Search

Background/aims: : With increased life expectancy, the management of elderly hepatocellular carcinoma (HCC) patients became a crucial issue, yet it is still challenging due to comorbidities and high surgical risks. While surgical resection is considered as primary treatment for eligible HCC patients, systematic evidence on its outcomes in elderly patients remains scarce. In this review, we aimed to analyze the efficacy and safety outcomes of surgical resection in elderly HCC patients., Methods: : The studies included in this meta-analysis were selected from Ovid-MEDLINE, Ovid-Embase, CENTRAL, KoreaMed, KMbase, and KISS databases following a predefined protocol. Efficacy outcomes included overall survival and disease-free survival, while the safety outcomes included postoperative mortality and complications., Results: : Patients in the elderly group (≥65 years) who underwent surgery exhibited non-inferior overall survival (hazard ratio [HR], 1.26; 95% confidence interval [CI], 0.92 to 1.74) and disease-free survival (HR, 1.03; 95% CI, 0.99 to 1.08) compared to the non-elderly group. Overall postoperative mortality exhibited no statistical difference (odds ratio [OR], 1.07; 95% CI, 0.87 to 1.31), but 30-day, 90-day, and in-hospital mortality were higher in the elderly group. The incidence of overall complications was higher in the elderly group (OR, 1.44; 95% CI, 1.22 to 1.69). Sensitivity analysis for the super elderly group (≥80 years) showed significantly higher in-hospital mortality compared to the non-super elderly group (OR, 2.51; 95% CI, 1.16 to 5.45)., Conclusions: : The efficacy outcome of surgical resection in the elderly HCC patients was not worse than that in the non-elderly HCC patients, while in-hospital mortality and complications rates were higher. Therefore, surgical resection should be purposefully considered in the elderly population, with careful candidate selection.

Background/aims: The aim of this study was to examine whether the efficacy of radiofrequency ablation (RFA) and surgical resection (SR) are comparable for hepatocellular carcinoma (HCC) less than 3 cm in elderly individuals aged 65 years or older., Methods: We used the National Health Insurance Service claims data in Korea, which was linked with liver cancer stage data from the Central Cancer Registry of the National Cancer Center, as well as death data from the National Statistical Office. Out of the 9213 registrants, we focused on 141 patients who underwent SR and 225 patients who underwent RFA when they were 65 years or older. To ensure comparability, a 1:1 propensity score (PS) matching was conducted., Results: The SR group had lower performance status and better liver function compared to the RFA group. Tumor diameter was larger in the SR group than in the RFA group (2.1 cm vs. 1.7 cm), and the proportion of stage II cases was higher (62.4% vs. 33.8%). After PS matching, the mortality rate in the RFA group did not significantly differ from the SR group (HR 1.33, 95% CI 0.86-2.06, P = 0.19). Also, liver related mortality was similar between the SR and RFA group after matching (log rank P = 0.13). However, recurrence free survival was significantly longer in the SR group than RFA group before and after matching (log rank P = 0.03)., Conclusion: In patients aged 65 years or older with resectable HCC, RFA demonstrates a therapeutic effect comparable to SR., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although the disease burden of elderly cancer patients is rapidly increasing, reliable scientific information, value and preference information of domestic patients, and standardized guidelines for determining the treatment of elderly cancer patients are lacking. The aim of this study is to compare the therapeutic effects of radiofrequency ablation (RFA) and surgery in hepatocellular carcinoma (HCC) patients aged 65 years or older. For the meta-analysis, the databases including PubMed (MEDLINE), EMBASE, OVID Medline, and the Cochrane Library were systematically searched. After the abstract-based review by two investigators, selected manuscripts were read in detail. The surgery group showed higher overall survival (OS) (HR 1.44, 95% CI 1.22-1.70) and disease-free survival (DFS) (HR 1.40, 95% CI 1.00-1.97) than the RFA group. This was also shown in small HCC of less than 3 cm (OS, HR 1.42, 95% CI 1.00-2.03; DFS, HR 1.32, 95% CI 0.91-1.91). This might be related to the high local recurrence in the RFA group (OR 4.90, 95% 2.16-11.08). On the other hand, adverse events were significantly lower in the RFA group (OR 0.22, 95% CI 0.14-0.36), which led to a decrease in the duration of hospital stay (mean difference -14.88 days, 95% CI -22.44--7.32). In elderly HCC patients, survival in the surgery group was significantly higher than in the RFA group, but various complications tended to increase; so, appropriate patient selection is required.

Objective: To compare the outcomes between robotic major hepatectomy (R-MH) and laparoscopic major hepatectomy (L-MH)., Background: Robotic techniques may overcome the limitations of laparoscopic liver resection. However, it is unknown whether R-MH is superior to L-MH., Methods: This is a post hoc analysis of a multicenter database of patients undergoing R-MH or L-MH at 59 international centers from 2008 to 2021. Data on patient demographics, center experience volume, perioperative outcomes, and tumor characteristics were collected and analyzed. Both 1:1 propensity-score matched (PSM) and coarsened-exact matched (CEM) analyses were performed to minimize selection bias between both groups., Results: A total of 4822 cases met the study criteria, of which 892 underwent R-MH and 3930 underwent L-MH. Both 1:1 PSM (841 R-MH vs. 841 L-MH) and CEM (237 R-MH vs. 356 L-MH) were performed. R-MH was associated with significantly less blood loss {PSM:200.0 [interquartile range (IQR):100.0, 450.0] vs 300.0 (IQR:150.0, 500.0) mL; P = 0.012; CEM:170.0 (IQR: 90.0, 400.0) vs 200.0 (IQR:100.0, 400.0) mL; P = 0.006}, lower rates of Pringle maneuver application (PSM: 47.1% vs 63.0%; P < 0.001; CEM: 54.0% vs 65.0%; P = 0.007) and open conversion (PSM: 5.1% vs 11.9%; P < 0.001; CEM: 5.5% vs 10.4%, P = 0.04) compared with L-MH. On subset analysis of 1273 patients with cirrhosis, R-MH was associated with a lower postoperative morbidity rate (PSM: 19.5% vs 29.9%; P = 0.02; CEM 10.4% vs 25.5%; P = 0.02) and shorter postoperative stay [PSM: 6.9 (IQR: 5.0, 9.0) days vs 8.0 (IQR: 6.0 11.3) days; P < 0.001; CEM 7.0 (IQR: 5.0, 9.0) days vs 7.0 (IQR: 6.0, 10.0) days; P = 0.047]., Conclusions: This international multicenter study demonstrated that R-MH was comparable to L-MH in safety and was associated with reduced blood loss, lower rates of Pringle maneuver application, and conversion to open surgery., Competing Interests: B.K.P.G. has received travel grants and honorariums from Johnson and Johnson, Olympus and Transmedic, the local distributor for the Da Vinci Robot. M.V.M. is a consultant for CAVA robotics LLC. J.P. reports a research grant from Intuitive Surgical Deutschland GmbH and personal fees or non-financial support from Johnson and Johnson, Medtronic, AFS Medical, Astellas, CHG Meridian, Chiesi, Falk Foundation, La Fource Group, Merck, Neovii, NOGGO, pharma-consult Peterson, and Promedicis. M. Schmelzle reports personal fees or other support outside of the submitted work from Merck, Bayer, ERBE, Amgen, Johnson and Johnson, Takeda, Olympus, Medtronic, and Intuitive. A.A.F. reports receiving speaker fees from Bayer. F.R. reports speaker fees and support outside the submitted work from Integra, Medtronic, Olympus, Corza, Sirtex, and Johnson and Johnson. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The aim of this study was to identify the treatment status and natural prognosis of hepatocellular carcinoma (HCC) patients aged 65 years or older in Korea. We analyzed 3,492 patients' data from the liver cancer stage of the Central Cancer Registry of National Cancer Center. The most common etiology of HCC was hepatitis B (32.7%), followed by hepatitis C. 2624 patients (69.2%) received first-line active treatment for HCC. The most frequently selected treatment was transarterial chemoembolization (TACE), followed by surgical resection and radiofrequency ablation (RFA). The proportion of patients receiving supportive care increased with age. Second-line treatment was performed in only 36.7% of cases, with all others choosing supportive care. Among the various treatments, liver transplantation was found to have the greatest effect in reducing the risk of death (HR [hazard ratio] 0.164, 95% CI [confidence interval] 0.061-0.444), followed by resection, RFA, radioembolization, and TACE. A similar pattern was observed when sub-analyzing the age group over 75 years old. The median survival for untreated HCC in Barcelona Clinic Liver Cancer stage 0/A/B/C/D was 3.7 years, 2.3 years, 7.9 months, 3.9 months, and 2.9 months, respectively. This study highlights the current status of elderly patients with HCC in Korea. While the proportion of patients receiving supportive care is high among the elderly, effective treatment can improve their survival rate., (© 2023. Springer Nature Limited.)

