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PURPOSE: The gender, age, lens culinaris agglutinin-reactive fraction of alphafetoprotein, alphafetoprotein, des-gamma-carboxyprothrombin (GALAD) score is a biomarker-based statistical model for the serologic diagnosis of hepatocellular carcinoma (HCC) that has been developed and validated using the case-control approach with a view to early detection. Performance has, however, been suboptimal in the first prospective studies which better reflect the real-world situation. In this article, we report the application of machine learning to a large, prospectively accrued, HCC surveillance data set. PATIENTS AND METHODS: Models were built on a cohort of 3,473 patients with chronic liver disease within a rigorous surveillance program between 1998 and 2014, during which 459 patients with HCC were detected. Two random forest (RF) models were trained. The first RF model uses the same variables as the original GALAD model (GALAD-RF); the second is based on routinely available clinical and laboratory features (RF-practical). For comparison, we evaluated a logistic regression GALAD model trained on this longitudinal prospective data set (termed GALAD-Ogaki). RESULTS: Models were evaluated using a repetitive cross-validation approach with the metrics averaged over 100 independent runs. As judged by area under the receiver operator curve (AUROC) and F1 score, the GALAD RF model significantly outperformed the original GALAD model. The RF-practical model also outperformed the original GALAD model in terms of both AUROC and F1 score, and both models outperformed the individual biomarkers. An online web application that implemented the GALAD-RF and RF-practical models is presented. CONCLUSION: RF-based models improve on the diagnostic performance of the original GALAD model in the setting of a standard HCC surveillance program. Further prospective validation studies are warranted using these models and could be expanded to offer prediction of risk of HCC development over defined periods of time. Machine learning is used to predict development of hepatocellular carcinoma in those with cirrhosis [ABSTRACT FROM AUTHOR]

Summary: Background: While surveillance improves the early detection of hepatocellular carcinoma (HCC), it is unclear whether this has improved prognosis in clinical practice. Aims: To investigate the characteristics and prognoses of patients with viral versus non‐viral HCC over the previous two decades in Japan, while HCC surveillance has been active. Methods: This multi‐centre study enrolled 6007 patients initially diagnosed with HCC between 2000 and 2020 at seven high‐volume academic centres. Patients were categorised based on dates of diagnosis: 2000–2006, 2007–2013 and 2014–2020. HCC characteristics and post‐diagnosis survival rates were compared between periods in patients with viral and non‐viral HCC. Results: The percentage of patients with non‐viral HCC increased during the study period. The maximal tumour size and percentage of patients with multinodular HCC decreased significantly over time in the viral HCC group but remained unchanged in the non‐viral HCC group. Liver function at diagnosis improved over time in both groups, but to a greater extent in the viral HCC group. Survival rates increased significantly with time in the viral HCC group, but not in the non‐viral HCC group. Conclusions: The prevalence of non‐viral HCC is increasing. Although the survival of patients with viral HCC improved significantly over the past two decades, there was no improvement in patients with non‐viral HCC. This was presumably due mainly to lower surveillance among patients with non‐viral HCC and failure to diagnose early‐stage HCC. [ABSTRACT FROM AUTHOR]

