ADV score was determined at 9log and was more prognostically significant in terms of tumor recurrence and patient survival than surgical curability or microvascular invasion. Further comparisons revealed that prognostic prediction with an ADV score cutoff at 9log was more accurate than that using the Eastern Hepatobiliary Surgery Hospital-PVTT score. ADV score is an integrated surrogate biomarker for post-resection prognosis in HCC with PVTT. Our prognostic prediction model using ADV scores provides reliable post-resection prognosis for patients with various grades of these tumors.

Background and aims Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4-1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor-infiltrating CD8+ T cells (CD8+ tumor-infiltrating lymphocytes [TILs]) and its association with distinct T-cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC). Approach and results Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA-sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4-1BB was most prominently expressed on CD8+ TILs. 4-1BB expression was almost exclusively detected on CD8+ T cells in the tumor-especially on programmed death 1 (PD-1)high cells and not PD-1int and PD-1neg cells. Compared to PD-1int and 4-1BBneg PD-1high CD8+ TILs, 4-1BBpos PD-1high CD8+ TILs exhibited higher levels of tumor reactivity and T-cell activation markers and significant enrichment for T-cell activation gene signatures. Per-patient analysis revealed positive correlations between percentages of 4-1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T-cell activation. Among highly exhausted PD-1high CD8+ TILs, 4-1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4-1BB-related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4-1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti-PD-1-mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T-cell activation. Conclusion 4-1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4-1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T-cell activation.

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., Graphical Abstract

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., Graphical Abstract

Summary Objectives Common symptoms after thyroidectomy include voice change and throat and neck discomfort. But no common questionnaire has been developed. This study was performed to evaluate the reliability and validity of the Thyroidectomy-related Voice and Symptom Questionnaire (TVSQ). Methods Fourty items of the TVSQ were divided into 20 items related to the “voice change” and “throat and neck discomfort” subcategories, using item generation. Through a reduction process, 20 items were removed and 20 items were used. For the patients after thyroidectomy, we evaluated the reliability and validity of each of the 20 items through item discrimination, test-retest reliability, concurrent validity, and external validity by comparing normal group and laryngeal disease patients. Also, the patients were compared before as well as 2 and 4 weeks after thyroidectomy. Results Item discrimination assessment showed a significant correlation between TVSQ total score and both the TVSQ “voice change” score (r = 0.908**) and TVSQ “throat and neck discomfort” score (r = 0.862**). Test-retest reliability assessment showed a significant correlation between TVSQ total scores at 2 and 4 weeks postoperatively (r = 0.764**). Concurrent validity assessment revealed that the TVSQ showed high correlations with other voice questionnaires (Voice Handicap Index, Reflux Finding Index, and Vocal Track Discomfort Scale; r = 0.538**–0.830**). External validity assessment revealed that the TVSQ was suitable for patients after thyroidectomy (P Conclusions Validity and reliability tests revealed that the TVSQ was suitable for assessment of the subjective feelings of patients with voice change and throat and neck discomfort after thyroidectomy.

BACKGROUND We assessed the prognostic impact of donor age on the outcome of adult living donor liver transplantation (LDLT). MATERIAL AND METHODS The study population comprised adult donor and recipients of right lobe grafts for LDLT performed from January 2005 to December 2016. There were 35 living donors aged ≥50 years (old-age donor group). As a control group, donors in their 20s (young-age donor group) were selected after one-to-one propensity score matching based on sex, model for end-stage liver disease (MELD) score, and primary diagnosis. RESULTS Donor age was 52.5±1.5 years versus 25.4±3.1 years in the old- and young-age donor groups, respectively. Remnant volumes of the 2 groups were 38.9±3.0% versus 38.1±2.9%, respectively (p=0.98). One-month regeneration rate of the remnant liver was 101.1±10.6% versus 104.5±11.8%, respectively (p=0.08), and there was no significant difference in the incidences of donor complications. Mean MELD score was 15 versus 14, respectively (p=0.82). Graft-to-recipient weight ratio was 1.02±0.43 versus 0.91±0.63, respectively (p=0.28). In the recipients, biliary complication occurred in 11.4% versus 8.6%, respectively (p=0.12), and there was no difference in 5-year survival rates of both groups (p=0.15). The 1-week and 1-month regeneration rates of the remnant left liver were 71.6±9.9% and 100.1±10.6% in the old-age group, respectively, whereas those were 80.2±12.1% and 104.5±11.8% in the young-age group, respectively (p=0.08). CONCLUSIONS Right lobe grafts from donors aged ≥50 years showed the usual recovery of graft function but rather delayed liver regeneration. Thus, old-aged donors should be selected prudently after consideration of hepatic resection rate, graft size, and hepatic steatosis.

BACKGROUND This study aimed to assess patterns of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) and to establish long-term surveillance protocols for late HCC recurrence. MATERIAL AND METHODS The 232 LT recipients experiencing subsequent HCC recurrence were categorized as Group 1, early recurrence (within 1 year of LT; n=117); Group 2, late recurrence (occurring in years 2-5; n=93); and Group 3, very late recurrence (after year 5; n=22). RESULTS Recurrence was detected by only elevated tumor marker levels in 11.1%, 30.1%, and 45.5% of patients in Groups 1, 2, and 3, respectively (p