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Background: Assess impact of direct-acting antivirals introduction on outcomes after liver resection for hepatocellular carcinoma., Methods: 391 patients (1991-2021) treated with resection for hepatocellular carcinoma on Hepatitis C background were divided according to receiving Hepatitis C treatment, treatment type, achievement of sustained virological response (SVR), time of resection pre- (Era 1, 1991-2011) and post-direct acting antivirals introduction (Era 2, 2012-2021). Survival was estimated with Kaplan-Meier curves, Cox regression analysis performed to identify survival predictors., Results: Majority of patients had single lesion (67.8%), diameter >2 cm in 60.6%, no evidence of macroscopic vascular invasion on imaging. Pathology showed vascular invasion in 69.6% of patients, 76.5% microvascular. Recurrence developed in 247 patients (63.2%). 194 patients (49.6%) achieved SVR. Overall survival at 1-, 3-, 5-years was 94.6%, 85.7%, 78.8% for patients who achieved SVR, 80.1%, 48.1%, 29.9% in those who did not (p < 0.001). 220 patients (56.3%) were in Era 1, 171 (43.7%) in Era 2. Survival at 1-, 3-, 5-years was 76.1%, 49%, 36% in Era 1, 94.5%, 82.5%, 70.3% in Era 2 (p < 0.001). SVR was an independent predictor of survival on multiple Cox Regression analysis., Conclusion: While many aspects of HCC management have evolved, SVR following direct-acting antivirals independently improves HCC resection outcomes., Competing Interests: Conflict of interest Chiara Rocha MD, Joseph Di Norcia MD, Chiara Di Renzo MD, Salvatore Amodeo MD, Yuki Bekki MD PhD, M Zeeshan Akhtar BM BCh DPhil FRCS: none. Parissa Tabrizian MD MSc FACS: scientific consultant for Bayer, AstraZeneca, Boston Scientific., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Immune checkpoint inhibitors (ICIs) have emerged as the primary treatment for advanced hepatocellular carcinoma (HCC) and have shown promise in the neoadjuvant setting prior to resection. Liver transplantation (LT) is the preferred treatment for unresectable early HCC or locally advanced disease post locoregional therapy, but the need for immunosuppression after LT conflicts with ICIs' immune augmenting effects. Neoadjuvant ICI may benefit select LT candidates, but challenges arise in understanding response indicators and managing post-LT risks. Reports of severe rejection after LT have raised concerns, though liver-specific factors may mitigate rejection risks, prompting exploration of pre-LT ICI usage. While focus has been on PD-1/PD-L1 inhibitors, the optimal pre-LT ICI regimen remains uncertain, and trials must emphasize careful patient selection and management. Living donor LT is advantageous because ICIs can be withheld for a predefined washout period. In the post-LT setting, use of ICIs is generally avoided, though a few reports suggest that PD-L1 expression in the transplanted liver may be a safety biomarker and that, despite the risk, ICI therapy may be better than supportive care for patients with otherwise-untreatable HCC recurrence. This expert opinion highlights the complexities in the management of HCC vis-à-vis LT. Prospective studies and biomarkers are needed to define safe and effective pre- and post-LT immunotherapy protocols., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of effective systemic therapies, particularly those involving immune-checkpoint inhibitors (ICIs), has substantially improved the outcomes of patients with advanced-stage HCC. Approximately 30% of patients are diagnosed with early stage disease and currently receive potentially curative therapies, such as resection, liver transplantation or local ablation, which result in median overall survival durations beyond 60 months. Nonetheless, up to 70% of these patients will have disease recurrence within 5 years of resection or local ablation. To date, the results of randomized clinical trials testing adjuvant therapy in patients with HCC have been negative. This major unmet need has been addressed with the IMbrave 050 trial, demonstrating a recurrence-free survival benefit in patients with a high risk of relapse after resection or local ablation who received adjuvant atezolizumab plus bevacizumab. In parallel, studies testing neoadjuvant ICIs alone or in combination in patients with early stage disease have also reported efficacy. In this Review, we provide a comprehensive overview of the current approaches to manage patients with early stage HCC. We also describe the tumour immune microenvironment and the mechanisms of action of ICIs and cancer vaccines in this setting. Finally, we summarize the available evidence from phase II/III trials of neoadjuvant and adjuvant approaches and discuss emerging clinical trials, identification of biomarkers and clinical trial design considerations for future studies., (© 2024. Springer Nature Limited.)

Purpose: There are limited data on antiviral treatment utilization and its impact on long-term outcomes of hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after hepatic resection. We aimed to determine the utilization and impact of antivirals in HBV- and HCV-related HCC., Methods: This cohort study included 1,906 participants (1,054 HBV-related HCC and 852 HCV-related HCC) from 12 international sites. All participants had HBV- or HCV-related HCC and underwent curative surgical resection. The primary outcome was the utilization of antiviral therapy, and the secondary outcome was long-term overall survival (OS)., Results: The mean (±standard deviation [SD]) age was 62.1 (±11.3) years, 74% were male, and 84% were Asian. A total of 47% of the total cohort received antiviral therapy during a mean (±SD) follow-up of 5.0 (±4.3) years. The overall antiviral utilization for participants with HBV-related HCC was 57% and declined over time, from 65% before 2010, to 60% from 2010 to 2015, to 47% beyond 2015, P < .0001. The overall utilization of antivirals for HCV-related HCC was 35% and increased over time, from 24% before 2015 to 74% from 2015 and beyond, P < .0001. The 10-year OS was lower in untreated participants for both HBV (58% v 61%) and HCV participants (38% v 82%; both P < .0001). On multivariable Cox regression analysis adjusted for relevant confounders, antiviral therapy initiated before or within 6 months of HCC diagnosis was independently associated with lower mortality in both HBV- (adjusted hazard ratio [aHR], 0.60 [95% CI, 0.43 to 0.83]; P = .002) and HCV-related HCC (aHR, 0.18 [95% CI, 0.11 to 0.31]; P < .0001)., Conclusion: Antiviral therapy is associated with long-term survival in people with HBV- or HCV-related HCC who undergo curative resection but is severely underutilized.

Objectives: Radiation segmentectomy using yttrium-90 plays an emerging role in the management of early-stage HCC. However, the value of early post-treatment MRI for response assessment is uncertain. We assessed the value of response criteria obtained early after radiation segmentectomy in predicting long-term response in patients with HCC., Materials and Methods: Patients with HCC who underwent contrast-enhanced MRI before, early, and 12 months after radiation segmentectomy were included in this retrospective single-center study. Three independent radiologists reviewed images at baseline and 1 st follow-up after radiation segmentectomy and assessed lesion-based response according to mRECIST, LI-RADS treatment response algorithm (TRA), and image subtraction. The endpoint was response at 12 months based on consensus readout of two separate radiologists. Diagnostic accuracy for predicting complete response (CR) at 12 months based on the 1 st post-treatment MRI was calculated., Results: Eighty patients (M/F 60/20, mean age 67.7 years) with 80 HCCs were assessed (median size baseline, 1.8 cm [IQR, 1.4-2.9 cm]). At 12 months, 74 patients were classified as CR (92.5%), 5 as partial response (6.3%), and 1 as progressive disease (1.2%). Diagnostic accuracy for predicting CR was fair to good for all readers with excellent positive predictive value (PPV): mRECIST (range between 3 readers, accuracy: 0.763-0.825, PPV: 0.966-1), LI-RADS TRA (accuracy: 0.700-0.825, PPV: 0.983-1), and subtraction (accuracy: 0.775-0.825, PPV: 0.967-1), with no difference in accuracy between criteria (p range 0.053 to > 0.9)., Conclusion: mRECIST, LI-RADS TRA, and subtraction obtained on early post-treatment MRI show similar performance for predicting long-term response in patients with HCC treated with radiation segmentectomy., Clinical Relevance Statement: Response assessment extracted from early post-treatment MRI after radiation segmentectomy predicts complete response in patients with HCC with high PPV (≥ 0.96)., Key Points: • Early post-treatment response assessment on MRI predicts response in patients with HCC treated with radiation segmentectomy with fair to good accuracy and excellent positive predictive value. • There was no difference in diagnostic accuracy between mRECIST, LI-RADS, and subtraction for predicting HCC response to radiation segmentectomy., (© 2023. The Author(s).)