High‐grade dysplasia carries significant risk of transformation to hepatocellular carcinoma (HCC). Despite this, at the current standard of care, all non‐malignant hepatic nodules including high‐grade dysplastic nodules are managed similarly. This is partly related to difficulties in distinguishing high‐risk pathology in the liver. We aimed to identify chromosome arm‐level somatic copy number alterations (SCNAs) that characterise the transition of liver nodules along the cirrhosis–dysplasia–carcinoma axis. We validated our findings on an independent cohort using blood‐derived cell‐free DNA. A repository of non‐cancer DNA sequences obtained from patients with HCC (n = 389) was analysed to generate cut‐off thresholds aiming to minimise false‐positive SCNAs. Tissue samples representing stages from the multistep process of hepatocarcinogenesis (n = 184) were subjected to low‐pass whole genome sequencing. Chromosome arm‐level SCNAs were identified in liver cirrhosis, dysplastic nodules, and HCC to assess their discriminative capacity. Samples positive for 1q+ or 8q+ arm‐level duplications were likely to be either HCC or high‐grade dysplastic nodules as opposed to low‐grade dysplastic nodules or cirrhotic tissue with an odds ratio (OR) of 35.5 (95% CI 11.5–110) and 16 (95% CI 6.4–40.2), respectively (p < 0.0001). In an independent cohort of patients recruited from Nottingham, UK, at least two out of four alterations (1q+, 4q−, 8p−, and 8q+) were detectable in blood‐derived cell‐free DNA of patients with HCC (n = 22) but none of the control patients with liver cirrhosis (n = 9). Arm‐level SCNAs on 1q+ or 8q+ are associated with high‐risk liver pathology. These can be detected using low‐pass sequencing of cell‐free DNA isolated from blood, which may be a future early cancer screening tool for patients with liver cirrhosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: The 'Prediction Of Survival in Advanced Sorafenib‐treated HCC' (PROSASH) model addressed the heterogeneous survival of patients with hepatocellular carcinoma (HCC) treated with sorafenib in clinical trials but requires validation in daily clinical practice. This study aimed to validate, compare and optimize this model for survival prediction. Methods: Patients treated with sorafenib for HCC at five tertiary European centres were retrospectively staged according to the PROSASH model. In addition, the optimized PROSASH‐II model was developed using the data of four centres (training set) and tested in an independent dataset. These models for overall survival (OS) were then compared with existing prognostic models. Results: The PROSASH model was validated in 445 patients, showing clear differences between the four risk groups (OS 16.9‐4.6 months). A total of 920 patients (n = 615 in training set, n = 305 in validation set) were available to develop PROSASH‐II. This optimized model incorporated fewer and less subjective parameters: the serum albumin, bilirubin and alpha‐foetoprotein, and macrovascular invasion, extrahepatic spread and largest tumour size on imaging. Both PROSASH and PROSASH‐II showed improved discrimination (C‐index 0.62 and 0.63, respectively) compared with existing prognostic scores (C‐index ≤0.59). Conclusions: In HCC patients treated with sorafenib, individualized prediction of survival and risk group stratification using baseline prognostic and predictive parameters with the PROSASH model was validated. The refined PROSASH‐II model performed at least as good with fewer and more objective parameters. PROSASH‐II can be used as a tool for tailored treatment of HCC in daily practice and to define pre‐planned subgroups for future studies. [ABSTRACT FROM AUTHOR]

Background: The neutrophil-lymphocyte ratio (NLR), a presumed measure of the balance between neutrophil-associated pro-tumour inflammation and lymphocyte-dependent antitumour immune function, has been suggested as a prognostic factor for several cancers, including hepatocellular carcinoma (HCC).Methods: In this study, a prospectively accrued cohort of 781 patients (493 HCC and 288 chronic liver disease (CLD) without HCC) were followed-up for more than 6 years. NLR levels between HCC and CLD patients were compared, and the effect of baseline NLR on overall survival amongst HCC patients was assessed via multivariable Cox regression analysis.Results: On entry into the study ('baseline'), there was no clinically significant difference in the NLR values between CLD and HCC patients. Amongst HCC patients, NLR levels closest to last visit/death were significantly higher compared to baseline. Multivariable Cox regression analysis showed that NLR was an independent prognostic factor, even after adjustment for the HCC stage.Conclusion: NLR is a significant independent factor influencing survival in HCC patients, hence offering an additional dimension in prognostic models. [ABSTRACT FROM AUTHOR]

Aim: To benchmark overall survival (OS) and time to radiological progression (TTP) of patients enrolled in randomized controlled trials (RCTs) assessing sorafenib in advanced hepatocellular carcinoma using individual participant survival data, and to meta-analyze prognostic factors for OS and TTP. Methods: RCTs were identified through literature search until December 2018. Individual participant survival was reconstructed with an algorithm from published Kaplan–Meier curves. Results: Ten RCTs were included. Median OS was 10.0 months (95% CI: 9.6–10.5), and median TTP was 4.1 months (95% CI: 3.8–4.3). Multivariable analyses showed HCV positivity, absence of macrovascular invasion and extra-hepatic disease as predictors of longer OS. Conclusion: We provided a benchmark for future studies on sorafenib. The present results can be used in the decision making for the early shift to second-line strategy. [ABSTRACT FROM AUTHOR]

