Safety and efficacy of early corticosteroid withdrawal in liver transplant recipients: A randomized controlled trial.

Backgrounds/Aims: Prolonged use of steroids after liver transplantation (LT) significantly increases the risk of diabetes or cardiovascular disease, which can adversely affect patient outcomes. Our study evaluated the effectiveness and safety of early steroid withdrawal within the first year following LT. Methods: This study was conducted as an open-label, multicenter, randomized controlled trial. Liver transplant recipients were randomly assigned to one of the following two groups: Group 1, in which steroids were withdrawn two weeks posttransplantation, and Group 2, in which steroids were withdrawn three months posttransplantation. This study included participants aged 20 to 70 years who were scheduled to undergo a single-organ liver transplant from a living or deceased donor at one of the four participating centers. Results: Between November 2012 and August 2020, 115 patients were selected and randomized into two groups, with 60 in Group 1 and 55 in Group 2. The incidence of new-onset diabetes after transplantation (NODAT) was notably higher in Group 1 (32.4%) than in Group 2 (10.0%) in the per-protocol set. Although biopsy-proven acute rejection, graft failure, and mortality did not occur, the median tacrolimus trough level/dose/weight in Group 1 exceeded that in Group 2. No significant differences in safety parameters, such as infection and recurrence of hepatocellular carcinoma, were observed between the two groups. Conclusions: The present study did not find a significant reduction in the incidence of NODAT in the early steroid withdrawal group. Our study suggests that steroid withdrawal three months posttransplantation is a standard and safe immunosuppressive strategy for LT patients.

A Unique Immune-Related Gene Signature Represents Advanced Liver Fibrosis and Reveals Potential Therapeutic Targets.

Innate and adaptive immune responses are critically associated with the progression of fibrosis in chronic liver diseases. In this study, we aim to identify a unique immune-related gene signature representing advanced liver fibrosis and to reveal potential therapeutic targets. Seventy-seven snap-frozen liver tissues with various chronic liver diseases at different fibrosis stages (1: n = 12, 2: n = 12, 3: n = 25, 4: n = 28) were subjected to expression analyses. Gene expression analysis was performed using the nCounter PanCancer Immune Profiling Panel (NanoString Technologies, Seattle, WA, USA). Biological meta-analysis was performed using the CBS Probe PINGSTM (CbsBioscience, Daejeon, Korea). Using non-tumor tissues from surgically resected specimens, we identified the immune-related, five-gene signature (CHIT1_FCER1G_OSM_VEGFA_ZAP70) that reliably differentiated patients with low- (F1 and F2) and high-grade fibrosis (F3 and F4; accuracy = 94.8%, specificity = 91.7%, sensitivity = 96.23%). The signature was independent of all pathological and clinical features and was independently associated with high-grade fibrosis using multivariate analysis. Among these genes, the expression of inflammation-associated FCER1G, OSM, VEGFA, and ZAP70 was lower in high-grade fibrosis than in low-grade fibrosis, whereas CHIT1 expression, which is associated with fibrogenic activity of macrophages, was higher in high-grade fibrosis. Meta-analysis revealed that STAT3, a potential druggable target, highly interacts with the five-gene signature. Overall, we identified an immune gene signature that reliably predicts advanced fibrosis in chronic liver disease. This signature revealed potential immune therapeutic targets to ameliorate liver fibrosis.

Strategy for Selective Middle Hepatic Vein Reconstruction in Living Donor Liver Transplantation Using Right Lobe Graft: A Retrospective Observational Study.

BACKGROUND: The aim of this study was to verify the safety and feasibility of our selection criteria for middle hepatic vein (MHV) reconstruction in living donor liver transplantation (LDLT) using right lobe grafts. METHODS: A total of 153 LDLTs were performed using right lobe grafts in a tertiary hospital from 2006 to 2016. Among them, 52 cases without MHV reconstruction were compared with 101 recipients who underwent LDLT using right lobe graft with MHV reconstruction. Both groups were compared regarding indications for reconstruction, short-term and long-term complications, operative details, and outcomes. RESULTS: The two groups differed only in cold ischemic time (108.19 ± 49.81 minutes vs 146.37 ± 58.74 minutes) preoperatively. Short-term posttransplant outcomes, long-term overall survival, and long-term disease-free survival showed no significant differences between the 2 groups. After propensity score matching for both groups with and without MHV reconstruction to eliminate selection bias, the 2 groups were comparable. CONCLUSIONS: We found that our selection criteria for performing MHV reconstruction in LDLT using right lobe graft were feasible and safe. A routine MHV reconstruction is not necessary if the right lobe graft graft-to-recipient weight ratio is ≥1.0, right hepatic vein draining territory volume is ≥0.8, and recipient Model for End-Stage Liver Disease score is <20.

