Publications by authors named "Dai Hoon Han"

60 Publications

Chronological analysis of surgical and oncological outcomes after the treatment of perihilar cholangiocarcinoma.

Ann Hepatobiliary Pancreat Surg 2021 Feb;25(1):62-70

Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

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, =0.020) and postoperative severe complication rate (51.3% vs. 26.4%, =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; =0.029), preoperative serum bilirubin at diagnosis (HR=1.585; 95% CI=1.058-2.374; =0.026), and tumor stage (III, IV) (HR=1.671; 95% CI: 1.133-2.464; =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%, =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.
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http://dx.doi.org/10.14701/ahbps.2021.25.1.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952679PMC
February 2021

Surgical outcomes of perihilar cholangiocarcinoma based on the learning curve of a single surgeon at a tertiary academic hospital: A retrospective study.

Ann Hepatobiliary Pancreat Surg 2021 Feb;25(1):54-61

Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

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; <0.001), amount of bleeding during operation (1127.86±689.54 and 613.05±548.31 ml; <0.001), and severe complication rates (47.6% and 27.1%, =0.034) were significantly smaller in the LPG. There was no significant difference in R0 resection rate (85.7% and 76.3%; =0.241) as well as long-term survival rate.

Conclusions: In this study, operation time, amount of bleeding during operation, length of hospital stay, and severe complication rate were improved after stabilization of the learning curve. However, R0 resection rate and survival outcomes were not significantly influenced by the learning curve for surgical treatment of HCCA.
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http://dx.doi.org/10.14701/ahbps.2021.25.1.54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952677PMC
February 2021

Robotic major liver resections: Surgical outcomes compared with open major liver resections.

Ann Hepatobiliary Pancreat Surg 2021 Feb;25(1):8-17

Division of Hepatobiliary and Pancreas, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

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, <0.001). However, estimated blood loss was lower in the robotic group compared with the open resection group (269 ml vs. 548 ml, =0.009). The overall postoperative complication rate of the robotic group was lower than that of the open resection group (31.4% vs. 58.3%, <0.001), but the major complication rate was similar between the two groups. Hospital stay was shorter in the robotic group (9.5 days vs. 15.1 days, =0.006). Among patients with HCC, cholangiocarcinoma, and colorectal liver metastasis, there was no difference in overall and disease-free survival between the two groups. After propensity score matching in 37 patients with HCC for each group, the robotic group still showed a shorter hospital stay and comparable long-term outcomes.

Conclusions: Robotic major liver resections provided improved perioperative outcomes and comparable long-term oncologic outcome compared with open resections. Therefore, robotic surgery should be considered one of the options for minimally invasive major liver resections.
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http://dx.doi.org/10.14701/ahbps.2021.25.1.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952658PMC
February 2021

Role of Preoperative Chemoradiotherapy in Clinical Stage II/III Rectal Cancer Patients Undergoing Total Mesorectal Excision: A Retrospective Propensity Score Analysis.

Front Oncol 2020 18;10:609313. Epub 2021 Jan 18.

Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

Background: Although the current standard preoperative chemoradiotherapy (PCRT) for stage II/III rectal cancer decreases the risk of local recurrence, it does not improve survival and increases the likelihood of preoperative overtreatment, especially in patients without circumferential resection margin (CRM) involvement.

Methods: Stage II/III rectal cancer without CRM involvement and lateral lymph node metastasis was radiologically defined by preoperative magnetic resonance imaging (MRI). Patients who received PCRT followed by total mesorectal excision (TME) (PCRT group) and upfront surgery (US) with TME (US group) between 2010 and 2016 were analyzed. We derived cohorts of PCRT group versus US group using propensity-score matching for stage, age, and distance from the anal verge. Three-year relapse-free survival rate, disease-free survival (DFS), and overall survival (OS) were compared between the two groups.

Results: A total of 202 patients were analyzed after propensity score matching. There were no differences in baseline characteristics. The median follow-up duration was 62 months (interquartile range, 46-87). There was no difference in the 3-year disease-free survival rate between the PCRT and US groups (83 vs. 88%, respectively; p=0.326). Likewise, there was no significant difference in the 3-year OS (89 vs. 91%, respectively; p=0.466). The 3-year locoregional recurrence rates (3 vs. 2% with US, p=0.667) and distant metastasis rates (16 vs. 11%, p=0.428) were not significantly different between the two groups. Time to completion of curative treatment was significantly shorter in the US group (132 days) than in the PCRT group (225 days) (p<0.001).

Conclusion: Using MRI-guided selection for better risk stratification, US without neoadjuvant therapy can be considered in early stage patients with good prognosis. PCRT may not be required for all stage II/III rectal cancer patients, especially for the MRI-proven intermediate-risk group (cT1-2/N1, cT3N0) without CRM involvement and lateral lymph node metastasis. Further prospective studies are warranted.
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http://dx.doi.org/10.3389/fonc.2020.609313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848147PMC
January 2021

Adjuvant radiotherapy and chemotherapy offer a recurrence and survival benefit in patients with resected perihilar cholangiocarcinoma.

J Cancer Res Clin Oncol 2021 Jan 20. Epub 2021 Jan 20.

Department of Radiation Oncology, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea.

Background And Objectives: The objective of this study was to investigate the benefits of adjuvant treatment for patients with resected perihilar cholangiocarcinoma (PHC).

Methods: Between 2001 and 2017, 196 patients with PHC adenocarcinoma underwent curative resection. The patients were divided into four groups according to adjuvant treatment type: surgery alone (S; N = 90), surgery with chemotherapy (S+CTx; N = 67), surgery with radiotherapy (S+RTx; N = 18), and surgery with chemoradiotherapy (S+ CRTx; N = 21).