Background & Aims: It remains controversial whether the eradication of hepatitis C virus (HCV) by interferon (IFN)‐free anti‐HCV therapy using direct‐acting antivirals (DAAs) suppresses or promotes hepatocellular carcinoma (HCC) development. We investigated the influence of HCV eradication by DAA therapy on HCC development, by observing changes of non‐hypervascular hypointense nodules (NHHNs) by gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging (EOB‐MRI). Methods: A total of 401 patients treated with DAA therapy who did not have a history of HCC were enrolled in this prospective cohort study. All patients underwent EOB‐MRI prior to the start of DAA therapy and were followed up periodically after therapy. The progression of NHHNs detected at baseline to typical HCC, as indicated by hypervascularization and the incidence of newly emergent NHHNs, was analyzed. Results: In comparison of patients who achieved sustained virologic response (SVR) with propensity score‐matched patients with persistent HCV infection, there was no difference in the incidence of hypervascularization of NHHNs to typical HCC among patients who had NHHNs at baseline. Among patients who did not have NHHNs at baseline, the incidence of the new emergence of NHHNs did not differ between study patients and propensity score–matched patients with persistent HCV infection. Conclusions: During a 2‐year observation period after SVR, the eradication of HCV by IFN‐free DAA therapy did not suppress or enhance HCC development. (UMIN000017020). See Editorial on Page 446 [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: The aim of this study was to estimate probabilities of achieving the statistical cure from hepatocellular carcinoma (HCC) with hepatic resection (HR) and liver transplantation (LT). Background: Statistical cure occurs when the mortality of a specific population returns to values of that of general population. Resection and transplantation are considered potentially curative therapies for HCC, but their effect on the residual entire life-expectancy has never been investigated. Methods: Data from 3286 HCC patients treated with LT (n = 1218) or HR (n = 2068) were used to estimate statistical cure. Disease-free survival (DFS) was the primary survival measure to estimate cure fractions through a nonmixture model. Overall survival (OS) was a secondary measure. In both, patients were matched with general population by age, sex, year, and race/ethnicity. Cure variations after LT were also adjusted for different waiting-list drop-outs. Results: Considering DFS, the cure fraction after LT was 74.1% and after HR was 24.1% (effect size >0.8). LT outperformed HR within all transplant criteria considered (effect size >0.8), especially for multiple tumors (>0.9) and even in presence of a drop-out up to 20% (>0.5). Considering OS, the cure fraction after LT marginally increased to 75.8%, and after that HR increased to 40.5%. The effect size of LT over HR in terms of cure decreased for oligonodular tumors (<0.5), became small for drop-out up to ∼20% (<0.2), and negligible for single tumors <5 cm (∼0.1). Conclusion: As other malignancies, statistical cure can occur for HCC, primarily with LT and secondarily with HR, depending on waiting-list capabilities and efficacy of tumor recurrence therapies after resection. [ABSTRACT FROM AUTHOR]

Background: Application of curative therapy for hepatocellular carcinoma is crucially dependent on underlying liver function. Using the recently described ALBI grade we examined the long-term impact of liver dysfunction on survival of early-stage hepatocellular carcinoma (HCC) patients.Methods: This cohort study comprised 2559 HCC patients from different geographic regions, all treated with curative intent. We also examined the relation between indocyanine green (ICG) clearance and ALBI score. Survival was measured from the date of treatment to the date of death or last follow-up.Results: The ALBI score correlated well with ICG clearance. Among those undergoing surgical resection, patients with ALBI grade-1 (good liver function) survived approximately twice as long as those with ALBI grade-2 (less good liver function), although more than 90% of these patients were classified as Child-Pugh (C-P) grade A. In the cohort receiving ablative therapies, there was a similar difference in survival between ALBI grade-1 and grade-2. Cox regression analysis confirmed that the ALBI score along with age, gender, aetiology and tumour factors (AFP, tumour size/number and vascular invasion) independently influenced survival in HCC patients receiving curative treatments.Conclusions: The ALBI score represents a simple approach to the assessment of liver function in patients with HCC. After potentially curative therapy, those with ALBI grade-1 survived approximately twice as long as those with ALBI grade-2. These data suggest that ALBI grade-1 patients are appropriately treated with surgical resection whereas ALBI grade-2 patients may, where the option exists, be more suitable for liver transplantation or the less invasive curative ablative therapies. [ABSTRACT FROM AUTHOR]

Hepatitis B viral (HBV) infection is the predominant etiology of hepatocellular carcinoma (HCC) in Asia. Our group previously reported a staging system known as the Chinese University Prognostic Index (CUPI) for HCC populations of which HBV infection is the predominant etiology. This study aims to validate CUPI and compare with other published staging systems. We analyzed a prospective cohort of patients with newly diagnosed HCC from 2003 to 2005. All patients were staged with CUPI, Barcelona Clinic Liver Cancer Classification (BCLC), Cancer of the Liver Italian Program score (CLIP), tumor-node-metastasis (TNM) and Okuda systems at diagnosis. They were followed with survival data and the performance of each staging system (in terms of homogeneity, discriminatory ability and monotonicity of gradient) were analyzed and compared. A total of 595 patients (80.2% with chronic HBV infection) were analyzed. The median follow-up was 41.4 months and the median survival was 6.6 months. Multivariate analyses identified symptomatic disease, ascites, vascular involvement, Child-Pugh-stage, alpha-fetoprotein and treatment to be the independent prognostic factors. CUPI could identify three groups with statistically significant survival difference ( P < 0.0001). Both CUPI and CLIP had the most favorable performance in terms of discriminatory ability, homogeneity and monotonicity. CUPI performed the best in predicting 3-month survival while CLIP performed better in predicting the outcome of 6- and 12-month survival rate. BCLC was inferior to CLIP and CUPI in the overall performance. We have validated CUPI in a population composed of predominant HBV-related HCC. CUPI is an appropriate staging system for HBV-related HCC. In patients with advanced HCC, both CUPI and CLIP offer good risk stratification. [ABSTRACT FROM AUTHOR]