Objective: This study aims at establishing benchmark values for best achievable outcomes following open major anatomic hepatectomy for liver tumors of all dignities., Background: Outcomes after open major hepatectomies vary widely lacking reference values for comparisons among centers, indications, types of resections, and minimally invasive procedures., Methods: A standard benchmark methodology was used covering consecutive patients, who underwent open major anatomic hepatectomy from 44 high-volume liver centers from 5 continents over a 5-year period (2016-2020). Benchmark cases were low-risk non-cirrhotic patients without significant comorbidities treated in high-volume centers (≥30 major liver resections/year). Benchmark values were set at the 75th percentile of median values of all centers. Minimum follow-up period was 1 year in each patient., Results: Of 8044 patients, 2908 (36%) qualified as benchmark (low-risk) cases. Benchmark cutoffs for all indications include R0 resection ≥78%; liver failure (grade B/C) ≤10%; bile leak (grade B/C) ≤18%; complications ≥grade 3 and CCI ® ≤46% and ≤9 at 3 months, respectively. Benchmark values differed significantly between malignant and benign conditions so that reference values must be adjusted accordingly. Extended right hepatectomy (H1, 4-8 or H4-8) disclosed a higher cutoff for liver failure, while extended left (H1-5,8 or H2-5,8) were associated with higher cutoffs for bile leaks, but had superior oncologic outcomes, when compared to formal left hepatectomy (H1-4 or H2-4). The minimal follow-up for a conclusive outcome evaluation following open anatomic major resection must be 3 months., Conclusion: These new benchmark cutoffs for open major hepatectomy provide a powerful tool to convincingly evaluate other approaches including parenchymal-sparing procedures, laparoscopic/robotic approaches, and alternative treatments, such as ablation therapy, irradiation, or novel chemotherapy regimens., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a U.S., Methods: The multicenter Hepatocellular Carcinoma Early Detection Strategy study of the National Institutes of Health prospectively enrolled patients with cirrhosis who underwent standard surveillance for HCC. Demographics, medical and family history, etiology of liver disease, and clinical features were evaluated for associations with HCC., Results: Between April 10, 2013 and December 31, 2021, 1723 patients were enrolled and confirmed eligible. During median follow-up of 2.2 years (range, 0-8.7 years), there were 109 incident cases of HCC for an incidence rate of 2.4 per 100 person-years: 88 (81%) patients with very early/early Barcelona Clinic Liver Cancer stage (0, A), 20 (18%) intermediate stage (B), and 1 (1%) unknown stage. Risk factor analyses were restricted to 1325 patients, including 95 incident HCC, with at least 6 months of follow-up. The majority were men (53.2%), obese or severely obese (median body mass index, 30.2 kg/m 2 ), and white (86.3%); 42.0% had history of hepatitis C virus infection, 20.7% had alcoholic liver disease, and 24.9% had nonalcoholic fatty liver disease. Fourteen risk factors for HCC were significant (P < .05) in univariate analyses, and a multivariate subset was selected using stepwise logistic regression. The multivariate subset contained gender (P < .001; male; odds ratio [OR], 2.47; 95% confidence interval [CI], 1.54-4.07), years with cirrhosis (P = .004; OR, 1.06; 95% CI, 1.02-1.1), family history of liver cancer (P = .02; yes; OR, 2.69; 95% CI, 1.11-5.86), age (per 5 years; P = .02; OR, 1.17; 95% CI, 1.03-1.33), obesity (P = .02; yes; OR, 1.7; 95% CI, 1.08-2.73), aspartate aminotransferase (log(1+AST); P = .06; OR, 1.54; 95% CI, 0.97-2.42), alpha-fetoprotein (log(1+AFP); P = .07; OR, 1.32; 95% CI, 0.97-1.77), and albumin (P = .10; OR, 0.7; 95% CI, 0.46-1.07)., Conclusions: Thus far, this is the largest prospective and geographically diverse study of a U.S. cohort of patients with cirrhosis that validates known risk factors for HCC (gender, age, obesity, years with cirrhosis, family history of liver cancer, baseline AFP, albumin, and AST). The incidence of HCC was 2.4% per 100 person-years., (Copyright © 2023 AGA Institute. All rights reserved.)