Background: The aim of this multicentric study was to investigate the impact of tumor location and size on the difficulty of Laparoscopic-Left Hepatectomy (L-LH)., Methods: Patients who underwent L-LH performed across 46 centers from 2004 to 2020 were analyzed. Of 1236 L-LH, 770 patients met the study criteria. Baseline clinical and surgical characteristics with a potential impact on LLR were included in a multi-label conditional interference tree. Tumor size cut-off was algorithmically determined., Results: Patients were stratified into 3 groups based on tumor location and dimension: 457 in antero-lateral location (Group 1), 144 in postero-superior segment (4a) with tumor size ≤40 mm (Group 2), and 169 in postero-superior segment (4a) with tumor size >40 mm (Group 3). Patients in the Group 3 had higher conversion rate (7.0% vs. 7.6% vs. 13.0%, p-value .048), longer operating time (median, 240 min vs. 285 min vs. 286 min, p-value <.001), greater blood loss (median, 150 mL vs. 200 mL vs. 250 mL, p-value <.001) and higher intraoperative blood transfusion rate (5.7% vs. 5.6% vs. 11.3%, p-value .039). Pringle's maneuver was also utilized more frequently in Group 3 (66.7%), compared to Group 1 (53.2%) and Group 2 (51.8%) (p = .006). There were no significant differences in postoperative stay, major morbidity, and mortality between the three groups., Conclusion: L-LH for tumors that are >40 mm in diameter and located in PS Segment 4a are associated with the highest degree of technical difficulty. However, post-operative outcomes were not different from L-LH of smaller tumors located in PS segments, or tumors located in the antero-lateral segments., (© 2023 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Introduction: Minimally invasive liver resection (MILR) is widely recognized as a safe and beneficial procedure in the treatment of both malignant and benign liver diseases. Hepatolithiasis has traditionally been reported to be endemic only in East Asia, but has seen a worldwide uptrend in recent decades with increasingly frequent and invasive endoscopic instrumentation of the biliary tract for a myriad of conditions. To date, there has been a woeful lack of high-quality evidence comparing the laparoscopic (LLR) and robotic (RLR) approaches to treatment hepatolithiasis., Methods: This is an international multicenter retrospective analysis of 273 patients who underwent RLR or LRR for hepatolithiasis at 33 centers in 2003-2020. The baseline clinicopathological characteristics and perioperative outcomes of these patients were assessed. To minimize selection bias, 1:1 (48 and 48 cases of RLR and LLR, respectively) and 1:2 (37 and 74 cases of RLR and LLR, respectively) propensity score matching (PSM) was performed., Results: In the unmatched cohort, 63 (23.1%) patients underwent RLR, and 210 (76.9%) patients underwent LLR. Patient clinicopathological characteristics were comparable between the groups after PSM. After 1:1 and 1:2 PSM, RLR was associated with less blood loss (p = 0.003 in 1:2 PSM; p = 0.005 in 1:1 PSM), less patients with blood loss greater than 300 ml (p = 0.024 in 1:2 PSM; p = 0.027 in 1:1 PSM), and lower conversion rate to open surgery (p = 0.003 in 1:2 PSM; p < 0.001 in 1:1 PSM). There was no significant difference between RLR and LLR in use of the Pringle maneuver, median Pringle maneuver duration, 30-day readmission rate, postoperative morbidity, major morbidity, reoperation, and mortality., Conclusion: Both RLR and LLR were safe and feasible for hepatolithiasis. RLR was associated with significantly less blood loss and lower open conversion rate., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The aim of the present study was to evaluate the per-lesion sensitivity and specificity of the Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) 2022 criteria for the noninvasive diagnosis of hepatocellular carcinoma (HCC), with intraindividual comparison of the diagnostic performance of magnetic resonance imaging with extracellular agents (ECA-MRI) and hepatobiliary agents (HBA-MRI)., Materials and Methods: Patients at high risk for HCC who were referred to a tertiary academic institution for hepatic lesions with size ≥ 10 mm between July 2019 and June 2022 were enrolled. A total of 91 patients (mean age, 58.1 years; 76 men and 15 women) with 118 lesions who underwent both ECA-MRI and HBA-MRI were eligible for final analysis. The per-lesion sensitivities and specificities of the KLCA-NCC 2022 criteria using ECA-MRI and HBA-MRI were compared using McNemar's test., Results: The 118 lesions were 93 HCCs, 4 non-HCC malignancies, and 21 benign lesions. On HBA-MRI, the "definite" HCC category showed significantly higher sensitivity than ECA-MRI (78.5% vs. 58.1%, p < 0.001), with identical specificity (92.0% vs. 92.0%, p > 0.999). For "probable" or "definite" HCC categories, there were no differences in the sensitivity (84.9% vs. 84.9%, p > 0.999) and specificity (84.0% vs. 84.0%, p > 0.999) between ECA-MRI and HBA-MRI., Conclusion: The "definite" HCC category of the KLCA-NCC 2022 criteria showed higher sensitivity in diagnosing HCC on HBA-MRI compared with ECA-MRI, without compromising specificity. There were no significant differences in the sensitivity and specificity of "probable" or "definite" HCC categories according to ECA-MRI and HBA-MRI.

