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Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., DKK3, SALL3, and SOX1) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress–related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis.Significance:Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.

Purpose:To evaluate the usefulness of the radiomic model in predicting early (≤2 years) and late (>2 years) recurrence after curative resection in cases involving a single hepatocellular carcinoma (HCC) 2–5 cm in diameter using preoperative gadoxetic acid–enhanced magnetic resonance imaging (MRI), in comparison with the clinicopathologic model.Experimental Design:This retrospective study included 167 patients with surgically resected and pathologically confirmed single HCC 2–5 cm in diameter (n = 167, training set:validation set = 128:39) who underwent preoperative gadoxetic acid–enhanced MRI between January 2010 and December 2015. A radiomic model, a clinicopathologic model, and a combined clinicopathologic-radiomic (CCR) model were built using a random survival forest to predict disease-free survival (DFS) in the following conditions: early DFS versus late DFS, dynamic phases, and the peritumoral area included in the segmentation.Results:The radiomic model showed a prognostic performance comparable with the clinicopathologic model only with 3-mm peritumoral border extension [c-index difference (radiomic-clinicopathologic), −0.021, P = 0.758]. The CCR model with the 3-mm border extension showed the highest c-index value but no statistically significant improvement over the clinicopathologic model [CCR, 0.716 (0.627–0.799); clinicopathologic model, 0.696 (0.557–0.799)].Conclusions:The prognostic value of the preoperative radiomic model with 3-mm border extension showed comparable performance with that of the postoperative clinicopathologic model for predicting DFS of early recurrence of HCC using gadoxetic acid–enhanced MRI. This suggests the importance of including peritumoral changes in the radiomic analysis of HCC.

Supplementary Table S1: Tissue specimens used for RNA-seq analysis. Supplementary Table S2: Tissues specimens used for immunohistochemical analysis. Supplementary Table S3: Gene signatures used in the study. Supplementary Table S4: Differentially methylated probes during hepatocarcinogenesis. Supplementary Table S5: Univariate and multivariate analysis for SPINK1 expression and HCC clinico-pathological features in TCGA-LIHC data.

Supplementary Materials and Methods

Supplementary Data

Supplementary Figure S1: Overall study design for multi-omic data analysis. Supplementary Figure S2: The distribution of beta-values in DNA methylation data. Supplementary Figure S3: The distribution of differentially methylated probes (DMPs). Supplementary Figure S4: Differentially methylated probes in the integrated data of GSE44970 and YSHCC. Supplementary Figure S5: Distribution of CNAs during stepwise hepatocarcinogenesis. Supplementary Figure S6: DNA methylation of oncogenes and TSGs during multi-step hepatocarcinogenesis. Supplementary Figure S7: Frequencies of nonsynonymous or missense mutations in each patient. Supplementary Figure S8: Functionally enriched expression in each step of hepatocarcinogenesis. Supplementary Figure S9: Validation of the three genes including SPINK1, CAP2, and RRAGD. Supplementary Figure S10: SPINK1 overexpression increases proliferation and invasion of Huh7 cells. Supplementary Figure S11: Correlation between methylation and expression. Supplementary Figure S12: Western blot of DNMT1 expression. Supplementary Figure S13: GRP78 expression under ER stress. Supplementary Figure S14: Effects of knockdown of p65 expression in the expression of GRP78 and SPINK1.

It is generally accepted that non-anatomical resection (NAR) in colorectal liver metastasis (CRLM) has comparable safety and efficacy compared to anatomical resection (AR); however, there are reports that AR may have better outcomes in KRAS mutated CRLM. This study aimed to determine the effects ofTwo hundred fifty patients who underwent hepatic resection of CRLM with known KRAS mutational status between 2007 and 2018 were analyzed. A total of 94 KRAS mutated CRLM and 156 KRAS wild-type CRLM were subdivided by surgical approach and compared for short- and long-term outcomes.In both KRAS wild-type and mutated type, there was no difference in estimated blood loss, postoperative complications, and 30-day mortality. There was no difference in disease-free survival (DFS) between AR and NAR in both groups (The presence of KRAS mutation may not be a significant factor when deciding the approach in simultaneous resection of CRLM.

