Search

Background: We sought to elucidate the impact of postoperative complications on patient outcomes relative to differences in alpha-fetoprotein-tumor burden score (ATS) among patients with hepatocellular carcinoma (HCC)., Methods: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. Moderate/severe complications were defined using the optimal cut-off value of the comprehensive complication index (CCI) based on the log-rank test., Results: A total of 1124 patients was included. CCI cut-off value of 16.6 was identified as the optimal prognostic threshold. Patients who experienced moderate/severe complications were more likely to have worse recurrence free survival [RFS] versus individuals who had no/mild complications (2-year RFS; no/mild complication: 55.9% vs. moderate/severe complication: 38.1% p < 0.001). Of note, low and medium ATS patients who experienced moderate/severe complications had a higher risk of recurrence (2-year RFS; no/mild complication: postoperative complications 70.0% vs. moderate/severe complication: 51.1%, p = 0.006; medium: no/mild complication: 50.8% vs moderate/severe complication: 56.7%, p = 0.01); however, postoperative complications were not associated with worse outcomes among patients with high ATS (no/mild complication: 39.1% vs. moderate/severe complication: 29.2%, p = 0.20)., Conclusion: These data serve to emphasize how reduction in postoperative complications may be crucial to improve prognosis, particularly among patients with favorable HCC characteristics., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: We sought to develop Artificial Intelligence (AI) based models to predict non-transplantable recurrence (NTR) of hepatocellular carcinoma (HCC) following hepatic resection (HR)., Methods: HCC patients who underwent HR between 2000-2020 were identified from a multi-institutional database. NTR was defined as recurrence beyond Milan Criteria. Different machine learning (ML) and deep learning (DL) techniques were used to develop and validate two prediction models for NTR, one using only preoperative factors and a second using both preoperative and postoperative factors., Results: Overall, 1763 HCC patients were included. Among 877 patients with recurrence, 364 (41.5%) patients developed NTR. An ensemble AI model demonstrated the highest area under ROC curves (AUC) of 0.751 (95% CI: 0.719-0.782) and 0.717 (95% CI:0.653-0.782) in the training and testing cohorts, respectively which improved to 0.858 (95% CI: 0.835-0.884) and 0.764 (95% CI: 0.704-0.826), respectively after incorporation of postoperative pathologic factors. Radiologic tumor burden score and pathological microvascular invasion were the most important preoperative and postoperative factors, respectively to predict NTR. Patients predicted to develop NTR had overall 1- and 5-year survival of 75.6% and 28.2%, versus 93.4% and 55.9%, respectively, among patients predicted to not develop NTR (p < 0.0001)., Conclusion: The AI preoperative model may help inform decision of HR versus LT for HCC, while the combined AI model can frame individualized postoperative care (https://altaf-pawlik-hcc-ntr-calculator.streamlit.app/)., Competing Interests: Conflicts of 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 © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The efficacy of immune checkpoint inhibitors (ICIs) combined with tyrosine kinase inhibitors (TKIs), trans-arterial chemoembolization (TACE), and radiotherapy to treat hepatocellular carcinoma (HCC) has not been well-defined. We performed a meta-analysis to characterize tumor response and survival associated with multimodal treatment of HCC., Methods: PubMed, Embase, Medline, Scopus, and CINAHL databases were searched (1990-2022). Random-effect meta-analysis was conducted to compare efficacy of treatment modalities. Odds ratios (OR) and standardized mean difference (SMD) were reported., Results: Thirty studies (4170 patients) met inclusion criteria. Triple therapy regimen (ICI + TKI + TACE) had the highest overall disease control rate (DCR) (87%, 95% CI 83-91), while ICI + radiotherapy had the highest objective response rate (ORR) (72%, 95% CI 54%-89%). Triple therapy had a higher DCR than ICI + TACE (OR 4.49, 95% CI 2.09-9.63), ICI + TKI (OR 3.08, 95% CI 1.63-5.82), and TKI + TACE (OR 2.90, 95% CI 1.61-5.20). Triple therapy demonstrated improved overall survival versus ICI + TKI (SMD 0.72, 95% CI 0.37-1.07) and TKI + TACE (SMD 1.13, 95% CI 0.70-1.48) (both p < 0.05). Triple therapy had a greater incidence of adverse events (AEs) compared with ICI + TKI (OR 0.59, 95% CI 0.29-0.91; p = 0.02), but no difference in AEs versus ICI + TACE or TKI + TACE (both p > 0.05)., Conclusion: The combination of ICIs, TKIs and TACE demonstrated superior tumor response and survival and should be considered for select patients with advanced HCC., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: Immune dysregulation may be associated with cancer progression. We sought to investigate the prognostic value of perioperative lymphopenia on short- and long-term outcomes among patients undergoing resection of hepatocellular carcinoma (HCC)., Methods: Patients undergoing resection of HCC between 2000 and 2020 were identified using an international database. The incidence and impact of perioperative lymphopenia [preoperative, postoperative day (POD) 1/3/5], defined as absolute lymphocyte count (ALC) <1000/μL, on short- and long-term outcomes was assessed., Results: Among 1448 patients, median preoperative ALC was 1593/μL [interquartile range (IQR) 1208-2006]. The incidence of preoperative lymphopenia was 14.0%, and 50.2%, 45.1% and 35.6% on POD1, POD3 and POD5, respectively. Preoperative lymphopenia predicted 5-year overall survival (OS) [lymphopenia vs. no lymphopenia: 49.1% vs. 66.1%] and 5-year disease-free survival (DFS) [25.0% vs. 41.5%] (both p < 0.05). Lymphopenia on POD1 (5-year OS: 57.1% vs. 71.2%; 5-year DFS: 30.0% vs. 41.1%), POD3 (5-year OS: 57.3% vs. 68.9%; 5-year DFS: 35.4% vs. 42.7%), and POD5 (5-year OS: 53.1% vs. 66.1%; 5-year DFS: 32.8% vs. 42.3%) was associated with worse long-term outcomes (all p < 0.05). Patients with severe lymphopenia (ALC <500/μL) on POD5 had worse 5-year OS and DFS (5-year OS: 44.7% vs. 54.3% vs. 66.1%; 5-year DFS: 27.8% vs. 33.3% vs. 42.3%) [both p < 0.05], as well as higher incidence of overall (45.5% vs. 25.3% vs. 30.9%; p = 0.013) and major complications (18.2% vs. 3.4% vs. 4.5%; p < 0.001) versus individuals with moderate (ALC 500-1000/μL) or no lymphopenia following hepatectomy for HCC. After adjusting for competing risk factors, prolonged lymphopenia was independently associated with higher hazards of death [hazard ratio (HR) 1.38, 95% CI 1.11-1.72] and recurrence (HR 1.22, 95% CI 1.02-1.45)., Conclusion: Perioperative lymphopenia had short- and long-term prognostic implications among individuals undergoing hepatectomy for HCC., (© 2024. Society of Surgical Oncology.)