Results: The median follow-up duration of the surviving patients was 58 months. The 5-year rate of overall survival (OS) was 32%. In multivariate analysis, receiving S+CTx and S+CRTx were significant prognostic factors for OS. In subgroup analyses of the R1 resection patients, the S+CRTx group showed better OS than the S group (p < 0.05). In subgroup analyses of the stage III-IVA patients with a negative resection margin, the S+CTx and S+CRTx groups showed superior OS than the S group (p < 0.05).

Conclusions: Our data suggest that adjuvant chemoradiotherapy might be considered for PHC patients with R1 resection. Adjuvant chemotherapy or chemoradiotherapy is suggested for stage III-IVA patients with R0 resection. The results of this study require validation through further prospective studies.
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http://dx.doi.org/10.1007/s00432-021-03524-7DOI Listing
January 2021

Appraisal of Long-Term Outcomes of Liver-Directed Concurrent Chemoradiotherapy for Hepatocellular Carcinoma with Major Portal Vein Invasion.

J Hepatocell Carcinoma 2020 17;7:403-412. Epub 2020 Dec 17.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.

Backgrounds And Aims: Molecular-targeted agents are acceptable standards to treat advanced-stage hepatocellular carcinoma (HCC), however, their therapeutic benefit, ie, sorafenib, was significantly offset in case of major vessel invasion. Liver-directed concurrent chemo-radiotherapy (LD-CCRT) provided favorable outcomes in terms of survivals and tumor shrinkage, so, we appraised its long-term therapeutic efficacy.

Patients And Methods: Advanced HCC patients with portal vein invasion (main trunk or the 1st order branch) were enrolled. During a 5-week radiotherapy course, concurrent hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and leucovorin was administered through an implanted port on the first and last 5 days. Four weeks after LD-CCRT, a maintenance HAIC using 5-fluorouracil and cisplatin was administered every 4 weeks.

Results: Among 152 patients, the objective response rates as the best response by modified Response Evaluation Criteria In Solid Tumors were 48.0% after LD-CCRT and 55.3% during subsequent HAIC maintenance. After LD-CCRT, biological responses in alpha-fetoprotein and protein induced by the absence of vitamin K or antagonist-II levels were achieved in 46.2% and 52.6%, respectively. Sixteen patients (10.5%) underwent curative resection or liver transplantation after down-staging. Median overall survival and progression-free survival were 13.5 and 6.9 months, respectively.

Conclusion: LD-CCRT followed by maintenance HAIC yielded favorable survival outcomes in advanced HCC patients with major portal vein invasion. Through initial tumor reduction, LD-CCRT induced down-staging with subsequent curative treatment feasible in 10.5% of patients, resulting in long-term survival. Further prospective trials are warranted to confirm these results.
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http://dx.doi.org/10.2147/JHC.S276528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751588PMC
December 2020

Clinical and survival outcomes after hepatectomy in patients with non-alcoholic fatty liver and hepatitis B-related hepatocellular carcinoma.

HPB (Oxford) 2020 Dec 10. Epub 2020 Dec 10.

Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea. Electronic address:

Background: 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).

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1016/j.hpb.2020.10.027DOI Listing
December 2020

Hepatocellular Carcinoma Risk According to Regimens for Eradication of Hepatitis C Virus; Interferon or Direct Acting Antivirals.

Cancers (Basel) 2020 Nov 18;12(11). Epub 2020 Nov 18.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

By pegylated interferon (PegIFN)-free direct-acting antivirals (DAAs) against hepatitis C virus (HCV) infection, a sustained virological response (SVR) rate >95% can be attained with a satisfactory tolerability and shorter treatment duration. However, it remains controversial whether there is any difference in prognosis depending on regimens-PegIFN or DAAs. We compared the probabilities of hepatocellular carcinoma (HCC) development between patients achieving an SVR by PegIFN/ribavirin (PegIFN group, n = 603) and DAAs (DAAs group, n = 479). The DAAs group was significantly older and had a higher proportion of cirrhosis than the PegIFN group. Before adjustment, the DAAs group had a higher HCC incidence than the PegIFN group ( < 0.001). However, by multivariate analyses, the DAAs (vs. PegIFN) group was not associated with HCC risk (adjusted hazard ratio 0.968, 95% confidence interval 0.380-2.468; = 0.946). Old age, male, higher body mass index, cirrhosis, and lower platelet count were associated with increased HCC risk (all < 0.05). After propensity score matching (PSM), a similar HCC risk between the two groups was observed ( = 0.372). We also compared HCC incidences according to sofosbuvir (SOF)-based and SOF-free DAAs, showing a similar risk in both groups before adjustment ( = 0.478) and after PSM ( = 0.855). In conclusion, post-SVR HCC risks were comparable according to treatment regimens; PegIFN- vs. DAA-based regimens and SOF-based vs. SOF-free DAA regimens. Further studies with a longer follow-up period are required.
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http://dx.doi.org/10.3390/cancers12113414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698608PMC
November 2020

Potential Regulatory Role of Human-Carboxylesterase-1 Glycosylation in Liver Cancer Cell Growth.

J Proteome Res 2020 12 18;19(12):4867-4883. Epub 2020 Nov 18.

Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea.

