INTRODUCTION:The PNPLA3 rs738409 C>G polymorphism has been associated with fibrosis and steatosis in Chronic Hepatitis C (CHC) patients. However, its impact on Hepatocellular Carcinoma (HCC) development in this population remains unclear. This study aimed to evaluate the impact of the PNPLA3 polymorphism on the risk of HCC development in CHC patients in Brazil. METHODS:This retrospective case-control study included 235 CHC patients with advanced fibrosis, 119 with HCC, and 116 without HCC. The PNPLA3 polymorphism was analyzed using both the dominant and recessive models. Multivariate logistic regression was performed to assess factors independently associated with HCC development. RESULTS:The HCC group exhibited a higher proportion of male patients (p < 0.0001), alcohol abuse (p < 0.001), tobacco consumption (p < 0.0001), and ALBI grade 2‒3 (p < 0.001). The PNPLA3 genotype frequencies were CC 45.4%, CG 46.2% and GG 8.4% in the HCC group, and CC 51.7%, CG 40.5% and GG 7.8% in the non-HCC group. No significant differences in genotype frequencies were observed for the dominant model (p = 0.33) or the recessive model (p = 0.92). Gender (p = 0.001), tobacco consumption (p < 0.001), and ALBI score (p = 0.012) were identified as independent factors associated with HCC development. However, the PNPLA3 G allele was not an independent factor associated with HCC risk in either the univariate analysis (OR = 1.15, 95% CI 0.63‒2.08, p = 0.65) or the multivariate analysis (OR = 0.99, 95% CI 0.49‒2.00, p = 0.98). CONCLUSION:The PNPLA3 rs738409 polymorphism was not associated with HCC development in CHC patients with advanced fibrosis in the Brazilian population. Further studies are required to confirm this finding.

Recent advances in the systemic treatment of advanced hepatocellular carcinoma (HCC) with immunotherapy have once again reignited discussion over the role of combined therapy in earlier stages. This year, different international meetings have presented recent results from clinical trials on adjuvant therapy alone (IMBrave-050) and combined with transarterial chemoembolization (EMERALD-1 and LEAP-12). Increased enthusiasm for the use of adjuvant and neoadjuvant therapy for liver transplantation, surgery, and local-regional treatment of HCC has been shown. However, the initial results from these trials should be interpreted cautiously as we wait for final analyses and effects on overall survival. In this position paper from the special interest group from the Latin American Association for the Study of Liver Diseases (ALEH), we underline the caveats of the applicability of these potential treatments in our region, explore points of agreement, and highlight areas of uncertainty. Moreover, we underscore the role of hepatologists in the clinical decision-making process and management of these patients.

Introduction and objectives : Hepatocellular carcinoma (HCC) is a main indication for liver transplantation (LT). Bridge therapy (BT) is recommended when waiting time on transplant list is longer than 6 months to prevent dropout. However, the prognostic role of locoregional treatment in post-LT outcomes needs to be better defined. Our aims were to evaluate the impact of BT on post-LT overall survival (OS) and recurrence-free survival (RFS) among LT recipients with HCC. Materials and Methods : Multicenter retrospective cohort study in HCC patients submitted to LT with clinical and radiological data analysis. Clinical features, BT and tumor response according to mRECIST were analyzed. Post-LT OS and RFS according to this were compared. Results : 1,119 patients were included. Waiting time on transplant list was longer than 6 months in 49% of patients and 67% underwent BT. Transarterial-chemoembolization/embolization were the most common treatments performed (80%). According to mRECIST, 37% showed complete response (CR), 38% partial response (PR), 12% stable disease (SD) and 13% progressive disease (PD). The OS was 63% in 5y in a mean follow-up of 28 months. Post-LT tumor recurrence was 8%. There were no differences in RFS or OS among patients who underwent or not BT. However, patients who achieved CR had a higher RFS compared to PR, SD or PD (p=0.019) and the objective response to treatment was an independent predictor of lower recurrence risk. Conclusions : In a large multicentric cohort of LT recipients we observed that patients that achieved CR after BT presented lower risk of post-LT tumor recurrence.

