BACKGROUND:The burden of hepatocellular carcinoma (HCC) increases worldwide. We report the current landscape of HCC, in France. METHODS:Carcinome HépatocellulaIrE en France (CHIEF) is a national, prospective, observational cohort initiated in 2019 with the aim of including 5000 patients with HCC, with a 5-year follow-up for each. CHIEF Epidemio 2000, is the first global analysis. RESULTS:In September 2021, 2043 patients were included in 32 centers. We analyzed 1640 patients, 86% men, 68-year-old, BMI 26.8. 70.8% of patients had cirrhosis (MELD score 9, Child-Pugh A in 77.8%, and portal hypertension in 39%. Liver disease was related to alcohol 58.5%, metabolic syndrome 39%, and virus 23.3%. HCC was confirmed by histology in 46.3%. The Milan criteria fulfilled 32.9%, median AFP 39 ng/ml, 5.9% portal thrombosis, and 10.7% metastases. BCLC classes 0, A, B, C, and D were 6.1, 29.8, 28.8, 32.1, and 3.2%, respectively. HCC was detected during a surveillance program in 35.2% associated with better survival (P < 0.001). Median follow-up was 17.76 months (29.1% deaths). The 6, 12, and 18 months overall survival rates were 84.9% (95% CI: 82.8-87), 76.7% (95% CI: 74.2-79.2), 69.3% (95% CI: 66.4-72.3). One-year survival for BCLC 0, A, B, C, and D was at 95.6, 89.7, 81.7, 54.9, and 40%, respectively (P < 0.0001). First-line treatment was curative, locoregional, or systemic in 40.5, 36.2, and 19.2%, with 1-year survival at 92.9, 82.2, and 57.8%, respectively (P < 0.0001). Atezolizumab-bevacizumab yielded a median overall survival of 17.05 months versus nine for TKI (P < 0.0001). CONCLUSION:In real-life data, metabolic syndrome becomes the second cause of HCC in France. The 1-year survival rates are high for all treatments applied, and Immunotherapy yields similar results than in trials.

Supplementary Figures S1-S6; Supplementary Materials and Methods; Supplementary Table S1.

INTRODUCTION:This document is a summary of the French Intergroup guidelines regarding the management of hepatocellular carcinoma (HCC) published in March 2019.METHOD:It is a collaborative work under the auspices of most of the French medical societies involved in the management of HCC. It is based on the previous guidelines published in 2017. Recommendations are graded in 3 categories according to the level of evidence of data found in the literature.RESULTS:The diagnosis and staging of HCC is essentially based on clinical, biological and imaging features. A pathological analysis obtained by a biopsy of tumoral and non-tumoral liver is recommended. HCCs can be divided into 2 groups, taking into account not only the tumor stage, but also liver function. HCCs accessible to curative treatments are tumors that are in Milan criteria or with an AFP score ≤ 2, mainly treated by surgical resection, local ablation or liver transplantation. Intermediate and advanced HCCs with no liver insufficiency, accessible only to palliative treatments, benefit from TACE, SIRT or systemic therapy according to the presence or absence of macrovascular invasion or extrahepatic spread.CONCLUSION:Such recommendations are in permanent optimization and each individual case must be discussed in a multidisciplinary expert board.

Sorafenib is the standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, identifying secreted biomarkers that predict sorafenib efficacy in all HCC patients remains challenging. It was recently reported that sorafenib interferes with protein homeostasis and inhibits global translation in tumour cells. A likely consequence of this inhibition would be the interruption of autocrine loops. The aim of the present study was to investigate the effect of sorafenib on two growth factors implicated in autocrine loops and HCC tumour invasion: amphiregulin (AREG) and vascular endothelial growth factor (VEGF). ELISA, quantitative polymerase chain reaction analysis, western blotting and a cytokine array were performed on HCC cell lines and the prognostic role of these two biomarkers in HCC patients was evaluated. Serum AREG and VEGF levels were assayed by ELISA in 55 patients with advanced HCC treated with sorafenib. It was observed that sorafenib decreased AREG, VEGF and cytokine expression at the transcriptional and post‑transcriptional levels. All HCC patients in our cohort had detectable concentrations of AREG and VEGF both at baseline and after sorafenib treatment. The decreased serum levels of AREG and VEGF after 15 days of sorafenib treatment were significantly associated with better overall and progression‑free survival. The results of the multivariate analysis demonstrated that a decrease in AREG was an independent prognostic indicator of overall survival (hazard ratio, 0.208; 95% confidence interval, 0.173‑0.673; P=0.0003). These results suggest that sorafenib inhibits auto-crine loops and that early decrease in serum AREG or VEGF levels predicts sorafenib efficacy in HCC patients.