Objective: To assess the performance of convolutional neural networks (CNNs) for semiautomated segmentation of hepatocellular carcinoma (HCC) tumors on MRI., Methods: This retrospective single-center study included 292 patients (237 M/55F, mean age 61 years) with pathologically confirmed HCC between 08/2015 and 06/2019 and who underwent MRI before surgery. The dataset was randomly divided into training (n = 195), validation (n = 66), and test sets (n = 31). Volumes of interest (VOIs) were manually placed on index lesions by 3 independent radiologists on different sequences (T2-weighted imaging [WI], T1WI pre-and post-contrast on arterial [AP], portal venous [PVP], delayed [DP, 3 min post-contrast] and hepatobiliary phases [HBP, when using gadoxetate], and diffusion-weighted imaging [DWI]). Manual segmentation was used as ground truth to train and validate a CNN-based pipeline. For semiautomated segmentation of tumors, we selected a random pixel inside the VOI, and the CNN provided two outputs: single slice and volumetric outputs. Segmentation performance and inter-observer agreement were analyzed using the 3D Dice similarity coefficient (DSC)., Results: A total of 261 HCCs were segmented on the training/validation sets, and 31 on the test set. The median lesion size was 3.0 cm (IQR 2.0-5.2 cm). Mean DSC (test set) varied depending on the MRI sequence with a range between 0.442 (ADC) and 0.778 (high b-value DWI) for single-slice segmentation; and between 0.305 (ADC) and 0.667 (T1WI pre) for volumetric-segmentation. Comparison between the two models showed better performance in single-slice segmentation, with statistical significance on T2WI, T1WI-PVP, DWI, and ADC. Inter-observer reproducibility of segmentation analysis showed a mean DSC of 0.71 in lesions between 1 and 2 cm, 0.85 in lesions between 2 and 5 cm, and 0.82 in lesions > 5 cm., Conclusion: CNN models have fair to good performance for semiautomated HCC segmentation, depending on the sequence and tumor size, with better performance for the single-slice approach. Refinement of volumetric approaches is needed in future studies., Key Points: • Semiautomated single-slice and volumetric segmentation using convolutional neural networks (CNNs) models provided fair to good performance for hepatocellular carcinoma segmentation on MRI. • CNN models' performance for HCC segmentation accuracy depends on the MRI sequence and tumor size, with the best results on diffusion-weighted imaging and T1-weighted imaging pre-contrast, and for larger lesions., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: According to the Barcelona Clinic Liver Cancer (BCLC) staging system, liver resection (LR) is recommended for early-stage (BCLC-A) hepatocellular carcinoma (HCC) but not for intermediate-stage (BCLC-B). This study aimed to assess the outcomes of LR in these patients using a subclassification tumour burden score (TBS)., Methods: All consecutive patients that underwent LR for BCLC-A and BCLC-B HCC between 01/2010 and 12/2020 in 4 tertiary referral centers were included. Clinical outcomes and overall survival (OS) were assessed in relation to TBS and BCLC stages., Results: Among 612 patients included, 562 were classified as BCLC-A and 50 as BCLC-B. The incidence of overall postoperative complications (56.0 vs 41.5%, p = 0.053) and mortality (0 vs 1.6%, p = 1.000) were similar between BCLC-A and BCLC-B patients. OS was significantly higher for BCLC A/low TBS than BCLC B/low TBS (p = 0.009), while patients with medium and high TBS had similar OS, irrespective of BCLC stage (respectively p = 0.103 and p = 0.343)., Conclusions: Patients with medium and high TBS had comparable OS and DFS, irrespective of BCLC A or B stage, and postoperative morbidity was comparable. These results highlight the need for refinement of the BCLC staging system, and LR could be considered for selected intermediate stage (BCLC-B) according to the tumour burden., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13 + CH25H + IL-21 + PD-1 + CD4 + T helper cells ("CXCL13 + T H ") and Granzyme K + PD-1 + effector-like CD8 + T cells, whereas terminally exhausted CD39 hi TOX hi PD-1 hi CD8 + T cells dominated in nonresponders. CD4 + and CD8 + T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1 + TCF-1 + (Progenitor-exhausted) CD8 + T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8 + T cell differentiation occurs upon ICB. We found that these Progenitor CD8 + T cells interact with CXCL13 + T H within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". These results suggest that discrete intratumoral niches that include mregDC and CXCL13 + T H control the differentiation of tumor-specific Progenitor exhasuted CD8 + T cells following ICB., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Successful treatment of hepatitis C reduces liver inflammation and fibrosis; however, patients remain at risk of developing hepatocellular carcinoma (HCC)., Aims: To identify risk factors for new-onset HCC in patients cured of hepatitis C., Methods: Imaging, histological, and clinical data on patients whose first HCC was diagnosed >12 months of post-SVR were analyzed. Histology of 20 nontumor tissues was analyzed in a blinded manner using the Knodel/Ishak/HAI system for necroinflammation and fibrosis/cirrhosis stage and the Brunt system for steatosis/steatohepatitis. Factors associated with post-SVR HCC were identified by comparison with HALT-C participants who did not develop post-SVR HCC., Results: Hepatocellular carcinoma was diagnosed in 54 patients (45 M/9F), a median of 6 years of post-SVR [interquartile range (IQR) =1.4-10y] at a median age of 61 years (IQR, 59-67). Approximately one-third lacked cirrhosis, and only 11% had steatosis on imaging. The majority (60%) had no steatosis/steatohepatitis in histopathology. The median HAI score was 3 (1.25-4), indicating mild necroinflammation. In a multivariable logistic regression model, post-SVR HCC was positively associated with non-Caucasian race (p = 0.03), smoking (p = 0.03), age > 60 years at HCC diagnosis (p = 0.03), albumin<3.5 g/dL (p = 0.02), AST/ALT>1 (p = 0.05), and platelets <100 × 10 3 cells/μL (p < 0.001). Alpha fetoprotein ≥4.75 ng/mL had 90% specificity and 71% sensitivity for HCC occurrence. Noncirrhotic patients had larger tumors (p = 0.002) and a higher prevalence of vascular invasion (p = 0.016) than cirrhotic patients., Conclusions: One-third of patients with post-SVR HCC did not have liver cirrhosis; most had no steatosis/steatohepatitis. Hepatocellular carcinomas were more advanced in noncirrhotic patients. Results support AFP as a promising marker of post-SVR HCC risk., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: We previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy., Design: We performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients., Results: Our integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-βcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes., Conclusion: We have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC., Competing Interests: Competing interests: JA and JN are staff scientists from Bristol-Myers Squibb. JML is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha Ltd and AstraZeneca. The remaining coauthors have nothing to disclose related to this manuscript., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Increased life expectancy and improved perioperative management have resulted in increased utilization of hepatectomy for hepatocellular carcinoma (HCC) among elderly patients. However, individualized model for predicting the surgical safety and efficacy is lacking. The present study aimed to develop a safety and efficacy-associated risk calculator for HCC in the elderly after resection (SEARCHER)., Methods: From an international multicenter database, elderly patients who underwent curative-intent hepatectomy for HCC were stratified by patient age: 65-69 years, 70-74 years, 75-79 years, and ≥80 years. Short- and long-term outcomes among the 4 groups were compared. Univariate and multivariate analyses of risk factors of postoperative major morbidity, cancer-specific survival (CSS) and overall survival (OS) were performed in the training cohort. A nomogram-based online calculator was then constructed and validated in the validation cohort., Results: With increasing age, the risk of postoperative major morbidity and worse OS increased (P = 0.001 and 0.020), but not postoperative mortality and CSS (P = 0.577 and 0.890) among patients across the 4 groups. Based on three nomograms to predict major morbidity, CSS and OS, the SEARCHER model was constructed and made available at https://elderlyhcc.shinyapps.io/SEARCHER. The model demonstrated excellent calibration and optimal performance in both the training and validation cohorts, and performed better than the several commonly-used conventional scoring and staging systems of HCC., Conclusions: With higher potential postoperative major morbidity and worse OS as patients age, the decision of whether to perform a hepatectomy for HCC needs to be comprehensively considered in the elderly. The proposed SEARCHER model demonstrated good performance to individually predict safety and efficacy of hepatectomy in elderly patients with HCC., Competing Interests: Declaration of competing interest None reported., (Copyright © 2022 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: Patients with hepatocellular carcinoma (HCC) at Barcelona Clinic Liver Cancer (BCLC) early-stage A (BCLC A) not suitable for surgery are first considered for ablation. Nonetheless, objective responses and long-term results for ablation in tumors larger than 3 to 4 cm are suboptimal, creating an unmet clinical need. This phase 2 trial studied combination of transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT) for BCLC A patients with a solitary HCC from 4 to 7 cm., Methods and Materials: Eligible patients were BCLC A, Child-Pugh score ≤7, Eastern Cooperative Oncology Group performance status 0 presenting with a single HCC from 4 to 7 cm not suitable for resection or liver transplantation. Treatment consisted of 2 sessions of drug-eluting bead-TACE within 1 month followed by immediate SBRT. SBRT delivered 35 to 50 Gy in 5 fractions. The primary endpoint was best objective response rate (ORR) by modified Response Evaluation Criteria in Solid Tumours (mRECIST). Secondary endpoints were overall survival (OS), progression-free survival (PFS), and toxic effects., Results: From 2014 to 2020, 32 were enrolled in a single institution with median follow-up of 37 months. Thirty patients had at least 1 posttreatment scan to assess response. ORR in the target lesion was 91%: 63% complete response (CR; n = 20), 28% partial response (n = 9), and 3% progression of disease (n = 1). Median time to CR was 10.1 months. Median OS was not yet reached and median PFS was 35 months. Patients achieving CR had a trend toward improved PFS (P = .09). Toxic effects were low., Conclusions: This phase 2 trial showed very promising ORR when combining TACE + SBRT in large, unresectable HCC, which translates into excellent OS and PFS. These results provide the rationale for exploring this combination in larger phase 2 and 3 clinical trials and a space where SBRT might offer unique clinical advantage., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: Transarterial 90 Y radioembolization (TARE) is increasingly being used for hepatocellular carcinoma (HCC) treatment. However, tumor response assessment after TARE may be challenging. We aimed to assess the diagnostic performance of gadoxetate disodium MRI for predicting complete pathologic necrosis (CPN) of HCC treated with TARE, using histopathology as the reference standard., Methods: This retrospective study included 48 patients (M/F: 36/12, mean age: 62 years) with HCC treated by TARE followed by surgery with gadoxetate disodium MRI within 90 days of surgery. Two radiologists evaluated tumor response using RECIST1.1, mRECIST, EASL, and LI-RADS-TR criteria and evaluated the percentage of necrosis on subtraction during late arterial, portal venous, and hepatobiliary phases (AP/PVP/HBP). Statistical analysis included inter-reader agreement, correlation between radiologic and pathologic percentage of necrosis, and prediction of CPN using logistic regression and ROC analyses., Results: Histopathology demonstrated 71 HCCs (2.8 ± 1.7 cm, range: 0.5-7.5 cm) including 42 with CPN, 22 with partial necrosis, and 7 without necrosis. EASL and percentage of tumor necrosis on subtraction at the AP/PVP were independent predictors of CPN (p = 0.02-0.03). Percentage of necrosis, mRECIST, EASL, and LI-RADS-TR had fair to good performance for diagnosing CPN (AUCs: 0.78 - 0.83), with a significant difference between subtraction and LI-RADS-TR for reader 2, and in specificity between subtraction and other criteria for both readers (p-range: 0.01-0.04). Radiologic percentage of necrosis was significantly correlated to histopathologic degree of tumor necrosis (r = 0.66 - 0.8, p < 0.001)., Conclusions: Percentage of tumor necrosis on subtraction and EASL criteria were significant independent predictors of CPN in HCC treated with TARE. Image subtraction should be considered for assessing HCC response to TARE when using MRI., Key Points: • Percentage of tumor necrosis on image subtraction and EASL criteria are significant independent predictors of complete pathologic necrosis in hepatocellular carcinoma treated with 90 Y radioembolization. • Subtraction, mRECIST, EASL, and LI-RADS-TR have fair to good performance for diagnosing complete pathologic necrosis in hepatocellular carcinoma treated with 90 Y radioembolization., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Unresectable solitary very early to early stage hepatocellular carcinoma is managed with ablation for curative intent. Radiation segmentectomy is a treatment option that delivers radioactive 90 yttrium ( 90 Y)-bound microspheres transarterially to a segment of liver. The aim of this study was to assess the safety and efficacy of radiation segmentectomy in patients with unresectable hepatocellular carcinoma deemed unfavourable for ablation., Methods: RASER was a single-centre, single-arm study that included adults (>18 years) with solitary hepatocellular carcinoma with unfavourable location for ablation, without metastasis or macrovascular invasion. Eligibility criteria included measurable disease 3 cm or less in diameter, Child-Pugh score A-B7, an Eastern Cooperative Oncology Group score of 0, and adequate haematological and organ function. The primary endpoint was target tumour response measured by mRECIST. Patients were followed up with imaging and office visits for up to 24 months. The trial is registered with ClinicalTrials.gov (NCT03248375), and is completed., Findings: Individuals were enrolled between Aug 3, 2016, and April 4, 2019, and the last patient follow-up occurred on March 31, 2021. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. Initial target lesion complete response was observed in 24 (83%) of 29 patients, and partial response was observed in five (17%) of patients. All patients had an initial objective response and 26 (90%) individuals had a sustained complete response. Four (14%) patients had grade 3 leukopenia and two (7%) had grade 3 thrombocytopenia. There were two (7%) non-laboratory-related grade 3 adverse events (one arterial injury and one ascites). The most frequent (>10% patients) grade 1 or 2 adverse events were fatigue (nine [31%]); nausea, vomiting, or anorexia (seven [24%]); abdominal discomfort (six [21%]), leukopenia (nine [31%]), thrombocytopenia (four [14%]), increased alkaline phosphatase (four [14%]), increased alanine or aspartate aminotransferase (four [14%]), increased bilirubin (four [14%]), and decreased albumin (six [21%]). There was one death that was not treatment related., Interpretation: Radiation segmentectomy was efficacious, with a low proportion of high-grade adverse events in patients with unresectable very early to early stage hepatocellular carcinoma with suboptimal location for ablation. These results suggest that radiation segmentectomy should be further investigated as a potential curative treatment option for well selected patients., Funding: Boston Scientific., Competing Interests: Declaration of interests EK receives grant support, consulting fees, and is on the medical advisory board of Boston Scientific. RL is on the medical advisory board of Boston Scientific. AF receives royalties from Merit Medical; stock in Adient Medical; and consulting fees from Boston Scientific, Terumo, and Embolx. JL recieves grant support from Bayer Healthcare Pharmaceuticals, Eisai Inc, Boehringer-Ingelheim, and Ipsen; and consulting fees from Eli Lilly, Bayer, Merck, Bristol-Myers Squibb, Ipsen, Glycotest, Genentech, Roche, and AstraZeneca. PT received an honorarium from Bayer. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Because of the increased number of sequential treatments used for advanced hepatocellular carcinoma (HCC), there is a need for surrogate endpoints of overall survival (OS). We analyze whether objective response (OR) is an independent predictor and surrogate endpoint of OS., Patients and Methods: A systematic review of randomized clinical trials (RCT) in advanced HCC published between 2010 and 2020 was conducted to explore OS surrogacy of OR by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). In parallel, RCTs exploring the impact of OR on OS in a time-dependent multivariate analysis were integrated in a meta-analysis., Results: Of 65 RCTs identified in advanced HCC, we analyzed 34 studies including 14,056 patients that reported OS and OR by either RECIST (n = 23), mRECIST (n = 5), or both (n = 6). When exploring surrogacy, the trial-level correlation between OR odds ratio and OS HR was R = 0.677 by mRECIST and R = 0.532 by RECIST. Meta-analysis of five RCTs assessing predictors of survival in multivariate analysis found that patients with OR by mRECIST presented a pooled HR for OS of 0.44 (95% confidence interval, 0.27-0.70; P < 0.001) compared with nonresponders. Responses to atezolizumab-bevacizumab had a greater impact on OS than tyrosine kinase inhibitor responses., Conclusions: OR-mRECIST is an independent predictor of OS in patients with advanced HCC. Although correlation of OR-mRECIST and OS is better than with OR-RECIST, the level of surrogacy is modest. Thus, it can be used as endpoint in proof-of-concept phase II trials, but the data do not support its use as a primary endpoint of phase III investigations assessing systemic therapies., (©2021 American Association for Cancer Research.)