Introduction and Objectives The PNPLA3 rs738409 C>G polymorphism has been associated with hepatocellular carcinoma (HCC) and liver cirrhosis regardless of the etiology, although the association was stronger with non-viral etiologies. However, the influence of PNPLA3 polymorphism on Hepatitis C Virus (HCV) and whether this polymorphism could be a risk factor for HCV-related HCC is not well defined. We aimed to evaluate the influence of the PNPLA3 rs738409 C>G polymorphism on the risk of HCC occurrence in HCV patients in Brazil. Materials and Methods This study included 90 patients with HCV-related cirrhosis and HCC who underwent liver transplantation or resection at a tertiary center in Brazil and 111 patients non-HCC with HCV-related cirrhosis, as the control group. The rs738409 polymorphism was detected in the DNA extracted from patients' blood samples using the TaqMan assay. All clinical data were collected using the Research Electronic Data Capture (REDCap) tool. The statistical analyses were performed using Jamovi software version 2.3.23. Results In the HCV+HCC group there was a higher proportion of male gender (79.1% vs. 45.9%, p<0.001), history of alcoholism (80.5% vs. 22.5%, p<0.001) and smoking (68.9% vs. 25.2%, p<0.001), however there was no statistical difference in age (p=0.519) and BMI (p=0.403) between both groups. The genotype frequencies of the rs738409 polymorphism in the HCV+HCC group was CC 41,2% CC and CG/GG 58,8% vs. controls CC 49,5% and CG/GG 50,5%. The presence of the G allele was not an independent factor associated with the risk of HCC occurrence (r=0,199, p=0.53). Conclusions Even in an admixed population such as the Brazilian, there was no association between the PNPLA3 rs738409 C>G polymorphism and the risk of developing HCV-related HCC, as previously shown in published studies in caucasian and oriental population.

Conflict of interest: No Introduction and Objectives: Hepatitis C virus (HCV) still is the leading cause of hepatocellular carcinoma (HCC) in Brazil, even after the new treatments with DAAs. HCC surveillance is recommended based on liver fibrosis, whereby patients with advanced fibrosis are suitable for screening. Therefore, there is a need for tools to improve risk stratification in this population. Our aim was to assess whether the ALBI score performed at first evaluation of patients with HCV-related cirrhosis could stratify the risk of developing HCC. Patients / Materials and Methods: This study included 108 patients with HCV-related cirrhosis evaluated in the outpatient units in Hospital de Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. Clinical data from the first evaluation and ALBI score with first the laboratory tests were used for the statistical analysis. The last follow-up was at the last HCC screening image in patients who did not develop HCC and at HCC diagnosis in those who did. The statistical analyses were performed using Jamovi software version 2.3.23. Results and Discussion: During follow-up, with a mean duration of 5.28 ± 4.72 years, 32 patients developed HCC. Patients who developed HCC had significantly lower albumin values (p=0.039) and a higher proportion of ALBI grade 2 (p=0.036) at the first outpatient assessment. Evaluating HCC risk over time by Kaplan-Meier, patients with ALBI grade 2 had a significantly higher risk of developing HCC than patients with ALBI grade 1 (p=0.019) when assessed at 1 year (17% vs. 8.2%), 2 years (29.3% vs. 15.4%), 5 years (40.9% vs. 21.4%) and 10 years (47.4% vs. 23.9%). Patients with ALBI grade 2 had a two-fold higher risk of developing HCC during follow-up (OR 2.27, 95%CI 1.12-4.59, p=0.023). Conclusions: Assessment of baseline ALBI score can improve HCC risk stratification in patients with HCV-related cirrhosis.