Background: The aMAP score is a proposed model to predict the development of hepatocellular carcinoma (HCC) among high-risk patients with chronic hepatitis. The role of the aMAP score to predict long-term survival among patients following resection of HCC has not been determined., Methods: Patients undergoing resection for HCC between 2000 and 2020 were identified using a multi-institutional database. The impact of the aMAP score on long-term outcomes following HCC resection was assessed., Results: Among 1377 patients undergoing resection for HCC, a total of 972 (70.6 %) patients had a low aMAP score (≤63), whereas 405 (29.4 %) individuals had a high aMAP score (≥64). aMAP score was associated with 5-year OS in the entire cohort (low vs high aMAP score:66.5 % vs. 54.3 %, p < 0.001). aMAP score predicted 5-year OS following resection among patients with HBV-HCC (low vs. high aMAP:68.8 % vs. 55.6 %, p = 0.01) and NASH/other-HCC (64.7 % vs. 53.7, p = 0.04). aMAP score could sub-stratify 5-year OS among patients undergoing HCC resection within (low vs. high aMAP:81.5 % vs. 67.4 %, p < 0.001) and beyond (55.9 % vs. 38.8 %, p < 0.001) Milan criteria., Discussion: The aMAP score predicted postoperative outcomes following resection of HCC within and beyond Milan criteria. Apart from a surveillance tool, the aMAP score can also be used as a prognostic tool among patients undergoing resection of HCC., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: We sought to investigate whether minimally invasive hepatectomy (MIH) was superior to open hepatectomy (OH) in terms of achieving textbook outcome in liver surgery (TOLS) after resection of hepatocellular carcinoma (HCC)., Methods: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. TOLS was defined by the absence of intraoperative grade ≥2 events, R1 resection margin, posthepatectomy liver failure, bile leakage, major complications, in-hospital mortality, and readmission., Results: A total of 1039 patients who underwent HCC resection were included in the analysis. Although most patients underwent OH (n = 724 [69.7%]), 30.3% (n = 315) underwent MIH. Patients who underwent MIH had a lower tumor burden score (3.6 [IQR, 2.6-5.2] for MIH vs 6.1 [IQR, 3.9-10.1] for OH) and were more likely to undergo minor hepatectomy (84.1% [MIH] vs 53.6% [OH]) than patients who had an OH (both P < .001). After propensity score matching to control for baseline differences between the 2 cohorts, the incidence of TOLS was comparable among patients who had undergone MIH (56.6%) versus OH (64.8%) (P = .06). However, MIH was associated with a shorter length of hospital stay (6.0 days [IQR, 4.0-8.0] for MIH vs 9.0 days [IQR, 6.0-12.0] for OH). Among patients who had MIH, the odds ratio of achieving TOLS remained stable up to a tumor burden score of 4; after which the chance of TOLS with MIH markedly decreased., Conclusion: Patients with HCC who underwent resection with MIH versus OH had a comparable likelihood of TOLS, although MIH was associated with a short length of stay., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Background: Medicaid expansion (ME) has contributed to transforming the United States healthcare system. However, its effect on palliative care of primary liver cancers remains unknown. This study aimed to evaluate the association between ME and the receipt of palliative treatment in advanced-stage liver cancer., Methods: Patients diagnosed with stage IV hepatocellular carcinoma or intrahepatic cholangiocarcinoma were identified from the National Cancer Database and divided into pre-expansion (2010-2013) and postexpansion (2015-2019) cohorts. Logistic regression identified predictors of palliative treatment. Difference-in-difference (DID) analysis assessed changes in palliative care use between patients living in ME states and patients living in non-ME states., Results: Among 12,516 patients, 4582 (36.6%) were diagnosed before expansion, and 7934 (63.6%) were diagnosed after expansion. Overall, rates of palliative treatment increased after ME (18.1% [pre-expansion] vs 22.3% [postexpansion]; P < .001) and are more pronounced among ME states. Before expansion, only cancer type and education attainment were associated with the receipt of palliative treatment. Conversely, after expansion, race, insurance, location, cancer type, and ME status (odds ratio [OR], 1.23; 95% CI, 1.06-1.44; P = .018) were all associated with palliative care. Interestingly, the odds were higher if treatment involved receipt of pain management (OR, 2.05; 95% CI, 1.23-2.43; P = .006). Adjusted DID analysis confirmed increased rates of palliative treatment among patients living in ME states relative to non-ME states (DID, 4.4%; 95% CI, 1.2-7.7; P = .008); however, racial disparities persist (White, 5.6; 95% CI, 1.4-9.8; P = .009; minority, 2.6; 95% CI, -2.5 to 7.6; P = .333)., Conclusion: The implementation of ME contributed to increased rates of palliative treatment for patients residing in ME states after expansion. However, racial disparities persist even after ME, resulting in inequitable access to palliative care., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Background: Case volume has been associated with improved outcomes for patients undergoing treatment for hepatocellular carcinoma, often with higher hospital expenditures. We sought to define the cost-effectiveness of hepatocellular carcinoma treatment at high-volume centers., Methods: Patients diagnosed with hepatocellular carcinoma from 2013 to 2017 were identified from Medicare Standard Analytic Files. High-volume centers were defined as the top decile of facilities performing hepatectomies in a year. A multivariable generalized linear model with gamma distribution and a restricted mean survival time model were used to estimate costs and survival differences relative to high-volume center status. The incremental cost-effectiveness ratio was used to define the additional cost incurred for a 1-year incremental gain in survival., Results: Among 13,666 patients, 8,467 (62.0%) were treated at high-volume centers. Median expenditure was higher ($19,148, interquartile range $15,280-$29,128) among patients treated at high-volume centers versus low-volume centers ($18,209, interquartile range $14,959-$29,752). Despite similar median length-of-stay (6 days, interquartile range 4-9), a slightly higher proportion of patients were discharged to home from high-volume centers (n = 4,903, 57.9%) versus low-volume centers (n = 2,868, 55.2%) (P = .002). A 0.14-year (95% confidence interval 0.06-0.22) (1 month and 3 weeks) survival benefit was associated with an incremental cost of $1,070 (95% confidence interval $749-$1,392) among patients undergoing surgery at high-volume centers. The incremental cost-effectiveness ratio for treatment at a high-volume center was $7,951 (95% confidence interval $4,236-$21,217) for an additional year of survival, which was below the cost-effective threshold of $21,217., Conclusion: Surgical care at high-volume centers offers the potential to deliver cancer care in a more cost-effective and value-based manner., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Although systemic postoperative therapy after surgery for colorectal liver metastases is generally recommended, the benefit of adjuvant chemotherapy has been debated. We used machine learning to develop a decision tree and define which patients may benefit from adjuvant chemotherapy after hepatectomy for colorectal liver metastases., Methods: Patients who underwent curative-intent resection for colorectal liver metastases between 2000 and 2020 were identified from an international multi-institutional database. An optimal policy tree analysis was used to determine the optimal assignment of the adjuvant chemotherapy to subgroups of patients for overall survival and recurrence-free survival., Results: Among 1,358 patients who underwent curative-intent resection of colorectal liver metastases, 1,032 (76.0%) received adjuvant chemotherapy. After a median follow-up of 28.7 months (interquartile range 13.7-52.0), 5-year overall survival was 67.5%, and 3-year recurrence-free survival was 52.6%, respectively. Adjuvant chemotherapy was associated with better recurrence-free survival (3-year recurrence-free survival: adjuvant chemotherapy, 54.4% vs no adjuvant chemotherapy, 46.8%; P < .001) but no overall survival significant improvement (5-year overall survival: adjuvant chemotherapy, 68.1% vs no adjuvant chemotherapy, 65.7%; P = .15). Patients were randomly allocated into 2 cohorts (training data set, n = 679, testing data set, n = 679). The random forest model demonstrated good performance in predicting counterfactual probabilities of death and recurrence relative to receipt of adjuvant chemotherapy. According to the optimal policy tree, patient demographics, secondary tumor characteristics, and primary tumor characteristics defined the subpopulation that would benefit from adjuvant chemotherapy., Conclusion: A novel artificial intelligence methodology based on patient, primary tumor, and treatment characteristics may help clinicians tailor adjuvant chemotherapy recommendations after colorectal liver metastases resection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: We sought to develop and validate a preoperative model to predict survival after recurrence (SAR) in hepatocellular carcinoma (HCC)., Background: Although HCC is characterized by recurrence as high as 60%, models to predict outcomes after recurrence remain relatively unexplored., Methods: Patients who developed recurrent HCC between 2000 and 2020 were identified from an international multi-institutional database. Clinicopathologic data on primary disease and laboratory and radiologic imaging data on recurrent disease were collected. Multivariable Cox regression analysis and internal bootstrap validation (5000 repetitions) were used to develop and validate the SARScore. Optimal Survival Tree analysis was used to characterize SAR among patients treated with various treatment modalities., Results: Among 497 patients who developed recurrent HCC, median SAR was 41.2 months (95% CI 38.1-52.0). The presence of cirrhosis, number of primary tumors, primary macrovascular invasion, primary R1 resection margin, AFP>400 ng/mL on the diagnosis of recurrent disease, radiologic extrahepatic recurrence, radiologic size and number of recurrent lesions, radiologic recurrent bilobar disease, and early recurrence (≤24 months) were included in the model. The SARScore successfully stratified 1-, 3- and 5-year SAR and demonstrated strong discriminatory ability (3-year AUC: 0.75, 95% CI 0.70-0.79). While a subset of patients benefitted from resection/ablation, Optimal Survival Tree analysis revealed that patients with high SARScore disease had the worst outcomes (5-year AUC; training: 0.79 vs. testing: 0.71). The SARScore model was made available online for ease of use and clinical applicability ( https://yutaka-endo.shinyapps.io/SARScore/ )., Conclusion: The SARScore demonstrated strong discriminatory ability and may be a clinically useful tool to help stratify risk and guide treatment for patients with recurrent HCC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This study aimed to develop a tool based on preoperative factors to predict the risk of perioperative complications based on the Comprehensive Complication Index (CCI) and long-term survival outcomes after liver resection for primary liver cancer., Methods: Patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) undergoing curative-intent hepatectomy between 1990 and 2020 were identified using a multi-institutional international database., Results: Among 1411 patients who underwent curative-intent hepatic resection (HCC: 997, 70.7%; ICC: 414, 29.3%), median patient age was 66.0 years (IQR, 57.0-73.0), and most patients were male (n = 1001, 70.9%). In the postoperative setting, 699 patients (49.5%) experienced a complication; moreover, 112 patients (7.9%) had major complications. Although most patients had a favorable risk complication-overall survival (CompOS) profile (CCI score > 40 risk of <30% and median survival of >5 years: n = 778, 55.1%), 553 patients (39.2%) had an intermediate-risk profile, and 80 patients (5.7%) had a very unfavorable risk profile (CCI score > 40 risk of ≥30% and/or median survival of ≤1.5 years). The areas under the curve of the test and validation cohorts were 0.73 and 0.76, respectively., Conclusion: The CompOS risk model accurately stratified patients relative to short- and long-term risks, identifying a subset of patients at a high risk of major complications and poor overall survival., (Copyright © 2023 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Background: We sought to characterize the risk of postoperative complications relative to the surgical approach and overall synchronous colorectal liver metastases tumor burden score., Methods: Patients with synchronous colorectal liver metastases who underwent curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. Propensity score matching was employed to control for heterogeneity between the 2 groups. A virtual twins analysis was performed to identify potential subgroups of patients who might benefit more from staged versus simultaneous resection., Results: Among 976 patients who underwent liver resection for synchronous colorectal liver metastases, 589 patients (60.3%) had a staged approach, whereas 387 (39.7%) patients underwent simultaneous resection of the primary tumor and synchronous colorectal liver metastases. After propensity score matching, 295 patients who underwent each surgical approach were analyzed. Overall, the incidence of postoperative complications was 34.1% (n = 201). Among patients with high tumor burden scores, the surgical approach was associated with a higher incidence of postoperative complications; in contrast, among patients with low or medium tumor burden scores, the likelihood of complications did not differ based on the surgical approach. Virtual twins analysis demonstrated that preoperative tumor burden score was important to identify which subgroup of patients benefited most from staged versus simultaneous resection. Simultaneous resection was associated with better outcomes among patients with a tumor burden score <9 and a node-negative right-sided primary tumor; in contrast, staged resection was associated with better outcomes among patients with node-positive left-sided primary tumors and higher tumor burden score., Conclusion: Among patients with high tumor burden scores, simultaneous resection of the primary tumor and liver metastases was associated with an increased incidence of postoperative complications., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: A preoperative predictive score for hepatocellular carcinoma (HCC) can help stratify patients who undergo resection relative to long-term outcomes and tailor treatment strategies., Methods: Patients who underwent curative-intent hepatectomy for HCC between 2000 and 2020 were identified from an international multi-institutional database. A risk score (mFIBA) was developed using an Eastern cohort and then validated using a Western cohort., Results: Among 957 patients, 443 and 514 patients were included from the Eastern and Western cohorts, respectively. On multivariable analysis, alpha-feto protein (HR1.97, 95%CI 1.42-2.72), neutrophil-to-lymphocyte ratio (HR1.74, 95%CI 1.28-2.38), albumin-bilirubin grade (HR1.66, 95%CI 1.21-2.28), and imaging tumor burden score (HR1.25, 95%CI 1.12-1.40) were associated with OS. The c-index in the Eastern test and Western validation cohorts were 0.69 and 0.67, respectively. Notably, mFIBA score outperformed previous HCC staging systems. 5-year OS incrementally decreased with an increase in mFIBA. On multivariable Cox regression analysis, the mFIBA score was associated with worse OS (HR1.18, 95%CI 1.13-1.23) and higher risk of recurrence (HR1.16, 95%CI 1.11-1.20). An easy-to-use calculator of the mFIBA score was made available online (https://yutaka-endo.shinyapps.io/mFIBA&#95;score/)., Discussion: The online mFIBA calculator may help surgeons with clinical decision-making to individualize perioperative treatment strategies for patients undergoing resection of HCC., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Both textbook outcome (TO) and hospital volume have been identified as quality metrics following cancer surgery. We sought to examine whether TO or hospital volume is more important relative to long-term survival following surgical resection of hepatocellular carcinoma (HCC)., Methods: Patients who underwent surgery for HCC between 2004 and 2018 were identified using the National Cancer Database. TO was defined as R0 margin resection, no extended length of stay, no 30-day readmissions, and no 90-day mortality. The impact of TO and hospital case volume on long-term survival was determined using multivariable Cox regression., Results: Among 24,895 patients who underwent HCC resection, 9.0% (n = 2,252), 79.5% (n = 19,787), and 11.5% (n = 2,856) of patients were operated on at low-, medium-, and high-volume hospitals, respectively. Treatment at high-volume hospitals and achievement of a post-operative TO were independently associated with improved 5-year overall survival (OS). Pairwise comparison demonstrated that patients treated at high-volume hospitals who did not achieve a TO still had a better 5-year OS versus individuals treated at low-volume hospitals who did achieve a TO (5-year OS, no TO vs. TO: low-volume hospitals, 26.5% vs. 48.6%; high volume hospitals: 62.6% vs. 74.9%, respectively; p < 0.001). Overall, resection of HCC at a high-volume hospital was independently associated with a 54% reduction in mortality., Conclusion: Long-term survival following HCC resection was largely associated with hospital case volume rather than TO. The effect of TO on long-term outcomes was largely mediated by hospital case volume highlighting the importance of centralization of care for patients with HCC., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: Patients with hepatocellular carcinoma (HCC) may have a heterogeneous presentation, as well as different long-term outcomes following surgical resection. We sought to use machine learning to cluster patients into different prognostic groups based on preoperative characteristics., Methods: Patients who underwent curative-intent liver resection for HCC between 2000 and 2020 were identified from a large international multi-institutional database. A hierarchical cluster analysis was performed based on preoperative factors to characterize patterns of presentation and define disease-free survival (DFS)., Results: Among 966 with HCC, 3 distinct clusters were identified: Cluster 1 (n = 160, 16.5%), Cluster 2 (n = 537, 55.6%) and Cluster 3 (n = 269, 27.8%). Cluster 1 (n = 160, 16.5%) consisted of female patients (n = 160, 100%), low inflammation-based scores, intermediate tumor burden score (TBS) (median: 4.71) and high alpha-fetoprotein (AFP) levels (median 41.3 ng/mL); Cluster 2 consisted of male individuals (n = 537, 100%), mainly with a history of HBV infection (n = 429, 79.9%), low inflammation-based scores, intermediate AFP levels (median 26.0 ng/mL) and lower TBS (median 4.49); Cluster 3 was comprised of older patients (median age 68 years) predominantly male (n = 248, 92.2%) who had low incidence of HBV/HCV infection (7.1% and 8.2%, respectively), intermediate AFP levels (median 16.8 ng/mL), high inflammation-based scores and high TBS (median 6.58). Median DFS worsened incrementally among the three different clusters with Cluster 3 having the lowest DFS (Cluster 1: median not reached; Cluster 2: 34 months, 95% CI 23.0-48.0, Cluster 3: 19 months, 95% CI 15.0-29.0, p < 0.05)., Conclusion: Cluster analysis classified HCC patients into three distinct prognostic groups. Cluster assignment predicted DFS following resection of HCC with the female cluster having the most favorable prognosis following HCC resection., (© 2023. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background: Benchmarking is a process of continuous self-evaluation and comparison with best-in-class hospitals to guide quality improvement initiatives. We sought to define global benchmarks relative to liver resection for malignancy and to assess their achievement in hospitals in the United States., Methods: Patients who underwent curative-intent liver resection for hepatocellular carcinoma, intrahepatic cholangiocarcinoma, or colorectal or neuroendocrine liver metastases between 2000 and 2019 were identified from an international multi-institutional database. Propensity score matching was conducted to balance baseline characteristics between open and minimally invasive approaches. Best-in-class hospitals were defined relative to the achievement rate of textbook oncologic outcomes and case volume. Benchmark values were established relative to best-in-class institutions. The achievement of benchmark values among hospitals in the National Cancer Database was then assessed., Results: Among 2,624 patients treated at 20 centers, a majority underwent liver resection for hepatocellular carcinoma (n = 1,609, 61.3%), followed by colorectal liver metastases (n = 650, 24.8%), intrahepatic cholangiocarcinoma (n = 299, 11.4%), and neuroendocrine liver metastases (n = 66, 2.5%). Notably, 1,947 (74.2%) patients achieved a textbook oncologic outcome. After propensity score matching, 6 best-in-class hospitals with the highest textbook oncologic outcome rates (≥75.0%) were identified. Benchmark values were calculated for margin positivity (≤11.7%), 30-day readmission (≤4.1%), 30-day mortality (≤1.6%), minor postoperative complications (≤24.7%), severe complications (≤12.4%), and failure to achieve the textbook oncologic outcome (≤22.8%). Among the National Cancer Database hospitals, global benchmarks for margin positivity, 30-day readmission, 30-day mortality, severe complications, and textbook oncologic outcome failure were achieved in 62.9%, 27.1%, 12.1%, 7.1%, and 29.3% of centers, respectively., Conclusion: These global benchmarks may help identify hospitals that may benefit from quality improvement initiatives, aiming to improve patient safety and surgical oncologic outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Patients with mental illnesses face unique disparities in access to liver transplantation. We sought to compare rates of evaluation, transplantation, and post-transplant outcomes among patients with and without mental illnesses., Methods: Patients aged 18-75 with decompensated cirrhosis or hepatocellular carcinoma were identified from the Medicare Standard Analytic Files from 2014-2020. Regression analyses were used to examine the association between mental illness and evaluation by a transplant surgeon, receipt of transplant, and post-transplant outcomes., Results: Among 274,252 liver transplant candidates, 34,269 (12.5%) patients had depression and/or anxiety disorders and 8,184 (3.0%) had severe mental illnesses. The proportion of patients evaluated by a transplant surgeon was lower among patients with severe mental illnesses (14.1%), as well as individuals with depression and/or anxiety disorders (16.0%) versus the general population (18.5%) (p < 0.001). Similarly, utilization of transplantation rates was lower among patients with severe mental illness (1.1%) compared with depression and/or anxiety disorders (2.0%), as well as individuals without mental illnesses (3.8%) (p < 0.001). On multivariable regression analyses, mental illness remained independently associated with lower odds of evaluation and transplantation among patients with mental illnesses. In contrast, on adjusted analyses there were no differences in postoperative outcomes including perioperative complications, biliary complications, graft rejection, graft failure, and overall survival., Conclusion: Despite lower rates of evaluation and transplant, patients with mental illnesses did not experience differences in most postoperative outcomes compared with patients without a mental illness., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: Laparoscopic repeat hepatectomy (LRH) has increased, but appropriate indications for LRH are unclear. This study aimed to clarify appropriate indications for LRH., Methods: We retrospectively compared surgical outcomes between open RH (ORH) (n = 57) and LRH (n = 40) groups. To detect difficult cases of complete pure LRH, we examined patients with unplanned intraoperative hand-assisted laparoscopic surgery (HALS)/open conversion (n = 6)., Results: In the LRH versus ORH group, as previous hepatectomy, laparoscopic (75% vs. 12%, p < 0.001) and partial hepatectomy (Hr0) (73% vs. 37%, p = 0.002) were more frequently performed, and as RH procedure, partial hepatectomy (Hr0) (88% vs. 47%, p = 0.0002) was more frequently performed. S1 tumor cases were higher in ORH group (11% vs. 0%), but S2-6 cases were higher in LRH group (73% vs. 49%) (p = 0.02). In LRH group, compared to the pure LRH patients, HALS/open conversion patients underwent significantly more previous hepatectomy with more than lobectomy (Hr2-3) (33% vs. 2.9%, p = 0.033) and more RH procedures with segmentectomy (HrS) (33% vs. 2.9%, p = 0.03). All LRH requiring a repeat hepatic hilar approach were HALS conversions., Conclusion: Appropriate indications for LRH were previous hepatectomy was laparoscopic partial hepatectomy (Hr0), and RH procedure was partial hepatectomy (Hr0) for S2-6 tumor location. When RH is more than segmentectomy (HrS) requiring a repeat hepatic hilar approach, planned HALS or ORH may be a better approach than pure LRH., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: We sought to examine the prognostic impact of margin width at time of hepatocellular carcinoma (HCC) resection relative to the alpha-feto protein tumor burden score (ATS)., Patients and Methods: Patients who underwent curative-intent hepatectomy for HCC between 2000 and 2020 were identified from a multi-institutional database. The impact of margin width on overall survival and recurrence-free survival was examined relative to ATS using univariable and multivariable analyses., Results: Among 782 patients with HCC who underwent resection, median ATS was 6.5 [interquartile range (IQR) 4.3-10.2]. Most patients underwent R0 resection (n = 613, 78.4%); among patients who had an R0 resection, 325 (41.6%) had a margin width > 5 mm while 288 (36.8%) had a 0-5 mm margin width. Among patients with high ATS, an increasing margin width was associated with incrementally better overall and recurrence-free survival. In contrast, among patients with low ATS, margin width was not associated with long-term outcomes. On multivariable Cox regression analysis, each unit increase in ATS was independently associated with a 7% higher risk of death [hazard ratio (HR) 1.07; 95% confidence interval (CI) 1.03-1.11, p < 0.001]. While the incidence of early recurrence was not associated with margin width among patients with low ATS, wider margin width was associated with an incrementally lower incidence of early recurrence among patients with high ATS., Conclusion: ATS, an easy-to-use composite tumor-related metric, was able to risk stratify patients following resection of HCC relative to overall survival and recurrence-free survival. The therapeutic impact of resection margin width had a variable impact on long-term outcomes relative to ATS., (© 2023. Society of Surgical Oncology.)