Background: Laparoscopic-assisted (LALR) and hand-assisted (HALR) liver resections have been utilized during the early adoption phase by surgeons when transitioning from open surgery to pure LLR. To date, there are limited data reporting on the outcomes of LALR or HALR compared to LLR. The objective was to compare the perioperative outcomes after LALR and HALR versus pure LLR., Methods: This is an international multicentric analysis of 6609 patients undergoing minimal-invasive liver resection at 21 centers between 2004 and 2019. Perioperative outcomes were analyzed after propensity score matching (PSM) comparison between LALR and HALR versus LLR., Results: 5279 cases met study criteria of whom 5033 underwent LLR (95.3%), 146 underwent LALR (2.8%) and 100 underwent HALR (1.9%). After 1:4 PSM, LALR was associated with inferior outcomes as evidenced by the longer postoperative stay, higher readmission rate, higher major morbidity rate and higher in-hospital mortality rate. Similarly, 1:6 PSM comparison between HALR and LLR also demonstrated poorer outcomes associated with HALR as demonstrated by the higher open conversion rate and higher blood transfusion rate. All 3 approaches technical variants demonstrated the same oncological radicality (R1 rate)., Conclusion: LALR and HALR performed during the learning curve was associated with inferior perioperative outcomes compared to pure LLR., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The Iwate Score (IS) have not been well-validated for specific procedures, especially for right posterior sectionectomy (RPS). In this study, the utility of the IS was determined for laparoscopic (L)RPS and the effect of tumor location on surgical outcomes was investigated., Methods: Post-hoc analysis of 647 L-RPS performed in 40 international centers of which 596L-RPS cases met the inclusion criteria. Baseline characteristics and perioperative outcomes of patients stratified based on the Iwate score were compared to determine whether a correlation with surgical difficulty existed. A 1:1 Mahalanobis distance matching was utilized to investigate the effect of tumor location on L-RPS outcomes., Results: The patients were stratified into 3 levels of difficulty (31 intermediate, 143 advanced, and 422 expert) based on the IS. When using a stepwise increase of the IS excluding the tumor location score, only Pringle's maneuver was more frequently used in the higher surgical difficulty level (35.5%, 54.6%, and 65.2%, intermediate, advanced, and expert levels, respectively, Z = 3.34, p = 0.001). Other perioperative results were not associated with a statistical gradation toward higher difficulty level. 80 of 85 patients with a segment VI lesion and 511 patients with a segment VII lesion were matched 1:1. There were no significant differences in the perioperative outcomes of the two groups including open conversion, operating time, blood loss, intraoperative blood transfusion, postoperative stay, major morbidity, and mortality., Conclusion: Among patients undergoing L-RPS, the IS did not significantly correlate with most outcome measures associated with intraoperative difficulty and postoperative outcomes. Similarly, tumor location had no effect on L-RPS outcomes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Robotic liver resections (RLR) may have the ability to address some of the drawbacks of laparoscopic liver resections (LLR) but few studies have done a head-to-head comparison of the outcomes after anterolateral segment resections by the two techniques., Methods: A retrospective study was conducted of 3202 patients who underwent minimally invasive LR of the anterolateral liver segments at 26 international centres from 2005 to 2020. Two thousand six hundred and six cases met study criteria of which there were 358 RLR and 1868 LLR cases. Perioperative outcomes were compared between the two groups using a 1:3 Propensity Score Matched (PSM) and 1:1 Coarsened Exact Matched (CEM) analysis., Results: Patients matched after 1:3 PSM (261 RLR vs 783 LLR) and 1:1 CEM (296 RLR vs 296 LLR) revealed no significant differences in length of stay, readmission rates, morbidity, mortality, and involvement of or close oncological margins. RLR surgeries were associated with significantly less blood loss (50 mL vs 100 ml, P < .001) and lower rates of open conversion on both PSM (1.5% vs 6.8%, P = .003) and CEM (1.4% vs 6.4%, P = .004) compared to LLR. Though PSM analysis showed RLR to have a longer operating time than LLR (170 minutes vs 160 minutes, P = .036), this difference proved to be insignificant on CEM (167 minutes vs 163 minutes, P = .575)., Conclusion: This multicentre international combined PSM and CEM study showed that both RLR and LLR have equivalent perioperative outcomes when performed in selected patients at high-volume centres. The robotic approach was associated with significantly lower blood loss and allowed more surgeries to be completed in a minimally invasive fashion., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background/aims: Circulating tumor cells (CTCs) with cancer stemness have been demonstrated to be a direct cause of tumor recurrence, and only few studies have reported the role of CTCs in liver transplantation (LT) for hepatocellular carcinoma (HCC)., Methods: Epithelial cell adhesion molecule+ (EpCAM+), cluster of differentiation 90+ (CD90+) and EpCAM+/CD90+ CTCs were sorted via fluorescence-activated cell sorting, and transcripts level of EpCAM, K19 and CD90 in the peripheral blood were analyzed via real-time polymerase chain reaction preoperatively and on postoperative days 1 and 7 in 25 patients who underwent living donor liver transplantation (LDLT) for HCC. EpCAM protein was assessed in HCC tissue using immunohistochemical staining. The median follow-up duration was 40 months., Results: HCC after LDLT recurred in four out of 25 patients. Detection of EpCAM+ or CD90+ CTCs correlated well with their messenger RNA levels (p<0.05). EpCAM+ CTCs were readily detected in HCC tissue expressing EpCAM protein. The detection of EpCAM+ CTCs or EpCAM+/CD90+ CTCs before surgery and on postoperative day 1 was significantly associated with HCC recurrence after LT (all p<0.05). Pretransplant serum PIVKA-II >100 mAU/mL and postoperative day 1 EpCAM+/CD90+ CTCs were independent risk factors for HCC recurrence (hazard ratio, 14.64; 95% confidence interval, 1.08 to 198.20; p=0.043 and hazard ratio, 26.88; 95% confidence interval, 1.86 to 387.51; p=0.016, respectively)., Conclusions: EpCAM+/CD90+ CTCs can be used preoperatively and 1 day after LDLT as key biological markers in LT candidate selection and post-LDLT management.