USO1 isoforms differentially promote liver cancer progression by dysregulating the ER-Golgi network.

Alternative splicing of RNA transcripts plays an important role in cancer development and progression. Recent advances in RNA-seq technology have made it possible to identify alternately spliced events in various types of cancer; however, research on hepatocellular carcinoma (HCC) is still limited. Here, by performing RNA-seq profiling of HCC transcripts at isoform level, we identified tumor-specific and molecular subtype-dependent expression of the USO1 isoforms, which we designated as a normal form USO1-N (XM_001290049) and a tumor form USO1-T (NM_003715). The expression of USO1-T, but not USO1-N, was associated with worse prognostic outcomes of HCC patients. We confirmed that the expression of USO1-T promoted an aggressive phenotype of HCC, both in vitro and in vivo. In addition, structural modeling analyses revealed that USO1-T lacks an ARM10 loop encoded by exon 15, which may weaken the dimerization of USO1 and its tethering to GM130. We demonstrated that USO1-T ensured unstacking of the Golgi and accelerated the vesicles trafficking from endoplasmic reticulum (ER) to Golgi and plasma membrane in multiple liver cancer cells. ERK and GRASP65 were found to be involved in the USO1-T-mediated Golgi dysfunction. Conclusively, we provide new mechanophysical insights into the USO1 isoforms that differentially regulate the ER-Golgi network, promoting the heterogeneous HCC progression.

TPRG1-AS1 induces RBM24 expression and inhibits liver cancer progression by sponging miR-4691-5p and miR-3659.

BACKGROUND & AIMS: Noncoding RNAs (ncRNAs) play critical roles in hepatocellular carcinoma (HCC) progression. Here, by performing RNA-sequencing (RNA-Seq) profiling, we sought to identify novel ncRNAs that potentially drive the heterogeneous progression of liver cancers. METHODS: RNA-Seq profiles were obtained from 68 HCC specimens and 10 samples of adjacent non-tumour liver tissues. The functional significance of the potential driver ncRNAs was evaluated by cell experiments. RESULTS: TPRG1-AS1 was identified as a potential driver noncoding RNA that promotes heterogeneous liver cancer progression. TPRG1-AS1 induced tumour suppressor RNA-binding motif protein 24 (RBM24), suppressing tumour growth by activating apoptotic tumour cell death. In addition, we report that TPRG1-AS1 acts as a competing endogenous RNA (ceRNA) for RBM24, sponging miR-4691-5p and miR-3659 to interfere with their binding to RBM24. CONCLUSIONS: We suggest that TPRG1-AS1 is a novel ceRNA sponging miR-4691-5p and miR-3659, resulting in RBM24 expression and suppression of liver cancer growth. Our results provide new insights into the functions of ncRNAs in heterogeneous HCC progression.

Risk Factors for Beyond Milan Recurrence After Hepatic Resection for Single Hepatocellular Carcinoma No Larger Than 5 Centimeters.

