Search

Background & Aims: Hepatocellular carcinoma (HCC) is a highly fatal cancer characterized by high intra-tumor heterogeneity (ITH). A panoramic understanding of its tumor evolution, in relation to its clinical trajectory, may provide novel prognostic and treatment strategies., Methods: Through the Asia-Pacific Hepatocellular Carcinoma trials group (NCT03267641), we recruited one of the largest prospective cohorts of patients with HCC, with over 600 whole genome and transcriptome samples from 123 treatment-naïve patients., Results: Using a multi-region sampling approach, we revealed seven convergent genetic evolutionary paths governed by the early driver mutations, late copy number variations and viral integrations, which stratify patient clinical trajectories after surgical resection. Furthermore, such evolutionary paths shaped the molecular profiles, leading to distinct transcriptomic subtypes. Most significantly, although we found the coexistence of multiple transcriptomic subtypes within certain tumors, patient prognosis was best predicted by the most aggressive cell fraction of the tumor, rather than by overall degree of transcriptomic ITH level - a phenomenon we termed the 'bad apple' effect. Finally, we found that characteristics throughout early and late tumor evolution provide significant and complementary prognostic power in predicting patient survival., Conclusions: Taken together, our study generated a comprehensive landscape of evolutionary history for HCC and provides a rich multi-omics resource for understanding tumor heterogeneity and clinical trajectories., Impact and Implications: This prospective study, utilizing comprehensive multi-sector, multi-omics sequencing and clinical data from surgically resected hepatocellular carcinoma (HCC), reveals critical insights into the role of tumor evolution and intra-tumor heterogeneity (ITH) in determining the prognosis of HCC. These findings are invaluable for oncology researchers and clinicians, as they underscore the influence of distinct evolutionary paths and the 'bad apple' effect, where the most aggressive tumor fraction dictates disease progression. These insights not only enhance prognostic accuracy post-surgical resection but also pave the way for personalized treatment strategies tailored to specific tumor evolutionary and transcriptomic profiles. The coexistence of multiple subtypes within the same tumor prompts a re-appraisal of the utilities of depending on single samples to represent the entire tumor and suggests the need for clinical molecular imaging. This research thus marks a significant step forward in the clinical understanding and management of HCC, underscoring the importance of integrating tumor evolutionary dynamics and multi-omics biomarkers into therapeutic decision-making., Clinical Trial Number: NCT03267641 (Observational cohort)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is a deadly cancer with a high global mortality rate, and the downregulation of GATA binding protein 4 (GATA4) has been implicated in HCC progression. In this study, we investigated the role of GATA4 in shaping the immune landscape of HCC., Methods: HCC tumor samples were classified into "low" or "normal/high" based on GATA4 RNA expression relative to adjacent non-tumor liver tissues. The immune landscapes of GATA4-low and GATA4-normal/high tumors were analyzed using cytometry by time-of-flight, bulk/spatial transcriptomic analyses and validated by multiplex immunofluorescence., Results: GATA4-low tumors displayed enrichment in exhausted programmed cell death protein 1+ T cells, immunosuppressive regulatory T cells, myeloid-derived suppressor cells, and macrophages, highlighting the impact of GATA4 downregulation on immunosuppression. Spatial and bulk transcriptomic analyses revealed a negative correlation between GATA4 and C-C Motif Chemokine Ligand 20 (CCL20) expression in HCC. Overexpressing GATA4 confirmed CCL20 as a downstream target, contributing to an immunosuppressive tumor microenvironment, as evidenced by increased regulatory T cells and myeloid-derived suppressor cells in CCL20-high tumors. Lastly, the reduced expression of GATA4 and higher expression of CCL20 were associated with poorer overall survival in patients with HCC, implicating their roles in tumor progression., Conclusions: Our study reveals that GATA4 downregulation contributes to an immunosuppressive microenvironment, driven by CCL20-mediated enrichment of regulatory T cells and myeloid-derived suppressor cells in HCC. These findings underscore the critical role of GATA4 reduction in promoting immunosuppression and HCC progression., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Few studies have assessed the clinical implications of the combination of different prognostic indicators for overall survival (OS) and disease-free survival (DFS) of resected hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic factors in HCC patients for OS and DFS outcomes and establish a nomogram-based prognostic model to predict the DFS of HCC. A multicenter, retrospective European study was conducted through the collection of data on 413 consecutive treated patients with a first diagnosis of HCC between January 2010 and December 2020. Univariate and multivariate Cox regression analyses were performed to identify all independent risk factors for OS and DFS outcomes. A nomogram prognostic staging model was subsequently established for DFS and its precision was verified internally by the concordance index (C-Index) and externally by calibration curves. For OS, multivariate Cox regression analysis indicated Child-Pugh B7 score (HR 4.29; 95% CI 1.74-10.55; p = 0.002) as an independent prognostic factor, along with Barcelona Clinic Liver Cancer (BCLC) stage ≥ B (HR 1.95; 95% CI 1.07-3.54; p = 0.029), microvascular invasion (MVI) (HR 2.54; 95% CI 1.38-4.67; p = 0.003), R1/R2 resection margin (HR 1.57; 95% CI 0.85-2.90; p = 0.015), and Clavien-Dindo Grade 3 or more (HR 2.73; 95% CI 1.44-5.18; p = 0.002). For DFS, multivariate Cox regression analysis indicated BCLC stage ≥ B (HR 2.15; 95% CI 1.34-3.44; p = 0.002) as an independent prognostic factor, along with multiple nodules (HR 2.04; 95% CI 1.25-3.32; p = 0.004), MVI (HR 1.81; 95% CI 1.19-2.75; p = 0.005), satellite nodules (HR 1.63; 95% CI 1.09-2.45; p = 0.018), and R1/R2 resection margin (HR 3.39; 95% CI 2.19-5.25; < 0.001). The C-Index of the nomogram, tailored based on the previous significant factors, showed good accuracy (0.70). Internal and external calibration curves for the probability of DFS rate showed optimal consistency and fit well between the nomogram-based prediction and actual observations. MVI and R1/R2 resection margins should be considered as significant OS and DFS predictors, while satellite nodules should be included as a significant DFS predictor. The nomogram-based prognostic model for DFS provides a more effective prognosis assessment for resected HCC patients, allowing for individualized treatment plans., (© 2023. Italian Society of Surgery (SIC).)

Introduction: This video manuscript presents a unique case of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure performed in case of a giant hepatocellular carcinoma (> 15 cm in size) whereby both stages were completed via the pure laparoscopic approach., Methods: This case was performed in our institution in 2022. All data were obtained from the patient's records in our prospectively maintained database. Institutional Review Board (IRB) was not required for this publication., Results: A 67-year-old Chinese male with a history of chronic hepatitis B infection presented with a giant liver mass. Magnetic resonance imaging (MRI) scan demonstrated a tumour, with features compatible with hepatocellular carcinoma, measuring 15.4 cm in maximal diameter in the right lobe of the cirrhotic liver with no distal metastasis. The indocyanine green (ICG) retention test at 15 min was prolonged at 25.5%, and the CT volumetry showed a borderline future liver remnant (FLR) volume of 692 ml or 22.9% (based on measured volume) and a standardized FLR of 49%. Stage 1 ALPPS was successfully completed via the pure laparoscopic approach. He was well post-operatively, and a repeat CT volumetry at 7 days showed an increase in FLR to 826 ml, and the ICG retention test improved to 18.1%. The patient underwent pure laparoscopic second-stage ALPPS, 8 days later. The patient recovered well with no liver decompensation or local complications., Conclusion: The use of MIS for in 2-stage ALPPS procedure for giant HCCs larger than 10 cm is technically feasible and safe when attempted in high-volume centres by experienced surgeons, while benefiting from the advantages of MIS liver resection., (© 2023. The Society for Surgery of the Alimentary Tract.)