Background: 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)., Methods: 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., Results: 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., Conclusion: 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., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background & Aims: Extrahepatic metastasis from hepatocellular carcinoma (HCC) is a catastrophic event, yet organ-specific pathological characteristics of metastatic HCC remain unclear. We aimed to characterize the pathological aspects of HCC metastases to various organs., Methods: We collected intrahepatic HCC (cohort 1, n = 322) and extrahepatic metastatic HCC (cohort 2, n = 130) samples. Clinicopathological evaluation and immunostaining for K19, CD34, αSMA, fibroblast-associated protein (FAP), CAIX, VEGF, PD-L1, CD3, CD8, Foxp3, CD163 and epithelial-mesenchymal transition (EMT)-related markers were performed., Results: Independent factors for extrahepatic metastasis included BCLC stage B-C, microvascular invasion (MVI), vessels encapsulating tumour clusters (VETC)-HCC, K19 and FAP expression, and CD163+ macrophage infiltration (cohort 1, P < .05 for all). Lung metastases (n = 63) had the highest proportion of VETC-HCC and macrotrabecular-massive (MTM)-HCC. Lymph node metastases (n = 19) showed significantly high rates of EMT-high features, K19 expression, fibrous tumour stroma with αSMA and FAP expression, high immune cell infiltration, PD-L1 expression (combined positive score), CD3+, CD8+, Foxp3+ T cell and CD163+ macrophage infiltration (adjusted P < .05 for all). In both cohorts, EMT-high HCCs showed higher rates of K19 expression, fibrous tumour stroma, high immune cell infiltration, PD-L1 expression and CD3+ T cell infiltration, whereas EMT-low HCCs were more frequent among VETC-HCCs (P < .05 for all). Overall phenotypic features were not significantly different between paired primary-metastatic HCCs (n = 32)., Conclusions: Metastatic HCCs to various organs showed different pathological features. VETC and MTM subtypes were related to lung metastasis, whereas K19 expression, EMT-high features with fibrous tumour stroma and high immune cell infiltration were related to lymph node metastasis., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aims: This study aimed to investigate whether everolimus (EVR) affects long-term survival after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC)., Methods: The data from 303 consecutive patients with HCC who had undergone LT from January 2012 to July 2018 were retrospectively reviewed. The patients were divided into two groups: 1) patients treated with EVR in combination with calcineurin inhibitors (CNIs) (EVR group; n=114) and 2) patients treated with CNI-based therapy without EVR (non-EVR group; n=189). Time to recurrence (TTR) and overall survival (OS) after propensity score (PS) matching were compared between the groups, and prognostic factors for TTR and OS were evaluated., Results: The EVR group exhibited more aggressive tumor biology than the non-EVR group, such as a higher number of tumors (P=0.003), a higher prevalence of microscopic vascular invasion (P=0.017) and exceeding Milan criteria (P=0.029). Compared with the PS-matched non-EVR group, the PS-matched EVR group had significantly better TTR (P<0.001) and OS (P<0.001). In multivariable analysis, EVR was identified as an independent prognostic factor for TTR (hazard ratio [HR], 0.248; P=0.001) and OS (HR, 0.145; P<0.001)., Conclusion: Combined with CNIs, EVR has the potential to prolong long-term survival in patients undergoing LT for HCC. These findings warrant further investigation in a well-designed prospective study.

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., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Objectives: To investigate the value of preoperative gadoxetic acid-enhanced MRI for tumor staging and recurrence prediction of hepatocellular carcinoma (HCC) after primary liver transplantation (LT)., Methods: This multicenter retrospective study included 122 recipients who underwent living donor LT (LDLT) for untreated HCC and pre-transplant gadoxetic acid-enhanced MRI from January 2009 to December 2013. Disease-free survival (DFS) was evaluated. Milan criteria, tumor grade, and microvascular invasion (MVI) were analyzed on the pathological examination of the explanted liver., Results: The 1-, 3-, 5-, and 7-year DFS rates were 93.3%, 90.7%, 88.9%, and 86.1%, respectively. In the multivariable analysis, independent predictors of HCC recurrence were "beyond the Milan criteria" (hazard ratio [HR], 3.54; 95% confidence interval [CI], 1.13-11.12; p = 0.030) and peritumoral hypointensity on hepatobiliary phase (HBP) (HR, 18.30; 95% CI, 4.33-77.34; p < 0.001). Pre-transplant MRI yielded a 90.2% accuracy to categorize the Milan criteria when compared with the explanted liver. Peritumoral hypointensity on HBP was significantly associated with a worse tumor grade (p = 0.010) and MVI (p < 0.001). The 5-year DFS rate in patients with "beyond the Milan criteria" but the absence of peritumoral hypointensity on HBP was not different from that in patients "within the Milan criteria" (92.2% vs. 92.9%, p = 0.438)., Conclusions: Pre-transplant gadoxetic acid-enhanced MRI may assist in the HCC recurrence risk prediction., Key Points: • Lesions beyond the Milan criteria and peritumoral hypointensity on hepatobiliary phase (HBP) were independent predictors of HCC recurrence. • Peritumoral hypointensity on HBP significantly associated with a worse tumor grade and microvascular invasion.

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.

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., (©2019 American Association for Cancer Research.)

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., (©2019 American Association for Cancer Research.)

Background/aims: It is important to identify patients who are refractory to transarterial chemoembolization (TACE), which is performed for the treatment of hepatocellular carcinoma (HCC). We investigated the predictors of poor treatment outcomes in patients with recurrent HCC treated who were treated with TACE after curative resection., Methods: 428 patients with recurrent HCC after curative resection who were treated with TACE were enrolled., Results: The median age of the study population was 59.2 years. On multivariate analysis, ≥2 TACE procedures within 6 months (hazard ratio [HR] = 1.898), and the des-gamma carboxyprothrombin level (HR = 1.000) independently predicted the progression to Barcelona Clinic Liver Cancer (BCLC) stage C in patients with BCLC stage 0-B HCC (both P<0.05). In addition, ≥2 and ≥3 TACE procedures within 6 months independently predicted mortality in the entire study population (HR = 1.863 and 1.620, respectively). The probability of progression to BCLC stage C in patients with BCLC stage 0-B HCC and the mortality rate in the entire study population were significantly higher in patients treated with ≥2 TACE within 6 months than in those who underwent fewer procedures (P = 0.002 and P<0.001, respectively)., Conclusions: More than 2 TACE procedures within 6 months might be associated with the refractoriness to TACE in patients with recurrent HCC after curative resection., Competing Interests: The authors have declared that no competing interests exist.

