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Background Limited liver resections (LLRs) for tumours located in the posterosuperior segments of the liver are technically demanding procedures. This study compared outcomes of robotic (R) and laparoscopic (L) LLR for tumours located in the posterosuperior liver segments (IV, VII, and VIII). Methods This was an international multicentre retrospective analysis of patients who underwent R-LLR or L-LLR at 24 centres between 2010 and 2019. Patient demographics, perioperative parameters, and postoperative outcomes were analysed; 1 : 3 propensity score matching (PSM) and 1 : 1 coarsened exact matching (CEM) were performed. Results Of 1566 patients undergoing R-LLR and L-LLR, 983 met the study inclusion criteria. Before matching, 159 R-LLRs and 824 L-LLRs were included. After 1 : 3 PSM of 127 R-LLRs and 381 L-LLRs, comparison of perioperative outcomes showed that median blood loss (100 (i.q.r. 40–200) versus 200 (100–500) ml; P = 0.003), blood loss of at least 500 ml (9 (7.4 per cent) versus 94 (27.6 per cent); P < 0.001), intraoperative blood transfusion rate (4 (3.1 per cent) versus 38 (10.0 per cent); P = 0.025), rate of conversion to open surgery (1 (0.8 per cent) versus 30 (7.9 per cent); P = 0.022), median duration of Pringle manoeuvre when applied (30 (20–46) versus 40 (25–58) min; P = 0.012), and median duration of operation (175 (130–255) versus 224 (155–300); P < 0.001) were lower in the R-LLR group compared with the L-LLR group. After 1 : 1 CEM of 104 R-LLRs with 104 L-LLRs, R-LLR was similarly associated with significantly reduced blood loss and a lower rate of conversion to open surgery. Conclusion Based on a matched analysis of well selected patients, both robotic and laparoscopic access could be undertaken safely with good outcomes for tumours in the posterosuperior liver segments.

Lymph node metastasis in intrahepatic cholangiocarcinoma is a poor prognostic factor after radical surgery. However, unlike other biliary tract malignancies, the nodal stage of intrahepatic cholangiocarcinoma only reflects the presence of metastatic lymph nodes, not the number of metastatic lymph nodes. This study aimed to identify the prognostic impact of the metastatic lymph node number in intrahepatic cholangiocarcinoma.The data from 87 patients with intrahepatic cholangiocarcinoma who had undergone hepatectomy with 5 or more harvested lymph nodes and covering stations 12 and 8 based on the previous criteria from January 2006 to December 2019 were retrospectively reviewed. The hazard ratio according to the increasing metastatic lymph node number was calculated with other known prognostic factors for intrahepatic cholangiocarcinoma. The patients were then divided into 3 groups according to the metastatic lymph node number (N0 [n = 45]: no metastatic lymph nodes; NThe metastatic lymph node number was a prognostic factor of oncologic survival (disease-free survival: hazard ratio = 1.18 [1.05-1.32], P = .005; overall survival: hazard ratio = 1.21 [1.06-1.37], P = .004). Survival analysis revealed significantly poorer outcomes with an increasing metastatic lymph node number (disease-free survival: N0 vs NWith proper lymph node dissection, the number of metastatic lymph nodes is a prognostic factor of intrahepatic cholangiocarcinoma.

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.

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.

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.