We previously reported that human carboxylesterase 1 (CES1), a serine esterase containing a unique -linked glycosyl group at Asn79 (N79 CES1), is a candidate serological marker of hepatocellular carcinoma (HCC). CES1 is normally present at low-to-undetectable levels in normal human plasma, HCC tumors, and major liver cancer cell lines. To investigate the potential mechanism underlying the suppression of CES1 expression in liver cancer cells, we took advantage of the low detectability of this marker in tumors by overexpressing in multiple HCC cell lines, including stable Hep3B cells. We found that the population of -overexpressing (OE) cells decreased and that their doubling time was longer compared with mock control liver cancer cells. Using interactive transcriptome, proteome, and subsequent Gene Ontology enrichment analysis of -OE cells, we found substantial decreases in the expression levels of genes involved in cell cycle regulation and proliferation. This antiproliferative function of the N79 glycan of CES1 was further supported by quantitative real-time polymerase chain reaction, flow cytometry, and an apoptosis protein array assay. An analysis of the levels of key signaling target proteins via Western blotting suggested that overexpression exerted an antiproliferative effect via the PKD1/PKCμ signaling pathway. Similar results were also seen in another HCC cell line (PLC/RFP/5) after transient transfection with CES1 but not in similarly treated non-HCC cell lines (e.g., HeLa and Tera-1 cells), suggesting that CES1 likely exerts a liver cell-type-specific suppressive effect. Given that the -linked glycosyl group at Asn79 (N79 glycan) of CES1 is known to influence CES1 enzyme activity, we hypothesized that the post-translational modification of CES1 at N79 may be linked to its antiproliferative activity. To investigate the regulatory effect of the N79 glycan on cellular growth, we mutated the single -glycosylation site in CES1 from Asn to Gln (-N79Q) via site-directed mutagenesis. Fluorescence 2-D difference gel electrophoresis protein expression analysis of cell lysates revealed an increase in cell growth and a decrease in doubling time in cells carrying the N79Q mutation. Thus our results suggest that CES1 exerts an antiproliferative effect in liver cancer cells and that the single -linked glycosylation at Asn79 plays a potential regulatory role. These functions may underlie the undetectability of CES1 in human HCC tumors and liver cancer cell lines. Mass spectrometry data are available via ProteomeXchange under the identifier PXD021573.
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http://dx.doi.org/10.1021/acs.jproteome.0c00787DOI Listing
December 2020

Safety and feasibility of robotic major hepatectomy for novice surgeons in robotic liver surgery: A prospective multicenter pilot study.

Surg Oncol 2020 Dec 24;35:39-46. Epub 2020 Jul 24.

Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.

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.
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http://dx.doi.org/10.1016/j.suronc.2020.07.003DOI Listing
December 2020

Gadoxetic acid-enhanced MRI of macrotrabecular-massive hepatocellular carcinoma and its prognostic implications.

J Hepatol 2021 Jan 18;74(1):109-121. Epub 2020 Aug 18.

Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. Electronic address:

Background & Aims: Despite the clinical and genetic significance of macrotrabecular-massive hepatocellular carcinoma (MTM-HCC), its characteristics on imaging have not been described. This study aimed to characterise MTM-HCC on gadoxetic acid-enhanced MRI and to evaluate the diagnostic accuracy and prognostic value of these imaging characteristics.

Methods: We enrolled 3 independent cohorts from 2 tertiary care centres. The 3 cohorts consisted of a total of 476 patients who underwent gadoxetic acid-enhanced MRI and surgical resection for treatment-naïve single HCCs. Independent review of histopathology and MRI by 2 reviewers was performed for each cohort, and inter-reader agreement was evaluated. Based on the result of MRI review in the training cohort (cohort 1), we developed 2 diagnostic criteria for MTM-HCC and evaluated their prognostic significance. The diagnostic performance and prognostic significance were validated in 2 validation cohorts (cohorts 2 and 3).

Results: We developed 2 diagnostic MRI criteria (MRIC) for MTM-HCC: MRIC-1, ≥20% arterial phase hypovascular component; MRIC-2, ≥50% hypovascular component and 2 or more ancillary findings (intratumoural artery, arterial phase peritumoural enhancement, and non-smooth tumour margin). MRIC-1 showed high sensitivity and negative predictive value (88% and 95% in the training cohort, and 88% and 97% in the pooled validation cohorts, respectively), whereas MRIC-2 demonstrated moderate sensitivity and high specificity (47% and 94% in the training cohort, and 46% and 96% in the pooled validation cohorts, respectively). MRIC-2 was an independent poor prognostic factor for overall survival in both training and pooled validation cohorts.

Conclusions: Using gadoxetic acid-enhanced MRI findings, including an arterial phase hypovascular component, we could stratify the probability of MTM-HCC and non-invasively obtain prognostic information.

Lay Summary: Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a histopathologic subtype of HCC characterised by aggressive biological behaviour and poor prognosis. We developed imaging criteria based on liver MRI that could be used for the non-invasive diagnosis of MTM-HCC. HCCs showing imaging findings of MTM-HCC were associated with poor outcomes after hepatic resection.
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http://dx.doi.org/10.1016/j.jhep.2020.08.013DOI Listing
January 2021

Axillary lymph node dissection using a robotic surgical system: Initial experience.

J Surg Oncol 2020 Nov 11;122(6):1252-1256. Epub 2020 Aug 11.

Department of Plastic and Reconstructive Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.

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http://dx.doi.org/10.1002/jso.26141DOI Listing
November 2020

Outcomes of Robotic Living Donor Right Hepatectomy From 52 Consecutive Cases: Comparison With Open and Laparoscopy-assisted Donor Hepatectomy.

Ann Surg 2020 Jul 8. Epub 2020 Jul 8.

Department of Surgery, Division of Hepato-biliary and Pancreatic Surgery, Yonsei University College of Medicine, Seoul, South Korea.

Objective: To investigate the feasibility and safety of RLDRH SUMMARY OF BACKGROUND DATA:: Data for minimally invasive living-donor right hepatectomy, especially RLDRH, from a relatively large donor cohort that have not been reported yet.

Methods: From March 2016 to March 2019, 52 liver donors underwent RLDRH. The clinical and perioperative outcomes of RLDRH were compared with those of CODRH (n = 62) and LADRH (n = 118). Donor satisfaction with cosmetic results was compared between RLDRH and LADRH using a body image questionnaire.