Hepatic resection (HR) is considered a treatment of choice for a single hepatocellular carcinoma (HCC) ≤5 cm in patients with preserved liver function. However, it is possible for these patients to develop a severe form of recurrence (beyond Milan recurrence [BMR] criteria). This recurrence could have been avoided if liver transplantation (LT) was performed primarily, as LT is believed to yield a more favorable oncological outcome compared with HR. The aim of this study was to determine the risk factors for BMR after HR and to verify whether primary LT can provide a more favorable outcome in patients with BMR risk factors. Data from 493 patients who underwent HR for HCC ≤5 cm between 1995 and 2016 were analyzed. Among them, 74 patients (15%) experienced BMR. The 10-year survival rate of patients with BMR was significantly low compared with that of patients without BMR (22.6% versus 79.8%; P < 0.01). In multivariate analysis, calculated hepatic venous pressure gradient ≥7 mm Hg and microvascular invasion were identified as the risk factors for BMR (P < 0.05). During the same period, 63 eligible patients underwent LT as a primary treatment for HCC ≤5 cm. No significant difference in long-term survival rate was observed when no risk factor for BMR was present in the HR and LT groups (85.5% versus 100%; P = 0.39). However, 10-year survival was poorer in the HR group in the presence of risk factors for BMR (60.6% versus 91.8%; P < 0.001). Among the patients with HCCs ≤5 cm, which are resectable and transplantable, LT is indicated when calculated hepatic venous pressure gradient ≥7 mm Hg and/or microvascular invasion is present.

Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis.

Mitochondrial respiratory defects have been implicated in cancer progression and metastasis, but how they control tumor cell aggressiveness remains unclear. Here, we demonstrate that a mitochondrial respiratory defect induces nuclear factor-erythroid 2 like 1 (NFE2L1) expression at the transcriptional level via reactive oxygen species (ROS)-mediated STAT3 activation. We identified syntaxin 12 (STX12) as an effective downstream target of NFE2L1 by performing cDNA microarray analysis after the overexpression and depletion of NFE2L1 in hepatoma cells. Bioinformatics analysis of The Cancer Genome Atlas Liver Hepatocellular carcinoma (TCGA-LIHC) open database (n = 371) also revealed a significant positive association (r = 0.3, p = 2.49 × 10-9) between NFE2L1 and STX12 expression. We further demonstrated that STX12 is upregulated through the ROS/STAT3/NFE2L1 axis and is a key downstream effector of NFE2L1 in modulating hepatoma cell invasiveness. In addition, gene enrichment analysis of TCGA-LIHC also showed that epithelial-mesenchymal transition (EMT)-related core genes are significantly upregulated in tumors co-expressing NFE2L1 and STX12. The positive association between NFE2L1 and STX12 expression was validated by immunohistochemistry of the hepatocellular carcinoma tissue array. Finally, higher EMT gene enrichment and worse overall survival (p = 0.043) were observed in the NFE2L1 and STX12 co-expression group with mitochondrial defect, as indicated by low NDUFA9 expression. Collectively, our results indicate that NFE2L1 is a key mitochondrial retrograde signaling-mediated primary gene product enhancing hepatoma cell invasiveness via STX12 expression and promoting liver cancer progression.

18F-fluorodeoxyglucose PET/CT as an independent predictor for patients with hepatocellular carcinoma combined with major portal vein tumor thrombus.

PURPOSE: Hepatocellular carcinoma (HCC) patients with major portal vein tumor thrombosis (mPVTT) complications were generally characterized by extremely poor prognoses. The aim of this study was to explore the role of 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging in predicting HCC complicated by mPVTT. METHODS: Five hundred one HCC patients received surgery in our hospital during November 2008 to December 2014, among which 32 patients (6.4%) were diagnosed as HCC complicated by mPVTT. Six cases were excluded for reasons of complex medical conditions, including 2 cases of salvage liver transplantation, 2 cases of re-resection, 1 case of mPVTT combined with inferior vina cava tumor thrombosis, and 1 case of residual portal vein tumor thrombosis. Ultimately, 26 cases were enrolled in this study. The maximal tumor standardized uptake value (SUVmax) was identified as a predictive factor and detected. The univariate and multivariate regression analyses were performed to identify the prognostic factors for recurrence-free survival (RFS) and overall survival (OS) of HCC patients complicated by mPVTT. RESULTS: Our results showed that the median OS was 16 months. The 1-, 3-, and 5-year cumulative OS was 55.6%, 31.7%, and 31.7%, respectively. The multivariate regression analysis revealed that SUVmax ≥ 4.65 was the only independent risk factor for RFS and OS. CONCLUSION: SUVmax was an independent predictor for RFS and OS of patients suffering from both HCC and mPVTT. L ow SUVmax could serve as an effective factor for selecting candidates with low recurrence risks and for helping with improving patient survival after surgical resection.

Prognostic Analysis of Hepatocellular Carcinoma With Hepatitis C Virus Infection Using Epithelial-Mesenchymal Transition Gene Profiles.