Although laparoscopic minor liver resections (LLR) of posterosuperior (PS) segments are technically challenging, several expert centers are increasingly performing this procedure. In the present study, we introduced novel techniques, including the rubber band traction method and positional changes, and compared surgical outcomes of LLR for hepatocellular carcinoma (HCC) located in PS segments with open minor liver resection (OLR).From January 2008 to August 2019, 113 patients underwent laparoscopic (n = 55) or open (n = 58) minor liver resections for single small HCCs (5 cm) located in PS segments. Propensity score matching in a 1:1 ratio was conducted to minimize preoperative selection bias, and surgical outcomes were compared between the two groups.There was no intraoperative mortality or reoperation in either group. One conversion to open surgery was necessary due to severe post-operative adhesions. The matched LLR group compared to OLR had significantly shorter operative time (215.16 vs. 251.41 min, P = 0.025), lesser blood loss (218.11 vs. 358.92 mL, P = 0.046), lower complication rate (8.1% vs. 29.7%, P = 0.018), and shorter hospital stay (7.03 vs. 11.78 days, P = 0.001). Intraoperative transfusion, R0 resection, resection margin, 5-year disease-free survival and 5-year overall survival were comparable.Our standardized LLR provided improved short-term outcomes and similar long-term outcomes, when compared with OLR. With advanced techniques and accumulated surgical experience, LLR can be the first option for HCC in PS segments at expert centers.

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.

Although lymph node metastasis is a known factor predictive of a poor prognosis after radical surgery for intrahepatic cholangiocarcinoma (ICC), few studies have investigated lymph node dissection (LND) areas for accurate staging. The aim of this study was to identify the optimal LND level for ICC considering lymphatic flow. Clinical characteristics and pathologic nodal status (presence of metastasis) for 163 patients were reviewed according to tumor location. In the node-positive (N1) group, the distribution of metastatic nodes was described. The coverage of metastatic nodes according to dissection level was assessed, and the minimum dissection level for accurate ICC staging was estimated accordingly. For validation, the node-negative (N0) group was divided into two subgroups according to the estimated dissection level, and survival outcomes were compared. In the N1 group, expanding dissection to stations no. 12 and 8 covered 82.0% (n = 50) of metastatic cases regardless of tumor location. In survival analysis of N0 group, patients who underwent LND covering stations no. 8+12 showed better disease-free survival (DFS) and overall survival (OS), although the differences were not statistically significant (DFS: covering no. 12+8 vs. not covering no. 12+8, 109.0 months [24.2–193.8] vs. 33.0 months [10.3–55.7], p = 0.078; OS: covering no. 12+8 vs. not covering no. 12+8, 180.0 months [21.6–338.4] vs. 73.0 months [42.8–103.2], p = 0.080). LND including at least stations no. 12 (hepatoduodenal ligament) and 8 (common hepatic artery), regardless of tumor location, is recommended for accurate staging in ICC patients.

Right-side hepatectomy (RH) is used in oncological resection for perihilar cholangiocarcinoma (PHC); however, the decision between performing left-side hepatectomy (LH) or RH is still controversial. We compared surgical and oncologic outcomes of LH and RH in PHC type II or IV where either hepatectomy was expected to have a negative margin.From 2001 to 2020, 99 patients underwent major liver resection for type II or IV PHC. Patients with unilateral vascular invasion, unilateral tumor growth, and atrophy of unilateral liver were excluded. Preoperative characteristics, perioperative, and long-term outcomes were compared between the remaining RH and LH patients.After excluding 47 cases with side predominance, the RH group (n = 29) and LH group (n = 23) were compared. Clinical characteristics and disease severity did not differ between the groups. Portal vein embolization (RH: 48.3% vs. LH: 0.0%, p0.001) and days from diagnosis to operation (RH: 31.0 ± 16.2 vs. LH: 18.8 ± 13.4, p = 0.006) were significantly higher in the RH group. The RH group had statistically higher rate of postoperative hepatic failure (RH: 55.2% vs. LH: 21.7%, p = 0.015) and a higher mortality rate that was not significant (RH: 13.8% vs. LH: 0%, p = 0.120). The R0 resection rate (RH: 72.4% vs. LH: 78.3%, p = 0.629), median disease-free (p = 0.620), and overall (p = 0.487) survival did not differ between groups. R1 resection and lymph node metastasis were significant risk factors for disease-free survival in multivariate analysis.In type II or type IV PHC where either LH or RH was feasible, LH provided a shorter period of preoperative preparation, lower postoperative hepatic failure rate, similar R0 rate, and comparable long-term outcomes. LH should be considered a reasonable option in type II or IV PHC.