Background A prior in vitro study showed that idarubicin was the most cytotoxic agent for hepatocellular carcinoma (HCC) cell lines. Idarubicin-loaded beads for transarterial chemoembolization (TACE) were previously evaluated for the appropriate dose in a phase I dose-escalation study. Purpose To evaluate objective response rate (ORR), safety, and survival after TACE by using idarubicin-loaded beads for unresectable HCC. Materials and Methods This prospective single-arm phase II study was conducted between January 2015 and January 2017. Participants with unresectable HCC were included in the trial and underwent TACE with idarubicin-eluting beads. The primary end point was 6-month ORR assessed with independent central review by using modified Response Evaluation Criteria in Solid Tumors. Secondary end points were best ORR during the first 6 months, overall survival, progression-free survival, time to progression, and safety. A two-stage Fleming statistical design was used. Results Forty-six study participants (mean age, 71.2 years ± 10.2; six women and 40 men) were included; 44 participants underwent at least one TACE session. The 6-month ORR was 52% (23 of 44). The best ORR achieved was 68% (30 of 44). Fourteen of 44 (32%) participants underwent a curative treatment after TACE. Median progression-free survival, time to progression, and overall survival were 6.6 months, 9.5 months, and 18.6 months, respectively. TACE was discontinued for toxicity in four of 44 (9%) participants. The most frequent grade 3-4 adverse events were elevated aspartate aminotransferase (14 of 44, 32%), elevated γ-glutamyl transpeptidase (eight of 44, 18%), hyperbilirubinemia (seven of 44, 16%), elevated alanine aminotransferase (seven of 44, 16%), and pain (seven of 44, 16%). Conclusion Idarubicin-eluting beads showed a good safety profile and promising objective response rate and time to progression when used as part of a transarterial chemoembolization regimen for unresectable hepatocellular carcinoma. © RSNA, 2019 See also the editorial by Padia in this issue.

Data on alcohol-related HCC are limited. Our aim was to describe the incidence, management, and prognosis of alcohol compared to Hepatitis C (HCV)-related HCC at a national level. Incident cases of HCC were identified in French healthcare databases between 2009 and 2012 and analyzed retrospectively. Demographic data, type, location, and annual HCC-caseload of the hospitals where patients were first managed were retrieved. Survival of incident cases was computed from the time of diagnosis and adjusted for potential confounding variables. The study population included 14,060 incident cases of alcohol and 2581 HCV-related HCC. Alcohol-related HCC was more frequent than HCV-related HCC (29.37 and 5.39/100,000 adults/year, respectively) with an heterogeneous distribution on the French territory. The optimal treatment was less frequently curative (20.5% vs 35.9%; p < 0.001), and survival was significantly shorter (9.5 [9.0–10.0] versus 16.8 [15.5–18.7] months p < 0.001) in alcohol compared to HCV-related HCC, with marked variations between regions for a given risk factor. In multivariable analysis in the whole study population, curative treatment was a strong predictor of survival (adjusted HR 0.28 [0.27–0.30] months p < 0.001). Being managed at least once in a teaching hospital during follow-up was independently associated with receiving a curative treatment and survival. In France, incidence of alcohol-related HCC is high and prognosis is poor compared to HCV-related HCC, with marked variations between regions. These results should guide future health policy initiatives pertaining to HCC care. Importantly, increasing patient’ referral in expert centers could increase chances to receive curative treatment and improve outcomes.

Hepatocellular carcinoma is a major public health problem with one of the highest overall mortality compared to other cancers. The median overall survival in France in a hospital population with hepatocellular carcinoma is 9.4 months. Several publications reported a positive impact of hepatocellular carcinoma screening on diagnosis at an early-stage, eligibility for curative treatment and overall survival. However, the identification of patients to be included in a hepatocellular carcinoma screening program and the application of screening recommendations are not optimal. Other studies suggest a potentially negative impact of delayed diagnosis or treatment initiation on the patient's prognosis. Finally, marked variations between French regions and departments have been described in terms of access to curative treatment and overall survival. In this review article, we propose a state of play of the hepatocellular carcinoma patient's care pathway in France with the aim of identifying potential breaking points with negative impact on prognosis and of developing proposals for improvement.

Le carcinome hépatocellulaire représente un problème de santé publique majeur avec une mortalité globale parmi les plus élevées comparée à celle des autres cancers. La médiane de survie observée en France dans une population hospitalière avec carcinome hépatocellulaire est de 9,4 mois. De nombreuses équipes ont rapporté un impact positif du dépistage du carcinome hépatocellulaire sur le diagnostic à un stade précoce, sur l’éligibilité à un traitement curatif et sur la survie globale. Cependant, l’identification des patients à risque de carcinome hépatocellulaire devant entrer dans un programme de dépistage, et l’application des recommandations de dépistage sont insuffisantes. D’autres travaux suggèrent un impact potentiellement négatif sur le pronostic des patients du retard au diagnostic ou à la mise en route du traitement. Enfin, des variations marquées entre les régions et les départements français ont été décrites en ce qui concerne l’accès au traitement curatif et la survie globale. Dans cet article de synthèse, nous nous proposons de faire un état des lieux sur le parcours de soins du patient atteint de carcinome hépatocellulaire en France avec pour objectifs d’identifier les potentiels points de rupture pouvant avoir un impact sur le pronostic des patients et d’élaborer des propositions d’amélioration.

