Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma.

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-1loTOXlo, 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.

A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures.

Depending on the tissue microenvironment, T cells can differentiate into highly diverse subsets expressing unique trafficking receptors and cytokines. Studies of human lymphocytes have primarily focused on a limited number of parameters in blood, representing an incomplete view of the human immune system. Here, we have utilized mass cytometry to simultaneously analyze T cell trafficking and functional markers across eight different human tissues, including blood, lymphoid, and non-lymphoid tissues. These data have revealed that combinatorial expression of trafficking receptors and cytokines better defines tissue specificity. Notably, we identified numerous T helper cell subsets with overlapping cytokine expression, but only specific cytokine combinations are secreted regardless of tissue type. This indicates that T cell lineages defined in mouse models cannot be clearly distinguished in humans. Overall, our data uncover a plethora of tissue immune signatures and provide a systemic map of how T cell phenotypes are altered throughout the human body.

Defining Global Benchmarks for Laparoscopic Liver Resections: An International Multicenter Study.

OBJECTIVE: To establish global benchmark outcomes indicators after laparoscopic liver resections (L-LR). BACKGROUND: There is limited published data to date on the best achievable outcomes after L-LR. METHODS: This is a post hoc analysis of a multicenter database of 11,983 patients undergoing L-LR in 45 international centers in 4 continents between 2015 and 2020. Three specific procedures: left lateral sectionectomy (LLS), left hepatectomy (LH), and right hepatectomy (RH) were selected to represent the 3 difficulty levels of L-LR. Fifteen outcome indicators were selected to establish benchmark cutoffs. RESULTS: There were 3519 L-LR (LLS, LH, RH) of which 1258 L-LR (40.6%) cases performed in 34 benchmark expert centers qualified as low-risk benchmark cases. These included 659 LLS (52.4%), 306 LH (24.3%), and 293 RH (23.3%). The benchmark outcomes established for operation time, open conversion rate, blood loss ≥500 mL, blood transfusion rate, postoperative morbidity, major morbidity, and 90-day mortality after LLS, LH, and RH were 209.5, 302, and 426 minutes; 2.1%, 13.4%, and 13.0%; 3.2%, 20%, and 47.1%; 0%, 7.1%, and 10.5%; 11.1%, 20%, and 50%; 0%, 7.1%, and 20%; and 0%, 0%, and 0%, respectively. CONCLUSIONS: This study established the first global benchmark outcomes for L-LR in a large-scale international patient cohort. It provides an up-to-date reference regarding the "best achievable" results for L-LR for which centers adopting L-LR can use as a comparison to enable an objective assessment of performance gaps and learning curves.

Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC.

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-DRlo ) 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 Bhi PD-1lo 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-DRlo 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.

Multi-region sampling with paired sample sequencing analyses reveals sub-groups of patients with novel patient-specific dysregulation in Hepatocellular Carcinoma.

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.

Intraoperative blood transfusion does not impact overall and recurrence-free survival after curative hepatectomy for hepatocellular carcinoma: A propensity-score-matched and inverse probability of treatment-weighted study.

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.

Association of standardized liver volume and body mass index with outcomes of minimally invasive liver resections.

INTRODUCTION: While minimally invasive liver resections (MILR) have demonstrated advantages in improved post-operative recovery, widespread adoption is hampered by inherent technical difficulties. Our study attempts to analyze the role of anthropometric measures in MILR-related outcomes. METHODS: Between 2012 and 2020, 676 consecutive patients underwent MILR at the Singapore General Hospital of which 565 met study criteria and were included. Patients were stratified based on Body Mass Index (BMI) as well as Standardized Liver Volumes (SLV). Associations between BMI and SLV to selected peri-operative outcomes were analyzed using restricted cubic splines. RESULTS: A BMI of ≥ 29 was associated with increase in blood loss [Mean difference (MD) 69 mls, 95% CI 2 to 137] as well as operative conversions [Relative Risk (RR) 1.63, 95% CI 1.02 to 2.62] among patients undergoing MILR while a SLV of 1600 cc or higher was associated with an increase in blood loss (MD 30 mls, 95% CI 10 to 49). In addition, a BMI of ≤ 20 was associated with an increased risk of major complications (RR 2.25, 95% 1.16 to 4.35). The magnitude of differences observed in these findings increased with each unit change in BMI and SLV. CONCLUSION: Both BMI and SLV were useful anthropometric measures in predicting peri-operative outcomes in MILR and may be considered for incorporation in future difficulty scoring systems for MILR.