Background: Minor liver resections of posterosuperior segments (1, 4A, 7, 8) are challenging to perform laparoscopically and are mainly performed using an open approach. We determined the feasibility of robotic resections of posterosuperior segments and compared short-term outcomes with the open approach., Methods: Data on open and robotic minor (≤ 3 segments) liver resections including the posterosuperior segments, performed between 2009 and 2016, were collected retrospectively from four hospitals. Robotic and open liver resections were compared, before and after propensity score matching., Results: In total, 51 robotic and 145 open resections were included. After matching, 31 robotic resections were compared with 31 open resections. Median hospital stay was 4 days (interquartile range [IQR] 3-7) for the robotic group, versus 8 days (IQR 6-10) for the open group (p < 0.001). Median operative time was 222 min (IQR 164-505) for robotic cases versus 231 min (IQR 190-301) for open cases (p = 0.668). Median estimated blood loss was 200 mL (IQR 100-400) versus 300 mL (IQR 125-750), respectively (p = 0.212). In the robotic group, one patient (3%) had a major complication, versus three patients (10%) in the open group (p = 0.612). Readmissions were similar-10% in the robotic group versus 6% in the open group (p > 0.99). There was no mortality in either group., Conclusion: Minor robotic liver resections of the posterosuperior segments are safe and feasible and display a shorter length of stay than open resections in selected patients at expert centers.

Somatic mutations in the telomerase reverse transcriptase (TERT) promoter are related to telomerase activation and frequently occur at two hot spots located at -124 and -146 bp relative to the start codon in various cancers. Here, we investigated the occurrence and implications of genetic alterations in the TERT promoter in hepatitis B viral hepatocellular carcinoma (B viral HCC). TERT promoter mutations, especially -124C>T, clearly enhanced transcriptional activity in HCC cell lines. In contrast, TERT mRNA expression was lower in B viral HCC patients with TERT promoter mutations than in those without. We identified prospero homeobox protein 1 (PROX1) as a novel transcriptional activator of TERT; this protein was shown to have particularly strong binding affinity for the mutant TERT promoter. However, stable expression of the hepatitis B virus X (HBx) protein inhibited PROX1-mediated TERT expression in vitro. Our data suggest that TERT promoter mutations can enhance the promoter activity in HCC cell lines expressing PROX1 but are not the predominant mechanism of TERT upregulation in B viral HCC patients, based on the inhibition of PROX1-dependent transcriptional activation by HBx., (© 2018 UICC.)

Background: Locally advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) has a poor oncological outcome. This study evaluated the oncological outcomes and prognostic factors of surgical resection after downstaging with localized concurrent chemoradiotherapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC)., Methods: From 2005 to 2014, 354 patients with locally advanced HCC underwent CCRT followed by HAIC. Among these patients, 149 patients with PVTT were analyzed. Exclusion criteria included a total bilirubin ≥ 2 mg/dL, platelet count < 100,000/μL, and indocyanine green retention test (ICG R15) > 20%. During the same study period, 18 patients with PVTT underwent surgical resection as the first treatment. Clinicopathological characteristics and oncological outcomes between groups were compared., Results: Among 98 patients in the CCRT group, 26 patients (26.5%) underwent subsequent curative resection. The median follow-up period was 13 months (range 1-131 months). Disease-specific survival differed significantly between the resection after localized CCRT group and the resection-first group {median 62 months (95% confidence interval [CI] 22.99-101.01) versus 15 months (95% CI 10.84-19.16), respectively; P = 0.006}. Multivariate analyses showed that achievement of radiologic response was an independently good prognostic factor for both disease-specific survival (P = 0.039) and disease-free survival (P = 0.001) CONCLUSIONS: Localized CCRT could be an effective tool for identifying optimal candidates for surgical treatment with favorable tumor biology. Furthermore, with a 26.5% resection rate and 100% response in PVTT for resection after CCRT, our localized CCRT protocol may be ideal for PVTT.

Background: Major hurdles for laparoscopic right hepatectomy (LapRH) include difficulties in (1) mobilization and (2) applying hanging maneuver and (3) lack of experienced assistants. We discuss the protocolization of lapRH, introducing our simplified technique., Methods: The procedure was disassembled into six steps: (1) curtailed mobilization of the right liver so as to align the resection plane with the laparoscopic camera view, (2) inflow vascular control, (3) setting up the parenchymal resection applying the rubber band retraction method, (4) parenchymal resection approaching the caudate lobe, (5) a lifting-up maneuver using a laparoscopic grasper or retractor instead of the hanging maneuver, and (6) completion of resection dividing the caudate lobe, right hepatic vein, and remaining ligament., Results: Between March 2014 and August 2015, 13 LapRH surgeries were attempted. The patients consisted of eight males and five females with a mean age of 58.5 ± 11.6 years. Final pathological diagnoses were hepatocellular carcinoma in seven patients, intrahepatic duct stone in 4, and colorectal liver metastasis in 2. The mean total operative time was 381 ± 66 minutes, and the mean intraoperative estimated blood loss was 633 ± 619 ml. One patient was converted to open surgery. There was no clinically significant complication, and the mean length of stay after surgery was 9.1 ± 2.3 days., Conclusions: Protocolization and simplification of the procedure may allow professionals to better understand the respective process and determine appropriate port placements, resulting in safe and successful minimally invasive hepatectomy procedures.

Background: The clinical features of hepatocellular carcinoma (HCC) differ in patients with and without cirrhosis., Objective: We aimed to investigate the long-term outcomes of noncirrhotic HCC patients after curative resection., Methods: We retrospectively examined 649 consecutive patients with HCC who underwent curative resection from 1996 to 2012; 387 (59.6%) were cirrhotic and 262 (40.4%) were noncirrhotic., Results: The mean age was 54.7 years, and 511 (78.7%) of the study participants were men. The most common cause of HCC was hepatitis B virus (n = 419, 64.6%). Noncirrhotic tumors were larger and more advanced than cirrhotic tumors. However, the noncirrhotic group showed better disease-free survival (DFS) and overall survival (OS) after resection than the cirrhotic group (median 64.0 vs. 56.0 months for OS and 48.0 vs. 31.0 months for DFS, p < 0.05). The predictors for HCC recurrence were cirrhosis, tumor number, portal vein invasion, and major surgery., Conclusions: Noncirrhotic HCC showed better DFS and OS after resection than cirrhotic HCC, although noncirrhotic HCC presented more aggressively., (© 2017 S. Karger AG, Basel.)

