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Atezolizumab-bevacizumab is the new standard for advanced hepatocellular carcinoma (HCC) but its impact on portal hypertension (PHT) is unknown. We aimed to identify predictive factors of acute variceal bleeding (AVB) and to monitor PHT parameters under treatment.We conducted a prospective study including all cirrhotic patients treated with atezolizumab-bevacizumab since 2020. We performed monitoring of PHT using upper endoscopy at inclusion and at 6 months and hepatic venous pressure gradient (HVPG) at inclusion, 3 and 6 months after the beginning of treatment. We also included a retrospective series of patients treated with sorafenib. Time-to-events data were estimated by Kaplan-Meier with the log-rank test, along with Cox models.Forty-three patients treated with atezolizumab-bevacizumab were included (male 79.1%, Child-Pugh A 86%). At baseline, 48.8% were treated with curative anticoagulation, 16.3% already experienced AVB and 25.6% had large oesophageal varices (EV). Sorafenib group characteristics were similar. Vascular invasion was present in 60.5% and median was HVPG 8.5 mm Hg. No significant modification in HVPG and EV size was observed at 6 months in the whole cohort but also when considering vascular invasion and radiological response. 14% presented AVB within a median time of occurrence of 3 months, without bleeding-related death. In multivariate analysis, history of AVB (HR = 10.58, p = .03) was associated with AVB. AVB incidence was higher in atezolizumab-bevacizumab compared to sorafenib group (21% vs. 5% at 1 year, p = .02).Atezolizumab-bevacizumab treatment was associated with a higher risk of AVB compared to sorafenib. A history of AVB was associated with AVB during follow-up, which questions the use of bevacizumab in this setting.

Supplemental figures 1-10

Supplementary Table 5: Difference in gene expression between Immune High (IH) and Immune Low (IL) subgroups from the validation dataset (n=20, Coulouarn et al, Carcinogenesis, 2012) (33).

Supplementary Table 3: Difference in gene expression between IH1 and IH2 subtypes IH: Immune - High

Supplementary Table 1: Difference in gene expression between IL and IH subtypes

Supplementary Table 6: Difference in gene expression between Immune High 1 (IH1) and Immune High 2 (IH2) subgroups in the validation dataset (n=20, Coulouarn et al, Carcinogenesis, 2012) (33).

Supplementary Table 8: Molecular alterations identified in cHCC-CCA

Supplementary Table 7: Difference in gene expression between Immune Low 1 (IL1) and Immune Low 2 (IL2) subgroups in the validation dataset (n=20, Coulouarn et al. Carcinogenesis. 2012) (33).

Supplementary Table 4: Difference in gene expression between IL1 and IL2 subtypes IL: Immune - Low

Purpose:Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare malignancy associated with an overall poor prognosis. We aimed to investigate the immune profile of cHCC-CCA and determine its impact on disease outcome.Experimental Design:We performed a multicenter study of 96 patients with cHCC-CCA. Gene expression profile was analyzed using nCounter PanCancer IO 360 Panel. Densities of main immune cells subsets were quantified from digital slides of IHC stainings. Genetic alterations were investigated using targeted next-generation sequencing.Results:Two main immune subtypes of cHCC-CCA were identified by clustering analysis: an “immune-high” (IH) subtype (57% of the cases) and an “immune-low” (IL) subtype (43% of the cases). Tumors classified as IH showed overexpression of genes related to immune cells recruitment, adaptive and innate immunity, antigen presentation, cytotoxicity, immune suppression, and inflammation (P < 0.0001). IH cHCC-CCAs also displayed activation of gene signatures recently shown to be associated with response to immunotherapy in patients with HCC. Quantification of immunostainings confirmed that IH tumors were also characterized by higher densities of immune cells. Immune subtypes were not associated with any genetic alterations. Finally, multivariate analysis showed that the IH subtype was an independent predictor of improved overall survival.Conclusions:We have identified a subgroup of cHCC-CCA that displays features of an ongoing intratumor immune response, along with an activation of gene signatures predictive of response to immunotherapy in HCC. This tumor subclass is associated with an improved clinical outcome. These findings suggest that a subset of patients with cHCC-CCA may benefit from immunomodulating therapeutic approaches.