Limited liver resections in the posterosuperior segments: international multicentre propensity score-matched and coarsened exact-matched analysis comparing the laparoscopic and robotic approaches.

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.

Impact of non-liver-related previous abdominal surgery on the difficulty of minimally invasive liver resections: a propensity score-matched controlled study.

INTRODUCTION: The presence of previous abdominal surgery (PAS) has traditionally been considered to add difficulty to and increase risk of complications of laparoscopic procedures. This study aims to analyse the impact of non-liver-related PAS on the difficulty of minimally invasive liver resections (MILRs). MATERIALS AND METHODS: After exclusion of patients with concomitant major surgical procedures as well as previous liver resections, 515 consecutive patients undergoing MILR in Singapore General Hospital from 2006 to 2019 were analysed, consisting of 161 MILR in patients with previous abdominal surgery (WPAS) and 354 MILR in patients without previous abdominal surgery (WOPAS). Propensity score-matched (PSM) comparison was performed between WPAS and WOPAS groups. In addition, subgroup analysis was made comparing previous upper or lower abdominal surgery and open versus minimally invasive approach of PAS. Outcomes measured include those associated with operative difficulty such as open conversion rates, operative time, blood loss, as well as morbidity and mortality rates. RESULTS: MILR outcomes in patients WPAS are not inferior to those WOPAS. Overall open conversion rate was 8.2%, higher in patients WOPAS compared to patients WPAS (11.9% versus 3.5%, p = 0.015). Operating time (p = 0.942), blood loss (p = 0.063), intraoperative blood transfusion (p = 0.750), length of hospital stay (p = 0.206), morbidity (p = 0.217) and 30- and 90-day mortality (p = 1 & p = 0.367) were comparable between the two groups and subgroup analysis. CONCLUSION: Outcomes of MILR in patients with previous non-liver-related abdominal surgery are not inferior to patients without previous abdominal surgery.

Propensity-Score Matched Analyses Comparing Clinical Outcomes of Minimally Invasive Versus Open Distal Pancreatectomies: A Single-Center Experience.

BACKGROUND: Minimally invasive distal pancreatectomy (MIDP) is being adopted increasingly worldwide. This study aimed to compare the short-term outcomes of patients who underwent MIDP versus open distal pancreatectomy (ODP). METHODS: A retrospective review of all patients who underwent a DP in our institution between 2005 and 2019 was performed. Propensity score matching based on relevant baseline factors was used to match patients in the ODP and MIDP groups in a 1:1 manner. Outcomes reported include operative duration, blood loss, postoperative length of stay, morbidity, mortality, postoperative pancreatic fistula rates, reoperation and readmission. RESULTS: In total, 444 patients were included in this study. Of 122 MIDP patients, 112 (91.8%) could be matched. After matching, the median operating time for MIDP was significantly longer than ODP [260 min (200-346.3) vs 180 (135-232.5), p < 0.001], while postoperative stay for MIDP was significantly shorter [median 6 days (5-8) versus 7 days (6-9), p = 0.015]. There were no significant differences noted in any of the other outcomes measured. Over time, we observed a decrease in the operation times of MIDP performed at our institution. CONCLUSION: Adoption of MIDP offers advantages over ODP in terms of a shorter postoperative hospital stay, without an increase in morbidity and/or mortality but at the expense of a longer operation time.

Short- and long-term outcomes after minimally invasive versus open spleen-saving distal pancreatectomies.