BACKGROUND: Epithelial-mesenchymal transition genes have prognostic influence on hepatocellular carcinoma (HCC). Previously, the following four epithelial-mesenchymal transition-related genes were considered to be significantly influential: E-cadherin (CDH1), inhibitor of DNA binding 2 (ID2), matrix metalloproteinase 9 (MMP9), and transcription factor 3 (TCF3). A prognostic prediction model, NRISK4 = (-0.333 × [CDH1] - 0.400 × [ID2] + 0.339 × [MMP9] + 0.387 × [TCF3]) was constructed, but from patients with HCC with predominantly hepatitis B virus infection. We therefore aim to validate if this model also fits patients with HCC and hepatitis C virus (HCV) infection. METHODS: We collected HCC tissue samples from 67 patients with HCV infection. Discrimination of the NRISK4 was re-estimated using receiver operating curve analysis and we redefined the appropriate cutoff value. Using this cutoff value, patients were divided into two groups (high/low risk patients) and we compared their clinicopathological factors and prognosis. RESULTS: Area under the curve of NRISK4 prediction was 0.70 and an appropriate cutoff value was 3.19 in this cohort. Patients were divided into high- (n = 25) and low-risk (n = 42) patients for prognosis. There were no significant differences in tumor factors between the two groups. Cancer-specific survival rates at 5 y after surgery on high- and low-risk patients were 45% and 68%, respectively (P = 0.02). At 2 y after surgery, recurrence rates were 68% and 37% among high- and low-risk patients, respectively (P = 0.01). Aggressive recurrences were highly observed in the high-risk patients (P = 0.01). CONCLUSIONS: NRISK4 model could also successfully validate prognosis of patients with HCC with HCV infection similarly to in the previous report of patients with hepatitis B virus infection, especially in the early period after surgery.

Surgical Outcomes of Hepatocellular Carcinoma With Bile Duct Tumor Thrombus: A Korea-Japan Multicenter Study.

OBJECTIVE: To identify optimal surgical methods and the risk factors for long-term survival in patients with hepatocellular carcinoma accompanied by macroscopic bile duct tumor thrombus (BDTT). SUMMARY BACKGROUND DATA: Prognoses of patients with hepatocellular carcinoma accompanied by BDTT have been known to be poor. There have been significant controversies regarding optimal surgical approaches and risk factors because of the low incidence and small number of cases in previous reports. METHODS: Records of 257 patients from 32 centers in Korea and Japan (1992-2014) were analyzed for overall survival and recurrence rate using the Cox proportional hazard model. RESULTS: Curative surgery was performed in 244 (94.9%) patients with an operative mortality of 5.1%. Overall survival and recurrence rate at 5 years was 43.6% and 74.2%, respectively. TNM Stage (P < 0.001) and the presence of fibrosis/cirrhosis (P = 0.002) were independent predictors of long-term survival in the Cox proportional hazards regression model. Both performing liver resection equal to or greater than hemihepatectomy and combined bile duct resection significantly increased overall survival [hazard ratio, HR = 0.61 (0.38-0.99); P = 0.044 and HR = 0.51 (0.31-0.84); P = 0.008, respectively] and decreased recurrence rate [HR = 0.59 (0.38-0.91); P = 0.018 and HR = 0.61 (0.42-0.89); P = 0.009, respectively]. CONCLUSIONS: Clinical outcomes were mostly influenced by tumor stage and underlying liver function, and the impact of BDTT to survival seemed less prominent than vascular invasion. Therefore, an aggressive surgical approach, including major liver resection combined with bile duct resection, to increase the chance of R0 resection is strongly recommended.

Can we delineate preoperatively the right and ventral margins of caudate lobe of the liver?