Introduction: Currently, the impact of body mass index (BMI) on the outcomes of laparoscopic liver resections (LLR) is poorly defined. This study attempts to evaluate the impact of BMI on the peri-operative outcomes following laparoscopic left lateral sectionectomy (L-LLS). Methods: A retrospective analysis of 2183 patients who underwent pure L-LLS at 59 international centers between 2004 and 2021 was performed. Associations between BMI and selected peri-operative outcomes were analyzed using restricted cubic splines. Results: A BMI of >27kg/m2 was associated with increased in blood loss (Mean difference (MD) 21 mls, 95% CI 5–36), open conversions (Relative risk (RR) 1.13, 95% CI 1.03–1.25), operative time (MD 11 min, 95% CI 6–16), use of Pringles maneuver (RR 1.15, 95% CI 1.06–1.26) and reductions in length of stay (MD -0.2 days, 95% CI -0.3 to −0.1). The magnitude of these differences increased with each unit increase in BMI. However, there was a “U” shaped association between BMI and morbidity with the highest complication rates observed in underweight and obese patients. Conclusion: Increasing BMI resulted in increasing difficulty of L-LLS. Consideration should be given to its incorporation in future difficulty scoring systems in laparoscopic liver resections.

Background/aims Intrahepatic cholangiocarcinoma (iCCA) with a ductal plate malformation (DPM) pattern is a recently recognized rare variant. The genomic profile of iCCA with DPM pattern needs to be elucidated. Methods Cases of iCCA with DPM pattern were retrospectively reviewed based on the medical records, pathology slides, and magnetic resonance imaging (MRI) reports collected between 2010 to 2019 at a single center. Massive parallel sequencing was performed for >500 cancer-related genes. Results From a total of 175 iCCAs, five (2.9%) cases of iCCA with DPM pattern were identified. All cases were of the small duct type, and background liver revealed chronic B viral or alcoholic hepatitis. Three iCCAs with DPM pattern harbored MRI features favoring the diagnosis of hepatocellular carcinoma, whereas nonspecific imaging features were observed in two cases. All patients were alive without recurrence during an average follow-up period of 57 months. Sequencing data revealed 64 mutated genes in the five cases, among which FGFR and PTPRT were most frequently mutated (three cases each) including an FGFR-TNC fusion in one case. Mutations in ARID1A and CDKN2A were found in two cases, and mutations in TP53, BAP1, ATM, NF1, and STK11 were observed in one case each. No IDH1, KRAS, or PBRM1 mutations were found. Conclusions iCCAs with DPM pattern have different clinico-radio-pathologic and genetic characteristics compared to conventional iCCAs. Moreover, FGFR and ARID1A variants were identified. Altogether, these findings further suggest that iCCA with DPM pattern represents a specific subtype of small duct type iCCA.

Hepatocellular carcinoma (HCC) with distant metastasis is an absolute contraindication for liver transplantation (LT). However, it is still unclear whether LT is feasible or acceptable in such patients, albeit after being treated with a multidisciplinary approach and after any metastatic lesion is ruled out. We report one such successful treatment with living donor LT (LDLT) after completely controlling far-advanced HCC with inferior vena cava tumor thrombosis and multiple lung metastases. The patient has been doing well without HCC recurrence for eight years since LDLT. The current patient could be an anecdotal case, but provides a case for expanding LDLT indications in the context of advanced HCC and suchlike. (J Liver Cancer 2021;21:181-186)

The prevalence of non-alcoholic fatty liver disease-related hepatocellular carcinoma (NAFLD-HCC) has increased parallelly with that of metabolic syndrome. This study aimed to compare the clinical and survival outcomes of NAFLD-HCC and HBV-related HCC(HBV-HCC).The medical records of patients who underwent hepatectomy for HCC at Severance Hospital between 2005 and 2015 were retrospectively reviewed. Occult HBV infection was identified by nested PCR. Propensity score matching (PSM) was conducted to minimize lead-time bias caused by the lack of surveillance in NAFLD patients. Surgical and oncologic outcomes were compared between the two groups.There were 32 patients (7%) with NAFLD-HCC, 200 (46%) with HBV-HCC, and 194 (44%) with HBV/NAFLD-HCC (HBV and NAFLD). Before PSM, cirrhosis was more frequently detected in HBV-HCC patients (55% vs 15%, p 0.001) and the average tumor size was larger in the NAFLD-HCC group than in the HBV-HCC group (4.4 ± 3.3 cm vs 3.4 ± 1.8 cm, p = 0.014). After a median follow-up of 74 months (range 0-157 months), survival analyses before PSM showed better 5-year overall survival (OS) in HBV-HCC patients than in NAFLD-HCC patients (80% vs 63%, p = 0.041). After PSM, 5-year OS rates were similar (60% vs 63%, p = 0.978). There were no differences between the groups in recurrence-free or disease-specific survival before and after PSM.Patients with NAFLD-HCC were less likely to have underlying cirrhosis but more likely to have larger tumors at the time of diagnosis than patients with HBV-HCC. The OS of patients with NAFLD-HCC appeared to be worse than that of patients with HBV-HCC. Therefore, active HCC surveillance is recommended in patients with metabolic syndrome for the early detection of HCC.