INTRODUCTION: This study aimed to compare the perioperative outcomes of patients who underwent minimally invasive spleen-preserving distal pancreatectomy (MI-SPDP) versus open surgery SPDP (O-SPDP). It also aimed to determine the long-term vascular patency after spleen-saving vessel-preserving distal pancreatectomies (SSVDPs). METHODS: A retrospective review of 74 patients who underwent successful SPDP and met the study criteria was performed. Of these, 67 (90.5%) patients underwent SSVDP, of which 38 patients (21 open, 17 MIS) had adequate long-term post-operative follow-up imaging to determine vascular patency. RESULTS: Fifty-one patients underwent open SPDP, whereas 23 patients underwent minimally invasive SPDP, out of which 10 (43.5%) were laparoscopic and 13 (56.5%) were robotic. Patients who underwent MI-SPDP had significantly longer operative time (307.5 vs. 162.5 min, P = 0.001) but shorter hospital stay (5 vs. 7 days, P = 0.021) and lower median blood loss (100 vs. 200 cc, P = 0.046) compared to that of O-SPDP. Minimally-invasive spleen-saving vessel-preserving distal pancreatectomy (MI-SSVDP) was associated with poorer long-term splenic vein patency rates compared to O-SSVDP (P = 0.048). This was particularly with respect to partial occlusion of the splenic vein, and there was no significant difference between the complete splenic vein occlusion rates between the MIS group and open group (29.4% vs. 28.6%, P = 0.954). The operative time was statistically significantly longer in patients who underwent robotic surgery versus laparoscopic surgery (330 vs. 173 min, P = 0.008). CONCLUSION: Adoption of MI-spleen-preserving distal pancreatectomy (SPDP) is safe and feasible. MI-SPDP is associated with a shorter hospital stay, lower blood loss but longer operation time compared to O-SPDP. In the present study, MI-SSVDP was associated with poorer long-term splenic vein patency rates compared to O-SSVDP.

Repeat hepatectomy versus radiofrequency ablation in management of recurrent hepatocellular carcinoma: an average treatment effect analysis.

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.

International multicentre propensity score-matched analysis comparing robotic versus laparoscopic right posterior sectionectomy.

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

Comparison between short and long-term outcomes after minimally invasive versus open primary liver resections for hepatocellular carcinoma: A 1:1 matched analysis.

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.

Actual 10-year survivors and 10-year recurrence free survivors after primary liver resection for hepatocellular carcinoma in the 21st century: A single institution contemporary experience.

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.

Impact of liver cirrhosis on the difficulty of minimally-invasive liver resections: a 1:1 coarsened exact-matched controlled study.

INTRODUCTION: The impact of liver cirrhosis on the difficulty of minimal invasive liver resection (MILR) remains controversial and current difficulty scoring systems do not take in to account the presence of cirrhosis as a significant factor in determining the difficulty of MILR. We hypothesized that the difficulty of MILR is affected by the presence of cirrhosis. Hence, we performed a 1:1 matched-controlled study comparing the outcomes between patients undergoing MILR with and without cirrhosis including the Iwate system and Institut Mutualiste Montsouris (IMM) system in the matching process. METHODS: Between 2006 and 2019, 598 consecutive patients underwent MILR of which 536 met the study inclusion criteria. There were 148 patients with cirrhosis and 388 non-cirrhotics. One-to-one coarsened exact matching identified approximately exact matches between 100 cirrhotic patients and 100 non-cirrhotic patients. RESULTS: Comparison between MILR patients with cirrhosis and non-cirrhosis in the entire cohort demonstrated that patients with cirrhosis were associated with a significantly increased open conversion rate, transfusion rate, need for Pringles maneuver, postoperative, stay, postoperative morbidity and postoperative 90-day mortality. After 1:1 coarsened exact matching, MILR with cirrhosis were significantly associated with an increased open conversion rate (15% vs 6%, p = 0.03), operation time (261 vs 238 min, p < 0.001), blood loss (607 vs 314 mls, p = 0.002), transfusion rate (22% vs 9%, p = 0.001), need for application of Pringles maneuver (51% vs 34%, p = 0.010), postoperative stay (6 vs 4.5 days, p = 0.004) and postoperative morbidity (26% vs 13%, p = 0.029). CONCLUSION: The presence of liver cirrhosis affected both the intraoperative technical difficulty and postoperative outcomes of MILR and hence should be considered an important parameter to be included in future difficulty scoring systems for MILR.