Background: Immune checkpoint inhibitors (ICIs) have revolutionized treatment of advanced hepatocellular carcinoma. Integrated use of transarterial chemoembolization (TACE), a locoregional inducer of immunogenic cell death, with ICI has not been formally assessed for safety and efficacy outcomes., Methods: From a retrospective multicenter dataset of 323 patients treated with ICI, we identified 31 patients who underwent >1 TACE 60 days before or concurrently, with nivolumab at a single center. We derived a propensity score-matched cohort of 104 patients based on Child-Pugh Score, portal vein thrombosis, extrahepatic metastasis and alpha fetoprotein (AFP) who received nivolumab monotherapy. We described overall survival (OS), progression-free survival (PFS), objective responses according to modified RECIST criteria and safety in the multimodal arm in comparison to monotherapy., Results: Over a median follow-up of 9.3 (IQR 4.0-16.4) months, patients undergoing multimodal immunotherapy with TACE achieved a significantly longer median (95% CI) PFS of 8.8 (6.2-23.2) vs 3.7 (2.7-5.4) months (log-rank 0.15, p<0.01) in the monotherapy group. Multimodal immunotherapy with TACE demonstrated a numerically longer OS compared with ICI monotherapy with a median 35.1 (16.1-Not Evaluable) vs 16.6 (15.7-32.6) months (log-rank 0.41, p=0.12). In the multimodal treatment group, there were three (10%) grade 3 or higher adverse events (AEs) attributed to immunotherapy compared with seven (6.7%) in the matched ICI monotherapy arm. There were no AEs grade 3 or higher attributed to TACE in the multimodal treatment arm. At 3 months following each TACE in the multimodal arm, there was an overall objective response rate of 84%. There were no significant changes in liver functional reserve 1 month following each TACE. Four patients undergoing multimodal treatment were successfully bridged to transplant., Conclusions: TACE can be safely integrated with programmed cell death 1 blockade and may lead to a significant delay in tumor progression and disease downstaging in selected patients., Competing Interests: Competing interests: EK is a consultant for Koninklijke Philips Electronics (Amsterdam, Netherlands) and is on the advisory board for Onyx Pharmaceuticals (South San Francisco, California) and the speaker’s bureau for BTG International (West Conshohocken, Pennsylvania). RP is a consultant for Sirtex Medical (North Sydney, Australia) and Arstasis (Fremont, California). AF is a consultant for Surefire Medical (Westminster, Colorado) and Terumo Medical Corporation (Somerset, New Jersey) and is on the advisory board for Terumo Medical Corporation. DB is a consultant for Bayer Healthcare, Boston Scientific and Shionogi and lecturer for Falk Foundation. YH has research grants from Gilead Sciences and Bristol Myers Squibb and honoraria from Abbvie, Gilead Sciences, Bristol Myers Squibb, Ono Pharmaceutical, Merck Sharp & Dohme, Eisai, Eli Lilly, Ipsen and Roche, and serves as advisor for Abbvie, Gilead Sciences, Bristol Myers Squibb, Ono Pharmaceuticals, Eisai, Eli Lilly, Ipsen, Merck Sharp & Dohme and Roche. AS has research grants from AstraZeneca, Merck, Bristol Myers Squibb, Exelixis and Clovis and receives advisory board/consultant fees from AstraZeneca, Merck, Bristol Myers Squibb, Exelixis and Pfizer. AP is on the medical advisory board for Exelixis, Eisai, AstraZeneca and Genentech, safety review committee for Replimune and on the speaking bureau for Simply Speaking Hepatitis. MK is a consultant for Eisai, Ono Pharmaceutical Co, Merck Sharpe & Dohme Corp, Bristol Meyer Squibb and Roche; research contracts grants from Ono Pharmaceutical Co; grants from Eisai, Takeda, Otsuka, Taiho, EQ pharma, Gilead Sciences, Abbvie, Sumitomo Dainippon Pharma, Chugai, Ono Pharmaceutical; and is an honorary lecturer for Eisai, Bayer, Merck Sharpe & Dohme Corp, Bristol Meyer Squibb, EA Pharma, Eli Lilly and Chugai. TUM has served as an advisor and/or data-safety boards for Regeneron, Boehringer Ingelheim, Atara, Genentech, AstraZeneca, Chimeric Therapeutics, Riboscience, Celldex and Rockefeller University, and has research grants from Regeneron, Bristol-Myers Squibb and Boehringer Ingelheim. None of the other authors have identified a conflict of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To assess response to programmed death-1 (PD-1) monotherapy (nivolumab) in hepatocellular carcinoma (HCC) patients using RECIST1.1, modified RECIST (mRECIST), and immune RECIST (iRECIST). A secondary objective was to identify clinicolaboratory and imaging variables predictive of progressive disease (PD) and overall survival (OS)., Methods: Patients with HCC treated with nivolumab at a single institution from 5/2016 to 12/2019 with MRI or CT performed ≥ 4 weeks post treatment were retrospectively assessed. Patients who received concurrent locoregional, radiation, or other systemic therapies were excluded. Response was assessed by 2 observers in consensus using RECIST1.1, mRECIST, and iRECIST at 3/6/9/12-month time points. Time to progression (TTP) and OS were recorded. Clinicolaboratory and imaging variables were evaluated as predictors of PD and OS using uni-/multivariable and Cox regression analyses., Results: Fifty-eight patients (42M/16F) were included. 118 target lesions (TL) were identified before treatment. Baseline mean TL size was 49.1 ± 43.5 mm (range 10-189 mm) for RECIST1.1/iRECIST and 46.3 ± 42.3 mm (range 10-189 mm) for mRECIST. Objective response rate (ORR) was 21% for mRECIST/iRECIST/RECIST1.1, with no cases of pseudoprogression. Median OS and median TTP were 717 days and 127 days for RECIST1.1/mRECIST/iRECIST-iUPD (unconfirmed PD). Older age, MELD/Child-Pugh scores, AFP, prior transarterial radioembolization (TARE), and larger TL size were predictive of PD and/or poor OS using mRECIST/iRECIST. The strongest predictor of PD (HR = 2.49, 95% CI 1.29-4.81, p = 0.007) was TARE. The strongest predictor of poor OS was PD by mRECIST/iRECIST at 3 months (HR = 2.26, 95% CI 1.00-5.10, p = 0.05) with borderline significance., Conclusion: Our results show ORR of 21%, equivalent for mRECIST, iRECIST, and RECIST1.1 in patients with advanced HCC clinically treated with nivolumab., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background & Aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with a rapidly changing landscape of treatments. In the past 20 years, numerous randomized controlled trials (RCTs) have aimed at improving outcomes across disease stages. We aimed to analyze the current evidence and identify potential factors influencing response to therapies., Methods: We conducted a systematic review of phase III RCTs (2002-2020) across disease stages. A meta-analysis was designed to examine the relationship between etiology and outcome after systemic therapies with either tyrosine-kinase inhibitor (TKI)/antiangiogenic or immune checkpoint inhibitor (ICI) therapy., Results: Out of 10,100 studies identified, 76 were phase III RCTs. Among them, a rigorous screening algorithm identified 49 with high quality including a total of 22,113 patients undergoing adjuvant (n = 7) and primary treatment for early (n = 2), intermediate (n = 7), and advanced (first-line, n = 21; second-line, n = 12) stages of disease. Nine of these trials were positive, 6 treatments have been adopted in guidelines (sorafenib [2 RCTs], lenvatinib, atezolizumab+bevacizumab, regorafenib, cabozantinib and ramucirumab), but 2 were not (adjuvant CIK cells and sorafenib plus hepatic arterial infusion with FOLFOX). Meta-analysis of 8 trials including 3739 patients revealed ICI therapy to be significantly more effective in patients with viral hepatitis compared with nonviral-related HCC, whereas no differences related to etiology were observed in patients treated with TKI/anti-vascular endothelial growth factor., Conclusions: Among 49 high-quality RCTs conducted in HCC during 2002-2020, 9 resulted in positive results. A meta-analysis of systemic therapies suggests that immunotherapies may be more effective in viral etiologies., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The epidemiology of hepatitis B virus (HBV) infection differs between Asians and non-Asians, but little is known regarding the effect of ethnicity on outcomes of HBV-related hepatocellular carcinoma (HCC). We aim to characterize the presentation and survival outcomes in Asian and non-Asian patients with HBV-related HCC., Methods: We analyzed the baseline characteristics and long-term survival of 613 Asian and 410 non-Asian patients with HBV-related HCC from three US and one Spanish centre., Results: Overall, non-Asian patients were more likely to have HIV or hepatitis C co-infection, cirrhosis, decompensated liver disease and advanced BCLC stage (all P ≤ .04). Compared with Asians, non-Asians were more likely to be listed for transplantation (P < .0001) and undergo HCC treatment with curative intent (P = .003). Propensity-score matching on HCC diagnosis year, gender and age was performed to balance the two groups for survival analysis and yielded 370 pairs of patients. There was no significant difference in survival overall (P = .43) and among patients with cirrhosis (P = .57). Among patients without cirrhosis, non-Asians had poorer 5-year survival compared with Asians (37.6% vs 53.7%, P = .01), and was associated with poorer survival after adjusting for age, gender, diabetes, alcohol, co-infections, diagnosis date, antiviral therapy, BCLC stage and HCC treatment (adjusted HR 2.01 [95% CI 1.07-3.74], P = .03)., Conclusion: Among HBV-related HCC patients, non-Asians presented with more advanced BCLC stage compared to Asians. Non-Asian ethnicity was independently associated with twice the risk of mortality among patients without cirrhosis, but not among those with cirrhosis. Additional studies are needed to clarify this disparity., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To quantify hepatocellular carcinoma (HCC) and liver parenchyma stiffness using MR elastography (MRE) and serum alpha fetoprotein (AFP), before and 6 weeks (6w) after 90 Y radioembolisation (RE), and to assess the value of baseline tumour and liver stiffness (TS/LS) and AFP in predicting response at 6w and 6 months (6 m)., Methods: Twenty-three patients (M/F 18/5, mean age 68.3 ± 9.3 years) scheduled to undergo RE were recruited into this prospective single-centre study. Patients underwent an MRI exam at baseline and 6w following RE (range 39-47 days) which included MRE using a prototype 2D EPI sequence. TS, peritumoural LS/LS remote from the tumour, tumour size, and AFP were measured at baseline and at 6w. Treatment response was determined using mRECIST at 6w and 6 m., Results: MRE was technically successful in 17 tumours which were classified at 6w as complete response (CR, n = 7), partial response (PR, n = 4), and stable disease (SD, n = 6). TS and peritumoural LS were significantly increased following RE (p = 0.016, p = 0.039, respectively), while LS remote from tumour was unchanged (p = 0.245). Baseline TS was significantly lower in patients who achieved CR at 6w (p = 0.014). Baseline TS, peritumoural LS (both AUC = 0.857), and AFP (AUC = 0.798) showed fair/excellent diagnostic performance in predicting CR at 6w, but were not significant predictors of OR or CR at 6 m., Conclusion: Our initial results suggest that HCC TS and peritumoural LS increase early after RE. Baseline TS, peritumoural LS, and AFP were all significant predictors of CR to RE at 6w. These results should be confirmed in a larger study., Key Points: • Magnetic resonance elastography-derived tumour stiffness and peritumoural liver stiffness increase significantly at 6 weeks post radioembolisation whereas liver stiffness remote from the tumour is unchanged. • Baseline tumour stiffness and peritumoural liver stiffness are lower in patients who achieve complete response at 6 weeks post radioembolisation. • Baseline tumour size is significantly correlated with baseline tumour stiffness., (© 2021. European Society of Radiology.)