The combination of atezolizumab and bevacizumab (AtezoBev) is the current first-line treatment for patients with hepatocellular carcinoma (HCC). Our aim was to evaluate the prognostic role of alpha-foetoprotein (AFP) early response and its combination with albumin-bilirubin (ALBI) in these patients.Patients with HCC under AtezoBev with AFP 20 ng/ml were included in three centres. The optimal threshold of AFP variation after 3 weeks of treatment was identified for overall survival (OS) and radiological response (RR) using RECIST 1.1 and mRECIST and its ability to predict progression-free survival (PFS) and OS was tested using univariate and multivariate analysis in derivation and validation cohorts.Seventy-five patients with AFP values20 ng/ml were included. Fifty-eight patients were male with a median age of 63.5 years; 73% had cirrhosis and HCC stage was classified as BCLC B (18.7%) or C (81.3%). In the derivation cohort (n = 38), a decline in AFP ≥ 20% at 3 weeks (AFP early response) was associated with RR using mRECIST criteria (OR: 13.09 95% CI: 1.44-19.34 p = .02), PFS (HR: 0.42; 95% CI: 0.19-0.93, p = .03) and OS (HR: 0.35; 95% CI: 0.15-0.83, p = .01). AFP early response was confirmed as predictor of RR (p = .02 for mRECIST) and OS (p = .03) in the validation cohort (n= 37). In the whole cohort, the combination of ALBI and AFP early response was significantly associated with OS (p = .046) and PFS (p = .012) with a poor prognosis in patients belonging to the ALBI2-AFP non-responders class.AFP early response at 3 weeks predicts oncological outcomes in HCC patients treated with AtezoBev and combination with ALBI grade refines prognostic discrimination.

International audience; The aging of the population, the increased prevalence of chronic liver diseases in elderly and the need to broaden the list of potential liver donors enjoin us to better understand what is an aged liver. In this review, we provide a brief introduction to cellular senescence, revisit the main morphological and functional modifications of the liver induced by aging, particularly concerning metabolism, immune response and regeneration, and try to elude some of the signalling pathways responsible for these modifications. Finally, we discuss the clinical consequences of aging on chronic liver diseases and the implications of older age for donors and recipients in liver transplantation.

Meeting AbstractOS084

Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are two major complications of cirrhosis that are closely linked and impact patients prognosis, particularly acute variceal bleeding (AVB). Therefore, PHT screening and AVB prophylaxis are major issues to improve the outcome of the patients, but practices may vary among physicians.We submitted hepatologists, gastroenterologists and digestive oncologists to a questionnaire of 70 items about PHT screening and management to evaluate their practice.95 out of 847 physicians responded to the questionnaire (hepatologists 63.2%, Oncologists/gastroenterologists 36.8%). In patients with advanced HCC, PHT was assessed by endoscopy in 80.0% of cases. HCC progression motivated a new for 12.6% of respondents while no intent to control was declared for 49.5% of them. AVB primary prophylaxis for large size esophageal varices (EV) was impacted by the presence of red marks at endoscopy. In the absence of a red mark, prophylaxis with non-selective betablockers (NSSB) was proposed in 70.5% of cases for patients undergoing TKI and 63.2% undergoing Atezolizumab/Bevacizumab, whereas the combination of endoscopic band ligation (EBL) and NSBB was preferred in 41.1% of patients undergoing TKI versus 53.7% undergoing Atezolizumab/Bevacizumab in case of a red mark. The initiation of a systemic treatment was lower in patients with an history of AVB6 months, which was even more significant for Atezolizumab/Bevacizumab combination (51.6%) compared to tyrosine kinase inhibitors (72.6%) (p0.001). Atezolizumab/Bevacizumab was initiated in 43% of participants in case of AVB6 months versus 95% if6 months (p0.001). In case of AVB on Atezolizumab/Bevacizumab, 43.2% continued the treatment after regression of EV, 24.2% continued Atezolizumab alone and 14.7% permanently stopped the treatment.Strategies for screening and management of PHT in advanced HCC remain very heterogeneous among physicians, suggesting the need to improve PHT knowledge and dedicated studies for advanced HCC.