Both laparoscopic living donor right hemihepatectomy (LLDRH) and robotic living donor right hemihepatectomy (RLDRH) have been developed for minimally invasive donor hepatectomy (MIDH), although comparative analysis between the two surgical modalities is lacking. This study aims to compare surgical outcomes of LLDRH and RLDRH at a single institution.From March 2016 to March 2022, 171 patients who underwent MILH of right liver were enrolled and divided into RLDRH and LLDRH. Two surgeons with experience in both techniques performed all procedures. Clinical characteristics, perioperative outcomes of donor and recipient, and donor anatomic variations were compared between both groups, and learning curves were estimated. Subgroup analysis was also performed, including only donors recruited after 2019, when LLDRH was initiated at our institution.RLDRH and LLDRH were performed for 102 and 69 patients, respectively. Operative time was significantly longer for RLDRH than LLDRH (464 vs. 407 min, P 0.001), although estimated blood loss was lower in RLDRH (104 vs. 238 mL, P = 0.002). Incidence of major complications was similar in both groups. After 2019, significantly more RLDRH vs. LLDRH patients had variation in the hepatic artery (14.3% vs. 2.9%, P = 0.020) and portal vein (16.1% vs. 4.3%, P = 0.027). Learning curve for RLDRH was stabilized after approximately the 16th case, whereas that of LLDRH stabilized immediately.RLDRH resulted in less intraoperative bleeding and comparable postoperative outcomes than LLDRH. Moreover, since 2019, RLDRH has been employed more frequently for donors with hilar structure anatomic variations. Based on our single-center experience, we propose that standardized procedures for RLDRH might help set up pure minimally invasive procedures for donor hepatectomy and facilitate safe implementation of laparoscopic approaches.

Backgrounds/Aims Although it is difficult to master the surgical learning curve for treatment of perihilar cholangiocarcinoma (HCCA), there have been no studies on surgical outcomes between a novice and an experienced surgeon. Thus, the current study attempted to evaluate surgical outcomes from a single surgeon based on learning curve for surgical treatment of HCCA. Methods From January 2008 to December 2016, a single surgeon performed surgical treatment for 108 patients with HCCA at Severance Hospital, Seoul, Korea. Among them, 101 patients with curative surgical resection were included in this study. The learning curve was assessed by a moving average graph and CUSUM method using operation time. Surgical outcomes between the early period group (EPG) and the late period group (LPG) were compared according to learning curve. Results Operation time (603.17±117.59 and 432.03±91.77 minutes; p

Backgrounds/Aims Laparoscopic major liver resections are still considered innovative procedures despite the recent development of laparoscopic liver surgery. Robotic surgery has been introduced as an innovative system for laparoscopic surgery. In this study, we investigated surgical outcomes after major liver resections using robotic systems. Methods From January 2009 to October 2018, 70 patients underwent robotic major liver resections, which included conventional major liver resections and right sectionectomy. The short-term and long-term outcomes were compared with 252 open major resections performed during the same period. Results Operative time was longer in the robotic group (472 min vs. 349 min, p