A wide variety of non-surgical therapies can result in clinical responses in patients with hepatocellular carcinoma. Two recent studies have suggested that transarterial chemoembolisation can, in highly selected patients with good liver function, result in an improvement in survival. No other approaches have, to date, demonstrated convincing evidence of survival advantage. [ABSTRACT FROM AUTHOR]

Researchers interested in developing treatments for hepatocellular carcinoma (HCC) face three sets of problems; one set common to all clinical trialists at the beginning of the 21st century, one set related to phase I/II studies (‘early drug development’) and one set related to the design of phase III (randomised, controlled trials). This review is concerned with the challenges faced in designing high quality clinical trials in patients with HCC. Specific published trials are not discussed other than by way of illustration of the problems faced. [Copyright &y& Elsevier]

Objective: Although many attempts have been made to identify tumour-specific α-fetoprotein (AFP) glycoforms or other serological markers for the diagnosis of hepatocellular carcinoma (HCC), none of the available markers has, so far, shown satisfactory sensitivity and specificity. Here we aimed to apply classification tree and neural network algorithms to interpret the levels of multiple serological liver markers to improve overall specificity and sensitivity, particularly with a view to discriminating between liver cirrhosis with and without HCC. Methods: We developed classification trees and neural networks that identified serological liver marker profiles comprising AFP, α1-antitrypsin (A1AT), α2-macroglobulin (A2MG), thyroxine-binding globulin (TBG), transferrin and albumin as well as sex and age, which might permit the diagnosis of HCC. Data were collected from 65 HCC patients, 51 patients with liver cirrhosis alone (LC) and 51 normal healthy subjects. Results: The generated classification trees and neural networks showed similar diagnostic values in differentiating HCC from LC. The classification trees identified AFP, A1AT and albumin as the most important classification parameters, whereas the neural networks identified A2MG, AFP, A1AT and albumin as the predominant factors. The classification logic of the classification trees indicated that more HCC cases could be identified among cases with slightly elevated AFP levels by using the serum levels of A1AT and albumin. The neural networks were also useful for the identification of the HCC cases when the AFP levels were below 500 ng/ml (p < 0.005). The neural networks could identify HCC cases with AFP levels within the normal range, but the classification trees could not. By combining the conventional AFP test and the neural networks, the overall diagnostic sensitivity for HCC was significantly increased from 60.0 to 73.8% (p < 0.05) while maintaining a high specificity (88.2%). The sensitivities for tumors of different sizes were similar. Conclusion: The neural network algorithm appeared to be more powerful than the classification tree algorithm in the identification of the distinctive serological liver marker profiles for the diagnosis of the HCC subgroup without significant elevation in serum AFP levels. By incorporating serological levels of other liver markers and including data from a large number of patients and control subjects, it should prove possible to develop a versatile neural network for early diagnosis of HCC.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The development of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) frequently follows persistent HBV infection and may arise in individuals who are hepatitis B e antigen (HBeAg) negative, indicating the possible presence of precore/core mutants. It is unclear whether precore/core mutants are associated with tumour development or are selected for after chromosomal integration of the wild-type viral DNA. We studied the status and sequence variation of the precore/core region of HBV in 56 patients with HBV-associated HCC and in various corresponding non-tumour tissues by Southern blot analysis, polymerase chain reaction and direct sequencing. Southern blot showed that integrated HBV DNA existed in 43 of 56 HCC tissues. Sequence analysis revealed mutations in 65% of the HCC (26/40) and 45% (14/31) of the corresponding non-tumour tissues. The mutation at nucleotide (nt) 1896, known to prevent HBeAg synthesis, was detected in 40% (16/40) of the tumours and in 35.4% (11/31) of the non-tumour tissues. Other mutations were found at nt 1899 (eight of 40 in HCC; three of 31 in non-tumour tissues), nt 1898 (seven of 40 in HCC; two of 31 in non-tumour tissues), nt 1912 (seven of 40 in HCC; none of 31 in non-tumour tissues) and nt 1886 (three of 40 in HCC; none of 31 in non-tumour tissues). To determine whether this finding merely reflected the prevalence of such mutants in this geographical region, HBV DNA from the sera of patients (also in this region) with acute and chronic hepatitis were sequenced. The nt 1896 mutant was found in 5.6% (one of 18) of patients with acute hepatitis B and in 22.8% (nine of 35) of patients with chronic hepatitis B. However, the nt 1898 mutation was not found in any of these sera. The precore/core mutant was observed with increasing frequency from acute hepatitis to chronic hepatitis, non-tumour and HCC, and this difference in frequency was significant between HCC and acute hepatitis B groups (P < 0.01), suggesting that the precore/core mutant or hepatocytes harbouring this mutant may be under immune selection and that such mutations may facilitate integration and subsequent tumour development. [ABSTRACT FROM AUTHOR]

Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, and serum levels of AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy-prothrombin (DCP), can improve early-stage HCC detection in a Caucasian HBV/HCV cohort. In a retrospective German single-center study, 182 patients with HBV, 223 with HCV and 168 with other etiology (OE) of chronic liver disease (CLD) were enrolled. HCC was confirmed in 52 HBV, 84 HCV and 60 OE CLD patients. The diagnostic performance of the single biomarkers in HCC detection was compared to the GALAD model. At initial diagnosis, most patients were at (very) early BCLC 0 (n = 14/7%) or A (n = 56/29%) or intermediate stage BCLC B (n = 93/47%) HCC in all three subgroups. In the BCLC 0/A cohort, GALAD exhibited an AUC of 0.94 discriminating HCC from non-HCC, surpassing AFP (AUC 0.86), AFP-L3 (AUC 0.83) and DCP (AUC 0.83). In the HBV population, GALAD achieved an AUC of 0.96, in HCV an AUC of 0.98 and in OE an AUC of 0.99, clearly superior to the biomarkers alone. Furthermore, in HCV patients GALAD showed a significantly higher specificity (89%) versus AFP (64%) alone. In chronic viral hepatitis, the GALAD model showed superior performance in detection of early-stage HCC, while exhibiting higher specificity in HCV patients compared to AFP alone. We conclude that the GALAD score shows potential for HCC surveillance in Caucasian HBV/HCV patients. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusion This study aimed to compare the determinants and impact of hepatocellular carcinoma (HCC) surveillance rates for people with metabolic dysfunction‐associated steatotic liver disease (MASLD) versus other chronic liver diseases.A dataset of HCC patients from a UK hospital (2007–2022) was analyzed. The Mann–Whitney U‐test compared continuous variables. The χ2 and two‐tailed Fisher exact tests compared categorical data. Regression modeling analyzed the impact of MASLD on the size and number of HCC nodules and curative treatment. The Cox proportional hazards model assessed the influence of MASLD on overall survival.A total of 176 of 687 (25.6%) HCC patients had MASLD. Fewer people with MASLD HCC were enrolled in HCC surveillance compared to non‐MASLD HCC (38 [21.6%] vs 215 [42.1%], P < 0.001). Patients with MASLD HCC were less likely to have been under secondary care (n = 57 [32.4%] vs 259 [50.7%], P < 0.001) and less likely to have cirrhosis (n = 113 [64.2%] vs 417 [81.6%], P < 0.001). MASLD was associated with a 12.3‐mm (95% confidence interval [CI] 10.8–14.0 mm) greater tumor diameter compared to people without MASLD (P = 0.002). Patients with MASLD HCC had 0.62 reduced odds (95% CI 0.43–0.91) of receiving curative treatment compared to non‐MASLD HCC (P = 0.014). Overall survival was similar for patients with MASLD HCC versus non‐MASLD HCC (hazard ratio 1.03, 95% CI 0.85–1.25, P = 0.748).Patients with MASLD are less likely to have been enrolled in HCC surveillance due to undiagnosed cirrhosis or presenting with non‐cirrhotic HCC. Patients with MASLD HCC present with larger tumors and are less likely to receive curative treatment. [ABSTRACT FROM AUTHOR]