Purpose: The aim of this article was to evaluate the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on preoperative F-FDG PET/CT for predicting intrahepatic recurrence-free survival (IHRFS), extrahepatic metastasis-free survival (EHMFS), and overall survival (OS) in patients with very early/early hepatocellular carcinoma (HCC)., Patients and Methods: We retrospectively enrolled 132 patients with very early/early HCC who underwent F-FDG PET/CT followed by surgery. The maximum tumor SUV-to-mean normal liver SUV ratio, MTV, and TLG were measured for each patient. Prognostic significances of PET/CT parameters and clinicopathologic factors for IHRFS, EHMFS, and OS were evaluated. Cumulative IHRFS, EHMFS, and OS were calculated using the Kaplan-Meier method., Results: Thirty-three (25%) and 21 (15.9%) of 132 patients experienced intrahepatic and extrahepatic recurrence, respectively, during a median follow-up period of 38.1 months. In multivariate analysis, none of the factors were significant for IHRFS. Metabolic tumor volume and TLG were only significant factors for EHMFS and OS (P < 0.05). The 5-year EHMFS rates were 94.8% in patients with low MTV and TLG, and 62.1% and 63.2% in patients with high MTV and TLG, respectively (P < 0.001). The 5-year OS rates were 92.6% and 92.4% in patients with low MTV and TLG, and 63.3% and 64.3% in patients with high MTV and TLG, respectively (P < 0.001)., Conclusions: Metabolic tumor volume and TLG on preoperative PET/CT were independent prognostic factors for EHMFS and OS but not IHRFS in patients with very early/early HCC. Therefore, patients with high MTV or TLG should be closely observed for extrahepatic metastasis using systemic evaluations.

Background: This study was designed to compare perioperative and oncologic outcomes between minimally invasive liver resection (MILR) and conventional open liver resection (COLR) for hepatocellular carcinoma (HCC) using a propensity-score matched analysis., Methods: Ninety-nine patients who received MILR were matched with 198 patients treated with COLR out of 928 patients with HCC who received curative liver resection from 2002 to 2012. A multivariable logistic model based on factors related to the patient, tumor, and surgical procedure was used to estimate a propensity score., Results: The MILR group experienced significantly less intraoperative blood loss (mean: 389.55 vs 580.66 mL; P = 0.008), lower complication rates (13.1% vs 24.7%; P = 0.020), and a shorter length of hospital stay (mean: 8.40 vs 13.39 days; P < 0.001). The two groups did not differ significantly in disease-free (P = 0.701) or overall survival (P = 0.086)., Conclusions: MILR produced better perioperative and comparable oncologic outcomes than COLR for HCC. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: A few studies have reported only short-term outcomes of various robotic and laparoscopic liver resection types; however, published data in left lateral sectionectomy (LLS) have been limited. The aim of this study was to compare the long- and short-term outcomes of robotic and laparoscopic LLS., Methods: We retrospectively compared demographic and perioperative data as well as postoperative outcomes of robotic (n = 12) and laparoscopic (n = 31) LLS performed between May 2007 and July 2013. Resection indications included malignant tumors (n = 31) and benign lesions (n = 12) including intrahepatic duct (IHD) stones (n = 9)., Results: There were no significant differences in perioperative outcomes of estimated blood loss, major complications, or lengths of stay, but operating time was longer in robotic than in laparoscopic LLS (391 vs. 196 min, respectively) and the operation time for IHD stones did not differ between groups (435 vs. 405 min, respectively; p = 0.190). Disease-free (p = 0.463) and overall (p = 0.484) survival of patients with malignancy did not differ between groups. The 2- and 5-year disease-free survival rates were 63.2 and 36.5 %, respectively. However, robotic LLS costs were significantly higher than laparoscopic LLS costs ($8183 vs. $5190, respectively; p = 0.009)., Conclusions: Robotic LLS was comparable to laparoscopic LLS in surgical outcomes and oncologic integrity during the learning curve. Although robotic LLS was more expensive and time intensive, it might be a good option for difficult indications such as IHD stones.

Locally advanced hepatocellular carcinoma (HCC) with portal vein thrombosis carries a 1-year survival rate <10%. Localized concurrent chemoradiotherapy (CCRT), followed by hepatic arterial infusion chemotherapy (HAIC), was recently introduced in this setting. Here, we report our early experience with living donor liver transplantation (LDLT) in such patients after successful down-staging of HCC through CCRT and HAIC. Between December 2011 and September 2012, eight patients with locally advanced HCC at initial diagnosis were given CCRT, followed by HAIC, and underwent LDLT at the Severance Hospital, Seoul, Korea. CCRT [45 Gy over 5 weeks with 5-fluorouracil (5-FU) as HAIC] was followed by HAIC (5-FU/cisplatin combination every 4 weeks for 3-12 months), adjusted for tumor response. Down-staging succeeded in all eight patients, leaving no viable tumor thrombi in major vessels, although three patients first underwent hepatic resections. Due to deteriorating liver function, transplantation was the sole therapeutic option and offered a chance for cure. The 1-year disease-free survival rate was 87.5%. There were three instances of post-transplantation tumor recurrence during follow-up monitoring (median, 17 months; range, 10-22 months), but no deaths occurred. Median survival time from initial diagnosis was 33 months. Four postoperative complications recorded in three patients (anastomotic strictures: portal vein, 2; bile duct, 2) were resolved through radiologic interventions. Using an intensive tumor down-staging protocol of CCRT followed by HAIC, LDLT may be a therapeutic option for selected patients with locally advanced HCC and portal vein tumor thrombosis.

Hypoxia is known to be important in the generation and maintenance of stemness; however, its clinical significance is yet to be determined in human hepatocellular carcinoma. The expression of stemness (K19, EpCAM) and hypoxia (carbonic anhydrase-IX (CAIX))-related markers were investigated by immunohistochemistry in three hepatocellular carcinoma cohorts. The clinicopathologic features, response to transarterial chemoembolization, and outcomes were compared. In cohort 1 (n=14, biopsy-transarterial chemoembolization-resection-matched hepatocellular carcinoma), all K19-, EpCAM-, or CAIX-positive hepatocellular carcinomas on initial biopsy (6/6, 100%) showed residual tumors after transarterial chemoembolization, whereas 75% (6/8) of all-negative hepatocellular carcinomas on biopsy showed complete necrosis in the post-transarterial chemoembolization-resected specimens. In cohort 2 (n=85, explanted hepatocellular carcinomas with/without transarterial chemoembolization; totally necrotic hepatocellular carcinoma after transarterial chemoembolization was not included), the expression of K19, EpCAM, and CAIX, and their coexpression, was more frequently observed with a greater number of transarterial chemoembolization sessions, and the expression of these markers was also correlated to each other. CAIX expression was shown to be an independent factor for recurrence and survival, and combination of CAIX with Milan criteria significantly increased the time-dependent integrative area under the curve values for recurrence and survival. In cohort 3 (n=339, resected hepatocellular carcinomas without transarterial chemoembolization), CAIX(+) hepatocellular carcinomas exhibited higher K19 and EpCAM expression, and more invasive pathological features. CAIX expression and TNM stage were independent predictors of extrahepatic recurrence, and the addition of CAIX to the TNM stage significantly increased time-dependent integrative area under the curve values. In conclusion, the expression of stemness (K19, EpCAM) and hypoxia (CAIX)-related markers were correlated each other, and hepatocellular carcinoma expressing these markers showed resistance to transarterial chemoembolization and poorer outcome. Evaluation for both markers of stemness and hypoxia may have an additional value in predicting hepatocellular carcinoma outcome, especially for transarterial chemoembolization-treated hepatocellular carcinomas.