Background & Aims: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs.Methods: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling.Results: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA (“Nestin High”, >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies.Conclusion: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy. Lay summary: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.

Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are complications of cirrhosis which often coexist, rending the management more complex. HCC is generally considered as a contraindication for transjugular intrahepatic portosystemic shunt (TIPS). We studied the outcome of 8 patients treated by TIPS after HCC diagnosis between 2010-2020. TIPS wasn't associated with worsening of liver function or tumor spreading and all patients underwent liver transplantation. TIPS should be considered in case of HCC, especially for variceal bleeding or as a bridge to HCC treatments that are discarded due to PHT levels/ascites by improving liver function before liver transplantation.

BACKGROUND AND AIM The prognostic value of transient elastography (TE) in cirrhotic patients with hepatocellular carcinoma (HCC) treated by percutaneous radiofrequency ablation (RFA) is currently unknown. METHOD(S) We included patients with histologically proven cirrhosis and with a first diagnosis of HCC inside Milan criteria treated by percutaneous RFA, and with TE available the year before treatment with 10 shots and interquartile range/median

BACKGROUND AND AIMS Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are major complication of cirrhosis which significantly contribute to morbidity and mortality. In this review, we aim to describe the consequences of both angiogenesis and inflammation in the pathogenesis of PHT and HCC, but also the difficulty to propose adapted treatment when PHT and HCC coexist in the same patients. METHODS Studies for review in this article were retrieved from the PubMed database using literature published in English until March 2021. RESULTS Portal hypertension occurs secondary to an increase of intrahepatic vascular resistances, the opening of portosystemic collateral vessels and the formation of neovessels, related to vascular endothelial growth factor (VEGF). Recently, bacterial translocation-mediated inflammation was also identified as a major contributor to PHT. Interestingly, VEGF and chronic inflammation also contribute to HCC occurrence. As PHT and HCC often coexist in the same patient, management of PHT and its related complications as well as HCC treatment appear more complex. Indeed, PHT-related complications such as significant ascites may hamper the access to HCC treatment and the presence of HCC is also independently associated with poor prognosis in patients with acute variceal bleeding related to PHT. Due to their respective mechanism of action, the combination of Atezolizumab and Bevacizumab for advanced HCC may impact the level of PHT and its related complications and to date, no real-life data are available. CONSLUSIONS Appropriate evaluation and treatment of PHT remains a major issue in order to improve the outcome of HCC patients.