Introduction: Approximately 15% of patients experience a resectable intrahepatic recurrence after an index curative-intent hepatectomy for colorectal liver metastases (CRLM). We sought to investigate the impact of recurrence timing and tumor burden score (TBS) at the time of recurrence on overall survival among patients undergoing repeat hepatectomy., Methods: Patients with CRLM who experienced recurrent intrahepatic disease after initial hepatectomy between 2000 and 2020 were identified from an international multi-institutional database. The impact of time-TBS, defined as TBS divided by the time interval of recurrence, was assessed relative to overall survival., Results: Among 220 patients, the median age was 60.9 years (interquartile range [IQR]: 53.0-69.0), and 144 (65.5%) patients were male. Most patients experienced multiple recurrences (n = 120, 54.5%) within 12 months after the initial hepatectomy (n = 139, 63.2%). The median tumor size of the recurrent CRLM was 2.2 cm (IQR: 1.5-3.0 cm) with a median TBS of 3.5 (2.3-4.9) at the time of recurrence. Overall, 121 (55.0%) patients underwent repeat hepatectomy, whereas 99 (45.0%) individuals were treated with systemic chemotherapy or other nonsurgical treatments; repeat hepatectomy was associated with better postrecurrence survival (PRS) (p < 0.001). Three-year PRS incrementally worsened (low time-TBS: 71.7%, 95% confidence interval [CI], 57.9-88.8 vs. medium: 63.6%, 95% CI, 47.7-84.8 vs. high: 49.2%, 95% CI, 31.1-77.7, p = 0.02) as time-TBS values increased. Each unit increase in time-TBS score was independently associated with a 41% higher possibility of death (hazard ratio: 1.41; 95% CI, 1.04-1.90, p = 0.03)., Conclusions: Time-TBS was associated with long-term outcomes after repeat hepatectomy for recurrent CRLM. Time-TBS may be an easy tool to help select patients who may benefit the most from repeat hepatic resection of recurrent CRLM., (© 2023 Wiley Periodicals LLC.)