PURPOSE: Complete removal of the caudate lobe, which is sometimes necessary, is accomplished via isolated caudate lobectomy or hepatectomy that includes the caudate lobe. It is impossible, however, to confirm the right and ventral margins of the caudate lobe by preoperative imaging. This study was undertaken to determine whether we could identify the right and ventral margins of the caudate lobe preoperatively using Synapse 3D visualization software. METHODS: Ninety-four preoperative 3-dimensional (3D) computed tomographic images (1-mm slices) of the liver from candidate donors were examined. The images of the caudate lobe were subjected to a counter-staining method according to Synapse 3D to delineate their dimensions. We first examined whether the right margin of the caudate lobe exceeded the plane formed by the root of the right hepatic vein (RHV) and the right side of the inferior vena cava (IVC). Second, we determined whether the ventral margin of the caudate lobe exceeded the plane formed by the root of the middle hepatic vein (MHV) and the root of the RHV. RESULTS: For the right margin, 17 cases (18%) exceeded the RHV-IVC plane by a mean of 10.2 mm (range, 2.4-27.2 mm). For the ventral margin, 28 cases (30%) exceeded the MHV-RHV plane by a mean of 17.4 mm (range, 1.2-49.1 mm). CONCLUSION: Evaluating the anatomy of caudate lobe using Synapse 3D preoperatively could be helpful for more precise anatomical resection of the caudate lobe.

Molecular classification of hepatocellular adenoma: A single-center experience.

BACKGROUNDS/AIMS: Hepatocellular adenoma (HCA) is a rare benign tumor that has a risk of malignant transformation into hepatocellular carcinoma (HCC) and bleeding. The aim of this study was to analyze the characteristics of HCA by performing molecular classification. METHODS: We retrospectively collected data from nine patients who were diagnosed with HCA from 1995 to 2016. The patients underwent liver surgery due to the existence of clinical symptoms. Immunohistochemical (IHC) staining was performed to classify the subgroups of HCA. RESULTS: Four patients with both ß-catenin and inflammation were classified as ß-IHCA. Two patients were defined as ß-HCA. Two patients were classified as HHCA. Only one patient was defined as IHCA. None of the patients had unclassified HCA. Seven of nine patients had a malignant transformation. By comparing the characteristics of HCA between two groups, we found the mean tumor size in the malignant transformation group was greater than the non-malignant transformation group. CONCLUSIONS: Taken together, the mean tumor size and activation of catenin ß1 mutation status might be the risk factors for the malignant transformation of HCA into HCC. Moreover, IHCA without the catenin ß1 mutation could also have a possibility of malignant transformation into HCC.

Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer.

Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of-function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN-007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients.

Longterm Analysis of Biliary Complications After Duct-to-Duct Biliary Reconstruction in Living Donor Liver Transplantations.

Biliary complication (BC) is still regarded as the Achilles' heel of a living donor liver transplantation (LDLT). This study aims to evaluate the longterm outcomes of the duct-to-duct (DD) biliary reconstruction using 7-0 suture and to identify the risk factors of BCs after LDLTs. Data of 140 LDLTs between 2006 and 2015 were analyzed. All biliary reconstructions were performed as DD anastomoses using 7-0 suture: 102 for the right lobe, 20 for the left lobe, and 18 for right posterior sector grafts. BC was defined as a bile leakage (BL) or a biliary stricture (BS), and the median follow-up time after LDLT was 65 months. A total of 19 recipients (13.5%) developed BCs (8 BLs and 16 BSs) after LDLT. The survival rates between recipients with and without BCs were 83% and 86.7%, respectively (P = 0.88). In univariate analyses, the risk factors for BC were small diameter of the graft's bile duct, long warm ischemic time, small graft-to-recipient weight ratio, and no use of external biliary stent (EBS). The graft's bile duct diameter ≤ 3 mm and no use of EBS were determined as independent risk factors (hazard ratios of 9.74 and 7.68, respectively) in multivariate analyses. The 116 recipients with EBS had no BL, 11 had BSs (9%), while 24 without EBS had 8 BLs (33%) and 5 BSs (21%). After a propensity score match between the recipients with and without EBS, the EBS group (24) developed only 1 BS (4%). In conclusion, DD anastomosis using 7-0 suture combined with EBS could provide favorable longterm outcomes after LDLT, which should thus be considered the surgical technique of choice for LDLTs.

High spatial resolution navigated 3D T1-weighted hepatobiliary MR cholangiography using Gd-EOB-DTPA for evaluation of biliary anatomy in living liver donors.