Preoperative Predictors of Futile Resection of Intraabdominal Extrahepatic Metastases from Hepatocellular Carcinoma.

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.

Validation and comparison of the Iwate, IMM, Southampton and Hasegawa difficulty scoring systems for primary laparoscopic hepatectomies.

BACKGROUND: Various difficulty scoring systems (DSS) have been formulated to grade the complexity of laparoscopic hepatectomies (LH). This study aims to externally validate and compare 4 contemporary DSS including the Iwate, Institut Mutualiste Montsouris (IMM), Southampton and Hasegawa DSS in predicting the intraoperative technical difficulty and postoperative outcomes after LH. METHODS: Retrospective review of 548 consecutive patients who underwent LH of which 455 met the study inclusion criteria. Outcomes measures of technical difficulty included operation time, Pringles maneuver, blood loss and blood transfusion rate. Postoperative outcomes measured included morbidity, major morbidity and postoperative hospital stay. RESULTS: There was a statistically significant progressive increase in blood loss, blood transfusion rate, operation time and postoperative stay associated with all 4 DSS. There was also good calibration with respect to blood loss, operation time, Pringles maneuver, open conversion rate, postoperative morbidity, postoperative major morbidity and postoperative stay for all 4 DSS. The Southampton score demonstrated the poorest calibration in terms of operation time and discrimination in terms of application of Pringles maneuver and major morbidity amongst all 4 systems. CONCLUSION: All 4 DSS significantly correlated with outcome measures associated with intraoperative technical difficulty and postoperative outcomes. The Southampton DSS was the poorest system in our cohort of patients.

Outcome of minimally invasive liver resection for extrapancreatic biliary malignancies: A single-institutional experience.

BACKGROUND: Minimally invasive liver resection (MILR) has been increasingly adopted over the past decade, and its application has been expanded to the management of extrapancreatic biliary malignancies (EPBMs). We aimed to evaluate the peri- and post-operative outcome of patients undergoing MILR for suspected EPMB. METHODS: Forty-four consecutive patients who underwent MILR with a curative intent for EPBM at Singapore General Hospital between 2011 and 2018 were identified from a prospectively maintained surgical database. Clinical and operative data were analysed and compared to provide information and make comparisons on peri- and post-operative outcomes. RESULTS: A total of 26, 5 and 13 patients underwent MILR for intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PHC) and gallbladder carcinoma (GBCA), respectively. Six major hepatectomies were performed, of which one was laparoscopic assisted and another was robot assisted. Ten patients underwent posterosuperior segmentectomies. There was one open conversion. The mean operative time was 266.5 min, and the mean blood loss was 379 ml. The mean length of hospital stay was 4.7 days with no incidences of 30- and 90-day mortality. The rate of recurrence-free survival (RFS) was 75% (at least 12-month follow-up). There was a significantly higher rate of robot-assisted procedures in patients undergoing MILR for GBCA/PHC as compared to ICC (P = 0.034). Patients undergoing posterosuperior segmentectomies required longer operative time (P = 0.018) with an increased need for (P = 0.001) and duration of (P = 0.025) Pringles manoeuvre. There were no differences in operative time, blood loss, morbidity, mortality or RFS between the above groups. CONCLUSION: Minimally invasive surgery can be adopted safely with a low open conversion rate for EPBMs.

Development of a nomogram to predict outcome after liver resection for hepatocellular carcinoma in Child-Pugh B cirrhosis.

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/mm3, 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.