BACKGROUND AND AIMS Data about the prognosis of salvage transjugular intrahepatic portosystemic shunt (TIPS) using covered stents for refractory variceal bleeding caused by portal hypertension are scarce. We aimed to assess survival and to identify predictors of mortality in these patients. APPROACH AND RESULTS One hundred sixty-four patients with cirrhosis from five centers treated with salvage TIPS between 2007 and 2017 were retrospectively divided into a derivation cohort (83 patients) and a validation cohort (81 patients). Comparisons were performed using the Mann-Whitney and Fischer's exact test. Six-week overall survival (OS) was correlated with variables on the day of the TIPS using Kaplan-Meier curves with log-rank test and univariate/multivariate analyses using the Cox model. Eighty-three patients were included in the derivation cohort (male, 78%; age, 55 years, alcohol-associated cirrhosis, 88%; Model for End-Stage Liver Disease [MELD], 19 [15-27]; arterial lactate, 3.7 mmol/L [2.0-8.3]). Six-week OS rate was 58%. At multivariate analysis, the MELD score (OR, 1.064; 95% CI, 1.005-1.126; P = 0.028) and arterial lactate (OR, 1.063; 95% CI, 1.013-1.114; P = 0.032) were associated with 6-week OS. Six-week OS rates were 100% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15 and 5% in patients with lactate ≥12 mmol/L and/or MELD score ≥ 30. The 81 patients of the validation cohort had similar MELD and arterial lactate level but lower creatinine level (94 vs 106 µmol/L, P = 0.008); 6-week OS was 67%. Six-week OS rates were 86% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15 and 10% for patients with lactate ≥12 mmol/L and/or MELD score ≥ 30. In the overall cohort, rebleeding rate was 15.8% at 6 weeks, and the acute-on-chronic liver failure grade (OR, 1.699; 95% CI, 1.056-1.663; P = 0.040) was independently associated with rebleeding. CONCLUSIONS After salvage TIPS, 6-week mortality remains high and can be predicted by MELD score and lactate. Survival rate at 6 weeks was >85% in patients with arterial lactate ≤2.5 mmol/L and MELD score ≤ 15, while mortality was >90% for lactate ≥12 mmol/L and/or MELD score ≥ 30.

Purpose: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare malignancy associated with an overall poor prognosis. We aimed to investigate the immune profile of cHCC-CCA and determine its impact on disease outcome. Experimental Design: We performed a multicenter study of 96 patients with cHCC-CCA. Gene expression profile was analyzed using nCounter PanCancer IO 360 Panel. Densities of main immune cells subsets were quantified from digital slides of IHC stainings. Genetic alterations were investigated using targeted next-generation sequencing. Results: Two main immune subtypes of cHCC-CCA were identified by clustering analysis: an “immune-high” (IH) subtype (57% of the cases) and an “immune-low” (IL) subtype (43% of the cases). Tumors classified as IH showed overexpression of genes related to immune cells recruitment, adaptive and innate immunity, antigen presentation, cytotoxicity, immune suppression, and inflammation (P < 0.0001). IH cHCC-CCAs also displayed activation of gene signatures recently shown to be associated with response to immunotherapy in patients with HCC. Quantification of immunostainings confirmed that IH tumors were also characterized by higher densities of immune cells. Immune subtypes were not associated with any genetic alterations. Finally, multivariate analysis showed that the IH subtype was an independent predictor of improved overall survival. Conclusions: We have identified a subgroup of cHCC-CCA that displays features of an ongoing intratumor immune response, along with an activation of gene signatures predictive of response to immunotherapy in HCC. This tumor subclass is associated with an improved clinical outcome. These findings suggest that a subset of patients with cHCC-CCA may benefit from immunomodulating therapeutic approaches.

International audience; Hepatitis B infection (HBV) is one of the most common causes of hepatocellular carcinoma (HCC) worldwide. The age of occurrence, prognosis and incidence vary dramatically depending on the region of the world. This geographic variation is largely dependent on the contrasting incidence of HBV, age of transmission of the virus, the timing of integration into the human genome, and different HBV genotypes, as well as environmental factors. It results in a wide difference in viral interaction with the immune system, genomic modulation and the consequent development of HCC in an individual. In this review, we describe many factors implicated in HCC development, provide insight regarding at-risk populations and explain societal recommendations for HCC surveillance in persons living with HBV in different continents of the world.