Background and Aims: Mutations in TERT (telomerase reverse transcriptase) promoter are established gatekeepers in early hepatocarcinogenesis, but little is known about other molecular alterations driving this process. Epigenetic deregulation is a critical event in early malignancies. Thus, we aimed to (1) analyze DNA methylation changes during the transition from preneoplastic lesions to early HCC (eHCC) and identify candidate epigenetic gatekeepers, and to (2) assess the prognostic potential of methylation changes in cirrhotic tissue., Approach and Results: Methylome profiling was performed using Illumina HumanMethylation450 (485,000 cytosine-phosphateguanine, 96% of known cytosine-phosphateguanine islands), with data available for a total of 390 samples: 16 healthy liver, 139 cirrhotic tissue, 8 dysplastic nodules, and 227 HCC samples, including 40 eHCC below 2cm. A phylo-epigenetic tree derived from the Euclidean distances between differentially DNA-methylated sites (n = 421,997) revealed a gradient of methylation changes spanning healthy liver, cirrhotic tissue, dysplastic nodules, and HCC with closest proximity of dysplasia to HCC. Focusing on promoter regions, we identified epigenetic gatekeeper candidates with an increasing proportion of hypermethylated samples (beta value > 0.5) from cirrhotic tissue (<1%), to dysplastic nodules (≥25%), to eHCC (≥50%), and confirmed inverse correlation between DNA methylation and gene expression for TSPYL5 (testis-specific Y-encoded-like protein 5), KCNA3 (potassium voltage-gated channel, shaker-related subfamily, member 3), LDHB (lactate dehydrogenase B), and SPINT2 (serine peptidase inhibitor, Kunitz type 2) (all P < 0.001). Unsupervised clustering of genome-wide methylation profiles of cirrhotic tissue identified two clusters, M1 and M2, with 42% and 58% of patients, respectively, which correlates with survival (P < 0.05), independent of etiology., Conclusions: Genome-wide DNA-methylation profiles accurately discriminate the different histological stages of human hepatocarcinogenesis. We report on epigenetic gatekeepers in the transition between dysplastic nodules and eHCC. DNA-methylation changes in cirrhotic tissue correlate with clinical outcomes., (© 2020 by the American Association for the Study of Liver Diseases.)

Cancer testis antigens (CTAs) are an extensive gene family with a unique expression pattern restricted to germ cells, but aberrantly reactivated in cancer tissues. Studies indicate that the expression (or re-expression) of CTAs within the MAGE-A family is common in hepatocellular carcinoma (HCC). However, no systematic characterization has yet been reported. The aim of this study is to perform a comprehensive profile of CTA de-regulation in HCC and experimentally evaluate the role of MAGEA3 as a driver of HCC progression. The transcriptomic analysis of 44 multi-regionally sampled HCCs from 12 patients identified high intra-tumor heterogeneity of CTAs. In addition, a subset of CTAs was significantly overexpressed in histologically poorly differentiated regions. Further analysis of CTAs in larger patient cohorts revealed high CTA expression related to worse overall survival and several other markers of poor prognosis. Functional analysis of MAGEA3 was performed in human HCC cell lines by gene silencing and in a genetic mouse model by overexpression of MAGEA3 in the liver. Knockdown of MAGEA3 decreased cell proliferation, colony formation and increased apoptosis. MAGEA3 overexpression was associated with more aggressive tumors in vivo. In conclusion MAGEA3 enhances tumor progression and should be considered as a novel therapeutic target in HCC., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AL has received grant support from Pfizer and Genentech, and lecture fees from Exelixis for unrelated projects. MRdG has received grant support from Genentech for unrelated projects. AV has received consulting fees from Guidepoint and Fujifilm; advisory board fees from Exact Sciences, Nucleix and NGM Pharmaceuticals. JML has received grant support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen and consulting fees from Bayer HealthCare Pharmaceuticals, Merck, Eisai Inc, Bristol-Myers Squibb, Celsion Corporation, Eli Lilly, Roche, Genentech, Glycotest, Nucleix, Can-Fite Biopharma, AstraZeneca, and Exelixis.

Background: Evidence-based decision-making is critical to optimize the benefits and mitigate futility associated with surgery for patients with malignancies. Untreated hepatocellular carcinoma (HCC) has a median survival of only 6 months. The objective was to develop and validate an individualized patient-specific tool to predict preoperatively the benefit of surgery to provide a survival benefit of at least 6 months following resection., Methods: Using an international multicenter database, patients who underwent curative-intent liver resection for HCC from 2008 to 2017 were identified. Using random assignment, two-thirds of patients were assigned to a training cohort with the remaining one-third assigned to the validation cohort. Independent predictors of postoperative death within 6 months after surgery for HCC were identified and used to construct a nomogram model with a corresponding online calculator. The predictive accuracy of the calculator was assessed using C-index and calibration curves., Results: Independent factors associated with death within 6 months of surgery included age, Child-Pugh grading, portal hypertension, alpha-fetoprotein level, tumor rupture, tumor size, tumor number and gross vascular invasion. A nomogram that incorporated these factors demonstrated excellent calibration and good performance in both the training and validation cohorts (C-indexes: 0.802 and 0.798). The nomogram also performed better than four other commonly-used HCC staging systems (C-indexes: 0.800 vs. 0.542-0.748)., Conclusions: An easy-to-use online prediction calculator was able to identify patients at highest risk of death within 6 months of surgery for HCC. The proposed online calculator may help guide surgical decision-making to avoid futile surgery for patients with HCC.

Hepatobiliary cancers which include hepatocellular carcinoma (HCC) and biliary tract cancers (i.e., cholangiocarcinoma and gallbladder carcinoma) are associated with significant morbidity and mortality based on the stage of the disease at presentation. With improved screening for hepatobiliary malignancies in patients with risk factors and with widespread use of laparoscopic cholecystectomy, hepatobiliary malignancies, including incidental diagnosis of gallbladder carcinoma, are on the rise. Definitive treatment of hepatobiliary malignancies include surgical resection, ablation, and liver transplantation. However, management of these cancers is challenging due to the complex hepatobiliary anatomy and the need for meticulous perioperative management especially in patients with advanced liver disease. The management and prognosis of hepatobiliary malignancies vary widely based on the stage of presentation, with surgical options providing the possibility of definitive cure in patients presenting with early-stage disease. Surgical resection for HCC results in good outcomes if performed in ideal candidates. For patients with early HCC who are not candidates for surgical resection, ablation and liver transplantation should be considered. Similarly, surgical resection is also the definitive treatment for biliary tract cancers, and liver transplantation can be curative in selected patients with perihilar cholangiocarcinoma after neoadjuvant chemoradiotherapy. The role of routine adjuvant chemotherapy and radiotherapy is not clearly established, but adjuvant therapies can offer better outcomes in patients with advanced disease at presentation. Outcomes of surgical management of hepatobiliary cancers seem to be improving. Given the complex decision-making process involved, multidisciplinary evaluation is essential to provide and coordinate the best treatments for these patients., (© 2020 by the American Association for the Study of Liver Diseases.)