Backgrounds/aims Despite advances in surgical techniques and perioperative supportive care, radical resection of hilar cholangiocarcinoma is the only modality that can achieve long-term survival. We chronologically investigated surgical and oncological outcomes of hilar cholangiocarcinoma and analyzed the factors affecting overall survival. Methods We retrospectively enrolled 165 patients with hilar cholangiocarcinoma who underwent liver resection with a curative intent. The patients were divided into groups based on the period when the surgery was performed: period I (2005-2011) and period II (2012-2018). The clinicopathological characteristics, perioperative outcomes, and survival outcomes were analyzed. Results The patients' age, serum CA19-9 levels, and serum bilirubin levels at diagnosis were significantly higher in the period I group. There were no differences in pathological characteristics such as tumor stage, histopathologic status, and resection status. However, perioperative outcomes, such as estimated blood loss (1528.8 vs. 1034.1 mL, p=0.020) and postoperative severe complication rate (51.3% vs. 26.4%, p=0.022), were significantly lower in the period II group. Regression analysis demonstrated that period I (hazard ratio [HR]=1.591; 95% confidence interval [CI]=1.049-2.414; p=0.029), preoperative serum bilirubin at diagnosis (HR=1.585; 95% CI=1.058-2.374; p=0.026), and tumor stage (III, IV) (HR=1.671; 95% CI: 1.133-2.464; p=0.010) were significantly associated with poor prognosis. The 5-year survival rate was better in the period II patients than in the period I patients (35.1% vs. 21.0%, p=0.0071). Conclusions The surgical and oncological outcomes were better in period II. Preoperative serum bilirubin and advanced tumor stage were associated with poor prognosis in patients with hilar cholangiocarcinoma.

Lymph node (LN) metastasis is one factor indicating a poor prognosis after radical surgery for intrahepatic cholangiocarcinoma (ICC). Although several guidelines have recommended that LN dissection be strongly considered at the time of ICC surgery, no clear evidence regarding the appropriate number of harvested LNs has been established. Thus, we aimed to identify the minimum number of harvested LNs required for ICC by using a Bayesian Weibull model. Data from 142 patients who underwent radical hepatectomy (R0) for ICC from January 2000 to December 2018 were retrospectively reviewed. A Bayesian Weibull model was developed to analyze the effect of number of harvested LNs on survival of patients without (N0; n = 71) and with (N1; n = 71) metastatic nodes. We also compared the percentage of N1 patients (i.e., the N1 rate) in each of the five subgroups categorized according to the number of harvested LNs (1–4, 5–8, 9–12, 13–16, and ≥ 17). In patients with 5 or more harvested LNs, the hazard ratio (HR) for LN metastasis was above the reference line (the HR with 5 harvested LNs, 1.95 (1.09–3.45)). The N1 rate of the 1–4 harvested LNs subgroup was lower than that of the other subgroups (e.g., 1–4 vs. 5–8; 16.1% vs. 39.4%, p = 0.014). Our results suggest that at least 5 LNs should be harvested in patients who undergo radical surgery for ICC to promote accurate staging.

Background/Aims To investigate whether serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) can predict the recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection. Methods Patients with chronic hepatitis B (CHB) who underwent curative resection for HCC between 2004 and 2015 were eligible for the study. Recurrence was sub-classified as early (2.14 experienced recurrence more frequently than those with a WFA+-M2BP level ≤2.14 (P=0.011 by log-rank test), and had poorer postoperative outcomes than those with a WFA+-M2BP level ≤2.14 in terms of overall recurrence (56.0 vs. 34.5%, P=0.047) and early recurrence (52.0 vs. 20.7%, P=0.001). Conclusions WFA+-M2BP level is an independent predictive factor of HBV-related HCC recurrence after curative resection. Further studies should investigate incorporation of WFA+-M2BP level into tailored postoperative surveillance strategies for patients with CHB.

Background: Despite the rapid advances that minimally invasive liver resection has gained in recent decades, open conversion is still inevitable in some circumstances. In this study, we aimed to determine the risk factors for open conversion after minimally invasive left lateral sectionectomy, and its impact on perioperative outcomes. Methods: This is a post hoc analysis of 2,445 of 2,678 patients who underwent minimally invasive left lateral sectionectomy at 45 international centers between 2004 and 2020. Factors related to open conversion were analyzed via univariate and multivariate analyses. One-to-one propensity score matching was used to analyze outcomes after open conversion versus non-converted cases. Results: The open conversion rate was 69/2,445 (2.8%). On multivariate analyses, male gender (3.6% vs 1.8%, P = .011), presence of clinically significant portal hypertension (6.1% vs 2.6%, P = .009), and larger tumor size (50 mm vs 32 mm, P < .001) were identified as independent factors associated with open conversion. The most common reason for conversion was bleeding in 27/69 (39.1%) of cases. After propensity score matching (65 open conversion vs 65 completed via minimally invasive liver resection), the open conversion group was associated with increased operation time, blood transfusion rate, blood loss, and postoperative stay compared with cases completed via the minimally invasive approach. Conclusion: Male sex, portal hypertension, and larger tumor size were predictive factors of open conversion after minimally invasive left lateral sectionectomy. Open conversion was associated with inferior perioperative outcomes compared with non-converted cases.