Results: Although RLDRH was associated with longer operative time (minutes) (RLDRH, 493.6; CODRH, 404.4; LADRH, 355.9; P < 0.001), mean estimated blood loss (mL) was significantly lower (RLDRH, 109.8; CODRH, 287.1; LADRH, 265.5; P = 0.001). Postoperative complication rates were similar among the 3 groups (RLDRH, 23.1%; CODRH, 35.5%; LADRH, 28.0%; P = 0.420). Regarding donor satisfaction, body image and cosmetic appearance scores were significantly higher in RLDRH than in LADRH. After propensity score matching, RLDRH showed less estimated blood loss compared to those of CODRH (RLDRH, 114.7 mL; CODRH, 318.4 mL; P < 0.001), but complication rates were similar among the three groups (P = 0.748).

Conclusions: RLDRH resulted in less blood loss compared with that of CODRH and similar postoperative complication rates to CODRH and LADRH. RLDRH provided better body image and cosmetic results compared with those of LADRH. RLDRH is feasible and safe when performed by surgeons experienced with both robotic and open hepatectomy.
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http://dx.doi.org/10.1097/SLA.0000000000004067DOI Listing
July 2020

Liver-directed combined radiotherapy as a bridge to curative surgery in locally advanced hepatocellular carcinoma beyond the Milan criteria.

Radiother Oncol 2020 11 31;152:1-7. Epub 2020 Jul 31.

Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background And Purpose: Liver-directed combined radiotherapy (LDCRT) can provide substantial tumor control, which may be an effective bridge to curative surgery for selected patients. We aimed to investigate the outcomes of LDCRT for locally advanced hepatocellular carcinoma (LAHCC) beyond the Milan criteria.

Materials And Methods: We identified 1078 patients diagnosed with LAHCC who received LDCRT and compared the outcomes based on no surgery, conversion to surgical resection, and liver transplantation (LT). Predictive factors for conversion to curative surgery were identified using logistic regression analysis.

Results: The most frequently used LDCRT strategies were concurrent chemoradiation (CCRT) (497 patients, 46.1%) and transarterial chemoembolization (TACE) plus radiotherapy (251 patients 23.3%). After LDCRT, 96 (8.9%) and 42 patients (3.9%) received surgical resection and LT, respectively. After a median follow-up of 14.4 months, the 5-year overall survival (OS) rate was 16.5% for all patients. Conversion to curative surgery group had higher 5-year OS (surgical resection vs. LT vs. no surgery: 58.1% vs. 54.3% vs. 10.2%, p < 0.001). Patients aged < 60 years with a single tumor, no treatment history, pre-treatment Child class A, lower pre-treatment tumor marker levels, and radiologic complete or partial response (all p < 0.050) had a higher chance of conversion to surgery.

Conclusion: LDCRT could convert tumors to within the Milan criteria as a bridge to curative surgery, and improved long-term survival for the selected patients. Clinicians should consider LDCRT followed by curative surgery for young patients who are treatment-naïve and have good liver function with favorable tumor characteristics showing radiologic response to LDCRT.
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http://dx.doi.org/10.1016/j.radonc.2020.07.046DOI Listing
November 2020

Major Laparoscopic Versus Open Resection for Hepatocellular Carcinoma: A Propensity Score-Matched Analysis Based on Surgeons' Learning Curve.

Ann Surg Oncol 2021 Jan 29;28(1):447-458. Epub 2020 Jun 29.

Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1245/s10434-020-08764-4DOI Listing
January 2021

Recommended Minimal Number of Harvested Lymph Nodes for Intrahepatic Cholangiocarcinoma.

J Gastrointest Surg 2020 May 6. Epub 2020 May 6.

Department of Hepatobiliary and Pancreatic Surgery, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.

Background: 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.

Methods: 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).

Results: 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).

Conclusion: Our results suggest that at least 5 LNs should be harvested in patients who undergo radical surgery for ICC to promote accurate staging.
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http://dx.doi.org/10.1007/s11605-020-04622-6DOI Listing
May 2020

A nomogram based on liver stiffness predicts postoperative complications in patients with hepatocellular carcinoma.

J Hepatol 2020 10 30;73(4):855-862. Epub 2020 Apr 30.

Department of Medical and Surgical Sciences, General Surgery and Transplantation Unit, University of Bologna, Italy. Electronic address:

Background & Aims: Liver stiffness measurement (LSM), assessed by transient elastography (Fibroscan), has been demonstrated to predict post-hepatectomy liver failure in patients who undergo hepatic resection for hepatocellular carcinoma (HCC). However, other complications are also likely to be related to the underlying grade of liver fibrosis. Herein, we aimed to identify predictors of postoperative complications and to build and develop a novel nomogram able to identify patients at risk of developing severe complications.

Methods: Data from patients who underwent hepatectomy for HCC between 2006 and 2016 at 2 referral centres were retrospectively reviewed. All surgical complications were recorded and scored using the comprehensive complication index (CCI), ranging from 0 (uneventful course) to 100 (death). A CCI ≥26.2 was used as a threshold to define severe complications.

Results: During the study period, 471 patients underwent hepatic resection for HCC. Among them, 50 patients (10.6%) had a CCI ≥26.2. Age, model for end-stage liver disease (MELD) score and LSM values, together with serum albumin, were independent predictors of high CCI. The nomogram built on these variables was internally validated and showed good performance (optimism-corrected c-statistic = 0.751). A regression equation to predict the CCI was also established by multiple linear regression analysis: [LSM (kPa) × 0.254] + [age (years) × 0.118] + [MELD score (pt.) × 1.050] - [albumin (g/dl) × 2.395] - 3.639.

Conclusion: A novel nomogram, combining LSM values, age and liver function tests provided an excellent preoperative prediction of high CCI in patients with resectable HCC. This predictive model could be used as a reference for clinicians and surgeons to help them in clinical decision-making.

Lay Summary: Liver stiffness measurement is increasingly being used to assess the degree of liver fibrosis in patients with cirrhosis and/or chronic hepatitis. Using Fibroscan, we developed a novel nomogram to predict severe complications following liver resection for hepatocellular carcinoma, according to the new comprehensive complication index. This tool could be used as a reference for clinicians and surgeons to help them in clinical decision-making.
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http://dx.doi.org/10.1016/j.jhep.2020.04.032DOI Listing
October 2020

Propensity score-matching analysis for single-site robotic cholecystectomy versus single-incision laparoscopic cholecystectomy: A retrospective cohort study.