Left lateral sectionectomy (LLS) is one of the most commonly performed minimally invasive liver resections. While laparoscopic (L)-LLS is a well-established technique, over traditional open resection, it remains controversial if robotic (R)-LLS provides any advantages of L-LLS.A post hoc analysis of 997 patients from 21 international centres undergoing L-LLS or R-LLS from 2006 to 2020 was conducted. A total of 886 cases (214 R-LLS, 672 L-LLS) met study criteria. 1:1 and 1:2 propensity score matched (PSM) comparison was performed between R-LLSL-LLS. Further subset analysis by Iwate difficulty was also performed. Outcomes measured include operating time, blood loss, open conversion, readmission rates, morbidity and mortality.Comparison between R-LLS and L-LLS after PSM 1:2 demonstrated statistically significantly lower open conversion rate in R-LLS than L-LLS (0.6% versus 5%, p = 0.009) and median blood loss was also statistically significantly lower in R-LLS at 50 (80) versus 100 (170) in L-LLS (p = 0.011) after PSM 1:1 although there was no difference in the blood transfusion rate. Pringle manoeuvre was also found to be used more frequently in R-LLS, with 53(24.8%) cases versus to 84(12.5%) L-LLS cases (p 0.001). There was no significant difference in the other key perioperative outcomes such as operating time, length of stay, postoperative morbidity, major morbidity and 90-day mortality between both groups.R-LLS was associated with similar key perioperative outcomes compared to L-LLS. It was also associated with significantly lower blood loss and open conversion rates compared to L-LLS.

Controversies exist among liver surgeons regarding clinical outcomes of the laparoscopic versus the robotic approach for major complex hepatectomies. The authors therefore designed a study to examine and compare the perioperative outcomes of laparoscopic left hepatectomy or extended left hepatectomy (L-LH/L-ELH) versus robotic left hepatectomy or extended left hepatectomy (R-LH/R-ELH) using a large international multicenter collaborative database.An international multicenter retrospective analysis of 580 patients undergoing L-LH/L-ELH or R-LH/R-ELH at 25 specialized hepatobiliary centers worldwide was undertaken. Propensity score-matching (PSM) was used at a 1:1 nearest-neighbor ratio according to 15 perioperative variables, including demographics, tumor characteristics, Child-Pugh score, presence of portal hypertension, multiple resections, histologic diagnosis, and Iwate difficulty grade.Before the PSM, 190 (32 %) patients underwent R-LH/R-ELH, and 390 (68 %) patients underwent L-LH/L-ELH. After the matching, 164 patients were identified in each arm without significant differences in demographics, preoperative variables, medical history, tumor pathology, tumor characteristics, or Iwate score. Regarding intra- and postoperative outcomes, the rebotic approach had significantly less estimated blood loss (EBL) (100 ml [IQR 200 ml] vs 200 ml [IQR 235 ml]; p = 0.029), fewer conversions to open operations (n = 4 [2.4 %] vs n = 13, [7.9 %]; p = 0.043), and a shorter hospital stay (6 days [IQR 3 days] vs 7 days [IQR 3.3 days]; p = 0.009).Both techniques are safe and feasible in major hepatic resections. Compared with L-LH/L-ELH, R-LH/R-ELH is associated with less EBL, fewer conversions to open operations, and a shorter hospital stay.

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.