Objective: We sought to evaluate the impact of liver transplantation (LT) programs on the prognosis of hepatocellular carcinoma (HCC) patients who underwent liver resection (LR) and noncurative intent treatment., Background: LT programs have an array of resources and services that would positively affect the prognosis of patients with HCC., Methods: Patients who underwent LT, LR, radiotherapy (RT), or chemotherapy (CTx) for HCC between 2004 and 2018 were included in the National Cancer Database. Institutions with LT programs were defined as those that performed 1 or more LT for at least 5 years. Centers were stratified by hospital volume. The impact of LT programs was assessed after propensity score matching to achieve covariate balance., Results: A total of 71,735 patients were identified, of which 7997 received LT (11.1%), 12,683 LR (17.7%), 15,675 RT (21.9%), and 35,380 CTx (49.3%). Among a total of 1267 distinct institutions, 94 (7.4%) were categorized as LT programs. Designation as an LT program was also associated with a high volume of LR and noncurative intent treatment (both P <0.001). After propensity score matching, LT programs were associated with better survival among LR and noncurative intent treatment patients. Although hospital volume was also associated with improved prognosis, LT programs were associated with additional survival benefits in noncurative intent treatment. On the other hand, no such benefit was noted in patients who underwent LR., Conclusions: The presence of an LT program was associated with a higher volume of LR and noncurative intent treatment. Furthermore, designation as an LT program had a "halo effect" on the prognosis of patients undergoing RT/CTx that went beyond the procedure-volume effect., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The impact of Medicaid expansion (ME) on hepatocellular carcinoma (HCC) remains controversial, and heterogeneous effects on care processes may relate to sociodemographic factors. We sought to evaluate the association between ME and receipt of surgery in early-stage HCC., Methods: Patients diagnosed with early-stage HCC between 40 and 64 years of age were identified from the National Cancer Database and divided into pre- (2004-2012) and post- (2015-2017) expansion cohorts. Logistic regression was used to identify predictors of surgical treatment. Difference-in-difference (DID) analysis assessed changes in surgical treatment between patients living in ME and non-ME states., Results: Among 19,745 patients, 12,220 (61.9%) were diagnosed before ME and 7525 (38.1%) after. Although overall utilization of surgery decreased after expansion (ME, pre-expansion: 62.2% versus post-expansion: 51.6%; non-ME, pre-expansion: 62.1% versus post-expansion: 50.8%, p < 0.001), this trend varied relative to insurance status. Notably, receipt of surgery increased among uninsured/Medicaid patients living in ME states after expansion (pre-expansion: 48.1%, post-expansion: 52.3%, p < 0.001). Moreover, treatment at academic or high-volume facilities increased the likelihood of undergoing surgery before expansion. After expansion, treatment at an academic facility and living in an ME state (OR 1.28, 95% CI 1.07-1.54, p < 0.01) were predictors of surgical treatment. DID analysis demonstrated increased utilization of surgery for uninsured/Medicaid patients living in ME states relative to non-ME states (uninsured/Medicaid: 6.4%, p < 0.05), although no differences were noted among patients with other insurance statuses (overall: 0.7%, private: -2.0%, other: 0.3%, all p > 0.05)., Conclusions: Implementation of ME heterogeneously impacted utilization of care in early-stage HCC. Notably, uninsured/Medicaid patients residing in ME states demonstrated increased utilization of surgical treatment after expansion., (© 2023. Society of Surgical Oncology.)