The incidence of hepatocellular carcinoma (HCC) is expected to increase in the coming years, and strategies to mitigate the burden of this disease are needed in different regions. Geographic variations in epidemiology and risk factors, such as viral hepatitis and metabolic disease, pose challenges in adopting programs for early detection programs and management of patients with HCC. Brazil, like other countries, has high economic and social inequality, with heterogeneous access to health care. Viral hepatitis is the main risk factor but there is growing awareness of fatty liver disease. Risk factor monitoring and screening programs are unmet priorities because patients are often diagnosed at later stages. Advances in the management of patients with HCC have been made in recent years, including new tools for selecting patients for liver transplantation, sophisticated surgical techniques, and new systemic agents. High-volume academic centers often achieve favorable results through the adoption and application of established treatments, but this is not a reality in most regions of Brazil, because of disparities in wealth and resources. As HCC management requires a coordinated and multidisciplinary team, the role of local referral centers in decentralizing access to treatments and promoting health education in different regions should be encouraged and supported.

Prognostic markers in advanced hepatocellular carcinoma (HCC) are relevant for clinical decisions. Variations in inflammatory indexes, such as neutrophil-to-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio (PLR), may correlate with outcomes. In the present study, it was aimed to assess the prognostic role of inflammation indexes in patients with HCC and the evolutionary behavior of these variables within the first month of treatment in a cohort of patients treated with sorafenib from 2009-2021. Subgroups were divided based on the median of each variable ('low' or 'high)'. Survival was estimated using the Kaplan-Meier method. Hazard Ratio (HR) with 95% confidence interval (CI) were estimated using Cox regression models. A total of 373 patients were included, most Child-Pugh-A (83.1%) and BCLC-C (74%). Child-Pugh-A (P=0.011), performance status 0 (P<0.001), no ascites (P<0.001) and NLR<2.6 (P<0.001) were independently associated with improved survival. Baseline PLR was not correlated with survival (P=0.137). Patients who maintained low NLR at baseline and at 1 month (reference subgroup) had improved survival (18.6 months, 95% CI:15.4-22.0) compared with the subgroup that maintained high NLR at baseline and at 1 month (4.2 months, 95% CI:3.6-5.9), with HR: 3.80 (95% CI: 2.89-4.96). The subgroup with low NLR at baseline and high NLR at 1 month had a worse prognosis compared with the reference group (HR:1.4, 95% CI: 1.1-2.0), whereas the subgroup with high NLR at baseline and low at 1 month had similar outcome (HR:1.2, 95% CI: 0.8-1.6). It was concluded that evolutionary variation of NLR has a prognostic role in HCC patients under systemic therapy. This finding suggested that systemic inflammation and early modulation of the immune environment during treatment may correlate with outcomes.

Introduction and objectives: Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) and PBC over-lap syndrome (AIH/PBC) have been associated with a higher risk of hepatocellular carcinoma (HCC) and extra-hepatic malignancy (EHM). This study aims to assess potential risk factors associated with cancer development in PBC and AIH/PBC. Materials and methods: The Brazilian Cholestasis Study Group database was reviewed to compare clinical and laboratory features of PBC patients with HCC and EHM with those without cancer. Results: Among the 752 PBC patients enrolled, 64 of them with AIH/PBC, 87 cancers were identified in 72 patients, including 20 cases of HCC and 67 of EHM. Patients with HCC had a higher prevalence of cirrhosis