PURPOSE: To determine the feasibility of high-resolution navigated three-dimensional (3D) T1-weighted hepatobiliary MR cholangiography (Nav T1 MRC) using Gd-EOB-DTPA for biliary visualization in living liver donors and to assess added value of 3D T1-weighted hepatobiliary MRCs in improving the confidence and diagnostic accuracy of biliary anatomy in complementary to T2-weighted MRCs. METHODS: Twenty-nine right liver donors underwent 3D T2 MRC, 2D T2 MRC, breath-hold T1-weighted hepatobiliary MRC (BH T1 MRC), and Nav T1 MRC. Two readers independently reviewed and compared 3D/2D MRC set, added BH T1 MRC set, and added Nav T1 MRC set for biliary diagnostic accuracy and confidence. For each MRC, biliary segments visualization and image quality were scored. RESULTS: Both BH T1 MRC and Nav T1 MRC improved accuracy and specificity in biliary diagnosis when added to 3D/2D T2 MRC-alone set, though without statistical significance (R1, 82.8% to 93.1%; R2, 82.8% to 89.7%). The added Nav T1 MRC set showed the highest diagnostic confidence with both readers. Both readers scored Nav T1 MRC with the highest visualization scores for branching ducts and overall ducts. CONCLUSION: Combining T1-weighted hepatobiliary MRCs to 3D/2D T2 MRC set improved accuracy for biliary anatomy diagnosis; time-efficient BH T1 MRC in axial and coronal planes should be considered as a key MRC sequence complementary to T2 MRCs. Given excellent biliary visualization and superior diagnostic confidence, Nav T1 MRC in selected subjects with breath-hold difficulties and inconclusive or complex biliary variations may assist in reaching a correct biliary diagnosis.

Prognostic significance of microvascular invasion in tumor stage for hepatocellular carcinoma.

BACKGROUND: The presence of microvascular invasion (McVI) in hepatocellular carcinoma (HCC) has been proposed as a cause of recurrence and poor survival, although this has not been officially emphasized in staging systems. Thus, we conducted a retrospective study to investigate the prognostic importance of McVI in tumor staging in patients with HCC who underwent hepatic resection. METHODS: A retrospective analysis was performed of patients who underwent hepatic resection for HCC at our center from 1994 to 2012. Patients with HCC were classified into four groups based on the presence of McVI and extent of gross vascular invasion (VI). RESULTS: The 5-year overall and recurrence-free survival rates of 676 patients were 63.3 and 42.6%, respectively. There was no difference in tumor recurrence or survival rate between patients with HCC and McVI without gross VI and those with gross VI confined to segmental/sectional branches. Multivariate analysis revealed that the extent of VI based on the presence of McVI and gross VI was independently associated with tumor recurrence and overall survival. CONCLUSIONS: McVI was revealed to be an important risk factor similar to gross VI confined to a segmental/sectional branch in patients with HCC who underwent hepatic resection. This finding should be considered when estimating the stage for prognosis.

Conditional Survival Analysis Demonstrates that Recurrence Risk of Surgically Treated Hepatocellular Carcinoma Evolves with Time.

OBJECTIVE: The study aim was to investigate long-term change in tumor recurrence risk in patients with hepatocellular carcinoma (HCC) after hepatic resection. Recurrence probability over time was estimated by conditional survival (CS) analysis. PATIENTS AND METHODS: Early-stage HCC patients with hepatic resection were selected for inclusion from our surgery database. Variables predictive of tumor recurrence were identified by univariate and multivariate analyses. Five-year recurrence-free CS probability was calculated for all patients and for risk groups stratified by independent predictors. RESULTS: In this series of 436 patients, tumor size >5 cm, microvascular invasion, positive resection margin, liver cirrhosis, and a indocyanine green retention ratio at 15 min (ICG-R15) >20% were independently predictive of tumor recurrence. The estimated 5-year recurrence-free CS probability improved with each additional year of recurrence-free survival, and the improvement was significantly greater in the high-risk than in the low- or intermediate-risk groups. CONCLUSION: CS provides added value during follow-up of early-stage HCC patients treated by surgical resection.

Mutations acquired by hepatocellular carcinoma recurrence give rise to an aggressive phenotype.