Alpha-foetoprotein (AFP), one of the first protein tumour markers discovered, is widely used today in clinical practice. Its application for the screening and diagnosis of hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour, is a matter of extensive debate. In addition to the studies focused on the role of the AFP in the diagnosis of HCC, in recent years AFP has been used to guide the therapeutic choice in HCC and monitor the treatment. Here, we summarize the latest studies that show the interest of AFP quantification in determining the suitability of liver transplantation or to follow-up on patients receiving the targeted treatment sorafenib. We also highlight the recent studies showing the active role of AFP in tumour progression, and the new modes of regulation of this tumour marker. Among these is the regulation of AFP through tumour proteostasis and the Unfolded Protein Response (UPR). We discuss the implications of this new knowledge in the therapeutic context, in terms of interpreting serum levels of AFP, and the new perspectives offered by AFP for the study of tumour proteostasis.

BACKGROUND:Sorafenib, a kinase inhibitor active against various solid tumours, induces oxidative stress and ferroptosis, a new form of oxidative necrosis, in some cancer cells. Clinically-applicable biomarkers that reflect the impact of sorafenib on the redox metabolism of cancer cells are lacking.METHODS:We used gene expression microarrays, real-time PCR, immunoblot, protein-specific ELISA, and gene reporter constructs encoding the enzyme luciferase to study the response of a panel of cancer cells to sorafenib. Tumour explants prepared from surgical hepatocellular carcinoma (HCC) samples and serum samples obtained from HCC patients receiving sorafenib were also used.RESULTS:We observed that genes of the metallothionein-1 (MT1) family are induced in the HCC cell line Huh7 exposed to sorafenib. Sorafenib increased the expression of MT1G mRNA in a panel of human cancer cells, an effect that was not observed with eight other clinically-approved kinase inhibitors. We identified the minimal region of the MT1G promoter that confers inducibility by sorafenib to a 133 base pair region containing an Anti-oxidant Response Element (ARE) and showed the essential role of the transcription factor NRF2 (Nuclear factor erythroid 2-Related Factor 2). We examined the clinical relevance of our findings by analysing the regulation of MT1G in five tumour explants prepared from surgical HCC samples. Finally, we showed that the protein levels of MT1 increase in the serum of some HCC patients receiving sorafenib, and found an association with reduced overall survival.CONCLUSION:These findings indicate that MT1 constitute a biomarker adapted for exploring the impact of sorafenib on the redox metabolism of cancer cells.

BACKGROUND & AIMS:Information on the incidence, management, and prognosis of hepatocellular carcinoma (HCC) is derived from population samples, regional data, or registries. Comprehensive national evaluations within a given country are lacking. This study aimed to investigate regional variations in HCC care within France. METHODS:This observational study analysed data from French administrative databases for more than 30,000 patients with HCC diagnosed between 2009 and 2012, and followed-up until 2013. The incidence of HCC, access to surgery, and survival, at both the national level and two geographical levels (the 21 French regions and 95 French departments into which France is divided administratively), were determined. The influence on outcome of the structure of the hospital where HCC was first managed was assessed. RESULTS:At the national level, the median survival was 9.4months and only 22.8% of patients had curative treatment. There were marked variations between regions and departments in incidence, access to curative treatment (range 1.3-28.8% and 8.1-32.3% respectively), and in median survival (range 5.7-12.1 and 4.3-16.5months respectively). The administrative type and annual HCC-caseload of the hospital where patients were first admitted also had an independent influence on treatment and survival. CONCLUSION:Despite full insurance coverage for all citizens, national measures to reduce inequities in the management of cancer patients, standardised recommendations for HCC surveillance and management, the percentage of patients undergoing curative treatment and their survival may vary four-fold depending on their postcode. The hospital in which patients are first managed has a clear influence on accessibility to both good care and survival. LAY SUMMARY:Population-based studies have highlighted large and sometimes unexpected differences between countries in the survival of patients with malignancy. As these differences are considered to indicate the overall effectiveness of health systems, in addition to the incidence of the cancer or quality of registration, variations within a given country should be minimal. However, similar to between countries differences, this study shows differences within the same country in the incidence, curative treatment rate, and survival of patients with HCC. Evidence that access to care and survival varies within a country can strengthen the impetus for government and clinicians to address these disparities.