Int J Surg 2020 Jun 22;78:138-142. Epub 2020 Apr 22.

Department of HBP Surgery, Yonsei University College of Medicine, Seoul, South Korea; Pancreaticobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea.

Background: Although the single-site robotic cholecystectomy(SSRC) has been performed with expectation of overcoming the limitation of single-incision laparoscopic cholecystectomy(SILC), there exists a lack of comparison studies involving SILC and SSRC. This study aimed to analyze surgical outcomes of single-site robotic cholecystectomy and single-incision laparoscopic cholecystectomy by propensity score-matching analysis.

Materials And Methods: From March 2009 to August 2015, 290 consecutive patients underwent SSRC or SILC at Severance Hospital, Seoul, Korea. Potential confounding factors for operative outcomes were adjusted by propensity score-matching analysis. One hundred four patients from each group were evaluated for perioperative outcomes and compared for a retrospective cohort study.

Results: There was no difference in potential cofounders such as gender, age, body mass index (BMI), and perioperative cholecystitis-related symptoms between two groups after propensity score-matching. However, mean operation time was shorter (56.69 ± 13.65 vs. 101.57 ± 27.05 min; p < 0.001) and median bleeding amount during surgery was less (0 (0-50) vs. 0 (0-100) mL; p < 0.001) in the SILC group. There was no significant difference between the two groups regarding conversion to conventional multiport cholecystectomy. Bile leakage due to perforation of the gallbladder during surgery was more common in the SILC group (6.7% vs. 17.3%; p = 0.019). Moreover, bile spillage rate was significantly increased in conjunction with a higher BMI in the SILC group, whereas BMI did not affect the bile leakage rate in the SSRC group.

Conclusions: SSRC is not superior to SILC except regarding bile spillage incidence. However, the technical stability and clinically undetected advantages of SSRC are expected to prompt surgeons to perform this more reliable procedure.
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http://dx.doi.org/10.1016/j.ijsu.2020.04.042DOI Listing
June 2020

What are the most important predictive factors for clinically relevant posthepatectomy liver failure after right hepatectomy for hepatocellular carcinoma?

Ann Surg Treat Res 2020 Feb 31;98(2):62-71. Epub 2020 Jan 31.

Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

Purpose: The risk of posthepatectomy liver failure (PHLF) after right hepatectomy remains substantial. Additional parameters such as computed tomography volumetry, liver stiffness measurement by FibroScan, indocyanine green retention rate at 15 minutes, and platelet count used to properly assess future liver remnant volume quality and quantity are of the utmost importance. Thus, we compared the usefulness of these modalities for predicting PHLF among patients with hepatocellular carcinoma after right hepatectomy.

Methods: We retrospectively reviewed patients who underwent right hepatectomy for hepatocellular carcinoma between 2007 and 2013. PHLF was determined according to International Study Group of Liver Surgery consensus definition and severity grading. Grades B and C were defined as clinically relevant posthepatectomy liver failure (CRPHLF). The results were internally validated using a cohort of 97 patients.

Results: Among the 90 included patients, 15 (16.7%) had CRPHLF. Multivariate analysis confirmed that platelet count < 140 (10/L) (hazard ratio [HR], 24.231; 95% confidence interval [CI], 3.623-161.693; P = 0.001) and remnant liver volume-to-body weight (RVL/BW) ratio < 0.55 (HR, 25.600; 95% CI, 4.185-156.590; P < 0.001) were independent predictors of CRPHLF. Among the 12 patients with a platelet count < 140 (10/L) and RLV/BW ratio < 0.55, 9 (75%) had CRPHLF. Likewise, 5 of 38 (13.2%) with only one risk factor developed CRPHL versus 1 of 40 (2.5%) with no risk factors. These findings were confirmed by the validation cohort.

Conclusion: RLV/BW ratio and platelet count are more important than the conventional RLV/TFLV, indocyanine green retention rate at 15 minutes, and liver stiffness measurement in the preoperative risk assessment for CRPHLF.
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http://dx.doi.org/10.4174/astr.2020.98.2.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002877PMC
February 2020

Prognostic significance of and risk prediction model for lymph node metastasis in resectable intrahepatic cholangiocarcinoma: do all require lymph node dissection?

HPB (Oxford) 2020 Oct 8;22(10):1411-1419. Epub 2020 Feb 8.

Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.

Background: Lymph node (LN) metastasis portends a worse prognosis following resection of intrahepatic cholangiocarcinoma (ICC); however, lymphadenectomy is not routinely performed, as its role remains controversial. Herein, we developed a risk model for LN metastasis by identifying its predictive factors and assessed a subset of patients who might not benefit from LN dissection (LND).

Methods: 210 patients who underwent curative-intent surgery for ICC were retrospectively reviewed. A preoperative risk model for LN metastasis was developed following identification of its preoperative predictive factors using the recursive partitioning method.

Results: In the multivariable analysis, CA 19-9 level of >120 U/mL, an enlarged LN on computed tomography, and a tumor location abutting the Glissonean pedicles were independent predictors of LN metastasis. The preoperative risk model classified the patients according to their risk: high, intermediate, and low risks at a rate of LN metastasis on final pathology of 60.9%, 35%, and 2.3%, respectively. In the subgroup analysis among the low-risk patients, performance of LND had no survival advantage over non-performance of LND.

Conclusion: Routine LND for preoperatively diagnosed ICC should be recommended to patients at an intermediate and a high risk of developing LN metastasis but may be omitted for low-risk patients.
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http://dx.doi.org/10.1016/j.hpb.2020.01.009DOI Listing
October 2020

Gross type of hepatocellular carcinoma reflects the tumor hypoxia, fibrosis, and stemness-related marker expression.