Background: Recurrence following liver resection (LR) for hepatocellular carcinoma (HCC) can be as high as 50-70%. While salvage liver transplantation may be feasible, patients may develop a non-transplantable recurrence (NTR) (recurrence beyond Milan criteria). We sought to identify preoperative risk factors to predict NTR after resection., Patients and Methods: Patients who underwent curative-intent LR for HCC were identified from a multi-institutional database. Preoperative factors associated with NTR were identified and a risk score model (NTR score) was developed and validated., Results: Among 1620 patients, 842 (52.0%) developed recurrence; among patients with recurrence, NTR occurred in 341 (40.5%) with a median recurrence-free survival (RFS) of 30 months (24.7-35.3 months). On multivariable analysis, factors associated with NTR included alpha fetoprotein (AFP) > 400 ng/mL [hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.33-2.19], albumin-bilirubin grade (ALBI) (referent low, medium ALBI: HR 1.41, 95% CI 1.10-1.81, high ALBI: HR 2.47, 95% CI 0.91-6.68), and tumor burden score (TBS) (referent low, high TBS: HR 2.55, 95% CI, 1.99-3.28). A simplified TBS-based NTR score was developed using the β-coefficients of each factor (C-index 0.68, 95% CI 0.65-0.71). Higher NTR score was associated with incrementally worse 5-year RFS (low 44.8%, medium 37.5%, high 24.5%) [area under the curve (AUC) 0.59] and increased incidence of NTR (low 13.7%, medium 25.4%, high 38.2%) (AUC 0.65) (both p < 0.001). Moreover, higher NTR score was associated with higher risk of extrahepatic recurrence (low 11.3%, medium 28.8%, high 37.5%) (p < 0.001)., Conclusion: NTR following curative-intent resection of HCC occurred in one in five patients. A simple TBS-based NTR score accurately predicted the risk of NTR and may help identify candidates for upfront resection versus transplantation., (© 2023. Society of Surgical Oncology.)

Background: Hospital volume affects outcomes of patients who underwent resection for hepatocellular carcinoma (HCC). We sought to assess the impact of minimally invasive hepatectomy (MIH) volume on short- and long-term outcomes among patients with HCC., Methods: Patients who underwent MIH for HCC from 2010 to 2018 were identified from the National Cancer Database. Multivariable modeling with restricted cubic splines (RCS) was utilized to identify the MIH hospital volume threshold. Textbook outcome (TO) was defined as no conversion to open resection, negative margins after resection (R0), no extended length-of-stay, no readmission, and no 90-day mortality., Results: Among 3268 patients who underwent MIH for HCC, median age was 65.0 (IQR 59.0-72.0) and the majority was male (n = 2308, 70.6%). MIH hospital volume ranged from 1 to 87 cases, with a median of 13 (IQR 7-23). Overall, 2151 (60.9%) patients achieved TO after resection. While particularly high rates of achievement were found for no 90-day mortality (n = 3106, 95.0%), no readmission (n = 3153, 96.5%), and R0 resection (n = 3,017, 92.3%), other TO components including no conversion to open (n = 2778, 85.0%) and no prolonged LOS (n = 2584, 79.1%) were achieved less frequently. Patients treated at high-volume centers (≥50 MIH cases) were more likely to experience TO (high volume centers, n = 334, 68.7% vs. low volume centers, n = 1656, 59.5%, p < 0.001) and better long-term survival (5-year OS; high volume centers, 64.7% vs. low volume centers, 54.6%, p < 0.001)., Conclusions: MIH hospital volume was associated with a higher likelihood of achieving TO and improved long-term survival among patients undergoing resection of HCC., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: Heterogeneity in hepatocellular carcinoma (HCC) still exists within the Barcelona clinic liver cancer (BCLC) subcategories. We developed a simple model to better discriminate and predict prognosis following resection., Methods: Patients who underwent curative-intent resection for HCC were identified from a multi-institutional database. Predictive factors of survival were identified to develop TAC (tumor burden score [TBS], alpha-fetoprotein [AFP], Child-Pugh CP]) score., Results: Among 1435 patients, median TBS was 5.1 (interquartile range [IQR]: 3.2-8.1), median AFP was 18.3 ng/ml (IQR 4.0-362.5), and 1391 (96.9%) patients were classified as CP-A. Factors associated with overall survival (OS) included TBS (low: referent; medium: HR 2.26, 95% CI: 1.73-2.96; high: HR = 3.35, 95% CI: 2.22-5.07), AFP (<400 ng/ml: referent; >400 ng/ml: HR = 1.56, 95% CI: 1.27-1.92), and CP (A: referent; B: HR = 1.81, 95% CI: 1.12-2.92) (all p < 0.05). A simplified risk score demonstrated superior concordance index, Akaike information criteria, homogeneity, and area under the curve versus BCLC (0.620 vs. 0.541; 5484.655 vs. 5536.454; 60.099 vs. 16.194; 0.62 vs. 0.55, respectively), and further stratified patients within BCLC groups relative to OS (BCLC 0, very low: 86.8%, low: 47.8%) (BCLC A, very low: 79.7%, low: 68.1%, medium: 52.5%, high: 35.6%) (BCLC B, low: 59.8%, medium: 43.7%, high: N/A)., Conclusion: TAC is a simple, holistic score that consistently outperformed BCLC relative to discrimination power and prognostication following resection of HCC., (© 2022 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Introduction: In order to investigate the optimal approach for synchronous colorectal liver metastases (sCRLM), we sought to use the "win ratio" (WR), a novel statistical approach, to assess the relative benefit of simultaneous versus staged surgical treatment., Methods: Patients who underwent hepatectomy for sCRLM between 2008 and 2020 were identified from a multi-institutional database. The WR approach was utilized to compare composite outcomes of patients undergoing simultaneous versus staged resection., Results: Among 1116 patients, 642 (57.5%) presented with sCRLM; 290 (45.2%) underwent simultaneous resection, while 352 (54.8%) underwent staged resection. In assessing the composite outcome, staged resection yielded a WR of 1.59 (95%CI 1.47-1.71) over the simultaneous approach for sCRLM. The highest WR occurred among patients requiring major hepatectomy (WR = 1.93, 95%CI 1.77-2.10) compared with patients who required minor liver resection (WR = 1.55, 95%CI 1.44-1.70)., Conclusions: Staged resection was superior to simultaneous resection for sCRLM based on a WR assessment., 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 Elsevier Inc. All rights reserved.)