Thirty-five years after its first description, alpha-fetoprotein (AFP) remains the gold standard by which other markers are judged. Serum levels above the reference range of 10 ng/mL occur in approximately 75% of cases of hepatocellular carcinoma (HCC). In individual patients, the serum AFP level behaves as if it reflects tumour mass. However, the specificity of AFP is relatively low because moderately raised levels are also found in some patients with uncomplicated chronic liver disease. Recently, tumour-specific AFP assays have been developed. These are based on the carbohydrate side-chains on the AFP molecule which exhibit characteristic differences in AFP of different origins. Monitoring response to treatment may often be more effectively carried out by serial estimation of AFP than by conventional imaging techniques. The relative specificity of AFP for HCC has also been employed to detect circulating HCC cells and to target gene therapy. [ABSTRACT FROM AUTHOR]

The article offers information on the trial endpoints for systemic therapy in patients with hepatocellular carcinoma (HCC). Topics discussed include role of sorafenib in improving patient survival which is the first-line systemic therapy for advanced HCC; role of surrogate endpoints in improving the efficiency and reducing the cost of drug development in HCC; and the data regarding response of patients to pembrolziumab.

This study investigated how material deprivation in Italy influences the stage of hepatocellular carcinoma (HCC) at diagnosis and the chance of cure. 4114 patients from the Italian Liver Cancer database consecutively diagnosed with HCC between January 2008 and December 2018 were analysed about severe material deprivation (SMD) rate tertiles of the region of birth and region of managing hospitals, according to the European Statistics on Income and Living Conditions. The main outcomes were HCC diagnosis modalities (during or outside surveillance), treatment adoption and overall survival. In more deprived regions, HCC was more frequently diagnosed during surveillance, while the incidental diagnosis was prevalent in the least deprived. Tumour characteristics did not differ among regions. The proportion of patients undergoing potentially curative treatments progressively decreased as the SMD worsened. Consequently, overall survival was better in less deprived regions. Patients who moved from most deprived to less deprived regions increased their probability of receiving potentially curative treatments by 1.11 times (95% CI 1.03 to 1.19), decreasing their mortality likelihood (hazard ratio 0.78 95% CI 0.67 to 0.90). Socioeconomic status measured through SMD does not seem to influence HCC features at diagnosis but brings a negative effect on the chance of receiving potentially curative treatments. Patient mobility from the most deprived to the less deprived regions increased the access to curative therapies, with the ultimate result of improving survival. • A Multicentre Italian study on the impact of material deprivation on hepatocellular carcinoma (HCC) outcome. • Patients were stratified according to the material deprivation rate of Italian regions. • HCC survival was better in less deprived Italian regions. • Migration from most to less deprived regions improved HCC survival. • Effect of deprivation was mainly because of different access to HCC curative treatments. [ABSTRACT FROM AUTHOR]

Background: This study investigated the impact of baseline liver function according to the Child–Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. Methods: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child–Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child–Pugh score 5 and ALBI grade 1 (group 1), (2) Child–Pugh score 5 and ALBI grade 2 (group 2), (3) Child–Pugh score 6 (group 3), and (4) Child–Pugh score ≥7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p < 0.05 and p < 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level <200 ng/mL as the significant predictors of a high objective response rate (p < 0.05 and p < 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p < 0.01). Conclusions: Patients with Child–Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Risk scores estimating a patient's probability of a hepatocellular carcinoma (HCC) diagnosis are abundant but are difficult to interpret in isolation. We compared the predicted HCC probability for individuals with cirrhosis and cured hepatitis C with the general population (GP). METHODS: All patients with cirrhosis achieving sustained viral response (SVR) in Scotland by April 2018 were included (N = 1,803). The predicted 3-year probability of HCC at time of SVR achievement was determined using the aMAP prognostic model. GP data on the total number of incident HCCs in Scotland, stratified by demographics, were obtained from Public Health Scotland. Predicted HCC risk of cirrhosis SVR patients was compared with GP incidence using 2 metrics: (i) incidence ratio: i.e., 3-year predicted probability for a given patient divided by the 3-year probability in GP for the equivalent demographic group and (ii) absolute risk difference: the 3-year predicted probability minus the 3-year probability in the GP. RESULTS: The mean predicted 3-year HCC probability among cirrhosis SVR patients was 3.64% (range: 0.012%–36.12%). Conversely, the 3-year HCC probability in the GP was much lower, ranging from <0.0001% to 0.25% depending on demographics. The mean incidence ratio was 410, ranging from 5 to >10,000. The mean absolute risk difference was 3.61%, ranging from 0.012% to 35.9%. An online HCC-GP comparison calculator for use by patients/clinicians is available at https://thrive-svr.shinyapps.io/RShiny/. DISCUSSION: Comparing a patient's predicted HCC probability with the GP is feasible and may help clinicians communicate risk information and encourage screening uptake. [ABSTRACT FROM AUTHOR]