Little is known about the mutational landscape of advanced hepatocellular carcinoma (HCC), and predictive biomarkers of response to systemic therapies are lacking. We aimed to describe the mutational landscape of advanced HCC and to identify predictors of primary resistance to systemic therapies using circulating tumor DNA (ctDNA). We prospectively enrolled 121 patients between October 2015 and January 2019. We performed targeted ultra-deep sequencing of 25 genes and Digital Droplet PCR of TERT promoter, including sequential samples throughout treatment. Primary endpoint was progression-free survival (PFS) stratified by mutation profiles in ctDNA. Secondary endpoints were overall survival and objective response rate. The most frequent mutations in ctDNA of advanced HCC were TERT promoter (51%), TP53 (32%), CTNNB1 (17%), PTEN (8%), AXIN1, ARID2, KMT2D, and TSC2 (each 6%). TP53 and CTNNB1 mutations were mutually exclusive. Patients with mutations in the PI3K/MTOR pathway had significantly shorter PFS than those without these mutations after tyrosine kinase inhibitors (2.1 vs 3.7 months, p < 0.001), but not after immune checkpoint inhibition (CPI). WNT pathway mutations were not associated with PFS, overall survival, or objective response after CPI. Serial profiling of ctDNA in a subset correlated with treatment response. Mutation profiling of ctDNA in advanced HCC shows similar mutation frequencies for known HCC drivers compared to early stages and identifies predictive biomarkers of response to systemic therapies.

Objective: Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention., Design: Liver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by i n vivo and ex vivo validation were used to identify chromatin modifiers and readers for HCC chemoprevention., Results: In patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients., Conclusion: Our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases., Competing Interests: Competing interests: The University of Strasbourg, INSERM, the IHU Strasbourg and Mount Sinai Hospital have filed a patent application on the clinical gene signature-based human cell culture model and uses thereof with YH and TFB as co-inventors (WO 2016174130 A1), which has been licensed to Alentis Therapeutics, Basel, Switzerland., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To develop an easy-to-use model to predict the probability of perioperative blood transfusion (PBT) in patients undergoing liver resection for hepatocellular carcinoma (HCC)., Method: 878 patients from Eastern Hepatobiliary Surgery Hospital of Shanghai were enrolled in the training cohort, while 691 patients from Tongji Hospital of Wuhan and 364 patients from two hospitals from Europe and America served as the Eastern and Western external validation cohorts, respectively. Independent predictors of PBT were identified and used for the nomogram construction. The predictive performance of the model was assessed using the concordance index (C-index) and calibration plot, and externally validated using the two independent cohorts. This model was compared with four currently available prediction risk scores., Results: Eight preoperative variables were identified as independent predictors of PBT, which were incorporated into the new nomogram model, with a C-index of 0.833 and a well-fitted calibration plot. The nomogram performed well on the externally Eastern and Western validation cohorts (C-indexes: 0.786 and 0.777). The discriminatory ability of the nomogram was superior to the four currently available prediction scores (C-indexes: 0.833 vs. 0.671-0.770). The nomogram was programmed into an online calculator, which is available at http://www.asapcalculate.top/Cal3&#95;en.html., Conclusion: A nomogram model, using an easy-to-access website, can be used to calculate the PBT risk and identify which patients undergoing HCC resection are at high risks of PBT and can benefit most by using blood conservation techniques., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: To assess the safety of locoregional treatment (LRT) combined with nivolumab for intermediate and advanced hepatocellular carcinoma (HCC)., Materials and Methods: A single-center retrospective review included 29 patients undergoing 41 LRTs-transarterial chemoembolization or yttrium-90 transarterial radioembolization-60 days before or concurrently with nivolumab. Demographic, clinical, and laboratory values and adverse events were reviewed before and after nivolumab initiation and after each LRT. Treatment response and time to progression were assessed using Modified Response Evaluation Criteria in Solid Tumors. Clinical events, including nivolumab termination, death, and time of last follow-up, were assessed., Results: Over a median nivolumab course of 8.1 months (range, 1.0-30) with a median of 14.2 2-week cycles (range, 1-53), predominantly Child-Pugh A (22/29) patients-12 Barcelona Clinic Liver Cancer (BCLC) B and 17 BCLC C-underwent 20 transarterial chemoembolization and 21 transarterial radioembolization LRTs at a median of 67 days (range, 48-609) after nivolumab initiation. Ten patients underwent multiple LRTs. During a median follow-up of 11.5 months (range, 1.8-35.1), no grade III/IV adverse events attributable to nivolumab were observed. There were five instances of grade III/IV hypoalbuminemia or hyperbilirubinemia within 3 months after LRT. There were no nivolumab-related deaths, and 30-day mortality after LRT was 0%., Conclusions: LRTs performed concurrently with nivolumab immunotherapy demonstrate an acceptable safety profile in patients with intermediate and advanced HCC., (Copyright © 2020 SIR. Published by Elsevier Inc. All rights reserved.)

Metabolic-associated fatty liver disease (MAFLD) is a major cause of liver-related complications, including hepatocellular carcinoma (HCC). While MAFLD-related HCC is known to occur in the absence of cirrhosis, our understanding of MAFLD-related HCC in this setting is limited. Here, we characterize MAFLD-related HCC and the impact of cirrhosis and screening on survival. This was a multicenter, retrospective, cohort study of MAFLD-related HCC. MAFLD was defined based on the presence of race-adjusted overweight, diabetes, or both hypertension and dyslipidemia in the absence of excess alcohol use or other underlying cause of liver disease. The primary outcome of interest was overall survival, and the primary dependent variables were cirrhosis status and prior HCC screening. We used Kaplan-Meier methods to estimate overall survival and Cox proportional hazards models and random forest machine learning to determine factors associated with prognosis. This study included 1,382 patients from 11 centers in the United States and East/Southeast Asia. Cirrhosis was present in 62% of patients, but under half of these patients had undergone imaging within 12 months of HCC diagnosis. Patients with cirrhosis were more likely to have early stage disease but less often received curative therapy. After adjustment, cirrhosis was not associated with prognosis, but the presence of cancer-related symptoms at diagnosis was associated with poorer prognosis. Conclusion: Cirrhosis was not associated with overall survival in this cohort of MAFLD-related HCC, while diagnosis in the presence of symptoms was associated with poorer prognosis. The HCC surveillance rate in patients with MAFLD-related HCC was disappointingly low in a multicenter cohort., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Purpose: To quantify diffusion and perfusion changes in hepatocellular carcinoma (HCC) induced by yttrium 90 ( 90 Y) radioembolization and to assess the value of dynamic contrast material-enhanced (DCE) MRI and intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) for predicting HCC response., Materials and Methods: Institutional review board approval was obtained for this prospective study (clinical trial registry NCT01871545). Twenty-four participants with HCC (mean age, 69 years ± 9 [standard deviation], 18 men) underwent multiparametric MRI, including IVIM DWI and gadoxetic acid DCE MRI before ( n = 24) and 6 weeks ( n = 21) after radioembolization. IVIM DWI and DCE MRI histogram parameters were quantified in HCCs and liver parenchyma. HCC response was assessed by using modified Response Evaluation Criteria in Solid Tumors at 6 weeks and 6-12 months after radioembolization. Logistic regression analysis was used to evaluate the diagnostic performance of baseline MRI and clinical parameters for prediction of response., Results: Twenty-five HCCs were analyzed (mean size, 3.6 cm ± 1.9). Radioembolization resulted in significantly decreased perfusion (DCE MRI arterial flow, P = .002; IVIM pseudodiffusion coefficient [ D* ], P = .014). Multivariate logistic regression selected combined serum α-fetoprotein and portal flow ( F p ) skewness (area under the curve [AUC] = 0.924) and combined D* standard deviation and F p kurtosis (AUC = 0.916) for prediction of objective and complete response at 6 weeks, respectively. Standard deviation of DCE MRI parameter arterial fraction was selected as the optimal predictor for complete response at 6-12 months (AUC = 0.857)., Conclusion: Diffusion and perfusion MRI can be used to evaluate the response of HCC to radioembolization. Pretreatment DCE MRI histogram parameters may be useful for radioembolization treatment stratification. Supplemental material is available for this article. © RSNA, 2020., (2020 by the Radiological Society of North America, Inc.)