Background: This study aimed to develop a holistic risk score incorporating preoperative tumor, liver, nutritional, and inflammatory markers to predict overall survival (OS) after hepatectomy for hepatocellular carcinoma (HCC)., Methods: Patients who underwent curative-intent surgery for HCC between 2000 and 2020 were identified using an international multi-institutional database. Preoperative predictors associated with OS were selected and a prognostic risk score model (PreopScore) was developed and validated using cross-validation., Results: A total of 1676 patients were included. On multivariable analysis, preoperative parameters associated with OS included α-feto protein (hazard ratio [HR]1.17, 95%CI 1.03-1.34), neutrophil-to-lymphocyte ratio (HR2.62, 95%CI 1.30-5.30), albumin (HR0.49, 95%CI 0.34-0.70), gamma-glutamyl transpeptidase (HR1.00, 95%CI 1.00-1.00), as well as vascular involvement (HR3.52, 95%CI 2.10-5.89) and tumor burden score (medium, HR3.49, 95%CI 1.62-7.58; high, HR3.21, 95%CI 1.40-7.35) on preoperative imaging. A weighted PreopScore was devised and made available online (https://yutaka-endo.shinyapps.io/PrepoScore&#95;Shiny/). Patients with a PreopScore 0-2, 2-3.5, and >3.5 had incrementally worse 5-year OS of 85.8%, 70.7%, and 52.4%, respectively (p < 0.001). The c-index of the test and validation cohort were 0.75 and 0.71, respectively. The PreopScore outperformed individual parameters and previous HCC staging systems., Discussion: The PreopScore can be used as a better guide to preoperatively identify patients and individualize pre-/post-operative strategies., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The prognostic role of tumor burden score (TBS) relative to albumin-bilirubin (ALBI) grade among patients undergoing curative-intent resection of ICC has not been examined., Methods: We identified patients who underwent curative-intent resection for ICC between 1990 and 2017 from a multi-institutional database. Multivariable analysis was performed to assess the effect of TBS relative to ALBI grade on both short- and long-term outcomes., Results: Among 724 patients, 360 (49.7%) patients had low TBS and low ALBI grade, 142 (19.6%) patients had low TBS and high ALBI grade, 138 (19.1%) patients had high TBS and low ALBI grade, and 84 patients (11.6%) had high TBS and high ALBI grade. Decreased tumor burden was associated with better long-term outcomes among patients with both low (5-year OS; low TBS vs. high TBS: 52.4% vs 21.4%; p < 0.001) and high ALBI grade (5-year OS; low TBS vs. high TBS: 40.7% vs 12.0%; p < 0.001). On multivariable analysis, higher ALBI grade was associated with greater odds of an extended hospital LOS (> 10 days) (OR 2.80, 95%CI 1.62-4.82; p < 0.001), perioperative transfusion (OR 2.04, 95%CI 1.25-3.36; p = 0.005), 90-day mortality (OR 2.56, 95%CI 1.12-5.81; p = 0.025), as well as a major complication (OR 1.99, 95%CI 1.13-3.49; p = 0.016) among patients with similar tumor burden. Of note, patients with high TBS and high ALBI grade had markedly worse overall survival compared with patients who had low TBS and low ALBI grade disease (HR 2.27; 95%CI 1.44-3.59; p < 0.001). Importantly, high TBS and high ALBI grade were strongly associated with both early recurrence (88.1%%) and 5-year risk of death (96.4%)., Conclusion: Both TBS (i.e., tumor morphology) and ALBI grade (i.e., hepatic function reserve) were strong predictors of outcomes among patients undergoing ICC resection. There was an interplay between TBS and ALBI grade relative to patient prognosis after hepatic resection of ICC with high ALBI grade predicting worse outcomes among ICC patients with different TBS., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background: The presence of microvascular invasion (MVI) has been highlighted as an important determinant of hepatocellular carcinoma (HCC) prognosis. We sought to build and validate a novel model to predict MVI in the preoperative setting., Methods: Patients who underwent curative-intent surgery for HCC between 2000 and 2020 were identified using a multi-institutional database. Preoperative predictive models for MVI were built, validated, and used to develop a web-based calculator., Results: Among 689 patients, MVI was observed in 323 patients (46.9%). On multivariate analysis in the test cohort, preoperative parameters associated with MVI included α-fetoprotein (AFP; odds ratio [OR] 1.50, 95% confidence interval [CI] 1.23-1.83), imaging tumor burden score (TBS; hazard ratio [HR] 1.11, 95% CI 1.04-1.18), and neutrophil-to-lymphocyte ratio (NLR; OR 1.18, 95% CI 1.03-1.35). An online calculator to predict MVI was developed based on the weighted β-coefficients of these three variables ( https://yutaka-endo.shinyapps.io/MVIrisk/ ). The c-index of the test and validation cohorts was 0.71 and 0.72, respectively. Patients with a high risk of MVI had worse disease-free survival (DFS) and overall survival (OS) compared with low-risk MVI patients (3-year DFS: 33.0% vs. 51.9%, p < 0.001; 5-year OS: 44.2% vs. 64.8%, p < 0.001). DFS was worse among patients who underwent an R1 versus R0 resection among those patients at high risk of MVI (R0 vs. R1 resection: 3-year DFS, 36.3% vs. 16.1%, p = 0.002). In contrast, DFS was comparable among patients at low risk of MVI regardless of margin status (R0 vs. R1 resection: 3-year DFS, 52.9% vs. 47.3%, p = 0.16)., Conclusion: Preoperative assessment of MVI using the online tool demonstrated very good accuracy to predict MVI., (© 2022. Society of Surgical Oncology.)

Background: The impact of early versus intermediate hepatocellular carcinoma (HCC) on short-term "optimal" outcomes remains ill-defined. This study sought to define the incidence of textbook oncologic outcomes (TOO), as well as to identify factors associated with TOO among patients with early versus intermediate HCC., Methods: Patients who underwent curative-intent liver resection for HCC (1998-2020) were identified from a multi-institutional database. Textbook oncologic outcome (TOO) was defined as negative surgical margins, no return to the operating room, no extended hospital stay, no severe complications, and no 90-day mortality or readmission. Patients were stratified as early HCC (BCLC 0 or BCLC A/Child-Pugh A) or intermediate HCC (BCLC A/Child-Pugh B or BCLC B). Multivariate logistic regression analysis was used to assess factors associated with TOO., Results: Among 1383 patients, the overall incidence of TOO was 69.0%. Patients with intermediate HCC were less likely to achieve a TOO (early [71.6 %] vs. intermediate [60.1%]; p < 0.001). On multivariate analysis, factors associated with decreased odds of a TOO were high tumor burden (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.33-1.00), high aspartate transaminase-platelet ratio index (APRI) (OR, 0.46; 95% CI, 0.30-0.70), Charlson Comorbidity Index (CCI) greater than 3 (OR, 0.67; 95% CI, 0.49-0.91), major liver resection (OR, 0.68; 95% CI, 0.52-0.90), and intermediate HCC (OR, 0.68; 95% CI, 0.50-0.93) (all p < 0.05). Notably, although high APRI, CCI greater than 3, and major liver resection contributed to lower odds of a TOO in early HCC, the only factor that adversely impacted TOO in intermediate HCC was high tumor burden., Conclusions: Patients with intermediate HCC and early HCC patients with liver dysfunction, comorbidities, or an extensive resection were less likely to achieve an "optimal" postoperative outcome., (© 2022. Society of Surgical Oncology.)