Introduction and Objectives: Chronic infection with hepatitis C virus (HCV) still affects millions of people around the world despite the recent development of very effective direct-acting antiviral (DAA) treatment. Even after a high cure rate, patients with advanced fibrosis should remain under surveillance due to the high risk of developing hepatocellular carcinoma. This study aimed to evaluate the prevalence and risk factors for hepatocellular carcinoma development in previously treated chronic HCV patients in an outpatient hepatology clinic at Clinic Hospital of the University of São Paulo of School Medicine in the city of São Paulo. Materials and Methods: This is a retrospective, observational and descriptive study of a series of cases in which 410 HCV patients were treated with three different antiviral regiments: Interferon plus Ribavirin (INF + RBV) or Protease Inhibitors (PI) or DAA, were followed for up to ten years (2011-2021). Demographic, clinical and laboratory data were obtained for electronic medical records. Results: the total sample of this study consists of 402 patients. Table 1 shows the patient demographic and clinical data. Of the 35 patients who developed HCC, 26 (74%) had F4-degree fibrosis. Logistic regression model was performed with the following variables: BMI (p=0.005), positive anti-HBC IgG (p=0.015), combination fibrosis and CHIILD-PUGH score A (p=0.001), B (p=0.012) and C(p< 0.001). Conclusions: In our cohort, obesity and anti-HBc IgG were significantly associated with a high risk of developing HCC. The type of antiviral treatment (IFN or DAA-based) was not associated with the risk of HCC.

Purpose:Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare primary liver malignancy often diagnosed at advanced stages. While there are limited data on the efficacy of specific agents, we aim to report outcomes of patients treated with systemic therapies and explore prognostic factors.Patients and Methods:Medical records of patients treated between 2010 and 2022 were reviewed. Treatments were defined after multidisciplinary assessment. Descriptive statistics were used for baseline demographics. Time-to-event outcomes were estimated using the Kaplan-Meier method, compared by log-rank and adjusted by a regression model. Radiomic features (including size, shape, and texture) of the primary lesion were extracted and dimensionality reduced. An unsupervised Gaussian Mixture Model (GMM) clustering was performed, and survival was compared between clusters.Results:We identified 23 patients: 12 males, with a median age of 23.6 years. At diagnosis, 82.6% had metastases, most frequently to the lungs (39.1%), lymph nodes (39.1%), and peritoneum (21.7%). Patients received a median of three lines (1-8) of treatment, including different regimens. Sorafenib (39.1%), capecitabine (30.4%), and capecitabine/interferon (13%) were the most used first-line regimens. The median time-to-failure was 3.8 months (95% CI: 3.2-8.7). Capecitabine + interferon (42.1%) and platinum combinations (39.1%) were the most used second-line regimens, with a time-to-failure of 3.5 months (95% CI: 1.5-11.6). Median overall survival was 26.7 months (95% CI: 15.1-40.4). A high baseline neutrophil-to-lymphocyte ratio (NLR) was associated with worse survival (p=0.02). Radiomic features identified three clusters, with one cluster (n=6) having better survival (40.4 vs 22.6 months, p=0.039). Tumor sphericity in the arterial phase was the most relevant characteristic associated with a better prognosis (accuracy=0.93).Conclusion:FLHCC has unique features compared to conventional HCC, including young onset, gender balance, and absence of hepatopathy. Systemic therapies can provide encouraging survival, but lack of uniformity precludes defining a preferable regimen. Radiomics and NLR were suggested to correlate with prognosis and warrant further validation.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2020 the updated recommendations for the diagnosis and treatment of HCC. Since then, new data have emerged in the literature, including new drugs approved for the systemic treatment of HCC that were not available at the time. The SBH board conducted an online single-topic meeting to discuss and review the recommendations on the systemic treatment of HCC. The invited experts were asked to conduct a systematic review of the literature on each topic related to systemic treatment and to present the summary data and recommendations during the meeting. All panelists gathered together for discussion of the topics and elaboration of the updated recommendations. The present document is the final version of the reviewed manuscript containing the recommendations of SBH and its aim is to assist healthcare professionals, policy-makers, and planners in Brazil and Latin America with systemic treatment decision-making of patients with HCC.