Background Minimally invasive right posterior sectionectomy (RPS) is a technically challenging procedure. This study was designed to determine outcomes following robotic RPS (R-RPS) and laparoscopic RPS (L-RPS). Methods An international multicentre retrospective analysis of patients undergoing R-RPS versus those who had purely L-RPS at 21 centres from 2010 to 2019 was performed. Patient demographics, perioperative parameters, and postoperative outcomes were analysed retrospectively from a central database. Propensity score matching (PSM) was performed, with analysis of 1 : 2 and 1 : 1 matched cohorts. Results Three-hundred and forty patients, including 96 who underwent R-RPS and 244 who had L-RPS, met the study criteria and were included. The median operating time was 295 minutes and there were 25 (7.4 per cent) open conversions. Ninety-seven (28.5 per cent) patients had cirrhosis and 56 (16.5 per cent) patients required blood transfusion. Overall postoperative morbidity rate was 22.1 per cent and major morbidity rate was 6.8 per cent. The median postoperative stay was 6 days. After 1 : 1 matching of 88 R-RPS and L-RPS patients, median (i.q.r.) blood loss (200 (100–400) versus 450 (200–900) ml, respectively; P 500 ml; P = 0.001), need for intraoperative blood transfusion (10.2 versus 23.9 per cent, respectively; P = 0.014), and open conversion rate (2.3 versus 11.4 per cent, respectively; P = 0.016) were lower in the R-RPS group. Similar results were found in the 1 : 2 matched groups (66 R-RPS versus 132 L-RPS patients). Conclusion R-RPS and L-RPS can be performed in expert centres with good outcomes in well selected patients. R-RPS was associated with reduced blood loss and lower open conversion rates than L-RPS.

Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., DKK3, SALL3, and SOX1) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress–related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis. Significance: Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.

Purpose: To evaluate the usefulness of the radiomic model in predicting early (≤2 years) and late (>2 years) recurrence after curative resection in cases involving a single hepatocellular carcinoma (HCC) 2–5 cm in diameter using preoperative gadoxetic acid–enhanced magnetic resonance imaging (MRI), in comparison with the clinicopathologic model. Experimental Design: This retrospective study included 167 patients with surgically resected and pathologically confirmed single HCC 2–5 cm in diameter (n = 167, training set:validation set = 128:39) who underwent preoperative gadoxetic acid–enhanced MRI between January 2010 and December 2015. A radiomic model, a clinicopathologic model, and a combined clinicopathologic-radiomic (CCR) model were built using a random survival forest to predict disease-free survival (DFS) in the following conditions: early DFS versus late DFS, dynamic phases, and the peritumoral area included in the segmentation. Results: The radiomic model showed a prognostic performance comparable with the clinicopathologic model only with 3-mm peritumoral border extension [c-index difference (radiomic-clinicopathologic), −0.021, P = 0.758]. The CCR model with the 3-mm border extension showed the highest c-index value but no statistically significant improvement over the clinicopathologic model [CCR, 0.716 (0.627–0.799); clinicopathologic model, 0.696 (0.557–0.799)]. Conclusions: The prognostic value of the preoperative radiomic model with 3-mm border extension showed comparable performance with that of the postoperative clinicopathologic model for predicting DFS of early recurrence of HCC using gadoxetic acid–enhanced MRI. This suggests the importance of including peritumoral changes in the radiomic analysis of HCC.

Background/aims Circulating tumor cells (CTCs) with cancer stemness have been demonstrated to be a direct cause of tumor recurrence, and only few studies have reported the role of CTCs in liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods Epithelial cell adhesion molecule+ (EpCAM+), cluster of differentiation 90+ (CD90+) and EpCAM+/CD90+ CTCs were sorted via fluorescence-activated cell sorting, and transcripts level of EpCAM, K19 and CD90 in the peripheral blood were analyzed via real-time polymerase chain reaction preoperatively and on postoperative days 1 and 7 in 25 patients who underwent living donor liver transplantation (LDLT) for HCC. EpCAM protein was assessed in HCC tissue using immunohistochemical staining. The median follow-up duration was 40 months. Results HCC after LDLT recurred in four out of 25 patients. Detection of EpCAM+ or CD90+ CTCs correlated well with their messenger RNA levels (p 100 mAU/mL and postoperative day 1 EpCAM+/CD90+ CTCs were independent risk factors for HCC recurrence (hazard ratio, 14.64; 95% confidence interval, 1.08 to 198.20; p=0.043 and hazard ratio, 26.88; 95% confidence interval, 1.86 to 387.51; p=0.016, respectively). Conclusions EpCAM+/CD90+ CTCs can be used preoperatively and 1 day after LDLT as key biological markers in LT candidate selection and post-LDLT management.