Background: This study was designed to investigate the correlation between postoperative recurrence of hepatocellular carcinoma (HCC) and perioperative expression and dynamic changes in cancer stem cell (CSC) markers in tumors and peripheral blood., Methods: In HCC patients who underwent curative resection (n = 64) or liver transplantation (LT) (n = 17), mRNA levels for K19, EpCAM, and CD44 in peripheral blood and HCC tissues before and after operation were examined using real-time RT-PCR. Postoperative recurrence was analyzed in patients who underwent resection. Study participants were divided into high and low ratio groups, according to the ratio of postoperative to preoperative mRNA levels for each marker., Results: K19 and CD44 mRNA levels in HCC tissues were higher in patients with recurrence than those without recurrence (p < 0.05 for all). Preoperative peripheral levels of K19 and EpCAM mRNA were higher in LT patients than in resection patients, and they were also significantly higher in cirrhotic patients of Child-Pugh Class B or C than those of Child-Pugh Class A (p < 0.05 for all). A high ratio of K19 mRNA was associated with lower relapse-free rate. Additionally, a high ratio for both K19 and CD44 mRNA was an independent poor prognostic factor for relapse-free survival (hazard ratio = 3.382, p = 0.016)., Conclusions: Preoperative peripheral levels of K19 and EpCAM mRNA were influenced by background liver status and HCC. Additionally, the ratio of postoperative to preoperative mRNA levels for CSC markers, especially K19 and CD44, was shown to be important to predict HCC recurrence.

We report on a case of a 57-year-old male who underwent a curative resection for hepatocellular carcinoma (HCC) with histological confirmation of a spontaneously necrotized tumor. Initial serum AFP level was 4,778 ng/mL. A 3.7 cm hyperechoic mass in segment 6 of the liver was observed on ultrasonography and dynamic contrast-enhanced liver MRI showed a 3.7 × 3.1 cm sized HCC. He was scheduled to undergo curative surgical resection under the clinical diagnosis of an early stage HCC (Barcelona Clinic Liver Cancer stage A). Without treatment, the serum AFP level declined rapidly to 50 ng/mL over five weeks. He underwent curative wedge resection of segment 6 of the liver. Histology revealed complete necrosis of the mass rimmed by inflamed fibrous capsule on a background of HBV-related cirrhosis with infiltration of lymphoplasma cells. Exact pathophysiology underlying this event is unknown. Among the proposed mechanisms of spontaneous neoplastic remission of HCC, circulatory disturbance and activation of host immune response offer the most scientific explanation for the complete histologic necrosis of HCC in the resected mass seen in our patient.

Background: Transection along the anterior fissure was proposed as a mechanism by which to open the third door of the liver. In this study, we investigated surgical outcomes of a ventral segment-preserving right hepatectomy (VSPRH) compared with those of conventional right hepatectomy in patients with hepatocellular carcinoma (HCC)., Methods: Between January 2007 and December 2010, 595 primary HCC patients underwent liver resection at the authors' institution. Among them, the 123 HCC patients who underwent a right hepatectomy were retrospectively analyzed. The patients were classified into two groups according to the type of resection: those who underwent a VSPRH (Group A; 27 cases) and those who underwent a conventional right hepatectomy (Group B; 96 cases)., Results: In Group A, expected remnant liver volume after a right hepatectomy was calculated to be 32.1 ± 7.2% of functional total liver volume (FTLV); remnant liver volume increased up to 54.7 ± 7.2% of FTLV after a VSPRH. Clinicopathologic characteristics and intraoperative data did not differ between the two groups. The liver-related complication rate was higher in Group B (P = 0.02). Overall survival and disease-free survival rates were similar (3-year disease-free survival (Group A: 67.8%; Group B: 71.7%; P = 0.65); 3-year overall survival (Group A: 91.7%; Group B: 87.4%; P = 0.26). In regard to long-term synthetic function, the 1-year postoperative serum albumin level was higher in Group A., Conclusions: A VSPRH yielded fewer liver-related complications and similar long-term oncologic outcomes, compared with conventional right hepatectomy in cirrhotic patients with a small left lobe volume. Therefore, VSPRH can be considered to be an alternative procedure for a right hepatectomy.

Background: This study evaluated the down-staging efficacy and impact on resectability of concurrent chemoradiotherapy (CCRT) followed by hepatic arterial infusion chemotherapy (HAIC) in locally advanced hepatocellular carcinoma, and identified prognostic factors of disease-free survival (DFS) and overall survival (OS) after curative resection., Methods: DFS and OS were investigated using clinicopathologic variables. Functional residual liver volume (FRLV) was assessed before CCRT and again before surgery in patients with major hepatectomy. Tumor marker response was defined as elevated tumor marker levels at diagnosis but levels below cutoff values before surgery (α-fetoprotein < 20 ng/mL, protein induced by vitamin K absence or antagonist-II < 40 mAU/mL)., Results: Of 243 patients who received CCRT followed by HAIC between 2005 and 2011, 41 (16.9 %) underwent curative resection. Tumor down-staging was demonstrated in 32 (78 %) of the resected patients. FRLV significantly increased from 47.5 to 69.9 % before surgery in patients who underwent major hepatectomy. In addition, the OS of the curative resection group was significantly higher than the OS of the CCRT followed by HAIC alone group (49.6 vs. 9.8 % at 5-year survival; p < 0.001). By multivariate analysis, the poor prognostic factors for DFS after curative resection were tumor marker non-response and the presence of a satellite nodule; however, tumor marker non-response was the only independent poor prognostic factor of OS., Conclusions: CCRT followed by HAIC increased resectability by down-staging tumors and increasing FRLV. Curative resection may provide good long-term survival in tumor marker responders who undergo CCRT followed by HAIC.