Background Robotic liver resection has not yet been widely implemented. We aimed to evaluate the feasibility and safety of robotic major liver resection by performing a prospective multicenter study. Methods From July 2017 to December 2018, five surgeons from five tertiary hospitals who were novices in robotic liver resection but experienced in open and laparoscopic liver resection performed 46 cases of robotic major anatomical liver resections. Perioperative clinical data and surgical data, including detailed procedure times were prospectively collected. All operations were performed according to a protocol for unify surgical techniques and instruments. Results Twenty-two cases of left hemihepatectomy, one case of extended left hemihepatectomy, 14 cases of right hemihepatectomy, two cases of right anterior sectionectomy, six cases of right posterior sectionectomy, and one case of central bisectionectomy were performed. The most common indications were hepatocellular carcinoma (21 cases) followed by intrahepatic duct stones (10 cases), intrahepatic cholangiocellular carcinoma (7 cases), liver metastases (3 cases), intraductal papillary neoplasms (2 cases), sarcoma (1 case), mucinous cystic neoplasm (1 case), and hemangioma (1 case). Surgical resection margins for all tumor cases were negative. The mean operation time was 378.58 ± 124.31 (190–696) minutes and the estimated intraoperative blood loss was 276.67 ± 397.41 mL (range, 10–2600 mL). Overall complications developed in 16 cases (34.8%). There were three cases of severe surgical complications (Clavien-Dindo classification of III or more). Only one of 46 cases was converted to conventional open left hemihepatectomy because of bleeding. The mean hospital stay was 7.3 ± 2.5 (4–18) days. Conclusions The results of this study indicate that robotic anatomic major liver resection can be safely performed by robotic beginners who are advanced open and laparoscopic liver surgeons.

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.

Surgical complications for surgeons still in the learning phase of major laparoscopic liver resection (LLR) have been frequently observed. We aimed to compare perioperative and long-term outcomes of laparoscopic and open surgery based on the surgeons’ learning curve for LLR after propensity score-matched (PSM) analysis. This was a retrospective study of all patients with a histologic diagnosis of hepatocellular carcinoma who underwent major hepatectomy between January 2013 and December 2018. A PSM analysis was used to compare the groups of patients who underwent LLR and open major liver resection (OLR) before and after the learning curve was maximized. Among 405 patients, 106 underwent LLR and 299 underwent OLR. The learning curve was maximized after 42 cases. Compared with OLR, LLR had more liver-related injury and grade III or higher complications during the learning phase. The LLR group had less blood loss, fewer transfusion requirements, and fewer liver-related complications during the ‘experienced’ phase. Hospital stay was significantly shorter during and after maximization of the learning curve in LLR compared with OLR. Operative time was comparable in the two phases. Overall, LLR was associated with less blood loss, fewer complications, and shorter hospital stay compared with open surgery. There was no significant difference in long-term survival outcomes between the two groups. LLR had a higher incidence of liver-related complications during the surgeon’s learning phase compared with OLR. This association was significantly diminished with surgeon experience. Overall perioperative outcomes such as estimated blood loss, surgical complications, and hospital stay remained better for LLR compared with OLR.

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.

OBJECTIVE To investigate whether subclassification of microscopic vascular invasion (MiVI) affects the long-term outcome after curative surgical resection or liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). SUMMARY OF BACKGROUND DATA The most important factor for TNM staging in HCC is MiVI, which includes all vascular invasions detected on microscopic examination. However, there is a broad spectrum of current definitions for MiVI. METHODS In total, 412 consecutive patients with HCC who underwent curative surgical resection without any preoperative treatment or gross vascular invasion were histologically evaluated for MiVI. Patients with MiVI were subclassified into 2 groups: microvessel invasion (MI; n = 164) only and microscopic portal vein invasion (MPVI; n = 36). Clinicopathologic features were compared between 2 groups (MI vs MPVI), whereas disease-free survival (DFS) and overall survival (OS) after resection were analyzed among 3 groups (no vascular invasion [NVI] vs MI vs MPVI). These subclassifications were validated in a cohort of 197 patients with HCC who underwent LT. RESULTS The MPVI group showed more aggressive tumor characteristics, such as higher tumor marker levels (alpha-fetoprotein, P = 0.006; protein induced by vitamin K absence-II, P = 0.001) and poorer differentiation (P = 0.011), than the MI group. In multivariate analysis, both MI and MPVI were independent prognostic factors for DFS (P = 0.001 and

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/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.

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.