Introduction Intestinal parasitic diseases are a global health problem. Due to its equatorial climate, vast territory with isolated areas and the precariousness of its population, intestinal parasitosis is considered to be a major issue in French Guiana but only few data are available and these mainly focus on specific population. We aimed at determining the parasitic index and at describing the characteristics of these infections in order to develop preventive strategies. Material and methods We retrospectively analysed all the parasitological samples recorded in the register of the two main laboratories of French Guiana between 2011 and 2016. The parasitic index was the percentage of parasitised patients in comparison with the total number of subjects studied. A patient who underwent several positive parasitological examinations was considered only once in the analysis at the time of the first sampling. Results A total of 15,220 parasitological samples of 9,555 patients were analysed and 2,916 were positive in 1,521 patients. The average infestation rate and parasitic index were 19.2% and 16.0%, respectively. The parasitic index remained stable between 2011 (18.2%) and 2016 (18.3%). The patients were mainly men (66.4%), with a median age of 33.0 years (26.3% of patients were under 18 years of age) and lived mainly in the Central Agglomeration (48.2%) and in West Guiana (37.4%). Hookworms were the most common parasite (25.2%) followed by Entamoeba coli (13.3%), Strongyloides stercoralis (10.9%) and Giardia intestinalis (10.8%). Among the infected patients, 31.0% presented mixed infections and 67.5% of them had at least one pathogenic parasite. The patients aged from 0 to 18 years presented significantly more polyparasitism (30.9%) than monoparasitism (24.3%, p, Author summary Intestinal parasitic diseases are a global public health problem which mostly affect developing countries where adequate water and sanitation facilities are lacking. Due to its equatorial climate, vast territory with isolated areas and the precariousness of its population, intestinal parasitosis is considered to be a major issue in French Guiana and came to be frequently detected during hospitalisations. However, only few data are available and no integrated control programs have been conducted. This is the first study that has been exploring and reporting epidemiological data on intestinal parasitic infections in French Guiana covering much of the territory. This work reports an average parasitic index of 16.0%, which was stable between 2011 (18.2%) and 2016 (18.3%) with a majority of Ancylostoma sp, Strongyloides stercoralis and Giardia intestinalis. Although it may not be representative of the entire Guyanese population, the parasitic index remained high and stable from 2011 to 2016 and it justifies the need for an active prevention program as it was already done in the other French overseas departments such as Martinique and Guadeloupe.

Background Patients affected by HCC represent a vulnerable population during the COVID-19 pandemic and may suffer from the unusual allocation of healthcare resources. The aim of this study was to determine the impact of the COVID-19 pandemic on the management of HCC patients within six French referral centers of the metropolitan area of Paris. Materials and methods We performed a multicenter, retrospective, cross-sectional study on the management of patients affected by HCC during the first six weeks of COVID-19 pandemic (exposed), compared to the same period in 2019 (unexposed). Were included all patients discussed in multidisciplinary tumor meeting (MTB) and/or undergoing radiological or surgical programmed procedure during the study period, in a curative or palliative intent. Endpoints were the number of patients with a modification in the treatment strategy, or a delay in decision-to-treatment. Results After screening, n=670 patients were included (n=293 Exposed to COVID, n=377 Unexposed to COVID). A decrease of the numbers of patients with HCC presented in MTB in 2020 (p=0.034) and with a first diagnosis of HCC (n=104 Exposed to COVID, n=143 Unexposed to COVID, p=0.083) was find. Modification in the treatment strategy was observed in 13.1% of patients, with no differences between the two periods. Nevertheless 21.5% versus 9.5% of patients experienced a treatment delay longer than 1 month in 2020 compared to 2019 (p, Graphical abstract, Highlights • In COVID period, a decrease of the numbers of patients with hepatocellular carcinoma presented in Multidisciplinary Tumour Board and, in particular, with a first diagnosis of HCC was find. • Globally, modification in the treatment strategy was observed in 13.1% of patients, with no differences between the two periods but the main reason was significantly different in 2020 compared to 2019: COVID-19 in 2020 vs tumour progression in 2019. • More than 21% of patients experienced a treatment delay longer than 1 month in COVID period compared to 9.5% in 2019 , specially, in subgroup with active, recurrent HCC. The main reasons for the delay of treatment in 2020 was COVID-19 infection related • In 2020, 7.1% of patients had a diagnosis of an active COVID-19 infection and 4/21 (19.1%) died., During COVID pandemic era, less patients with hepatocellular carcinoma (HCC) have been presented in multidisciplinary tumor bord, specially with a first diagnosis of HCC