Background: The clinical significance of spontaneous hepatocellular carcinoma (HCC) rupture association with recurrence pattern and long-term surgical outcomes remains under debate. We investigated the impact of spontaneous HCC rupture on recurrence pattern and long-term surgical outcomes after partial hepatectomy., Methods: From 2000 to 2012, 119 patients with diagnosed ruptured HCC were reviewed. To compare outcomes between staged hepatectomy in spontaneously ruptured HCC and hepatectomy in non-ruptured HCC, we performed propensity score-matching to adjust for significant differences in patient characteristics. Overall survival, disease-free survival, and recurrence pattern were compared between the matched groups., Results: Forty-four patients with newly diagnosed ruptured HCC and Child A class were initially treated with transcatheter arterial embolization for hemostasis. Three patients underwent emergency laparotomy, 18 underwent staged hepatectomy, and 23 received transarterial chemoembolization (TACE) alone after transcatheter arterial embolization. Among the 23 patients treated with TACE alone, 10 had resectable tumors. The staged hepatectomy group shows significantly higher overall survival with TACE alone than the resectable tumor group (P < 0.001). After propensity score-matching, overall survival, disease-free survival, and recurrence pattern were not significantly different between the ruptured HCC with staged hepatectomy group and the non-ruptured HCC with hepatectomy group. Peritoneal recurrence rates were similar at 14.3% versus 10.0%, respectively (P = 0.632)., Conclusions: Patients with spontaneously ruptured HCC with staged hepatectomy show comparable long-term survival and recurrence pattern as patients with non-ruptured HCC having similar tumor characteristics and liver functional status. Thus, spontaneous HCC rupture may not increase peritoneal recurrence and decrease long-term survival after partial hepatectomy.

Background: Recurrence of hepatocellular carcinoma (HCC) after curative resection continues to be a major cause of death. This prospective study is designed to investigate whether histological subclassification of cirrhosis using the Laennec system could predict recurrence in patients with hepatitis B virus (HBV)-related HCC after curative resection., Methods: Patients with HBV-related HCC who underwent curative resection and showed Laennec stage 3 to 4 were enrolled and the cases with stage 4 were subclassified histologically into three groups (stages 4A, 4B and 4C) according to the Laennec system. Between February 2006 and August 2009, 92 patients were recruited., Results: Stage 3, 4A, 4B and 4C were identified in 24 (26.1%), 15 (16.3%), 43 (46.7%) and 10 (10.9%) patients respectively. The cumulative incidence rates of recurrence at 1, 2 and 3 years were 24.2%, 40.5% and 55.1% respectively. On multivariate analysis, serum albumin [hazard ratio (HR), 0.528; 95% confidence interval (CI), 0.312-0.891; P=0.017] and Edmondson-Steiner grade III-IV (HR, 3.456; 95% CI, 1.123-10.517; P=0.031) were significantly correlated with early recurrence (<1 year), whereas stage 4C (HR, 5.426; 95% CI, 1.030-28.598; P=0.046) was the only independent risk factor for late recurrence (≥1 year)., Conclusions: Histological subclassification of cirrhosis using the Laennec system is a significant predictor of late recurrence in patients with HBV-related HCC after curative resection., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: This study aimed to classify transplantable recurrent hepatocellular carcinoma (HCC) after resection into subgroups according to the pattern of progression and to identify risk factors for each subgroup to select optimal candidates for salvage liver transplantation (LT)., Methods: The patients that met the Milan criteria (MC) and were child-pugh class A at initial hepatectomy were included in the study. Of these patients, the patients with transplantable recurrence were identified and further divided into two groups according to the recurrent HCC progression pattern. Group 1 contained patients with controlled tumors within the MC. Group 2 contained patients with progressive tumors that spread beyond the MC. A controlled tumor was defined as the absence of tumor recurrence after locoregional treatment for ≥12 months or control of a recurrent tumor within the MC by active locoregional treatment., Results: After curative resection of HCC, 114 patients with transplantable recurrence were identified: 70 were classified as group 1 and 44 as group 2. Overall survival after recurrence was significantly higher in group 1 compared to group 2 (65.4 vs 35.7 %, respectively; P < 0.003). Multiple logistic regression analysis showed that risk factors in group 1 were age >50 years and an indocyanine green retention at 15 min >10 %. The presence of a satellite nodule (SN) and/or microscopic portal vein invasion (mPVI) was the only independent risk factor identified in group 2. Among the 15 patients that underwent salvage LT, 2 of 3 patients (66.7 %) with SN and/or mPVI at initial hepatectomy developed extrahepatic recurrence., Conclusions: The patients with SN and/or mPVI at initial hepatectomy may not be candidates for salvage LT, and an extended observation time is required to determine tumor biology.

Background: Recent advances in surgical techniques and perioperative management have led to improved surgical outcomes, especially perioperative outcomes. The aim of this study was to review our experience with hepatic resection for hepatocellular carcinoma (HCC) over a ten-year period to determine how to improve long-term surgical outcomes., Methods: From January 1996 to December 2007, 610 patients underwent curative resection for HCC at Yonsei University Health System, Seoul, Korea. Prognostic factors for disease-free and overall survival were identified, and surgical outcomes were compared between two time periods: before 2003 and after 2003., Results: The 1-, 3-, and 5-year overall survival rates were 90.1%, 74.9% and 64.4%, respectively. The patients after 2003 tended to have improved overall survival. The survival rate after recurrence in patients with tumors > 3 cm was significantly greater after 2003. (P = 0.044)., Conclusions: The improved survival rates after 2003 may be explained by better selection of surgical candidates, a reduced perioperative transfusion rate due to improved surgical techniques, and active multimodal treatment for recurrent HCC.

Background: Preoperative liver stiffness (LS) measurement using transient elastography (TE) is useful for predicting late recurrence after curative resection of hepatocellular carcinoma (HCC). We developed and validated a novel LS value-based predictive model for late recurrence of HCC., Methods: Patients who were due to undergo curative resection of HCC between August 2006 and January 2010 were prospectively enrolled and TE was performed prior to operations by study protocol. The predictive model of late recurrence was constructed based on a multiple logistic regression model. Discrimination and calibration were used to validate the model., Results: Among a total of 139 patients who were finally analyzed, late recurrence occurred in 44 patients, with a median follow-up of 24.5 months (range, 12.4-68.1). We developed a predictive model for late recurrence of HCC using LS value, activity grade II-III, presence of multiple tumors, and indocyanine green retention rate at 15 min (ICG R15), which showed fairly good discrimination capability with an area under the receiver operating characteristic curve (AUROC) of 0.724 (95% confidence intervals [CIs], 0.632-0.816). In the validation, using a bootstrap method to assess discrimination, the AUROC remained largely unchanged between iterations, with an average AUROC of 0.722 (95% CIs, 0.718-0.724). When we plotted a calibration chart for predicted and observed risk of late recurrence, the predicted risk of late recurrence correlated well with observed risk, with a correlation coefficient of 0.873 (P<0.001)., Conclusion: A simple LS value-based predictive model could estimate the risk of late recurrence in patients who underwent curative resection of HCC.