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.)

Hepatocellular carcinoma (HCC) is the third deadliest and sixth most common cancer in the world. Histone-lysine N-methyltransferase EHMT2 (also known as G9a) is a histone methyltransferase frequently overexpressed in many cancer types, including HCC. We showed that Myc-driven liver tumours have a unique H3K9 methylation pattern with corresponding G9a overexpression. This phenomenon of increased G9a was further observed in our c-Myc-positive HCC patient-derived xenografts. More importantly, we showed that HCC patients with higher c-Myc and G9a expression levels portend a poorer survival with lower median survival months. We demonstrated that c-Myc interacts with G9a in HCC and cooperates to regulate c-Myc-dependent gene repression. In addition, G9a stabilises c-Myc to promote cancer development, contributing to the growth and invasive capacity in HCC. Furthermore, combination therapy between G9a and synthetic-lethal target of c-Myc, CDK9, demonstrates strong efficacy in patient-derived avatars of Myc-driven HCC. Our work suggests that targeting G9a could prove to be a potential therapeutic avenue for Myc-driven liver cancer. This will increase our understanding of the underlying epigenetic mechanisms of aggressive tumour initiation and lead to improved therapeutic and diagnostic options for Myc-driven hepatic tumours., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

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.)

Background: Recent studies have associated laparoscopic surgery with better overall survival (OS) in patients with hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM). The potential benefits of laparoscopic liver resection (LLR) over open liver resection (OLR) have not been demonstrated in patients with intrahepatic cholangiocarcinoma (iCC)., Methods: A systematic review of the PubMed, EMBASE, and Web of Science databases was performed to search studies comparing OS and perioperative outcome for patients with resectable iCC. Propensity-score matched (PSM) studies published from database inception to May 1, 2022 were eligible. A frequentist, patient-level, one-stage meta-analysis was performed to analyze the differences in OS between LLR and OLR. Second, intraoperative, postoperative, and oncological outcomes were compared between the two approaches by using a random-effects DerSimonian-Laird model., Results: Six PSM studies involving data from 1.042 patients (530 OLR vs. 512 LLR) were included. LLR in patients with resectable iCC was found to significantly decrease the hazard of death (stratified hazard ratio [HR]: 0.795 [95% confidence interval [CI]: 0.638-0.992]) compared with OLR. Moreover, LLR appears to be significantly associated with a decrease in intraoperative bleeding (- 161.47 ml [95% CI - 237.26 to - 85.69 ml]) and transfusion (OR = 0.41 [95% CI 0.26-0.69]), as well as with a shorter hospital stay (- 3.16 days [95% CI - 4.98 to - 1.34]) and a lower rate of major (Clavien-Dindo ≥III) complications (OR = 0.60 [95% CI 0.39-0.93])., Conclusions: This large meta-analysis of PSM studies shows that LLR in patients with resectable iCC is associated with improved perioperative outcomes and, being conservative, yields similar OS outcomes compared with OLR., (© 2023. The Author(s).)

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.)

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: Despite recent advances in immunotherapy for hepatocellular carcinoma (HCC), the overall modest response rate underscores the need for a better understanding of the tumor microenvironment (TME) of HCC. We have previously shown that CD38 is widely expressed on tumor-infiltrating leukocytes (TILs), predominantly on CD3 + T cells and monocytes. However, its specific role in the HCC TME remains unclear., Methods: In this current study, we used cytometry time-of-flight (CyTOF), bulk RNA sequencing on sorted T cells, and single-cell RNA (scRNA) sequencing to interrogate expression of CD38 and its correlation with T cell exhaustion in HCC samples. We also employed multiplex immunohistochemistry (mIHC) for validating our findings., Results: From CyTOF analysis, we compared the immune composition of CD38-expressing leukocytes in TILs, non-tumor tissue-infiltrating leukocytes (NIL), and peripheral blood mononuclear cells (PBMC). We identified CD8 + T cells as the dominant CD38-expressing TILs and found that CD38 expression was significantly higher in CD8 + T RM in TILs than in NILs. Furthermore, through transcriptomic analysis on sorted CD8 + T RM from HCC tumors, we observed a higher expression of CD38 along with T cell exhaustion genes, including PDCD1 and CTLA4, compared to the circulating memory CD8 T cells from PBMC. This was validated by scRNA sequencing that revealed co-expression of CD38 with PDCD1, CTLA4, and ITGAE (CD103) in T cells from HCC tumors. The protein co-expression of CD38 and PD-1 on CD8 + T cells was further demonstrated by mIHC on HCC FFPE tissues, marking CD38 as a T cell co-exhaustion marker in HCC. Lastly, the higher proportions of CD38 + PD-1 + CD8 + T cells and CD38 + PD-1 + T RM were significantly associated with the higher histopathological grades of HCC, indicating its role in the aggressiveness of the disease., Conclusion: Taken together, the concurrent expression of CD38 with exhaustion markers on CD8 + T RM underpins its role as a key marker of T cell exhaustion and a potential therapeutic target for restoring cytotoxic T cell function in HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Reolo, Otsuka, Seow, Lee, Lee, Nguyen, Lim, Wasser, Chua, Lim, Leow, Chung, Goh, Chow, DasGupta, Yeong and Chew.)

Background: Liver transplantation remains the optimal treatment for multifocal hepatocellular carcinoma (HCC). However, due to resource constrains, other therapeutic modalities such as liver resection (LR), are frequently utilized. LR, however, has to be balanced against potential morbidity and mortality along with the risks of early recurrence leading to futile surgery. In this study, we evaluated preoperative factors, including inflammatory indices, in predicting early (< 1 year) recurrence in patients who underwent LR for multifocal HCC., Methods: This was a post hoc analysis of 250 consecutive patients with multifocal HCC who underwent LR., Results: After exclusion of 10 patients with 30-day/in-hospital mortality, 240 were included of which 134 (55.8%) developed early recurrence. Hepatitis B/C aetiology, 3/ > more hepatic nodules and elevated alpha-fetoprotein (AFP) ≥ 200 ng/ml were significant independent preoperative predictors of early recurrence. The early recurrence rate was 72.1% when 2 out of 3 significant predictive factors were present. The conglomerate of all 3 factors predicted early recurrence of 100% with a statistically significant association between number of predictive factors and early recurrence (p < 0.001)., Conclusion: Better patient selection via the use of preoperative predictive factors of early recurrence such as hepatitis B/C aetiology, ≥ 3 nodules and elevated AFP ≥ 200 ng/ml may assist in identifying patients in whom LR is deemed futile and improve resource allocation., (© 2023. The Society for Surgery of the Alimentary Tract.)

Introduction: Our primary objective was to determine if receiving intraoperative blood transfusion was a significant prognostic factor for overall and recurrence-free survival after curative resection of hepatic cellular carcinoma (HCC)., Methodology: Between 2001 and 2018, 1092 patients with histologically proven primary HCC who underwent curative liver resection were retrospectively reviewed. Primary study endpoints were recurrence-free survival (RFS) and overall survival (OS). The main analysis was undertaken using propensity-score matching (PSM) to minimize confounding and selection biases in the comparison of patients with or without transfusion., Results: There were 220 patients who received and 666 patients who did not receive intraoperative blood transfusion. The PSM cohort consisted of 163 pairs of patients. After PSM, the only perioperative outcome that appeared to significantly affect whether patients would receive blood transfusion was median blood loss (p = 0.001). In the PSM cohort, whether patients received blood transfusion was neither associated with OS (p = 0.759) nor RFS (p = 0.830). When the volume of blood transfusion was analyzed as a continuous variable, no significant dose-response relationship between blood transfusion volume and HR for OS and RFS was noted., Conclusion: Intraoperative blood transfusion had no significant impact on the survival outcomes in patients who receive curative resection in primary HCC., (© 2022 Wiley Periodicals LLC.)