Recurrence of hepatocellular carcinoma (HCC) even after curative resection causes dismal outcomes of patients. Here, to delineate the driver events of genomic and transcription alteration during HCC recurrence, we performed RNA-Seq profiling of the paired primary and recurrent tumors from two patients with intrahepatic HCC. By comparing the mutational and transcriptomic profiles, we identified somatic mutations acquired by HCC recurrence including novel mutants of GOLGB1 (E2721V) and SF3B3 (H804Y). By performing experimental evaluation using siRNA-mediated knockdown and overexpression constructs, we demonstrated that the mutants of GOLGB1 and SF3B3 can promote cell proliferation, colony formation, migration, and invasion of liver cancer cells. Transcriptome analysis also revealed that the recurrent HCCs reprogram their transcriptomes to acquire aggressive phenotypes. Network analysis revealed CXCL8 (IL-8) and SOX4 as common downstream targets of the mutants. In conclusion, we suggest that the mutations of GOLGB1 and SF3B3 are potential key drivers for the acquisition of an aggressive phenotype in recurrent HCC.

Plugged percutaneous biopsy of the liver in living-donor liver transplantation recipients suspected to have graft rejection.

Background Percutaneous biopsy is a widely-accepted technique for acquiring histologic samples of the liver. When there is concern for bleeding, plugged percutaneous biopsy (PPB) may be performed, which involves embolization of the biopsy tract. Purpose To evaluate the efficacy and safety of PPB of the liver in patients suspected to have graft rejection after living-donor liver transplantation (LDLT). Material and Methods During January 2007 and December 2013, 51 patients who underwent PPB of the liver under the suspicion of post-LDLT graft rejection were retrospectively analyzed. A total of 73 biopsies were performed. Biopsy was performed with a 17-gauge core needle and 18-gauge cutting needle. The needle tract was embolized using gelatin sponge (n = 44) or N-butyl cyanoacrylate (NBCA) (n = 29). The specimens were reviewed to determine their adequacy for histologic diagnosis. We reviewed all medical records after PPB. Results Specimens were successfully acquired in all procedures (100%). They were adequate for diagnosis in 70 cases (95.9%) and inadequate in three (1.3%). Average of 9.8 complete portal tracts was counted per specimen. One minor complication (1.4%) occurred where the patient had transient fever after the procedure. Conclusion PPB is easy and safe to perform in LDLT recipients and provides high diagnostic yield.

Risk factor for ischemic-type biliary lesion after ABO-incompatible living donor liver transplantation.

AIM: To evaluate the risk factors for ischemic-type biliary lesion (ITBL) after ABO-incompatible (ABO-I) adult living donor liver transplantation (ALDLT). METHODS: Among 141 ALDLTs performed in our hospital between 2008 and 2014, 27 (19%) were ABO-I ALDLT and 114 were ABO-identical/compatible ALDLT. In this study, we extensively analyzed the clinico-pathological data of the 27 ABO-I recipients to determine the risk factors for ITBL after ABO-I ALDLT. All ABO-I ALDLT recipients underwent an identical B-cell depletion protocol with preoperative rituximab, plasma exchange (PE), and operative splenectomy. The median follow-up period after transplantation was 26 mo. The clinical outcomes of the 27 ABO-I ALDLT recipients were compared with those of 114 ABO-identical/compatible ALDLT recipients. RESULTS: ITBL occurred in four recipients (14.8%) between 45 and 112 d after ABO-I ALDLT. The overall survival rates were not different between ABO-I ALDLT and ABO-identical/compatible ALDLT (P = 0.303). Among the ABO-I ALDLT recipients, there was no difference between patients with ITBL and those without ITBL in terms of B-cell and T-cell count, serum isoagglutinin titers, number of PEs, operative time and transfusion, use of graft infusion therapy, or number of remnant B-cell follicles and plasma cells in the spleen. However, the perioperative NK cell counts in the blood of patients with ITBL were significantly higher than those in the patients without ITBL (P < 0.05). Preoperative NK cell count > 150/µL and postoperative NK cell count > 120/µL were associated with greater relative risks (RR) for development of ITBL (RR = 20 and 14.3, respectively, P < 0.05). CONCLUSION: High NK cell counts in a transplant recipient's blood are associated with ITBL after ABO-I ALDLT. Further research is needed to elucidate the molecular mechanism of NK cell involvement in the development of ITBL.