Sorafenib has been the standard of care for patients with advanced hepatocellular carcinoma and although immunotherapeutic approaches are now challenging this position, it retains an advantage in HCV-seropositive patients. We aimed to quantify the rate of tumour progression in patients receiving sorafenib and relate this figure to survival, both overall, and according to viral status. Using serial data from an international clinical trial we applied a joint model to combine survival and progression over time in order to estimate the rate of tumour growth as assessed by tumour burden and serum alpha-fetoprotein, and the impact of treatment on liver function. High tumour burden at baseline was associated with an increased risk of death. In patients still alive at the end of the study, the progression in relation to tumour burden was very low compared to those who died within the study. Overall, the change in mean tumour burden was 0.12 mm per day or an absolute growth rate of 3.6 mm/month. Median doubling time was 665 days. For those who progressed above 0.12 mm per day or the 12% rate, median survival was 234 days compared to 384 days if the rate was below 12%. Tumour growth rate and serum alpha-fetoprotein rise were significantly lower in those who were HCV seropositive as was the rate of decline in liver function. These results were replicated in 2 independent patient groups. Our analysis suggests that sorafenib treatment is associated with improved survival in patients with advanced hepatocellular carcinoma mainly by decreasing the rate of tumour growth and liver function deterioration among patients with HCV infection. Among patients receiving sorafenib for advanced hepatocellular carcinoma the rate of tumour growth (as assessed by changes in tumour size and the biomarker alpha-fetoprotein) and the deterioration of liver function is less in those who have the hepatitis C virus, than in those who do not. [Display omitted] Among patients receiving sorafenib for advanced hepatocellular carcinoma: • The overall rate of increase in tumour burden was 12%. • Above the 12% rate median survival was 234 days, compared to 384 days if below. • High tumour burden at baseline was associated with an increased risk of death. • Tumour growth rate, AFP rises and rate of decline in liver function were lower in those who were HCV seropositive. [ABSTRACT FROM AUTHOR]

The popular sense of the word "cure" implies that a patient treated for a specific disease will return to have the same life expectancy as if he/she had never had the disease. In analytic terms, it translates into the concept of statistical cure which occurs when a group of patients returns to having similar mortality to a reference population. The aim of this study was to assess the probability of being cured from hepatocellular carcinoma (HCC) by hepatic resection. Data from 2,523 patients undergoing resection for HCC were used to fit statistical cure models, to compare disease-free survival (DFS) after surgery to the survival expected for patients with chronic hepatitis and/or cirrhosis and the general population, matched by sex, age, race/ethnicity and year of diagnosis. The probability of resection enabling patients with HCC to achieve the same life expectancy as those with chronic hepatitis and/or cirrhosis was 26.3%. The conditional probability of achieving this result was time-dependent, requiring about 8.9 years to be accomplished with 95% certainty. Considering the general population as a reference, the cure fraction decreased to 17.1%. Uncured patients had a median DFS of 1.5 years. In multivariable analysis, patient's age and the risk of early HCC recurrence (within 2 years) were independent determinants of the chance of cure (p <0.001). The chances of being cured ranged between 36.0% for individuals at low risk of early recurrence to approximately 3.6% for those at high risk. Estimates of the chance of being cured of HCC by resection showed that cure is achievable, and its likelihood increases with the passing of recurrence-free time. The data presented herein can be used to inform decision making and to provide patients with accurate information. Data from 2,523 patients who underwent resection for hepatocellular carcinoma were used to estimate the probability that resection would enable treated patients to achieve the same life expectancy as patients with chronic hepatitis and/or cirrhosis, and the general population. Herein, the cure model suggests that in patients with hepatocellular carcinoma, resection can enable patients to achieve the same life expectancy as those with chronic liver disease in 26.3% of cases and as the general population in 17.1% of cases. • DFS in resected patients with HCC was compared to DFS in those with chronic liver disease w/o HCC, and the general population. • Resected patients with HCC could achieve the same life expectancy as those with chronic liver disease in 26.3% of cases. • Resection enables patients with HCC to achieve the same life expectancy as the general population in 17.1% of cases. • Patients resected in more recent years had higher cure probabilities, probably due to effective antiviral therapies. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Recurrence is frequent within 2 years of surgical resection of hepatocellular carcinoma. • In this large collaboration, we identify readily available, clinical parameters which influence early recurrence. • A simple and extensively validated statistical model for estimating early recurrence risk using an online calculator. • This facility will enhance patient counselling and will help in design of adjuvant clinical trials. Background & Aims Resection is the most widely used potentially curative treatment for patients with early hepatocellular carcinoma (HCC). However, recurrence within 2 years occurs in 30–50% of patients, being the major cause of mortality. Herein, we describe 2 models, both based on widely available clinical data, which permit risk of early recurrence to be assessed before and after resection. Methods A total of 3,903 patients undergoing surgical resection with curative intent were recruited from 6 different centres. We built 2 models for early recurrence, 1 using preoperative and 1 using pre and post-operative data, which were internally validated in the Hong Kong cohort. The models were then externally validated in European, Chinese and US cohorts. We developed 2 online calculators to permit easy clinical application. Results Multivariable analysis identified male gender, large tumour size, multinodular tumour, high albumin-bilirubin (ALBI) grade and high serum alpha-fetoprotein as the key parameters related to early recurrence. Using these variables, a preoperative model (ERASL-pre) gave 3 risk strata for recurrence-free survival (RFS) in the entire cohort – low risk: 2-year RFS 64.8%, intermediate risk: 2-year RFS 42.5% and high risk: 2-year RFS 20.7%. Median survival in each stratum was similar between centres and the discrimination between the 3 strata was enhanced in the post-operative model (ERASL-post) which included 'microvascular invasion'. Conclusions Statistical models that can predict the risk of early HCC recurrence after resection have been developed, extensively validated and shown to be applicable in the international setting. Such models will be valuable in guiding surveillance follow-up and in the design of post-resection adjuvant therapy trials. Lay summary The most effective treatment of hepatocellular carcinoma is surgical removal of the tumour but there is often recurrence. In this large international study, we develop a statistical method that allows clinicians to estimate the risk of recurrence in an individual patient. This facility enhances communication with the patient about the likely success of the treatment and will help in designing clinical trials that aim to find drugs that decrease the risk of recurrence. [ABSTRACT FROM AUTHOR]