Background: Conventional differential expression (DE) testing compares the grouped mean value of tumour samples to the grouped mean value of the normal samples, and may miss out dysregulated genes in small subgroup of patients. This is especially so for highly heterogeneous cancer like Hepatocellular Carcinoma (HCC)., Methods: Using multi-region sampled RNA-seq data of 90 patients, we performed patient-specific differential expression testing, together with the patients' matched adjacent normal samples., Results: Comparing the results from conventional DE analysis and patient-specific DE analyses, we show that the conventional DE analysis omits some genes due to high inter-individual variability present in both tumour and normal tissues. Dysregulated genes shared in small subgroup of patients were useful in stratifying patients, and presented differential prognosis. We also showed that the target genes of some of the current targeted agents used in HCC exhibited highly individualistic dysregulation pattern, which may explain the poor response rate., Discussion/conclusion: Our results highlight the importance of identifying patient-specific DE genes, with its potential to provide clinically valuable insights into patient subgroups for applications in precision medicine., (© 2023. The Author(s).)

IL-17-producing CD8 (Tc17) T cells have been shown to play an important role in infection and chronic inflammation, however their implications in hepatocellular carcinoma (HCC) remain elusive. In this study, we performed cytometry by time-of-flight (CyTOF) and revealed the distinctive immunological phenotypes of two IFNγ + and IFNγ - Tc17 subsets that were preferentially enriched in human HCC. Single-cell RNA-sequencing analysis further revealed regulatory circuits governing the different phenotypes of these Tc17 subsets. In particular, we discovered that IFNγ - Tc17 subset demonstrated pro-tumoral characteristics and expressed higher levels of CCL20. This corresponded to increased tumor infiltration of T regulatory cells (Treg) validated by immunohistochemistry in another independent HCC cohort, demonstrating the immunosuppressive functions of IFNγ - Tc17 subset. Most importantly, higher intra-tumoral proportions of IFNγ - Tc17 were associated with poorer prognosis in patients with HCC and this was further validated in The Cancer Genome Atlas (TCGA) HCC cohort. Taken together, this compendium of transcriptomic and proteomic data of Tc17 subsets sheds light on the immunosuppressive phenotypes of IFNγ - Tc17 and its implications in HCC progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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: An updated systematic review and meta-analysis was conducted to compare radiofrequency ablation (RFA) versus repeat hepatectomy (RH) for patients with recurrent hepatocellular carcinoma (rHCC) after a previous liver resection., Methods: PubMed, EMBASE, and Cochrane databases were searched from inception to October 2021 for randomized controlled trials and propensity-score matched studies. Individual participant survival data of disease-free survival (DFS) and overall survival (OS) were extracted and reconstructed followed by one-stage and two-stage meta-analysis. Secondary outcomes were major complications and length of hospital stay (LOHS)., Results: A total of seven studies (1317 patients) were analysed. In both one-stage and two-stage meta-analysis, there was no significant difference in OS between the RFA and RH cohorts (Hazard Ratio (HR) 1.15, 95% CI 0.98-1.36, P = 0.094 and HR 1.12, 95% CI 0.77-1.64, P = 0.474 respectively), while the RFA group had a higher hazard rate of disease recurrence compared to the RH group (HR 1.30, 95% CI 1.13-1.50, P &lt; 0.001 and HR 1.31, 95% CI 1.09-1.57, P = 0.013, respectively). RFA was associated with fewer major complications and shorter LOHS versus RH (Odds Ratio 0.34, 95% CI 0.15-0.76, P = 0.009 and Weighted Mean Difference - 4.78, 95% CI - 6.30 to - 3.26, P &lt; 0.001, respectively)., Conclusions: RH may be associated with superior DFS for rHCC, at the expense of higher morbidity rate and longer LOHS. However, OS is comparable between both modalities. As such, these techniques may be utilized as complementary strategies depending on individual patient and disease factors. Large-scale, randomized, prospective studies are required to corroborate these findings., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background and Aims: Hypoxia is one of the central players in shaping the immune context of the tumor microenvironment (TME). However, the complex interplay between immune cell infiltrates within the hypoxic TME of HCC remains to be elucidated., Approach and Results: We analyzed the immune landscapes of hypoxia-low and hypoxia-high tumor regions using cytometry by time of light, immunohistochemistry, and transcriptomic analyses. The mechanisms of immunosuppression in immune subsets of interest were further explored using in vitro hypoxia assays. Regulatory T cells (Tregs) and a number of immunosuppressive myeloid subsets, including M2 macrophages and human leukocyte antigen-DR isotype (HLA-DR lo ) type 2 conventional dendritic cell (cDC2), were found to be significantly enriched in hypoxia-high tumor regions. On the other hand, the abundance of active granzyme B hi PD-1 lo CD8 + T cells in hypoxia-low tumor regions implied a relatively active immune landscape compared with hypoxia-high regions. The up-regulation of cancer-associated genes in the tumor tissues and immunosuppressive genes in the tumor-infiltrating leukocytes supported a highly pro-tumorigenic network in hypoxic HCC. Chemokine genes such as CCL20 (C-C motif chemokine ligand 20) and CXCL5 (C-X-C motif chemokine ligand 5) were associated with recruitment of both Tregs and HLA-DR lo cDC2 to hypoxia-high microenvironments. The interaction between Tregs and cDC2 under a hypoxic TME resulted in a loss of antigen-presenting HLA-DR on cDC2., Conclusions: We uncovered the unique immunosuppressive landscapes and identified key immune subsets enriched in hypoxic HCC. In particular, we identified a potential Treg-mediated immunosuppression through interaction with a cDC2 subset in HCC that could be exploited for immunotherapies., (© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: The Memorial Sloan Kettering Cancer Center nomogram, the predictive scoring system of Yamamoto et al, and the 3-point transfusion risk score of Lemke et al are models used to determine the probability of receiving intraoperative blood transfusion in patients undergoing liver resection. However, the external validity of these models remains unknown. The objective of this study was to evaluate their predictive performance in an external cohort of patients with hepatocellular carcinoma. We also aimed to identify predictors of blood transfusion and develop a new predictive model for blood transfusion., Methods: Post hoc analysis of our prospective database of 1,081 patients undergoing liver resection for hepatocellular carcinoma from 2001 to 2018. The predictive performance of current prediction models was evaluated using C statistics. Demographic and clinical variables as predictors of blood transfusion were assessed. Using logistic regression, an alternative model was created., Results: The Lemke transfusion risk score performed better than the Memorial Sloan Kettering Cancer Center nomogram (0.69, 95% confidence interval 0.66-0.73 vs 0.66, 95% liver resection 0.62-0.69) (P &lt; .001). The model from Yamamoto et al performed comparably with no statistically significant differences found through pairwise comparison. In our alternative model, hemoglobin level, albumin level, liver resection type, and tumor size were independent predictors of blood transfusion. The new HATS model obtained a C statistic of 0.74 (95% confidence interval 0.71-0.78), performing significantly better than the previous 3 models (P ≤ 0.001 for all)., Conclusion: The existing Memorial Sloan Kettering Cancer Center, Yamamoto et al, and Lemke et al had nomograms with the suboptimal accuracy of predicting risk of intraoperative blood transfusion in patients undergoing liver resection for hepatocellular carcinoma. The proposed HATS model was more accurate at predicting patients at risk of blood transfusion., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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: Few studies have evaluated the outcomes of curative liver resection (LR) in octogenarian patients, analysed cancer-specific survival (CSS) with HCC-related death or explored the age-varying effect of HCC-related death in elderly patients undergoing LR. We aim to determine the effect of age on the short and long-term outcomes of LR for HCC., Methodology: Between 2000 and 2018, 1,092 patients with primary HCC who underwent LR with curative intent were retrospectively reviewed. The log-rank test and Gray's test were used to assess the equality of survivor functions and competing risk-adjusted cumulative incidence functions between patients in the three age categories respectively. Regression adjustment was used to control for confounding bias via a Principal Component Analysis. Quantile, Firth logistic, Cox, and Fine-Gray competing risk regression were used to analyse continuous, binary, time-to-event, and cause-specific survival respectively. Restricted cubic splines were used to illustrate the dose-effect relationship between age and patient outcomes., Results: The study comprised of 764 young patients (<70 years), 278 septuagenarians (70-79 years old) and 50 octogenarians (≥80 years). Compared to young patients, octogenarians had significantly lower 5-year OS(62.1% vs 37.7%, p < 0.001). However, there was no significant difference in 1-year RFS(73.1% vs 67.0%, p = 0.774) or 5-year CSS (5.4% vs 15.2%, p = 0.674). Every 10-year increase in age was significantly associated with an increase length of stay (p < 0.001), postoperative complications (p = 0.004) and poorer OS(p = 0.018) but not significantly associated with major complications (p = 0.279), CSS(p = 0.338) or RFS(p = 0.941)., Conclusion: Age by itself was associated with OS after LR for HCC but was not a significant risk factor for HCC-related death., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Immune evasion is key to cancer initiation and later at metastasis, but its dynamics at intermediate stages, where potential therapeutic interventions could be applied, is undefined. Here we show, using multi-dimensional analyses of resected tumours, their adjacent non-tumour tissues and peripheral blood, that extensive immune remodelling takes place in patients with stage I to III hepatocellular carcinoma (HCC). We demonstrate the depletion of anti-tumoural immune subsets and accumulation of immunosuppressive or exhausted subsets along with reduced tumour infiltration of CD8 T cells peaking at stage II tumours. Corresponding transcriptomic modification occur in the genes related to antigen presentation, immune responses, and chemotaxis. The progressive immune evasion is validated in a murine model of HCC. Our results show evidence of ongoing tumour-immune co-evolution during HCC progression and offer insights into potential interventions to reverse, prevent or limit the progression of the disease., (© 2022. The Author(s).)