Hepatol Int 2020 Mar 29;14(2):239-248. Epub 2020 Jan 29.

Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Background: Hepatocellular carcinoma (HCC) is subclassified into five gross types, namely, vaguely nodular (VN), single nodular (SN), single nodular with extranodular growth (SNEG), confluent multinodular (CM), and infiltrative (INF) type. However, the pathological background underlying differences in biological behavior of different gross types of HCC remains unclear.

Methods: The histopathological features, clinical outcomes of HCC gross types, and their relationships with stemness-related marker status and fibrotic/hypoxic tumor microenvironment (TME) were evaluated in 266 resected HCCs. The stemness-related markers (CD24, CD44, CD133, SALL4, YAP1, K19 and EpCAM), fibrous tumor stroma (αSMA), and hypoxia (CAIX) were evaluated with immunohistochemistry.

Results: Poorer differentiation, reduced capsule formation, higher microvascular invasion, larger tumor size and larger area of necrosis were observed in order of VN-SN-SNEG-CM-INF type (p = 0.005 for all, linear-by-linear association). The expression of summed stemness-related markers and hypoxic/fibrotic TME showed an increasing trend in order of VN-SN-SNEG-CM-INF type (p < 0.005), and their expression well correlated with each other. INF type was found only in HCCs with hypoxic/fibrotic TME or high expression of stemness-related markers. CAIX expression and tumor necrosis ≥ 30% were independent prognostic markers for disease-specific survival. Early recurrence-free survival showed a significant difference based on gross types, revealing best outcome with VN type and worst outcome with INF type.

Conclusion: The marker expression of stemness-related and hypoxic/fibrotic TME of HCC showed an increasing trend in order of VN-SN-SNEG-CM-INF gross types, and their cross-talk may be involved in the determination of various gross-morphological features and their distinct biological behavior.
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http://dx.doi.org/10.1007/s12072-020-10012-6DOI Listing
March 2020

Functions of human liver CD69CD103CD8 T cells depend on HIF-2α activity in healthy and pathologic livers.

J Hepatol 2020 06 24;72(6):1170-1181. Epub 2020 Jan 24.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. Electronic address:

Background & Aims: Human liver CD69CD8 T cells are ~95% CD103 and ~5% CD103. Although CD69CD103CD8 T cells show tissue residency and robustly respond to antigens, CD69CD103CD8 T cells are not yet well understood.

Methods: Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with cirrhosis during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A. Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative reverse transcription PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α.

Results: Human liver CD69CD103CD8 T cells exhibited HIF-2α upregulation with a phenotype of tissue residency and terminal differentiation. CD103 cells comprised non-hepatotropic virus-specific T cells as well as hepatotropic virus-specific T cells, but CD103 cells exhibited only hepatotropic virus specificity. Although CD103 cells were weaker effectors on a per cell basis than CD103 cells, following T cell receptor or interleukin-15 stimulation, they remained the major CD69CD8 effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69CD103CD8 T cells. In addition, HIF-2α expression in liver CD69CD103CD8 T cells was significantly increased in patients with acute hepatitis A or cirrhosis.

Conclusions: Liver CD69CD103CD8 T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69CD103CD8 T cells with HIF-2α upregulation is observed during liver pathology.

Lay Summary: The immunologic characteristics and the role of CD69CD103CD8 T cells, which are a major population of human liver CD8 T cells, remain unknown. Our study shows that these T cells have a terminally differentiated tissue-resident phenotype, and their effector functions depend on a transcription factor, HIF-2α. Furthermore, these T cells were activated and expressed higher levels of HIF-2α in liver pathologies, suggesting that they play an important role in immune responses in liver tissues and the pathogenesis of human liver disease.
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http://dx.doi.org/10.1016/j.jhep.2020.01.010DOI Listing
June 2020

Identification of ALDH6A1 as a Potential Molecular Signature in Hepatocellular Carcinoma via Quantitative Profiling of the Mitochondrial Proteome.

J Proteome Res 2020 04 10;19(4):1684-1695. Epub 2020 Mar 10.

Yonsei Proteome Research Center, Yonsei University, Seoul 03722, Republic of Korea.

Various liver diseases, including hepatocellular carcinoma (HCC), have been linked to mitochondrial dysfunction, reduction of reactive oxygen species (ROS), and elevation of nitric oxide (NO). In this study, we subjected the human liver mitochondrial proteome to extensive quantitative proteomic profiling analysis and molecular characterization to identify potential signatures indicative of cancer cell growth and progression. Sequential proteomic analysis identified 2452 mitochondrial proteins, of which 1464 and 2010 were classified as nontumor and tumor (HCC) mitochondrial proteins, respectively, with 1022 overlaps. Further metabolic mapping of the HCC mitochondrial proteins narrowed our biological characterization to four proteins, namely, ALDH4A1, LRPPRC, ATP5C1, and ALDH6A1. The latter protein, a mitochondrial methylmalonate semialdehyde dehydrogenase (ALDH6A1), was most strongly suppressed in HCC tumor regions (∼10-fold decrease) in contrast to LRPPRC (∼6-fold increase) and was predicted to be present in plasma. Accordingly, we selected ALDH6A1 for functional analysis and engineered Hep3B cells to overexpress this protein, called ALDH6A1-O/E cells. Since ALDH6A1 is predicted to be involved in mitochondrial respiration, we assessed changes in the levels of NO and ROS in the overexpressed cell lines. Surprisingly, in ALDH6A1-O/E cells, NO was decreased nearly 50% but ROS was increased at a similar level, while the former was restored by treatment with -nitroso--acetyl-penicillamine. The lactate levels were also decreased relative to control cells. Propidium iodide and Rhodamine-123 staining suggested that the decrease in NO and increase in ROS in ALDH6A1-O/E cells could be caused by depolarization of the mitochondrial membrane potential (ΔΨ). Taken together, our results suggest that hepatic neoplastic transformation appears to suppress the expression of ALDH6A1, which is accompanied by a respective increase and decrease in NO and ROS in cancer cells. Given the close link between ALDH6A1 suppression and abnormal cancer cell growth, this protein may serve as a potential molecular signature or biomarker of hepatocarcinogenesis and treatment responses.
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http://dx.doi.org/10.1021/acs.jproteome.9b00846DOI Listing
April 2020

Subclassification of Microscopic Vascular Invasion in Hepatocellular Carcinoma.