Background: Currently, there are no recognized or validated biomarkers to identify hepatocellular carcinoma patients (HCC) likely to benefit from anti-PD-1 therapy. We evaluated the relationship between neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) and survival outcomes, pretreatment and after three doses (posttreatment) of nivolumab in HCC patients., Methods: Medical records of HCC patients treated with nivolumab between June 2016 and July 2018 were reviewed. Kaplan-Meier analysis and the log-rank test were used to calculate and compare overall survival between NLR < 5 Vs ≥ 5 and among PLR tertiles., Results: A total of 103 patients were identified. Median age was 66 (29-89) years. Median treatment duration was 26 (2-149) weeks. Sixty-four (62%) patients had Child-Pugh class A (CP-A) liver function. Barcelona Clinic Liver Cancer stage was B in 20 (19%) and C in 83 (81%) patients. CP-A patients who achieved a partial or complete response had significantly lower posttreatment NLR and PLR (P < .001 for both) compared to patients who had stable disease or progression of disease. No relationship was observed between response and pretreatment NLR and PLR. NLR < 5 was associated with improved OS compared to NLR ≥ 5 both pretreatment (23 Vs10 months, P = .004) and posttreatment (35 Vs 9 months, P < .0001). Survival also differed significantly among PLR tertiles both pre- (P = .05) and posttreatment (P = .013). In a multivariable model, posttreatment NLR (HR = 1.10, P < .001) and PLR (HR = 1.002, P < .001) were strongly associated with survival. In a composite model of posttreatment NLR and PLR, a combination of high NLR and PLR was associated with an eightfold increased risk of death (HR = 8.3, P < .001)., Conclusions: This study suggests a strong predictive role of these inflammatory cell ratios in the posttreatment setting in HCC patients treated with anti anti-PD-1 therapy and should be evaluated in a larger cohort., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To assess the value of qualitative and quantitative MRI radiomics features for noninvasive prediction of immuno-oncologic characteristics and outcomes of hepatocellular carcinoma (HCC)., Methods: This retrospective, IRB-approved study included 48 patients with HCC (M/F 35/13, mean age 60y) who underwent hepatic resection or transplant within 4 months of abdominal MRI. Qualitative imaging traits, quantitative nontexture related and texture features were assessed in index lesions on contrast-enhanced T1-weighted and diffusion-weighted images. The association of imaging features with immunoprofiling and genomics features was assessed using binary logistic regression and correlation analyses. Binary logistic regression analysis was also employed to analyse the association of radiomics, histopathologic and genomics features with radiological early recurrence of HCC at 12 months., Results: Qualitative (r = - 0.41-0.40, p < 0.042) and quantitative (r = - 0.52-0.45, p < 0.049) radiomics features correlated with immunohistochemical cell type markers for T-cells (CD3), macrophages (CD68) and endothelial cells (CD31). Radiomics features also correlated with expression of immunotherapy targets PD-L1 at protein level (r = 0.41-0.47, p < 0.029) as well as PD1 and CTLA4 at mRNA expression level (r = - 0.48-0.47, p < 0.037). Finally, radiomics features, including tumour size, showed significant diagnostic performance for assessment of early HCC recurrence (AUC 0.76-0.80, p < 0.043), while immunoprofiling and genomic features did not (p = 0.098-0929)., Conclusions: MRI radiomics features may serve as noninvasive predictors of HCC immuno-oncological characteristics and tumour recurrence and may aid in treatment stratification of HCC patients. These results need prospective validation., Key Points: • MRI radiomics features showed significant associations with immunophenotyping and genomics characteristics of hepatocellular carcinoma. • Radiomics features, including tumour size, showed significant associations with early hepatocellular carcinoma recurrence after resection.

Background: A clear definition of "early recurrence" after hepatocellular carcinoma (HCC) resection is still lacking. This study aimed to determine the optimal cutoff between early and late HCC recurrence, and develop nomograms for pre- and postoperative prediction of early recurrence., Methods: Patients undergoing HCC resection were identified from a multi-institutional Chinese database. Minimum P-value approach was adopted to calculate optimal cut-off to define early recurrence. Pre- and postoperative risk factors for early recurrence were identified and further used for nomogram construction. The results were externally validated by a Western cohort., Results: Among 1501 patients identified, 539 (35.9%) were recurrence-free. The optimal length to distinguish between early (n = 340, 35.3%) and late recurrence (n = 622, 64.7%) was 8 months. Multivariable logistic regression analyses identified 5 preoperative and 8 postoperative factors for early recurrence, which were further incorporated into preoperative and postoperative nomograms (C-index: 0.785 and 0.834). The calibration plots for the probability of early recurrence fitted well. The nomogram performance was maintained using the validation dataset (C-index: 0.777 for preoperative prediction and 0.842 for postoperative prediction)., Conclusions: An interval of 8 months was the optimal threshold for defining early HCC recurrence. The two web-based nomograms have been published to allow accurate pre- and postoperative prediction of early recurrence. These may offer useful guidance for individual treatment or follow up for patients with resectable HCC., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

It would be impossible to summarise all of the significant developments in the surgical management of hepatocellular carcinoma (HCC), even just over the past year, in a manuscript of this scope. Thus, we have selected topics for discussion that are the subject of current controversy and have attempted to present balanced points of view. Hepatic resection and transplantation are both mature modalities, and for the most part technical advances and improvements in candidate selection are incremental. The ability to readily cure hepatitis C stands out as the most impactful development in the field over recent years, especially in Western countries where hepatitis C has long been the chief aetiology underlying HCC and a predictor of poor outcomes after surgery, but its full implications remain to be clarified. The rising incidence of non-alcoholic steatohepatitis-related HCC and what it means with regard to surgical HCC management is an area of great current interest. With advancing technology, non-surgical locoregional treatments are gaining increasing application as potentially curative therapies. In addition, the advances in molecular and genomic assessment of HCC hold promise for personalising treatment and prognostication. The possible role of immunotherapy as an adjuvant to resection is being aggressively investigated. While liver surgery maintains an important role, the care of patients with HCC is more and more a team effort and needs to take place in the context of a well-integrated interdisciplinary programme to achieve the best outcomes for patients., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: To evaluate the diagnostic performance of contrast-enhanced CT vs. MRI with extracellular contrast agents (EC-MRI) vs. MRI with gadoxetic acid (EOB-MRI) for HCC detection in patients with liver cirrhosis using liver explant as the reference. The additional value of hepatobiliary phase (HBP) post Gadoxetic acid was also assessed., Methods: Two-hundred seventy-seven consecutive patients who underwent liver transplantation over a 9 year period and imaging within 90 days of were retrospectively included. Imaging consisted in CT (n = 100), EC-MRI (n = 77) and EOB-MRI (n = 100), the latter subdivided into dynamic EOB-MRI and full EOB-MRI (dynamic+HBP). Three radiologists retrospectively categorized lesions ≥ 1 cm using the LI-RADSv2017 algorithm. Dynamic EOB-MRI was re-evaluated with the addition of HBP. Results were correlated with explant pathology., Results: Pathology demonstrated 265 HCCs (mean size 2.1 ± 1.4 cm) in 177 patients. Per-patient sensitivities were 86.3% for CT, 89.5% for EC-MRI, 92.8% for dynamic EOB-MRI and 95.2% for full EOB-MRI (pooled reader data), with a significant difference between CT and dynamic/full EOB-MRI (p = 0.032/0.002), and between EC-MRI and full EOB-MRI (p = 0.047). Per-lesion sensitivities for CT, EC-MRI, dynamic EOB-MRI and full EOB-MRI were 59.5%,78.5%,69.7% and 76.8%, respectively, with a significant difference between MRI groups and CT (p-range:0.001-0.04), and no difference between EC-MRI and dynamic EOB-MRI (p = 0.949). For HCCs 1-1.9 cm, sensitivities were 34.4%, 64.6%, 57.3% and 67.3%, respectively, with all MRI groups significantly superior to CT (p ≤ 0.01) and full EOB-MRI superior to dynamic EOB-MRI (p = 0.002)., Conclusions: EOB-MRI outperforms CT and EC-MRI for per-patient HCC detection sensitivity, and is equivalent to EC-MRI for per-lesion sensitivity. MRI methods outperform CT for detection of HCCs 1-1.9 cm., Key Points: • MRI is superior to CT for HCC detection in patients with liver cirrhosis. • EOB-MRI outperforms CT and MRI using extracellular contrast agents (EC-MRI) for per-patient HCC detection sensitivity, and is equivalent to EC-MRI for per-lesion sensitivity. • The addition of hepatobiliary phase images improves HCC detection when using gadoxetic acid.

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.