Introduction: We performed this study in order to investigate the impact of tumour size on the difficulty of MILR, as well as to elucidate the optimal tumour size cut-off/s to distinguish between 'easy' and 'difficult' MILRs., Materials and Methods: This is retrospective review of 603 consecutive patients who underwent MILR between 2006 and 2019 of which 461 met the study inclusion criteria. We first conducted an exploratory analysis to visualize the associations between tumor size and various surrogates of laparoscopic difficulty in order to determine to optimal tumor size cutoff for stratification. Visual inspection of flexible spline-based models as well as quantitative evidence determined that perioperative outcomes differed between patients with tumor size of 30-69 mm and tumours ≥70 mm. These cutoffs were used for further downstream analyses., Results: The cohort of 461 patients was divided into 3 groups based on tumour diameter size. Patients with larger tumours experienced longer operating times ((P Group 2 vs 1 <0.001, P Group 3 vs 1 <0.001, P Group 3 vs 2 <0.001), higher blood loss (P Group 2 vs 1 <0.001, P Group 3 vs 1 <0.001, P Group 3 vs 2 <0.001), as well as significantly longer hospital stay (P Group 2 vs 1 <0.001, P Group 3 vs 1 <0.001, P Group 3 vs 2 <0.001). There was a monotonic trend towards increasing blood transfusion rates (P = 0.006), overall morbidity (P = 0.029) and 90-day mortality rates (P = 0.047) with increasing tumour size., Conclusion: Although tumour size of 30 mm serves as an optimal cut-off for predicting difficult resections as per the Iwate criteria, a trichotomy (<30 mm, 30-69 mm, ≥70 mm) may provide additional granularity. Further large-scale prospective studies are needed to corroborate these findings., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: The exact role of laparoscopic liver resection (LLR) in patients with hepatocellular carcinoma (HCC) and underlying liver cirrhosis (LC) is not well defined. In this meta-analysis, both long- and short-term outcomes following LLR versus open liver resection (OLR) were analysed., Methods: PubMed, EMBASE, Scopus and Web of Science databases were searched systematically for randomised controlled trials (RCTs) and propensity-score matched (PSM) studies reporting outcomes of LLR versus OLR of HCC in patients with cirrhosis. Primary outcome was overall survival (OS). This was analysed using one-stage (individual participant data meta-analysis) and two-stage (aggregate data meta-analysis) approaches. Secondary outcomes were operation duration, blood loss, blood transfusion, Pringle manoeuvre utilization, overall and major complications, length of hospital stay (LOHS), 90-day mortality and R0 resection rates., Results: Eleven studies comprising 1618 patients (690 LLR versus 928 OLR) were included for analysis. In the one-stage meta-analysis, an approximately 18.7 per cent lower hazard rate (HR) of death in the LLR group (random effects: HR 0.81, 95 per cent confidence interval [C.I.] 0.68 to 0.96; P = 0.018) was observed. Two-stage meta-analysis resulted in a pooled HR of 0.84 (95 per cent C.I. 0.74 to 0.96; P = 0.01) in the overall LLR cohort. This indicated a 16-26 per cent reduction in the HR of death for patients with HCC and cirrhosis who underwent LLR. For secondary outcomes, LLR was associated with less blood loss (mean difference [MD] -99 ml, 95 per cent C.I. -182 to -16 ml), reduced overall complications (odds ratio 0.49, 95 per cent C.I. 0.37 to 0.66) and major complications (odds ratio 0.45, 95 per cent C.I. 0.26 to 0.79), and shorter LOHS (MD -3.22 days, 95 per cent C.I. -4.38 to -2.06 days)., Conclusion: Laparoscopic resection of HCC in patients with cirrhosis is associated with improved survival and perioperative outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The management of HCC differs depending on the extent of disease. Surgery may be offered in selected cases of T4 disease as defined by AJCC 8th. However, outcome data post partial hepatectomy (PH) for T4 disease is scarce. We sought to evaluate the outcomes of patients post resection of T4 HCC and assess preoperative predictive factors of early recurrence., Methods: We performed a retrospective review of 235 consecutive patients who underwent resection for T4 HCC from 2001 to 2018 at our institution., Results: Median overall survival was 35.9 months (95% CI 25.7-46.0). 109 patients (49.5%) developed recurrence, of which 94 patients (42.7%) experienced early recurrence within 12 months. Median time to recurrence was 38.1 months. Multivariate analysis demonstrated that vascular invasion were significant independent preoperative predictor of early recurrence post resection. Patients who experienced early recurrence had a significantly shorter median overall survival 14.3 months (95% CI 25.7-46.0) compared to those who did not (55.5 months, 95% CI 40.6-70.8, p = .000)., Conclusion: Selected patients with T4 HCC may benefit from PH. Macrovascular invasion was associated with early recurrence within 12 months., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Therapeutic synergism between radiotherapy and immune checkpoint blockade has been observed in preclinical models of hepatocellular carcinoma. We aimed to study the safety and efficacy of sequential radioembolisation with yttrium-90-resin microspheres (Y90-radioembolisation) followed by nivolumab in patients with advanced hepatocellular carcinoma., Methods: Patients with Child-Pugh A cirrhosis and advanced hepatocellular carcinoma not suitable for curative surgery were treated with Y90-radioembolisation followed by intravenous nivolumab 240 mg 21 days after Y90-radioembolisation and every 2 weeks thereafter. The primary endpoint, assessed in the per-protocol population, was the objective response rate, determined by RECIST version 1.1, defined as the proportion of patients with a confirmed complete or partial response observed for lesions both within and outside the Y90-radioembolisation field. This study is registered with ClinicalTrials.gov, NCT03033446 and has been completed., Findings: 40 patients were enrolled, of whom 36 received Y90-radioembolisation followed by nivolumab. One (3%) patient had a complete response and ten (28%) had a partial response; the objective response rate was 30·6% (95% CI 16·4-48·1). The most common treatment-related adverse events of any grade were pruritus (18 [50%] of 36 patients) and maculopapular rash (13 [36%]). Two (6%) patients experienced grade 3-4 treatment-related adverse events: one patient had a grade 3 increase in alanine aminotransferase levels, grade 3 bilirubin increase, and grade 4 increase in aspartate aminotransferase levels, while the other had a grade 3 maculopapular rash. Five (14%) patients had a treatment-related serious adverse event (Steven-Johnson syndrome, hepatitis E infection, fever, liver abscesses, and ascites)., Interpretation: Y90-radioembolisation followed by nivolumab resulted in an encouraging objective response rate in patients with advanced hepatocellular carcinoma, although the activity observed was not as high as the study was powered for. This strategy should be further evaluated in patients with Barcelona Clinic Liver Clinic (BCLC) stage B hepatocellular carcinoma that is ineligible or refractory to transarterial chemoembolisation and patients with BCLC C disease without extrahepatic spread., Funding: National Medical Research Council Singapore, Bristol-Myers Squibb, Sirtex., Competing Interests: Declaration of interests DT declares support for the current manuscript from Bristol-Myers Squibb, Sirtex, and NMRC Singapore (CIRG/1470/2017); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen, Eisai, and Bristol-Myers Squibb; and consulting fees from Novartis, Bristol-Myers Squibb, and Merck Sharpe Dohme. CSP declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Bristol-Myers Squibb, Ipsen, Lilly, AstraZeneca, and Roche; consulting fees from Bristol-Myers Squibb, Roche, Ipsen, Servier, Eisai, and AstraZeneca; a leadership or fiduciary role for Ministry of Health Singapore Medishield Life Cancer Drug committee; and stock or stock options with Bristol-Myers Squibb. DN declares support for the present manuscript from Sirtex; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sirtex. JL declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol-Myers Squibb, Ipsen, and Bayer; and research funding from Bayer. PKHC declares grants or contracts from Sirtex Medical, Ipsen, IQVIA, New B Innovation, Perspectum, AMiLi, MiRXES, Genentech, and Engine Biosciences; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Sirtex Medical, Ipsen, Oncosil, Bayer, Roche, New B Innovation, Merck Sharpe Dohme, BTG Plc, Eisai, Abbott, AstraZeneca, IQVIA, Genentech, Worrell Guerbet, LEK Consulting, and COR2ED; and a leadership or fiduciary role, and stock or stock options for AVATAMED. TCW declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events and consulting fees from Sirtex. KL, AG, NKA, TSH, TH, FI, JL, MN, TCK, KSL, CHS, GGBB, HLH, NK, RL, BG, AC, THC, TCH, TL, JY, ZWW, and CCY declared no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with high rates of recurrence post-resection. Repeat hepatectomy (RH) and radiofrequency ablation (RFA) are the mainstays for managing recurrent HCC following initial curative resection. This retrospective study aims to determine the average treatment effect of RH and RFA in patients with recurrent HCC., Patients and Methods: From 2000 to 2016, a total of 219 consecutive patients with recurrent HCC who underwent either RH or RFA were included in the study. The analysis was performed using inverse probability of treatment weighting (IPTW), and propensity score-matched (PSM) methods., Results: The minor and major post-operative morbidity after propensity score-matched analysis for the RH group was 30.0% and 6.0%, respectively, and 19.2% and 0.0% (p = 0.1006), respectively, for the RFA group. After propensity score matching, the median OS for RH and RFA was 85.5 (IQR, 33.5-not reached) and 53.3 months (IQR, 27.5-not reached) (p = 0.8474), respectively. There was no significant difference in 90-day mortality between both groups (p = 0.1287). RH showed improved long-term overall survival over RFA at the third [71.3% versus 65.7% (p = 0.0432)], fifth [59.9% versus 45.4% (p = 0.0271)] and tenth [35.4% versus 32.2% (p = 0.0132)] year follow-up, respectively. Median time to recurrence was 11.1 (IQR, 5.0-33.2) and 28.0 months (IQR, 9.1-not reached) (p = 0.0225) for the RFA and RH group, respectively., Conclusions: RH confers a late survival benefit compared with RFA for patients with recurrent HCC despite a higher morbidity rate., (© 2021. Society of Surgical Oncology.)