Background & Aims: Two recently developed composite models, the alpha-fetoprotein (AFP) score and Metroticket 2.0, could be used to select patients with hepatocellular carcinoma (HCC) who are candidates for liver transplantation (LT). The aim of this study was to compare the predictive performance of both models and to evaluate the net risk reclassification of post-LT recurrence between them using each model's original thresholds.Methods: This multicenter cohort study included 2,444 adult patients who underwent LT for HCC in 47 centers from Europe and Latin America. A competing risk regression analysis estimating sub-distribution hazard ratios (SHRs) and 95% CIs for recurrence was used (Fine and Gray method). Harrell's adapted c-statistics were estimated. The net reclassification index for recurrence was compared based on each model's original thresholds.Results: During a median follow-up of 3.8 years, there were 310 recurrences and 496 competing events (20.3%). Both models predicted recurrence, HCC survival and survival better than Milan criteria (p <0.0001). At last tumor reassessment before LT, c statistics did not significantly differ between the two composite models, either as original or threshold versions, for recurrence (0.72 vs. 0.68; p = 0.06), HCC survival, and overall survival after LT. We observed predictive gaps and overlaps between the model's thresholds, and no significant gain on reclassification. Patients meeting both models ("within-ALL") at last tumor reassessment presented the lowest 5-year cumulative incidence of HCC recurrence (7.7%; 95% CI 5.1-11.5) and higher 5-year post-LT survival (70.0%; 95% CI 64.9-74.6).Conclusions: In this multicenter cohort, Metroticket 2.0 and the AFP score demonstrated a similar ability to predict HCC recurrence post-LT. The combination of these composite models might be a promising clinical approach.Impact and implications: Composite models were recently proposed for the selection of liver transplant (LT) candidates among individuals with hepatocellular carcinoma (HCC). We found that both the AFP score and Metroticket 2.0 predicted post-LT HCC recurrence and survival better than Milan criteria; the Metroticket 2.0 did not result in better reclassification for transplant selection compared to the AFP score, with predictive gaps and overlaps between the two models; patients who met low-risk thresholds for both models had the lowest 5-year recurrence rate. We propose prospectively testing the combination of both models, to further optimize the LT selection process for candidates with HCC.& COPY; 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction: Hepatocellular carcinoma (HCC) has been associated to non-alcoholic fatty liver disease (NAFLD). We sought to investigate the immunoexpression of several glycolytic metabolism-associated markers in patients with HCC associated to NAFLD and associate these factors to their clinical-pathological characteristics. Methods: We evaluated 35 HCC specimens from 21 patients diagnosed with non-alcoholic steatohepatitis (NASH) undergoing liver resection (12 patients), liver transplantation (8 patients), or both (1 patient). Histological features, clinical aspects, demographic and biochemical data, as well as the immunohistochemical reactivity for monocarboxylate transporters 1, 2, and 4; their chaperone CD147; carbonic anhydrase IX; and glucose transporter-1 (GLUT1) were assessed. Results: Metabolic-associated cirrhosis was present in 12 of the 21 patients (8 child A and 4 child B scores). From 9 patients without cirrhosis, 3 presented NASH F3 and 6 NASH F2. Sixteen (76%) had diabetes mellitus, 17 (81%) arterial hypertension, and 19 (90%) body mass index above 25 kg/m(2); 8 (38%) had dyslipidemia. From 35 nodules, steatosis was found in 26, ballooning in 31 nodules, 25 of them diagnosed as steatohepatitic subtype of HCC. MCT4 immunoexpression was associated with extensive intratumoral fibrosis, advanced clinical stages, and shorter overall survival. GLUT1 was noticeable in nodules with extensive intratumoral steatosis, higher intratumoral fibrosis, and advanced clinical stages. Immunohistochemical expression of the metabolic biomarkers MCT4 and GLUT1 was higher in patients with Barcelona-clinic liver cancer B or C. GLUT1 correlated with higher degree of steatosis, marked ballooning, intratumoral fibrosis, and higher parenchymal necroinflammatory activity. Conclusion: Our data indicate that the expression of the glycolytic phenotype of metabolic markers, especially GLUT1 and MCT4, correlates with a more severe course of HCC occurring in NASH patients.