Hepatitis C virus infection has been the most common etiology in HCC-related liver transplantation (LT). Since 2014, direct-acting antivirals (DAAs) have dramatically improved HCV cure. We aimed to study the changing pattern of etiologies and impact in outcome in HCC-related LT according to HCV treatment-era through retrospective analysis of the Scientific Registry of Transplant Recipients (SRTR) database (1987-2017). A total of 27 855 HCC-related liver transplants were performed (median age 59 years, 77% male). In the DAA era (2014-2017) there has been a 14.6% decrease in LT for HCV-related HCC; however, HCV remains the most common etiology in 50% of cases. In the same era, there has been a 50% increase in LT for NAFLD-related HCC. Overall survival was significantly worse for HCV-related HCC compared to NAFLD-related HCC during pre-DAA era (2002-2013; P = .031), but these differences disappeared in the DAA era. In addition, HCV patients had a significant improvement in survival when comparing the DAA era with IFN era (P < .001). Independent predictors of survival were significantly different in the pre-DAA era (HCV, AFP, diabetes) than in the DAA era (tumor size). HCV-related HCC continues to be the main indication for LT in the DAA era, but patients' survival has significantly improved and is comparable to that of NAFLD-related HCC., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The benefit of transarterial radioembolization (TARE) in patients with unresectable hepatocellular carcinoma (HCC) is increasingly evidenced. However, data on outcome of liver transplantation or resection after TARE remain scarce. This study aimed to assess the safety and feasibility of surgery after TARE in patients with unresectable HCC., Methods: Patients exclusively undergoing TARE followed by either orthotopic liver transplantation (OLT) or liver resection (LR) for HCC between 2012 and 2016 were included. Primary outcomes were postoperative morbidity and mortality. Secondary outcomes were overall survival (OS) and response to TARE., Results: Among 349 patients with HCC treated with TARE, 32 (9%) underwent either OLT (n = 22) or LR (n = 10), which represent the study cohort. In this group, TARE induced decreased viable nodules (p < 0.001), an efficient downsizing (p < 0.001) as well as a significant downstaging based on BCLC classification (p < 0.001). Overall, major complications and mortality after surgery occurred in 5 (16%) and 1 (3%) patients, respectively. For the whole study cohort, OS was 47 months while survival rates at 1-, 3- and 5-years reached 97%, 86% and 86%, respectively., Discussion: Liver surgery after TARE is feasible and safe. This strategy allows to offer a curative treatment in a subset of patients with unresectable HCC., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction . Opioids may influence tumor recurrence and cancer-free survival in hepatocellular carcinoma (HCC). The relationship between intrathecal morphine administration, tumor recurrence, and patient survival after hepatectomy for HCC is unknown. Patients and Methods . This single-center, retrospective study included 1837 liver resections between July 2002 and December 2012; 410 cases were incorporated in the final univariate and multivariate analysis. Confirmatory propensity matching yielded 65 matched pairs (intrathecal morphine vs none). Primary outcomes were recurrence of HCC and survival. Secondary outcomes included characterization of factors associated with recurrence and survival. Results . Groups were similar except for increased coronary artery disease in the no intrathecal morphine group. All patients received volatile anesthesia. Compared with no intrathecal morphine (N = 307), intrathecal morphine (N = 103) was associated with decreased intraoperative intravenous morphine administration (median difference = 12.5 mg; 95% confidence interval [CI] = 5-20 mg). There was no difference in blood loss, transfusion, 3- or 5-year survival, or recurrence in the univariate analysis. Multivariate analysis identified covariates that significantly correlated with 5-year survival: intrathecal morphine (hazard ratio [HR] = 0.527, 95% CI = 0.296-0.939), lesion diameter (HR = 1.099, 95% CI = 1.060-1.141), vascular invasion (HR = 1.658, 95% CI = 1.178-2.334), and satellite lesions (HR = 2.238, 95% CI = 1.447-3.463). Survival analysis on the propensity-matched pairs did not demonstrate a difference in 5-year recurrence or survival. Discussion and Conclusion . Multivariate analysis revealed a significant association between intrathecal morphine and 5-year survival. This association did not persist after propensity matching. The association between intrathecal morphine and HCC recurrence and survival remains unclear and prospective work is necessary to determine whether an association exists.

Background & Aims: There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort., Methods: We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response)., Results: Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70-1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70-1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance., Conclusion: In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Patients with hepatocellular carcinoma (HCC) and gross vascular invasion (GVI) have poor outcomes with systemic therapy such as sorafenib. Both external beam radiation therapy (EBRT) and transarterial radioembolization (TARE) have been utilized for this patient population. We sought to compare outcomes using dual modality radiation (EBRT+TARE) versus EBRT alone in patients with HCC and GVI., Materials and Methods: Between 2011 and 2017, 45 patients with HCC and GVI were treated with EBRT±TARE at our institution. Progression-free survival (PFS) and overall survival (OS) were assessed and compared using Kaplan-Meier method and log-rank test. Univariable and multivariable Cox proportional hazards regression was used to assess the impact of the variables stage, etiology of cirrhosis, Child-Pugh (CP) score, and Karnofsky Performance Score (KPS) on PFS and OS., Results: Patient characteristics were well-balanced except for KPS (80 vs. 90) and CP score. Median OS for patients receiving EBRT+TARE was 263 days (95% confidence interval [CI]: 167, -) versus 193 days (95% CI: 51, 262) for EBRT alone (P=0.049). However, this did not hold up on MVA. When EBRT and TARE were delivered within 2 months as planned (n=12), median PFS was 218 days (95% CI: 44, -) for dual modality radiation versus 63 days (95% CI: 38, 137) for EBRT alone (P=0.048). When EBRT and TARE were delivered within 6 months, the difference in PFS was no longer seen (P=NS), because some patients received TARE as a salvage therapy., Conclusions: Dual modality radiation with EBRT and TARE may be associated with improved OS in patients with HCC and GVI. Dual modality radiation may be associated with improved PFS in patients with HCC and GVI compared with EBRT alone when EBRT and TARE are delivered within 2 months of each other as part of a planned dual modality treatment strategy. However, since this is a retrospective study with inherent selection bias, these findings need further validation in a prospective clinical trial for patients with HCC and GVI.

Background: The GALAD score is a serum biomarker-based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison with liver ultrasound for detection of HCC., Methods: A single-center cohort of 111 HCC patients and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) phase II HCC Study were analyzed., Results: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI), 0.93-97], which was higher than the AUC of ultrasound (0.82, P <0.01). At a cutoff of -0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early-stage HCC detection remained high at 0.92 (95% CI, 0.88-0.96; cutoff -1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85-0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single-center cohort, achieving an AUC of 0.98 (95% CI, 0.96-0.99; cutoff -0.18, sensitivity 95%, specificity 91%)., Conclusions: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score., Impact: The GALAD score was validated in the United States., (©2018 American Association for Cancer Research.)

Background: Hepatocellular carcinoma (HCC) is a common malignancy with a steadily rising incidence and associated morbidity and mortality. Cirrhosis of the liver is presently the leading risk factor for developing HCC. Abdominal imaging, with or without alpha-fetoprotein (AFP) testing, every 6 months is the current surveillance strategy for patients at risk. The available biomarkers for detecting this cancer at an early stage have inadequate sensitivity and specificity., Methods: The Hepatocellular carcinoma Early Detection Strategy (HEDS) study, a multi-center initiative of the National Cancer Institutes' (NCI) Early Detection Research Network (EDRN), launched an effort to establish what has become the nation's largest comprehensive biorepository and database on patients at high risk of developing HCC. The cohort has been developed in seven clinical centers across the USA. Subjects are enrolled for a five-year period involving data and specimen collection every six months in accordance with standard surveillance for HCC. Extensive clinical data are collected and specimens are stored at a central repository., Results: The database and biorepository contain longitudinally collected clinical data and serum and plasma samples from 1482 participants with cirrhosis and without evidence of HCC at baseline. Fifty-six percent are male, 85% Caucasian, 30% have a history of chronic HCV and 71% have compensated cirrhosis., Conclusions: The HEDS cohort provides opportunities for the continued study of the incidence and course of HCC in a comprehensively followed population of patients at high risk for this malignancy. Further, the EDRN biorepository provides a distinct opportunity for the development of novel biomarkers. Trial registry URL: https://edrn.nci.nih.gov/protocols/316-hepatocellular-carcinoma-early-detection-strategy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: African-Americans (AA) have a higher incidence of hepatocellular carcinoma (HCC) and lower survival. We characterized survival rates and clinical features associated with survival in AA vs. Caucasians with HCC over the past two decades., Methods: HCC patients from three US medical centers were matched by year of diagnosis (1991-2016): AA (n = 578)/Caucasian (n = 578) and placed in one of two groups-HCC diagnosed prior to 2010 or 2010 and after. Data were obtained from chart review and the National Death Index. Multivariate and survival analysis controlling for key predictors were conducted., Results: Prior to 2010, there was no difference in survival between Caucasians and AA (p = 0.61). After 2010, AA patients had poorer survival compared to Caucasians (35% vs. 44%, respectively, p = 0.044). Over time, survival improved for Caucasians (32% before 2010 vs. 44% after 2010, p = 0.003), but not AA (36% vs. 35%, p = 0.50). AA on presentation (in the after 2010 cohort) were more likely to have BCLC (Barcelona Clinic Liver Cancer) stage C (24% vs. 15%, p = 0.010) and less likely to receive treatment (85% vs. 93%, p = 0.002) compared to matched Caucasians. BCLC beyond stage A (aHR: 1.75, 95% CI: 1.26-2.43, p = 0.001) and child's class C (aHR 2.05, 95% CI: 1.23-3.41, p = 0.006) were the strongest predictors of mortality, while race was not., Conclusions: African-Americans presented with more advanced HCC and had poorer survival compared to Caucasians after 2010. Tumor stage was an independent predictor of mortality, but ethnicity was not. Further efforts are needed to improve early HCC diagnosis for AA.

Objectives: European liver transplant (LT) centers have moved away from using the Milan Criteria (MC) for hepatocellular carcinoma (HCC) patient selection, turning to models including tumor biological indices, namely alpha-fetoprotein (AFP). We present the first US model to incorporate an AFP response (AFP-R), with comparisons to MC and French-AFP models (F-AFP)., Methods: AFP-R was measured as differences between maximum and final pre-LT AFP in HCC patients undergoing LT at 3 US centers (2001 to 2013). Cox and competing risk-regression analyses identified predictors of recurrence-free survival (RFS)., Results: Of 1450 patients, 235 (16.2%) were outside MC. Tumor size, number, and AFP-R were independent predictors of RFS and were assigned weighted points based on Cox-regression analysis. An AFP-R consistently < 200 ng/mL predicted the best outcome. A 3-tiered competing-risk RFS model, the New York/California (NYCA) score, was developed, accurately discriminating between groups (P < 0.001), and correlating with overall survival (P < 0.001). Two hundred one of 235 patients outside MC (85.5%) would be recategorized into NYCA low/acceptable-risk groups. The c-statistic for our NYCA score is 0.731 compared with 0.613 for MC and 0.658 for F-AFP (P < 0.0001)., Conclusion: Incorporation of AFP-R into HCC selection criteria allows for MC expansion. As United Network for Organ Sharing considers adding AFP to selection algorithms, the NYCA score provides an objective, user-friendly tool for centers to appropriately risk-stratify patients.