Background: This study aims to compare the short- and long-term outcomes of patients undergoing minimally invasive liver resection (MILR) versus open liver resection (OLR) for nonrecurrent hepatocellular carcinoma (HCC)., Methods: Review of 204 MILR and 755 OLR without previous LR performed between 2005 and 2018. 1:1 coarsened exact matching (CEM) and 1:1 propensity-score matching (PSM) were performed., Results: Overall, 190 MILR were well-matched with 190 OLR by PSM and 86 MILR with 86 OLR by CEM according to patient baseline characteristics. After PSM and CEM, MILR was associated with a significantly longer operation time [230 min (interquartile range [IQR], 145-330) vs. 160 min (IQR, 125-210), p < .001] [215 min (IQR, 135-295) vs. 153.5 min (120-180), p < .001], shorter postoperative stay [4 days (IQR, 3-6) vs. 6 days (IQR, 5-8), p = .001)] [4 days (IQR, 3-5) vs. 6 days (IQR, 5-7), p = .004] and lower postoperative morbidity [40 (21%) vs. 67 (35.5%), p = .003] [16 (18.6%) vs. 27 (31.4%), p = .036] compared to OLR. MILR was also associated with a significantly longer median time to recurrence (70 vs. 40.3 months, p = .014) compared to OLR after PSM but not CEM. There was no significant difference in terms of overall survival and recurrence-free survival., Conclusion: MILR is associated with superior short-term postoperative outcomes and with at least equivalent long-term oncological outcomes compared to OLR for HCC., (© 2021 Wiley Periodicals LLC.)