Ann Surg 2020 Jan 14. Epub 2020 Jan 14.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Korea.

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 <0.001, respectively) and OS (P = 0.005 and <0.001, respectively). In the validation cohort, 5-year DFS was 89%, 67.9%, and 0% in the NVI, MI, and MPVI groups, respectively (P < 0.001), whereas 5-year OS was 79.1%, 55.0%, and 15.4%, respectively (P < 0.001).

Conclusions: Based on subclassification of MiVI in HCC, MPVI was associated with more aggressive clinicopathologic characteristics and poorer survival than MI only. Therefore, the original MiVI classification should be divided into MI and MPVI.
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http://dx.doi.org/10.1097/SLA.0000000000003781DOI Listing
January 2020

SQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity.

Autophagy 2020 11 10;16(11):1949-1973. Epub 2020 Jan 10.

Severance Biomedical Science Institute, Yonsei University College of Medicine , Seoul, Republic of Korea.

Lipotoxicity, induced by saturated fatty acid (SFA)-mediated cell death, plays an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The KEAP1 (kelch like ECH associated protein 1)-NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) pathway is a pivotal defense mechanism against lipotoxicity. We previously reported that SQSTM1/p62 has a cytoprotective role against lipotoxicity through activation of the noncanonical KEAP1- NFE2L2 pathway in hepatocytes. However, the underlying mechanisms and physiological relevance of this pathway have not been clearly defined. Here, we demonstrate that NFE2L2-mediated induction of SQSTM1 activates the noncanonical KEAP1-NFE2L2 pathway under lipotoxic conditions. Furthermore, we identified that SQSTM1 induces ULK1 (unc-51 like autophagy activating kinase 1) phosphorylation by facilitating the interaction between AMPK (AMP-activated protein kinase) and ULK1, leading to macroautophagy/autophagy induction, followed by KEAP1 degradation and NFE2L2 activation. Accordingly, the activity of this SQSTM1-mediated noncanonical KEAP1-NFE2L2 pathway conferred hepatoprotection against lipotoxicity in the livers of conventional - and liver-specific -knockout mice. Moreover, this pathway activity was evident in the livers of patients with nonalcoholic fatty liver. This axis could thus represent a novel target for NAFLD treatment. ACACA: acetyl-CoA carboxylase alpha; ACTB: actin beta; BafA1: bafilomycin A; CM-H2DCFDA:5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; FASN: fatty acid synthase; GSTA1: glutathione S-transferase A1; HA: hemagglutinin; Hepa1c1c7: mouse hepatoma cells; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch like ECH associated protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAC: N-acetyl-L-cysteine; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PA: palmitic acid; PARP: poly (ADP-ribose) polymerase 1; PRKAA1/2: protein kinase AMP-activated catalytic subunits alpha1/2; RBX1: ring-box 1; ROS: reactive oxygen species; SESN2: sestrin 2; SFA: saturated fatty acid; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; TBK1: TANK binding kinase 1; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; ULK1: unc-51 like autophagy activating kinase.
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http://dx.doi.org/10.1080/15548627.2020.1712108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595589PMC
November 2020

Unplanned conversion during minimally invasive liver resection for hepatocellular carcinoma: risk factors and surgical outcomes.

Ann Surg Treat Res 2020 Jan 30;98(1):23-30. Epub 2019 Dec 30.

Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

Purpose: Unplanned conversion is sometimes necessary during minimally invasive liver resection (MILR) of hepatocellular carcinoma (HCC). The aims of this study were to compare surgical outcomes of planned MILR and unplanned conversion and to investigate the risk factors after unplanned conversion.

Methods: We retrospectively analyzed 286 patients who underwent MILR with HCC from January 2006 to December 2017. All patients were divided into a MILR group and an unplanned conversion group. The clinicopathologic characteristics and outcomes were compared between the 2 groups. In addition, surgical outcomes in the conversion group were compared with the planned open surgery group (n = 505). Risk factors for unplanned conversion were analyzed.

Results: Of the 286 patients who underwent MILR, 18 patients (6.7%) had unplanned conversion during surgery. The unplanned conversion group showed statistically more blood loss, higher transfusion rate and postoperative complication rate, and longer hospital stay compared to the MILR group, whereas no such difference was observed in comparison with the planned open surgery group. There were no significant differences in overall and disease-free survival among 3 groups. The right-sided sectionectomy (right anterior and posterior sectionectomy), central bisectionectomy and tumor size were risk factors of unplanned conversion.

Conclusion: Unplanned conversion during MILR for HCC was associated with poor perioperative outcomes, but it did not affect long-term oncologic outcomes in our study. In addition, when planning right-sided sectionectomy or central bisectionectomy for a large tumor (more than 5 cm), we should recommend open surgery or MILR with an informed consent for unplanned open conversions.
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http://dx.doi.org/10.4174/astr.2020.98.1.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940425PMC
January 2020

Comparison study for surgical outcomes of right versus left side hemihepatectomy to treat hilar cholangiocellular carcinoma.

Ann Surg Treat Res 2020 Jan 30;98(1):15-22. Epub 2019 Dec 30.

Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

Purpose: Major liver resection and radical lymph node dissection has been accepted as a definite treatment of choice for hilar cholangiocarcinoma (HC). However, the perioperative and survival outcomes of right hemihepatectomy (RH) and left hemihepatectomy (LH) still remain controversial. Thus, this study aimed to compare the surgical and oncological outcomes of RH and LH in HC patients.