Background: Defining patterns and risk of recurrence can help inform surveillance strategies and patient counselling. We sought to characterize peak hazard rates (pHR) and peak time of recurrence among patients who underwent resection of hepatocellular carcinoma (HCC)., Methods: 1434 patients who underwent curative-intent resection of HCC were identified from a multi-institutional database. Hazard, patterns, and peak rates of recurrence were characterized., Results: The overall hazard of recurrence peaked at 2.4 months (pHR: 0.0384), yet varied markedly. The incidence of recurrence increased with Barcelona Clinic Liver Cancer (BCLC) stage 0 (29%), A (54%), and B (64%). While the hazard function curve for BCLC 0 patients was relatively flat (pHR: <0.0177), BCLC A patients recurred with a peak at 2.4 months (pHR: 0.0365). Patients with BCLC B had a bimodal recurrence with a peak rate at 4.2 months (pHR: 0.0565) and another at 22.8 months. The incidence of recurrence also varied according to AFP level (≤400 ng/mL: 52.6% vs. >400 ng/mL: 36.3%) and Tumor Burden Score (low: 73.7% vs. medium: 50.6% vs. high: 24.2%) (both p < 0.001)., Conclusion: Recurrence hazard rates for HCC varied substantially relative to both time and intensity/peak rates. TBS and AFP markedly impacted patterns of hazard risk of recurrence., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Resection of Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) remains controversial. While not recommended by the BCLC algorithm, some patients may indeed benefit from hepatectomy. We sought to identify that subset of patients who might derive long-term survival benefit from resection., Methods: Intermediate-stage HCC patients who underwent curative-intent resection were identified from an international multi-institutional database. Factors associated with long-term prognosis were identified using multivariate analysis and a risk score was developed and assessed., Results: Among 194 patients, most individuals had two tumors (n = 123, 63.4%) with a median size of 6.0 cm (IQR, 4.0-8.4) for a median tumor burden score (TBS) of 6.5 (IQR, 5.0-9.1); median alpha-fetoprotein (AFP) was 23.9 ng/mL (IQR, 5.0-503.2), and median overall survival (OS) was 69 months (IAR, 60.7-77.3). Factors associated with OS included AFP (referent ≤ 20 ng/mL, > 20 ng/mL: HR 1.78 95%CI, 1.09-2.89) and TBS (referent TBS ≤ 8.0, TBS > 8.0: HR 1.72 95%CI, 1.07-2.75). While 71 (36.6%) patients had neither risk factor, 79 (40.7%) and 44 (22.7%) had 1 or 2, respectively. A simplified score stratified patients relative to recurrence-free survival (RFS) (0: 33.6% vs. 1: 18.0% vs. 2: 14.7%) (AUC 0.60) and recurrence time (i.e., < 6 months after surgery) (0: 21.3% vs. 1: 43.1% vs. 2: 68.6%) (AUC 0.69) (both p < 0.001). Of note, a higher score was also associated with incrementally worse 5-year OS (0: 68.1% vs. 1: 61.0% vs. 2: 29.9%) (AUC 0.62) (p < 0.001)., Conclusion: Long-term OS and RFS outcomes varied considerably. Using a simple risk score, patients with low AFP and low TBS were identified as the subset of individuals most likely to benefit from resection., (© 2022. The Society for Surgery of the Alimentary Tract.)

Background: Post-hepatectomy liver failure (PHLF) is a dreaded complication following liver resection for hepatocellular carcinoma (HCC) with a high mortality rate. We sought to develop a score based on preoperative factors to predict PHLF., Methods: Patients who underwent resection for HCC between 2000 and 2020 were identified from an international multi-institutional database. Factors associated with PHLF were identified and used to develop a preoperative comorbidity-tumor burden-liver function (CTF) predictive score., Results: Among 1785 patients, 106 (5.9%) experienced PHLF. On multivariate analysis, several factors were associated with PHLF including high Charlson comorbidity index (CCI ≥ 5) (OR 2.80, 95%CI, 1.08-7.26), albumin-bilirubin (ALBI) (OR 1.99, 95%CI, 1.10-3.56), and tumor burden score (TBS) (OR 1.06, 95%CI, 1.02-1.11) (all p < 0.05). Using the beta-coefficients of these variables, a weighted predictive score was developed and made available online ( https://alaimolaura.shinyapps.io/PHLFriskCalculator/ ). The CTF score (c-index = 0.67) performed better than Child-Pugh score (CPS) (c-index = 0.53) or Barcelona clinic liver cancer system (BCLC) (c-index = 0.57) to predict PHLF. A high CTF score was also an independent adverse prognostic factor for survival (HR 1.61, 95%CI, 1.12-2.30) and recurrence (HR 1.36, 95%CI, 1.08-1.71) (both p = 0.01)., Conclusion: Roughly 1 in 20 patients experienced PHLF following resection of HCC. Patient (i.e., CCI), tumor (i.e., TBS), and liver function (i.e., ALBI) factors were associated with risk of PHLF. These preoperative factors were incorporated into a novel CTF tool that was made available online, which outperformed other previously proposed tools., (© 2022. The Society for Surgery of the Alimentary Tract.)

Background: The ability to predict the incidence, timing, and site of recurrence can be beneficial to select surgical candidates and inform appropriate postoperative surveillance. We sought to identify factors associated with risk and timing of recurrence after resection of hepatocellular carcinoma based on differences in tumor burden score., Methods: Patients who underwent curative-intent liver resection for hepatocellular carcinoma between 2000 and 2020 were identified from an international multi-institutional database. The incidence, timing, and pattern of recurrence was examined relative to traditional clinicopathological factors, as well as tumor burden score using hazard rates and multivariable analysis., Results: Among 1,994 patients (tumor burden score, low: n = 511, 25.6% vs medium: n = 1,286, 64.5% vs high: n = 197, 9.9%), the incidence of recurrence at 5 years was 50.4% (95% confidence interval 47.9-53.0); risk of recurrence varied relative to hepatocellular carcinoma tumor burden score (low: 36.0% vs medium: 54.4% vs high: 62.5%, P &lt; .001). Although intrahepatic recurrence was much more common in low tumor burden score (low: n = 106, 84.1% vs medium: n = 335, 71.7% vs high: n = 48, 56.5%; P &lt; .001), extrahepatic recurrence was more common in high tumor burden score (low: n = 18, 14.3% vs medium: n = 121, 25.9% vs high: n = 37, 43.5%; P &lt; .001). The peak hazard rate for intrahepatic recurrence among patients with a high tumor burden score was almost double the peak hazard noted among patients with a low tumor burden score (low: 0.047, 42.0 months vs medium: 0.051, 6.6 months vs high: 0.094, 15.0 months). Of note, the patients with high tumor burden score were also more likely to recur earlier (≤24 months) (low: n = 227, 44.4% vs medium: n = 686, 53.3% vs high: n = 144, 73.1%) with multiple tumors (low: n = 50, 36.5% vs medium: n = 271, 56.1% vs high: n = 52, 70.3%) and larger lesions (low: 1.8 [interquartile range 1.2-3.0] cm vs medium: 2.0 [interquartile range 1.3-3.0] cm vs high: 2.5 [interquartile range 1.6-4.4] cm) (all P &lt; .001). On multivariable analysis, high tumor burden score remained independently associated with risk of recurrence (referent, low; medium: hazard ratio = 1.49 [95% confidence interval 1.19-1.88], P = .001; high: hazard ratio = 1.95 [95% confidence interval 1.41-2.69]; P &lt; .001]., Conclusion: Tumor burden score was independently associated with higher risk of recurrence. Patients who underwent resection of high tumor burden score lesions were more likely to recur early with multiple tumors and at an extrahepatic site. Tumor burden score is an important tool in assessing risk, timing, and pattern of recurrence after resection of hepatocellular carcinoma., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Laparoscopic liver resection (LLR) is possible in many patients, but pure LLR is sometimes difficult to complete, and unplanned intraoperative hand-assisted laparoscopic surgery (HALS) or open conversion is sometimes necessary. However, appropriate indications and timing for conversion are unclear. This study aimed to clarify the indications for HALS and open conversion from pure LLR., Methods: We collected data from 208 patients who underwent LLR from January 2010 to February 2021 in our department. We retrospectively examined these data between cases of unplanned intraoperative HALS conversion, open conversion, and pure LLR, and clarified risk factors and indications for HALS or open conversion., Results: There were 191 pure LLRs, nine HALS conversions, and eight open conversions. In the HALS conversion group versus pure LLR group, body mass index (BMI) (27.0 vs. 23.7 kg/m 2 , p = 0.047), proportions of patients with history of upper abdominal surgery (78% vs. 33%; p = 0.006), repeat hepatectomy (56% vs. 15%; p = 0.002), S7 or S8 tumor location (67% vs. 35%; p = 0.049), and difficulty score (DS) ≥ 7 (56% vs. 19%; p = 0.008) were significantly higher, and surgical time (339 vs. 239 min; p = 0.031) was significantly longer. However, postoperative states were not significantly different between the two groups. The BMI cutoff value for risk of unplanned intraoperative conversion determined by receiver operating characteristic curve analysis was 25 kg/m 2 , and the proportion of patients with BMI ≥ 25 kg/m 2 (89% vs. 31%, p < 0.001) was significantly higher in the HALS conversion versus pure LLR group. In the open conversion group, although there were no significant differences compared to the HALS group in clinicopathological factors except for sex, blood loss was greater (1425 vs. 367 mL; p < 0.001)., Conclusion: Risk factors for considering HALS during LLR were patients with a history of upper abdominal surgery including repeat hepatectomy, BMI ≥ 25 kg/m 2 , S7 or S8 tumor location, DS ≥ 7, and prolonged surgical time. Furthermore, uncontrollable intraoperative bleeding was an indication for open conversion., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To validate the utility of hepatic resection combined with complementary radiofrequency ablation (RFA) compared with resection alone for patients with multiple hepatocellular carcinoma (HCC), and to compare these results with those of a previous report., Materials and Methods: A total of 78 HCC patients with multiple (≤5) tumours who were initially treated with hepatic resection only (Resection group) or with combined hepatic resection and RFA (Combination group) were included. Overall and disease-free survival were analysed., Results: There were 21 women and 57 men with a median age of 72.5 (64.3-76.8) years. Fifty-three patients were treated with resection alone and 25 received combination therapy. The 3-, 5-, and 7-year cumulative overall survival rates were 81.2%, 68.2%, and 57.1%, respectively, in the Resection group, and 81.3%, 59.6%, and 42.4%%, respectively, in the Combination group (hazard ratio [HR], 1.462; 95% confidence interval [CI], 0.682-3.136; p=0.329). The 1-, 3-, and 5-year cumulative disease-free survival rates were 61.4%, 45.7%, and 39.8%, respectively, in the Resection group, and 53.1%, 18.6%, and 0%, respectively, in the Combination group (HR, 2.080; 95% CI, 1.157-3.737; p=0.014). The overall survival rate was not significantly different between the Resection and Combination groups in patients within the up-to-seven HCC criteria (n=56; HR, 2.101; 95% CI, 0.805-5.486; p=0.130) or those beyond these criteria (n=22; HR, 0.804; 95% CI, 0.197-3.286; p=0.761)., Conclusions: The combination of hepatic resection and RFA therapy may be an effective strategy for HCC patients with multiple tumours., (Copyright © 2021. Published by Elsevier Ltd.)