Introduction: To investigate the changing trends in short- and long-term outcomes after partial hepatectomy(PH) for hepatocellular carcinoma(HCC) performed in the 21st century., Methods: A retrospective review was conducted on 1300 consecutive patients who underwent PH for HCC. The study cohort was divided into 3 time periods(P): P1(2000-2005), P2(2006-2011) and P3(20012-2017)., Results: Comparison between the patients' baseline demographic features across the 3 periods demonstrated that patients were significantly older, had decreasing frequency of hepatitis B, increasing non-alcoholic fatty liver disease, lower alpha-feto protein(AFP) level, lower creatinine levels, less likely to undergo emergency surgery, less likely to undergo major hepatectomy, more likely to undergo repeat resection and minimally-invasive surgery. There was also an increase in operation time, decrease in blood loss, increase frequency in the use of Pringles manoeuvre, decrease liver failure, decrease length of stay and decrease postoperative mortality. HCC resected were of smaller size, less likely to demonstrate microvascular invasion and less likely to have close margins. This was associated with significant improvement in overall survival and recurrence free interval over time. Period of resection was an independent predictor of 90-day mortality and OS on multivariate analysis., Conclusion: We observed a continuous improvement in postoperative outcomes including postoperative mortality and long-term survival after PH for HCC over the past 18 years., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Here, we examined the antigen specificities of HCC-infiltrating T cells and their relevance to tumor control. Using highly multiplexed peptide-MHC tetramer staining of unexpanded cells from blood, liver, and tumor tissues from 46 HCC patients, we detected 91 different antigen-specific CD8 + T cell populations targeting HBV, neoantigen, tumor-associated, and disease-unrelated antigens. Parallel high-dimensional analysis delineated five distinct antigen-specific tissue-resident memory T (Trm) cell populations. Intratumoral and intrahepatic HBV-specific T cells were enriched for two Trm cell subsets that were PD-1 lo TOX lo , despite being clonally expanded. High frequencies of intratumoral terminally exhausted T cells were uncommon. Patients with tumor-infiltrating HBV-specific CD8 + Trm cells exhibited longer-term relapse-free survival. Thus, non-terminally exhausted HBV-specific CD8 + Trm cells show hallmarks of active involvement and effective antitumor response, implying that these cells could be harnessed for therapeutic purposes., Competing Interests: Declaration of interests Y.C. and E.W.N. are inventors on US patent application (pending) held by A(∗)STAR, which includes the uses of tumor-reactive epitope sequences and the epitope-reactive TCRs for treatment against HBV-associated HCC. S.G.L. received research grants from Gilead Science, Merck, and Abbott Diagnostics. S.G.L. served as the advisory board member of Gilead Science, Abbvie, Abbott Diagnostics, Merck, Springbank, and Roche. E.W.N. is the co-founder, shareholder, and an advisor and is on the board of directors of ImmunoScape Pte. Ltd. and is an advisor for Neogene Therapeutics and Nanostring Technologies. P.K.H.C. has received honoraria from Sirtex Medical, Ipsen, Bristol Myers Squibb, Oncosoil, Bayer, Roche, New B Innovation, MSD, EISA, Abbott, IQVIA, Genetech, L.E.K. Consulting, and AstraZeneca in an advisory role., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: This systematic review and meta-analysis aimed to compare the outcomes of curative therapy (resection, transplantation, ablation) for hepatocellular carcinoma (HCC) arising from non-alcoholic fatty liver disease (NAFLD) and non-NAFLD etiologies., Methods: A systematic search of PubMed, EMBASE and Cochrane Library was conducted for studies comparing survival, peri- and post-operative outcomes. Quality assessment was performed using the Newcastle-Ottawa scale., Results: Findings for 5579 patients were pooled across 9 studies and examined. Analysis demonstrated improved disease-free survival (DFS; HR 0.85, 95% CI 0.74-0.98, p = 0.03) and overall survival (OS; HR 0.87; 95% CI 0.81-0.93; p < 0.0001) in NAFLD-HCC patients undergoing liver resection as compared to non-NAFLD HCC patients. NAFLD-HCC patients undergoing all forms of curative therapy were similarly associated with improved OS (HR 0.96; 95% CI 0.86-1.06; p = 0.40) and DFS (HR 0.85; 95% CI 0.74-0.98; p = 0.03), albeit results being significant only for DFS. Only 2 studies reported higher rates of peri- and post-operative complications in patients with NAFLD-HCC. Significant inter-study heterogeneity precluded further analysis., Conclusion: NAFLD-HCC patients can enjoy long-term survival benefit with aggressive curative therapy. Peri- and post-operative morbidity should be mitigated with pre-operative optimization of comorbidities, and deliberately close post-operative monitoring., Competing Interests: Declarations of interest None to declare., (Copyright © 2021. Published by Elsevier Ltd.)

Introduction: Laparoscopic liver resection (LLR) is increasingly being utilised worldwide for the management of both benign and malignant liver tumours. However, there is limited data to date regarding the safety and feasibility of this approach for huge (≥10 cm) hepatocellular carcinomas (HCCs). We present here our early experience performing LLR for huge HCCs., Methods: We conducted a retrospective review of 280 consecutive patients who underwent LLR by a single surgeon from 2012 to August 2020.15 patients had a preoperative radiological diagnosis of huge (≥10 cm) HCC. Coarsened exact-matched (CEM) weighting was used to compare them to 101 patients who underwent LLR for non-huge HCC., Results: After CEM-weighting, both groups were well-balanced for baseline variables. There was no difference in the rates of open conversion. The huge HCC patients had a higher mean Iwate difficulty score than the non-huge HCC patients (9.13 vs 6.53, p = 0.007). As such, the median operating time for the huge HCC group was longer (360 min vs 240min, p = 0.049). However, there were no significant differences in estimated blood loss, proportion of patients requiring blood transfusion, utilization of Pringle maneuver or median Pringle duration. Post-operatively, there were no significant differences in median LOS, overall and major morbidity rates, and 90-day mortality rates between both groups. Median resection margins were also similar for both cohorts., Conclusion: LLR may be performed successfully for selected patients with huge HCC, with encouraging perioperative outcomes and no compromise in oncologic efficacy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The management of post-liver resection recurrence is often the life-limiting factor in HCC treatment. While much has been published on intrahepatic recurrence and lung metastasis, there is a relative lack of data on intraabdominal extrahepatic metastasis (EHM). We sought to evaluate the outcomes of patients post-resection of intraabdominal EHM and assess preoperative factors predictive of early recurrence post-metastasectomy., Methods: We performed a retrospective review of 25 consecutive patients who underwent metastasectomy for intraabdominal EHM from 2003 to 2016 at our institution., Results: Of the 25 cases of EHM, 16 were in the peritoneum, 3 in the adrenal glands, 3 in the large bowel, 1 in the spleen, 1 in the pancreas and 1 in the omentum. Median overall survival was 27 months (IQR 15-89 months). Twenty-one patients (84%) developed recurrence post-metastasectomy of EHM of which 12 patients experienced early recurrence within 12 months. The median time to recurrence post-metastasectomy was 11(IQR 15.5) months. Multivariate analysis demonstrated both hepatitis B (11 (91.6%) versus 4 (44.4%), p = 0.00) status and high tumour grade (8 (66.6%) versus 3 (25%), p = 0.004) to be significant independent predictors of early recurrence. Patients who experienced early recurrence had a significantly shorter median overall survival (18 months (95% CI 12.9-23.0)) compared to those who did not (89 months (95% CI 24.8-153.1), p = 0.004)., Conclusion: Patients with EHM who underwent metastasectomy had a median overall survival of 27 months. Hepatitis B positivity and high primary tumour grade were preoperative predictors of futile surgery. All 7 patients who had both hepatitis B and high tumour grade experienced early recurrence post-metastasectomy.

Background: The utility of minimally-invasive liver resection (MILR) for deep centrally located tumours (CLT) remains controversial. We aimed to review our institution's experience and outcomes with minimally invasive central hepatectomy (CH) and right anterior sectionectomy (RAS) for CLT in a propensity score-matched (PSM) analysis., Methods: Retrospective review of a prospectively maintained surgical database revealed 23 patients who underwent MILR (6 CH, 17 RAS) and 53 patients who underwent open liver resection (OLR; 24 CH, 29 RAS) for CLT. PSM in a 1:1 ratio identified two groups of patients with similar baseline clinicopathological characteristics. Peri-operative outcomes were then compared., Results: There was one laparoscopic-assisted, one robot-assisted and two laparoscopic-converted-open procedures in the MILR cohort. Across the unmatched cohort, there was only one mortality (MILR) and five patients with major morbidity (all OLR). MILR was associated with a longer operating time (P < 0.001), but shorter post-operative hospital stay (P = 0.002) and decreased morbidity (P = 0.018) in the unmatched cohort. Examination of peri-operative outcomes after PSM revealed that MILR was similarly associated with a longer operating time (P = 0.001) and shortened post-operative hospital stay (P = 0.043). OLR was associated with a significantly reduced application of Pringle manoeuvre (P = 0.004). There were no significant differences between MILR and OLR with regards to blood loss, blood transfusions, morbidity and margin status in the PSM analysis., Conclusion: MILR for CLT is safe and feasible when performed by experienced surgeons. It is associated with shorter hospital stays but at the expense of longer operation times and more frequent application of Pringle manoeuver., (© 2021 Royal Australasian College of Surgeons.)