Simple Summary Cholangiocarcinoma (CCC) is a rare cancer, but its incidence and mortality have been increased in the past few decades worldwide, representing a global health problem. CCC is usually asymptomatic in early stages and, therefore, often diagnosed when the disease is already in advanced stages, which highly compromises therapeutic options, resulting in a dismal prognosis. The current diagnosis of CCC by non-invasive approaches such as serum biomarker, carbohydrate antigen 19-9 (CA 19-9), is not accurate enough due to the limitations in its low sensitivity, especially at the early stages of the disease. Therefore, new biomarkers with higher sensitivity and specificity are needed. As the clinical significance of dickkopf-related protein-1 (DKK-1) has been reported in various tumors including intrahepatic CCC (ICC), we aimed to identify the diagnostic and prognostic performance of the DKK-1 and its additive effect combined with CA 19-9 in patients with CCC. Abstract Dickkopf-related protein 1 (DKK-1) has a diagnostic and prognostic value in various malignant tumors. We investigated the diagnostic and prognostic performance of DKK-1 in combination with carbohydrate antigen 19-9 (CA 19-9) in cholangiocarcinoma (CCC) patients. Serum DKK-1 levels were measured using enzyme-linked immunosorbent assay. The receiver operating characteristic (ROC) curve, area under ROC (AUROC) analyses, Kaplan–Meier method, and Cox proportional hazard model were used to evaluate the diagnostic and prognostic performance of DKK-1 in combination with CA 19-9. We checked DKK-1 levels in 356 CCC patients and found that DKK-1 was significantly elevated only in 79 intrahepatic CCC (ICC) patients compared to controls (340.5 vs. 249.8 pg/mL, p = 0.002). The optimal cutoff level of DKK-1 used to identify ICC patients was 258.0 pg/mL (AUROC = 0.637, sensitivity = 59.5%, specificity = 56.9%, positive predictive value (PPV) = 40.5%, negative predictive value (NPV) = 74.0%, positive likelihood ratio (LR) = 1.38, and negative LR = 0.71). Using this cutoff, 47 (59.5%) patients were correctly diagnosed with ICC. DKK-1 in combination with CA 19-9 showed a better diagnostic performance (AUROC = 0.793, sensitivity = 74.7%, specificity = 56.3%, PPV = 45.7, NPV = 81.8, positive LR = 1.71, and negative LR = 0.45) than CA 19-9 alone. The low DKK-1 and CA 19-9 expression group had a significantly longer overall survival (OS) than the high expression group (p = 0.006). The higher level of DKK-1 and CA 19-9 was independently associated with shorter OS (hazard ratio = 3.077, 95% confidence interval 1.389–6.819, p = 0.006). The diagnostic and prognostic performance of DKK-1 in combination with CA 19-9 might be better than those of CA 19-9 alone in ICC patients.

Background/Aims: This study aimed to investigate whether everolimus (EVR) affects long-term survival after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC).Methods: The data from 303 consecutive patients with HCC who had undergone LT from January 2012 to July 2018 were retrospectively reviewed. The patients were divided into two groups: 1) patients treated with EVR in combination with calcineurin inhibitors (CNIs) (EVR group; n=114) and 2) patients treated with CNI-based therapy without EVR (non-EVR group; n=189). Time to recurrence (TTR) and overall survival (OS) after propensity score (PS) matching were compared between the groups, and prognostic factors for TTR and OS were evaluated.Results: The EVR group exhibited more aggressive tumor biology than the non-EVR group, such as a higher number of tumors (P=0.003), a higher prevalence of microscopic vascular invasion (P=0.017) and exceeding Milan criteria (P=0.029). Compared with the PS-matched non-EVR group, the PS-matched EVR group had significantly better TTR (P