OBJECTIVE:The aim of the present study was to evaluate the clinical features, Hepatocellular Carcinoma (HCC) screening, treatment modalities, and Overall Survival (OS) in a series of Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma (NAFLD-HCC) Brazilian patients. METHODS:This was a cross-sectional study at the Instituto do Cancer do Estado de São Paulo, at the Faculdade de Medicina da Universidade de São Paulo with the approval of the local research ethics committee. NAFLD patients with HCC diagnosed, from May 2010 to May 2019, were included. RESULTS:A total of 131 patients were included. Risk factors for NAFLD were present in 94.7% of the patients. Only 29% of patients were in the HCC screening program before diagnosis. HCC treatment was performed in 84.7% of patients. Cumulative survival at the end of the first year was 72%, second-year 52%, and fifth-year 32%. HCC screening before diagnosis was not significantly associated with higher cumulative survival. The independent factors associated with shorter general survival were BCLC C-D, p < 0.001, and the size of the largest nodule > 42 mm, p = 0.039. CONCLUSIONS:Although the efficacy of screening in our population regarding overall survival was hampered due to the sample size (29% had screening), BCLC stages C‒D and the size of the largest nodule larger than 42 mm were identified as independent factors of worse prognosis.

BACKGROUND & AIM:Liver transplantation (LT) selection models for hepatocellular carcinoma (HCC) have not been proposed to predict waitlist dropout because of tumour progression. The aim of this study was to compare the alpha-foetoprotein (AFP) model and other pre-LT models in their prediction of HCC dropout. METHODS:A multicentre cohort study was conducted in 20 Latin American transplant centres, including 994 listed patients for LT with HCC from 2012 to 2018. Longitudinal tumour characteristics, and patterns of progression were recorded at time of listing, after treatments and at last follow-up over the waitlist period. Competing risk regression models were performed, and model's discrimination was compared estimating Harrell's adapted c-statistics. RESULTS:HCC dropout rate was significantly higher in patients beyond (24% [95% CI 16-28]) compared to those within Milan criteria (8% [95% IC 5%-12%]; p < .0001), with a SHR of 3.01 [95% CI 2.03-4.47]), adjusted for waiting list time and bridging therapies (c-index 0.63 [95% CI 0.57; 0.69). HCC dropout rates were higher in patients with AFP scores >2 (adjusted SHR of 3.17 [CI 2.13-4.71]), c-index of 0.71 (95% CI 0.65-0.77; p = .09 vs Milan). Similar discrimination power for HCC dropout was observed between the AFP score and the Metroticket 2.0 model. In patients within Milan, an AFP score >2 points discriminated two populations with a higher risk of HCC dropout (SHR 1.68 [95% CI 1.08-2.61]). CONCLUSIONS:Pre-transplant selection models similarly predicted HCC dropout. However, the AFP model can discriminate a higher risk of dropout among patients within Milan criteria.

OBJECTIVES: To investigate whether quantitative textural features, extracted from pretreatment MRI, can predict sustained complete response to radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC). METHODS: In this IRB-approved study, patients were selected from a maintained six-year database of consecutive patients who underwent both pretreatment MRI imaging with a probable or definitive imaging diagnosis of HCC (LI-RADS 4 or 5) and loco-regional treatment with RFA. An experienced radiologist manually segmented the hepatic nodules in MRI arterial and equilibrium phases to obtain the volume of interest (VOI) for extraction of 107 quantitative textural features, including shape and first- and second-order features. Statistical analysis was performed to evaluate associations between textural features and complete response. RESULTS: The study consisted of 34 patients with 51 treated hepatic nodules. Sustained complete response was achieved by 6 patients (4 with single nodule and 2 with multiple nodules). Of the 107 features from the arterial and equilibrium phases, 20 (18%) and 25 (23%) achieved AUC >0.7, respectively. The three best performing features were found in the equilibrium phase: Dependence Non-Uniformity Normalized and Dependence Variance (both GLDM class, with AUC of 0.78 and 0.76, respectively) and Maximum Probability (GLCM class, AUC of 0.76). CONCLUSIONS: This pilot study demonstrates that a radiomic analysis of pre-treatment MRI might be useful in identifying patients with HCC who are most likely to have a sustained complete response to RFA. Second-order features (GLDM and GLCM) extracted from equilibrium phase obtained highest discriminatory performance.