Background: Laparoscopic liver resection for hepatocellular carcinoma (HCC) in Child-Pugh A cirrhosis has been demonstrated as beneficial. However, the role of laparoscopy in Child-Pugh B cirrhosis is undetermined. The aim of this retrospective cohort study was to compare open and laparoscopic resection for HCC with Child-Pugh B cirrhosis., Methods: Data on liver resections were gathered from 17 centres. A 1 : 1 propensity score matching was performed according to 17 predefined variables., Results: Of 382 available liver resections, 100 laparoscopic and 100 open resections were matched and analysed. The 90-day postoperative mortality rate was similar in open and laparoscopic groups (4.0 versus 2.0 per cent respectively; P = 0.687). Laparoscopy was associated with lower blood loss (median 110 ml versus 400 ml in the open group; P = 0.004), less morbidity (38.0 versus 51.0 per cent respectively; P = 0.041) and fewer major complications (7.0 versus 21.0 per cent; P = 0.010), and ascites was lower on postoperative days 1, 3 and 5. For laparoscopic resections, patients with portal hypertension developed more complications than those without (26 versus 12 per cent respectively; P = 0.002), and patients with a Child-Pugh B9 score had higher morbidity rates than those with B8 and B7 (7 of 8, 10 of 16 and 21 of 76 respectively; P < 0.001). Median hospital stay was 7.5 (range 2-243) days for laparoscopic liver resection and 18 (3-104) days for the open approach (P = 0.058). The 5-year overall survival rate was 47 per cent for open and 65 per cent for laparoscopic resection (P = 0.142). The 5-year disease-free survival rate was 32 and 37 per cent respectively (P = 0.742)., Conclusion: Patients without preoperative portal hypertension and Child-Pugh B7 cirrhosis may benefit most from laparoscopic liver surgery., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.

Background: At present, the majority of outcome studies of survival of hepatocellular carcinoma (HCC) post-liver resection (post-LR) present actuarial survival data, which often results in overestimation of survival. We sought to evaluate the actual 10-year survival post-LR for HCC and identify variables that are associated with long-term survival., Methods: We performed a retrospective review of 600 consecutive patients who underwent primary LR for HCC from 2000 to 2010 at our institution. Twenty-eight patients (4.7%) with 90-day mortality and 125 patients who were lost to follow-up within 10 years were excluded leaving 447 patients who met the study criteria., Results: There were 140 actual 10-year survivors of which 57 (40.7%) had a recurrence within 10 years. The actual 10-year overall survival (OS) rate of the 447 patients was 31.5% and the actual 10-year recurrence-free survival (RFS) was 18.6%. Multivariate analyses demonstrated that only age >65 years (OR, 0.29; p < .001) (OR, 0.973; p = .041) and presence of cirrhosis (OR. 0.37; p = .005) (OR, 0.31; p = .001) were independent factors negatively associated with actual 10-year OS and actual 10-year RFS, respectively., Conclusion: Approximately one-third of patients will survive over 10 years after LR for HCC. Amongst these 10-year survivors, 41% had developed recurrent cancer within 10-years of follow-up., (© 2020 Wiley Periodicals LLC.)

Background: Liver resection (LR) is the main modality of treatment for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM). Post-hepatectomy liver failure (PHLF) remains the most dreaded complication. We aim to create a prognostic score for early risk stratification of patients undergoing LR., Methodology: Clinical and operative data of 472 patients between 2000 and 2016 with HCC or CRLM undergoing major hepatectomy were extracted and analysed from a prospectively maintained database. PHLF was defined using the 50-50 criteria., Results: Liver cirrhosis and fatty liver were histologically confirmed in 35.6% and 53% of patients. 4.7% (n = 22) of patients had PHLF. A 90-day mortality was 5.1% (n = 24). Pre-operative albumin-bilirubin score (p = 0.0385), prothrombin time (p < 0.0001) and the natural logarithm of the ratio of post-operative day 1 to pre-operative serum bilirubin (SB) (ln( POD1 Bil/ pre-op Bil); p < 0.0001) were significantly independent predictors of PHLF. The PHLF prognostic nomogram was developed using these factors with receiver operating curve showing area under curve of 0.88. Excellent sensitivity (94.7%) and specificity (95.7%) for the prediction of PHLF (50-50 criteria) were achieved at cut-offs of 9 and 11 points on this model. This score was also predictive of PHLF according to Peak Bil > 7 and International Study Group for Liver Surgery criteria, intensive care unit admissions, length of stay, all complications, major complications, re-admissions and mortality (p < 0.05)., Conclusions: The PHLF nomogram ( https://tinyurl.com/SGH-PHLF-Risk-Calculator ) can serve as a useful tool for early identification of patients at high risk of PHLF before the 'point of no return'. This allows enforcement of closer monitoring, timely intervention and mitigation of adverse outcomes.

Background: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common primary liver cancers. With the increasing incidence of ICC over the past two decades in Asia, it is essential to differentiate between HCC and ICC. However, ICC may mimic the radiological appearance of HCC on computed tomography scans (CT) and magnetic resonance imaging (MRI), leading to misdiagnosis of ICC. The objective of this study is to evaluate and describe the association of specific pre-operative imaging characteristics (arterial enhancement, portal venous washout) in patients with histologically proven resected ICC in our centre., Methods: Data on patients with histology-proven ICC and mixed hepatocellular-cholangiocarcinomas (HCC-CC) who had undergone surgical resection at Singapore General Hospital (SGH) were identified from a prospectively maintained database. Pre-operative cross-sectional imaging reports were analysed., Results: Ninety-one patients underwent resection between 1 January 2000 and 31 December 2016. Among those with no risk factors for HCC, a significant percentage of patients with ICC (24.3%) show imaging characteristics of both arterial phase hyperenhancement and non-peripheral venous washout. Among patients with risk factors for HCC, between 20.0 and 33.3% of patients with pure ICC fulfilled the imaging criteria for HCC, and this proportion was generally even higher in the mixed HCC-CC group., Conclusions: A significant proportion of patients with pure ICC showed pre-operative imaging characteristics which fulfilled the diagnostic criteria for HCC. The differential of ICC should be borne in mind in populations where both malignancies are endemic.