Background Because of the mutual influence of liver dysfunction and malignancy, overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC). We developed a nomogram integrating albumin–bilirubin (ALBI) grade, a new index of hepatic reserve, and tumor characteristics of HCC for predicting OS following curative liver resection. Methods The nomogram was built to estimate the probabilities of 1, 3, and 5-y OS based on training cohort of 709 HCC, which was validated in an international independent dataset. The prognostic value of the nomogram was determined by concordance index (C-index), time-dependent receiver operating characteristics (tdROC), and decision curves, comparing with ALBI grade alone, the Cancer of the Liver Italian Program (CLIP), the Barcelona Clinic Liver Cancer (BCLC), and Okuda staging systems. Results Independent factors derived from multivariable Cox analysis of the training cohort to predict OS were tumor grade, microvascular invasion, tumor size and ALBI grade which were assembled into nomogram. The calibration curves for probability of OS showed optimal agreement between nomogram-prediction and actual observation, which was tested in validation cohort. The C-index, tdROC and decision curves showed the nomogram was superior to CLIP, ALBI grade, BCLC and Okuda. The patients could also be stratified into low, intermediate risk, and high risk of the mortality by the normogram in both development and validation cohorts. Conclusions The nomogram integrating hepatic reserve and tumor characteristics provided a highly accurate estimation of OS in patients with HCC after curative liver resection, contributing to assess patient prognosis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Whether liver resection or ablation should be the first-line treatment for very early/early hepatocellular carcinoma (HCC) in patients who are candidates for both remains controversial. The aim of this study was to determine if the newly-developed Albumin-Bilirubin (ALBI) grade might help in treatment selections and to evaluate the survival of patients treated with liver resection and radiofrequency ablation (RFA).Methods: Patients with BCLC stage 0/A HCC who were treated with curative liver resection and RFA from 2003 to 2013 were included. Baseline clinical and laboratory parameters were retrieved and reviewed from the hospital database. Liver function and its impact on survival was assessed by the ALBI score. Overall and disease-free survivals were compared between the two groups.Results: 488 patients underwent liver resection (n = 318) and RFA (n = 170) for BCLC stage 0/A HCC during the study period. Liver resection offered superior survival to RFA in patients with BCLC stage 0/A HCC in the whole cohort. After propensity score matching, liver resection offered superior overall survival and disease-free survival to RFA in patients with ALBI grade 1 (P = 0.0002 and P < 0.0001 respectively). In contrast, there were no significant differences in overall survival and disease-free survival between liver resection and RFA in patients with ALBI grade 2 (P = 0.7119 and 0.3266, respectively).Conclusions: Liver resection offered superior survival to RFA in patients with BCLC stage 0/A HCC. The ALBI grade could identify those patients with worse liver function who did not gain any survival advantage from curative liver resection. [ABSTRACT FROM AUTHOR]