Background: Liver transplantation (LT) is the treatment of choice for unresectable early hepatocellular carcinoma (HCC). Previous studies demonstrated that Alpha-fetoprotein (AFP) is an important biomarker of prognosis and tumor recurrence. Aims: The aim of our study was to analyze the role of AFP in the post-transplant outcomes of HCC patients undergoing LT. Methods: We conducted a multicenter, retrospective cohort study, analyzing medical records of 1,119 liver transplant recipients with HCC in Brazil. Survival curves were presented using the Kaplan-Meier and compared using the log-rank test. Univariate cox regression analysis was fitted. We performed an evaluation of the effect of the continuous variable on the risk ratio, to define the best ''cutoff point'' of AFP level at HCC diagnosis and pre-transplantation capable of differentiating patients from risk of recurrence and survival. Results: Among 1,119 cases, 81% of patients were male, with a mean age at transplantation of 58 years. At HCC diagnosis, 85% were within Milan Criteria (MC). Median pre-LT AFP was 9.7 ng/ml (0-40,800 ng/ml) and 51% of patients had pre-LT AFP ≤ 10 ng/ml. The overall survival was 63% in 5 years and post-LT HCC recurrence was observed in 8% of patients. We found AFP > 400ng/ml at HCC diagnosis and AFP pre-LT > 200ng/ml as the better “cutoff points” for both overall survival and recurrence risk. Patients with AFP pre-LT ≤ 200 ng/ml had a better overall survival and recurrence-free survival compared with patients with AFP > 200 ng/ml, respectively, 76% and 92% versus 67% and 66% in 5-years (p <0.001). Pre-LT AFP >200ng/ml and being outside MC at diagnosis were also independent risk factors for post-LT HCC recurrence and poor survival in multivariate analysis. Conclusions: Our study demonstrated role of AFP as a main pre-transplant prognostic factor, both to predict post-LT tumor recurrence and survival.

BACKGROUND & AIMS:Good outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and 'all-comers'. METHODS:This multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000-2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs. RESULTS:From 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8-55.8) and 38.2% (CI 25.4-52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [p <0.0001]) and not significantly higher for the UCSF-DS group (SHR 1.60 [p = 0.32]), compared with patients remaining within Milan. The all-comers presented more frequent features of aggressive HCC and higher tumour burden at explant. Among the UCSF-DS group, an AFP value of ≤20 ng/ml at listing was associated with lower recurrence (SHR 2.01 [p = 0.006]) and better survival. However, recurrence was still significantly high irrespective of AFP ≤20 ng/ml in all-comers. CONCLUSIONS:Patients within the UCSF-DS protocol at listing have similar post-transplant outcomes compared with those within Milan when successfully downstaged. Meanwhile, all-comers have a higher recurrence and inferior survival irrespective of response to LRT. Additionally, in the UCSF-DS group, an ALP of ≤20 ng/ml might be a novel tool to optimise selection of candidates for LT. CLINICAL TRIAL NUMBER:This study was registered as part of an open public registry (NCT03775863). LAY SUMMARY:Patients with more extended HCC (within the UCSF-DS protocol) successfully downstaged to the conventional Milan criteria do not have a higher recurrence rate after LT compared with the group remaining in the Milan criteria from listing to transplantation. Moreover, in the UCSF-DS patient group, an ALP value equal to or below 20 ng/ml at listing might be a novel tool to further optimise selection of candidates for LT.