Introduction: Although hepatectomy is the mainstay of curative therapy for hepatocellular carcinoma (HCC), post-operative complications remain high. Presently there is conflicting data on the impact of morbidity on oncologic outcomes. We sought to identify predictors for the occurrence of post-hepatectomy complications, as well as to analyse the impact on overall survival (OS) and recurrence-free survival (RFS)., Materials and Methods: We performed a retrospective review of 888 patients who underwent resection for HCC from 2001 to 2016 in our institution., Results: A total of 237 patients (26.7%) developed 254 complications of Clavien-Dindo Grade ≥2. Hepatitis B (p = 0.0397), elevated ASA score (p = 0.0002), higher platelet counts (p = 0.0277), raised pre-operative APRI scores (p = 0.0105) and bloodloss (p < 0.0001) were independently associated with the development of complications. After propensity-score matching, 458 patients were compared in a 1:1 ratio (229 with complications versus 229 without). Patients with complications had significantly longer median length of stay (9 days [IQR 7-15] versus 6 days [IQR 5-8], p < 0.0001), higher 90-day mortality rates as well as inferior OS (p = 0.0139), but there was no difference in RFS (p = 0.4577). Age (p = 0.0006), elevated Child Pugh points (p < 0.0001), microvascular invasion (p = 0.0002), multifocal tumours (p = 0.0002), R1 resection (p = 0.0443) and development of complications (p = 0.0091) were independent predictors of inferior OS., Conclusion: Post-operative morbidity affected both short-term and OS outcomes after hepatectomy for HCC. Hepatitis B, higher ASA scores, elevated preoperative APRI and increased blood loss were found to predict a higher likelihood of developing complications. This may potentially be mitigated by careful patient selection and adopting strict measures to minimise intraoperative bleeding., Competing Interests: Declaration of competing interest The authors confirm that this manuscript has not been published elsewhere previously, and has not been submitted for publication elsewhere.Dr Goh BK has received travel grants and honorarium from Transmedic the local distributor of the Da Vinci robotic platform, Johnson and Johnson, Medtronic and Baxter. The authors have no other conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Long non-coding RNAs (lncRNAs) are often aberrantly expressed in Hepatocellular Carcinoma (HCC). We hypothesize that lncRNAs modulate HCC prognoses through differential deregulation of key lncRNAs affecting important gene network in key cancer pathways associated with pertinent clinical phenotype. Here, we present a novel approach integrating lncRNA-mRNA expression profiles with clinical characteristics to identify lncRNA signatures in clinically-relevant co-expression lncRNA-mRNA networks residing in pertinent cancer pathways. Notably one network, associated with poorer prognosis, comprises five up-regulated lncRNAs significantly correlated (|Pearson Correlation Coefficient|≥ 0.9) with 91 up-regulated genes in the cell-cycle and Rho-GTPase pathways. All 5 lncRNAs and 85/91 (93.4%) of the correlated genes were significantly associated with higher tumor-grade while 3/5 lncRNAs were also associated with no tumor capsule. Interestingly, 2/5 lncRNAs that are correlated with numerous genes in this oncogenic network were experimentally shown to up-regulate genes involved in cell-cycle and transcriptional regulation. Another network comprising 4 down-regulated lncRNAs and 8 down-regulated metallothionein-family genes are significantly associated with tumor invasion. The identification of these key lncRNAs signatures that deregulate important network of genes in key cancer pathways associated with pertinent clinical phenotype may facilitate the design of novel therapeutic strategies targeting these 'master' regulators for better patient outcome.

Background: The evidence is conflicting regarding the effect of delays from the time of diagnosis to surgery on the survival in patients with hepatocellular carcinoma. We sought to investigate the impact of time to surgery on overall survival for patients who underwent curative resection for primary hepatocellular carcinoma., Methods: We performed a retrospective review of all patients who underwent liver resection for primary hepatocellular carcinoma between the years 2000 and 2015. Using 30-, 60-, and 90-day cutoffs, we investigated the effect of time to surgery on survival outcomes by dichotomizing the patients and using inverse probability of treatment weighting to ensure comparability. We also investigated time to surgery in prognostic subgroups by modeling the statistical interaction between time to surgery and the relevant prognostic variable in multivariable Cox models., Results: A total of 863 patients underwent liver resection for primary hepatocellular carcinoma during the study period. Using 30-, 60-, and 90-day cutoffs, time to surgery did not have a significant bearing on overall survival. For elderly patients (>70 years), patients with Child-Pugh B liver disease, American Society of Anesthesiologists status 2/3, tumor size >5cm, tumor size ≥10cm and presence of extrahepatic invasion, hazard ratio decreased and overall survival improved as time to surgery increased. However, for patients with liver cirrhosis or portal hypertension, increasing time to surgery was found to portend higher risks of death., Conclusion: Time to surgery does not have a significant bearing on overall survival, and modest delays even appear to be associated with improved survival in specific subsets of patients. The importance of these findings is that patients with hepatocellular carcinoma should be fully optimized before and not rushed to surgery because of concerns of tumor progression and a diminished survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background & Aims: Treatment allocation in patients with hepatocellular carcinoma (HCC) on a background of Child-Pugh B (CP-B) cirrhosis is controversial. Liver resection has been proposed in small series with acceptable outcomes, but data are limited. The aim of this study was to evaluate the outcomes of patients undergoing liver resection for HCC in CP-B cirrhosis, focusing on the surgical risks and survival., Methods: Patients were retrospectively pooled from 14 international referral centers from 2002 to 2017. Postoperative and oncological outcomes were investigated. Prediction models for surgical risks, disease-free survival and overall survival were constructed., Results: A total of 253 patients were included, of whom 57.3% of patients had a preoperative platelet count <100,000/mm 3 , 43.5% had preoperative ascites, and 56.9% had portal hypertension. A minor hepatectomy was most commonly performed (84.6%) and 122 (48.2%) were operated on by minimally invasive surgery (MIS). Ninety-day mortality was 4.3% with 6 patients (2.3%) dying from liver failure. One hundred and eight patients (42.7%) experienced complications, of which the most common was ascites (37.5%). Patients undergoing major hepatectomies had higher 90-day mortality (10.3% vs. 3.3%; p = 0.04) and morbidity rates (69.2% vs. 37.9%; p <0.001). Patients undergoing an open hepatectomy had higher morbidity (52.7% vs. 31.9%; p = 0.001) than those undergoing MIS. A prediction model for surgical risk was constructed (https://childb.shinyapps.io/morbidity/). The 5-year overall survival rate was 47%, and 56.9% of patients experienced recurrence. Prediction models for overall survival (https://childb.shinyapps.io/survival/) and disease-free survival (https://childb.shinyapps.io/DFsurvival/) were constructed., Conclusions: Liver resection should be considered for patients with HCC and CP-B cirrhosis after careful selection according to patient characteristics, tumor pattern and liver function, while aiming to minimize surgical stress. An estimation of the surgical risk and survival advantage may be helpful in treatment allocation, eventually improving postoperative morbidity and achieving safe oncological outcomes., Lay Summary: Liver resection for hepatocellular carcinoma in advanced cirrhosis (Child-Pugh B score) is associated with a high rate of postoperative complications. However, due to the limited therapeutic alternatives in this setting, recent studies have shown promising results after accurate patient selection. In our international multicenter study, we provide 3 clinical models to predict postoperative surgical risks and long-term survival following liver resection, with the aim of improving treatment allocation and eventually clinical outcomes., (Copyright © 2019. Published by Elsevier B.V.)

Background: Nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is on the rise worldwide, but data on long-term outcomes after curative operations are limited. The primary aim of this study was to characterize the perioperative and long-term outcomes after liver resection. The secondary aim was to investigate the influence of the histologic severity of nonalcoholic steatohepatitis and its impact on perioperative outcomes and long-term survival., Methods: A total of 996 patients who underwent liver resection for HCC in our institution were analyzed. Patients were categorized into subgroups of NAFLD vs non-NAFLD HCC based on histologic evidence of hepatic steatosis. Comparisons of patients' demographic, clinical, and surgical characteristics; postoperative complications; and survival outcomes were performed., Results: Eight hundred and forty-four patients had non-NAFLD HCC and 152 patients had NAFLD HCC. Comorbidities were significantly more common in the NAFLD group (p < 0.0001). In the non-NAFLD group, larger median tumor size, higher liver cirrhosis, and lower median neutrophil to lymphocyte ratio were observed (p < 0.0001). The NAFLD group had a greater amount of intraoperative blood loss, more postoperative complications, and longer length of stay. Five-year overall survival was significantly better in the NAFLD group (p = 0.0355). Significant factors that contribute to poorer survival outcomes include age, congestive cardiac failure, Child-Pugh's class B, cirrhosis, tumor size, multinodularity, and R1 resection. For NAFLD group, patients with abnormal parenchyma showed poorer survival and 5-year overall survival rates (64.8% vs 75.6%; p = 0.2291)., Conclusions: Nonalcoholic fatty liver disease-related HCC is associated with greater surgical morbidity and post-hepatectomy liver failure. Despite this, long-term survival outcomes are favorable compared with non-NAFLD etiologies., (Copyright © 2019 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)