Methods: From January 2000 to January 2018, a total of 326 patients underwent surgical resection for HC at Yonsei University College of Medicine in Seoul, Korea. Among the 326 patients, we excluded 130 patients and selected 196 patients, who underwent hemihepatectomy with caudate lobectomy. Among these 196 patients, 114 patients underwent RH, and 82 patients underwent LH. We compared the clinicopathological features as well as the surgical and oncologic outcomes of the RH and LH groups.

Results: There were no significant differences in disease-free survival (P = 0.473) or overall survival (P = 0.946) in the RH and LH groups. The LH group had fewer complications compared with the RH group, including postoperative ascites (RH: 15 [13.2%] . LH: 3 [3.7%], P = 0.023); however, the LH group had more bile leakage complications (RH: 5 [4.4%] . LH: 12 [14.6%], P = 0.012). The average time lag from portal vein embolization to operation was 25.80 ± 12.06 days (n = 45). There was no difference in postoperative liver failure (P = 0.402), although there were significantly more frequent ascites after RH (P = 0.023).

Conclusion: LH might be a good alternative option for the surgical treatment of HC given appropriate tumor location and biliary anatomy indications.
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http://dx.doi.org/10.4174/astr.2020.98.1.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940427PMC
January 2020

Stepwise development of laparoscopic liver resection skill using rubber traction technique.

HPB (Oxford) 2020 Aug 27;22(8):1174-1184. Epub 2019 Nov 27.

Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.

Background: To improve patient safety, we standardized our surgical technique and implemented a stepwise strategy for surgeons learning to perform laparoscopic liver resection (LLR). The aim of the study is to describe how the stepwise training approach and standardized LLR affects surgical outcomes.

Methods: Data from 272 consecutive patients who underwent LLR from January 2009 to December 2017 were retrospectively reviewed. The risk-adjusted cumulative sum (RA-CUSUM) of surgical failures (conversion to laparotomy, blood transfusion, or Clavien-Dindo grade ≥3) and the CUSUM of operative time were used to determine optimal number of operations needed to achieve the best surgical outcome.

Results: As the surgeon moved from simple to complex procedures, the complication rates, need for transfusions, and conversion rates did not increase over time. After 53 cases of minor LLR, a learning curve of 21 cases was achieved for right hepatectomy. Blood loss and operative time significantly improved thereafter. For minor anterolateral and posterosuperior segment resections, blood loss, and operative time significantly improved at the 37th and 31st case, respectively, given that the anterolateral segments had more complex surgeries performed.

Conclusion: Standardization of the operative technique and the implementation of a stepwise approach to training surgeons to perform LLRs could considerably improve surgical outcomes.
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http://dx.doi.org/10.1016/j.hpb.2019.11.001DOI Listing
August 2020

Clinicopathological characteristics of intrahepatic cholangiocarcinoma according to gross morphologic type: cholangiolocellular differentiation traits and inflammation- and proliferation-phenotypes.

HPB (Oxford) 2020 06 14;22(6):864-873. Epub 2019 Nov 14.

Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. Electronic address:

Background: Intrahepatic cholangiocarcinoma (iCCA) is subclassified into mass-forming (MF), periductal-infiltrative (PI), and mixed types grossly; however, their clinicopathological significance remains controversial.

Methods: Clinicopathological characteristics of iCCA gross types were analysed according to histopathological type (small-duct, large-duct, indeterminate) or cholangiolocellular differentiation trait (CDT) in 108 iCCAs. The expression levels of inflammation-marker (CRP, FGB) and proliferation-marker (phospho-ERK1/2, Ki-67) were evaluated by immunohistochemistry.

Results: There were 87 MF, 8 PI, and 13 mixed-gross type. Small-duct-type (39, 44.8%) and CDT (19, 21.8%) were found only in MF-gross type. The inflammation-marker expression was higher in MF-type than in PI- and mixed-gross types (P = 0.023). It was high in small-duct-type, middle in indeterminate-type, and low in large-duct-type (P = 0.015), and iCCAs with CDT showed higher inflammation-marker expression compared to those without (P < 0.001). Proliferation-marker expression did not differ according to gross type; however it was lower in iCCA with CDT compared to those without (P = 0.004). Subgrouping of the gross type according to histopathological type or CDT revealed that MF-type with small-duct-type or CDT had better overall survival compared to the others (P < 0.05).

Conclusion: MF-type iCCA is more heterogeneous than other gross types. High inflammation-marker/low proliferation-marker expression in MF-type with CDT or small-duct-type may be related to a good outcome.
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http://dx.doi.org/10.1016/j.hpb.2019.10.009DOI Listing
June 2020

Serum Wisteria floribunda agglutinin-positive human Mac-2 binding protein level predicts recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection.

Clin Mol Hepatol 2020 01 27;26(1):33-44. Epub 2019 Jun 27.

Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea.

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 years) or late (≥2 years).

Results: A total of 170 patients with CHB were selected. During the follow-up period (median, 22.6 months), 64 (37.6%) patients developed recurrence. In multivariate analyses, WFA+-M2BP level was an independent predictor of overall (hazard ratio [HR]=1.490), early (HR=1.667), and late recurrence (HR=1.416), together with male sex, des-gamma carboxyprothrombin level, maximal tumor size, portal vein invasion, and satellite nodules (all P<0.05). However, WFA+- M2BP level was not predictive of grade B-C posthepatectomy liver failure. The cutoff value that maximized the sum of sensitivity (30.2%) and specificity (90.6%) was 2.14 (area under receiver operating characteristic curve=0.632, P=0.010). Patients with a WFA+-M2BP level >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).

Conclusion: 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.
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http://dx.doi.org/10.3350/cmh.2018.0073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940487PMC
January 2020