No consensus has been reached on the postoperative treatment and follow-up duration for high-risk malignant gastrointestinal stromal tumor (GIST). We herein report a case of recurrent liver metastasis from gastric GIST in a patient who had been receiving adjuvant chemotherapy with imatinib mesylate for 10 years. A 78-year-old woman underwent local gastrectomy for a 20-cm gastric GIST with a mitotic index of 25/50 high-power fields (HPF) 17 years before. Partial hepatectomy for recurrent liver metastases was repeatedly performed 14 and 12 years before. After the second hepatectomy, postoperative adjuvant chemotherapy with imatinib mesylate was given for 10 years, during which no recurrence was observed. Two years after the completion of adjuvant chemotherapy, computed tomography revealed a 2-cm hepatic tumor; thus, laparoscopic partial hepatectomy was performed. Histopathological findings revealed a liver metastasis of gastric GIST with a mitotic count of 20/50 HPF and MIB-1 labeling index of 20%. Mutation analysis of the KIT gene revealed an exon 11 mutation. The patient is currently undergoing postoperative adjuvant chemotherapy with imatinib mesylate. The combination of surgery and long-term adjuvant chemotherapy for high-risk malignant GIST and liver metastases may be effective to achieve a good prognosis., (© 2021. Japanese Society of Gastroenterology.)

Epithelial‑mesenchymal transition (EMT) is considered a crucial event in the development of cancer metastasis. Metformin is a drug used in the treatment of type 2 diabetes. Recently, increasing evidence has indicated that metformin possesses anti‑tumor activities. However, the effects of metformin on EMT and metastases in pancreatic cancer remain unknown. Thus, the present study investigated whether metformin inhibits EMT of human pancreatic cancer cell lines. Pancreatic cancer cells were stimulated with transforming growth factor β1 (TGF‑β1), an activator of EMT signaling, with or without metformin. After 48 h, the levels of epithelial and mesenchymal markers were evaluated by western blot analysis, immunocytochemistry and RT‑qPCR. Cancer cell migration was evaluated by an in vitro wound healing assay. The cells stimulated with TGF‑β1 acquired an elongated and fusiform morphology, which was inhibited by metformin. The wound healing assay revealed that metformin significantly suppressed the TGF‑β1‑stimulated migration of pancreatic cancer cells. Following treatment with metformin, E‑cadherin expression (epithelial marker) was upregulated, and the levels of mesenchymal markers were downregulated, which had been increased by TGF‑β1 in these cells. Exposure of the cells to TGF‑β1 activated the Smad2/3 and Akt/mammalian target of rapamycin (mTOR) pathways, and this effect was inhibited by metformin, suggesting that metformin inhibits TGF‑β1‑induced‑EMT through the down‑regulation of the Smad pathway in PANC‑1 cells and the downregulation of the Akt/mTOR pathway in BxPC‑3 cells. In an animal model of surgical orthotopic implantation, metformin inhibited liver metastasis without a significant reduction in the size of the primary pancreatic tumor. On the whole, the findings of the present study suggest that metformin inhibits EMT and cancer metastasis through the Smad or Akt/mTOR pathway.

Canine hepatocellular carcinoma (HCC) is the most common primary hepatic tumour in dogs. MicroRNA (miRNA) dysregulation has been reported in human HCC and shown to have diagnostic and prognostic value; however, there are no data on miRNA expression in canine HCC. The aim of the present study was to investigate differentially expressed miRNAs in canine HCC. Analysis of miRNA expression in canine HCC tissues and cell lines by quantitative reverse transcription PCR showed that miR-1, miR-122, let-7a, and let-7g were downregulated, whereas miR-10b and miR-21 were upregulated in canine HCC. MET is one of the target genes of miR-1. MET was upregulated in canine HCC at the gene and protein levels, and a significant correlation between the concomitant downregulation of miR-1 and upregulation of MET was observed. Fast/intermediate-proliferating canine HCC cell lines had higher MET gene and protein expression levels than the slow-proliferating cell line. These findings suggest that miRNAs are differentially expressed in canine HCC, and that the miR-1/MET pathway may be associated with canine HCC cell proliferation., (© 2018 John Wiley & Sons Ltd.)

Background: The hypoxic microenvironment plays a crucial role in the malignant progression of tumor cells. Moreover, AKT, a serine/threonine kinase, is activated by various extracellular growth factors and is important for cell growth, survival, and motility of leukocytes, fibroblasts, endothelial cells, and tumor cells. Therefore, we aimed to design an anti-metastatic hypoxic cytotoxin which has inhibitory effects on AKT., Results: TX-2137 was designed and synthesized based on the structural similarity of a preexisting AKT1/2 kinase inhibitor and a hypoxic cytotoxin tirapazamine. TX-2137 effectively reduced the expression of phosphorylated AKT and matrix metalloproteinase 9 (MMP9) and showed strong inhibition of the proliferation of B16-F10, HT-1080, and MKN-45 cells. In addition, TX-2137 exhibited hypoxia-selective cytotoxicity towards A549 cells and inhibited liver metastasis of B16-F10 cells in a xenograft chick embryo model in the same way as doxorubicin., Conclusion: TX-2137 may be a potent lead compound in the development of a novel anti-metastatic AKT kinase inhibitor., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Laparoscopic liver resection (LLR) has several problems, such as technical complexity and patient and tumor factors. A difficulty scoring system to preoperatively evaluate the difficulty of LLR was established at the second International Consensus Conference on Laparoscopic Liver Resection. The aim of this study was to explore the clinical usefulness of the difficulty scoring system for LLR., Patients and Methods: From January 2010 to June 2015, the records of 78 patients who had undergone LLR were retrospectively reviewed. The patients' data were used to assign a difficulty score, and the correlations between scores and surgical outcomes were investigated., Results: The mean surgical time was 256 minutes, and the mean blood loss was 168 mL. The difficulty score significantly correlated with surgical time and blood loss, but not with morbidity and postoperative hospital stay. Multivariate analysis showed that the difficulty score was an independent predictor of prolonged surgical time., Conclusions: The difficulty score was found to be an effective predictor of surgical time for LLR.

Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment.

Purpose: We retrospectively evaluated the in vitro chemosensitivity of primary site and metastatic site tumors in colorectal cancer., Methods: Various resected tumor samples (33 from lymph nodes, 42 from liver, six from lung, and 68 primary tumors) were assessed via a collagen gel droplet-embedded culture drug sensitivity test to determine chemosensitivity to a single agent or a combination of agents., Results: Sensitivity to combination chemotherapy was significantly higher than that of monotherapy in the primary site group, lymph node group, and liver group. There was significant difference between chemosensitivity of primary site and that of liver metastasis in each agent (5-FU, p<0.001; SN38, p = 0.045; 5-FU/SN38, p<0.001; OHP, p = 0.037; 5-FU/OHP, p = 0.045)., Conclusions: Tumors showed greater in vitro chemosensitivity to combination therapy when compared with monotherapy. Further, tumors that had metastasized to the liver were more resistant to chemotherapy when compared with matched primary tumors.