Sorafenib increases the expression levels of MT1B in Huh7 cells. Figure S2: Pharmacological antioxidants prevent the induction of MT1B induced by sorafenib. Table S1: List of genes upregulated in Huh7 cells exposed to sorafenib (10 μM) for 9 h. Table S2: Summary of the characteristics of the hepatocellular carcinoma tumours used for short-term culture of tumour explants. Table S3: Summary of the clinical characteristics of HCC patients in the two cohorts. (DOC 185 kb)

Budd-Chiari syndrome (BCS) is a rare form of vascular disease. There is limited literature available regarding the prognosis of this disease. The aim of this study was to characterize the cumulative recurrence rates and to investigate the risk factors of recurrence in Chinese patients with BCS.Four hundred and seventy-one patients were diagnosed as having BCS in the Affiliated Hospital of Xuzhou Medical College (Jiangsu, China) between January 2008 and December 2012. Follow-ups were conducted by phone calls or correspondence. Cumulative recurrence rates were assessed with the Kaplan-Meier curves. Independent risk factors of recurrence were calculated with the Cox's proportional hazards regression model.Four hundred and twenty-five patients with BCS had complete follow-up data, in which 24 patients died, 98 patients had recurrence, with the median duration of follow-up being 19.3 months (range 3 to 61.4). The cumulative 1-, 2-, 3-, 4- and 5-year recurrence rates were 12%, 22%, 27%, 35% and 42%, respectively. Univariable and multivariable Cox's proportional hazards regression models showed that the risk factors of recurrence include: age ≤ 30 years (HR = 2.261, 95% CI: 1.412–3.621), differentiated typology (hepatic vein type: HR = 1.885, 95% CI: 1.045–3.402; combined type: HR = 2.088, 95% CI: 1.233–3.536), elevated lactate dehydrogenase (LDH) levels (HR = 1.125, 95% CI: 1.101–1.212) and the Child-Pugh class B/C (B: HR = 1.758, 95% CI: 1.057–2.926; C: HR = 2.626, 95% CI: 1.396–4.940).Regardless of thrombophilia and haematological causes, exceptionally found in Chinese patients, the 5-year recurrence rate of BCS was as high as 42%. Age ≤ 30 years, hepatic vein type, combined type, increased LDH levels and the Child-Pugh class B/C were independent predictors of BCS recurrence.

BACKGROUND/AIMSorafenib is the medical reference for treatment of hepatocellular carcinoma (HCC). Multiple forms of cytotoxicity are induced by sorafenib in HCC cells in vitro but it is unclear what extent of apoptosis and necrosis is induced in HCC patients receiving sorafenib.PATIENTS AND METHODSThe M30 and M65 biomarkers, which reflect the release of cytokeratin-18 and its apoptotic cleavage fragments, were measured in patients with HCC (n=36) and matched patients with cirrhosis (n=47). A serum sample was collected from 20 patients with HCC four weeks after the onset of treatment with sorafenib.RESULTSBasal serum levels of M30 and M65 were increased in patients with HCC compared to those with uncomplicated cirrhosis. No statistically significant increase in the level of M30 or M65 was found in the sera of patients with HCC after sorafenib.CONCLUSIONThe findings indicate that sorafenib is not a potent inducer of HCC cell death in most patients.

Un essai randomise comparant octreotide et absence de traitement specifique chez des malades atteints de carcinome hepatocellulaire (CHC) evolue avait precedemment montre un benefice en termes de survie globale chez les patients traites [1]. Le but de l'etude ici relatee a ete d'evaluer ce benefice dans un essai randomise multicentrique incluant un nombre suffisant de patients.

Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC). A decrease in the serum levels of Alpha-fetoprotein (AFP) is reported to be the biological parameter that is best associated with disease control by sorafenib. In order to provide a biological rationale for the variations of AFP, we analyzed the various steps of AFP production in human HCC cell lines exposed to sorafenib. Sorafenib dramatically reduced the levels of AFP produced by HCC cells independently of its effect on cell viability. The mRNA levels of AFP decreased upon sorafenib treatment, while the AFP protein remained localized in the Golgi apparatus. Sorafenib activated the Regulated Inositol-Requiring Enzyme-1α (IRE-1α) and the PKR-like ER Kinase (PERK)-dependent arms of the Unfolded Protein Response (UPR). The inhibition of IRE-1α partially restored the mRNA levels of AFP upon treatment with sorafenib. The inhibition of both pathways partially prevented the drop in the production of AFP induced by sorafenib. The findings provide new insights on the regulation of AFP, and identify it as a biomarker suitable for the exploration of HCC cell proteostasis in the context of therapeutic targeting.

Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour. The loss of function of the retinoblastoma (Rb) protein is an important event during liver carcinogenesis, but it is unclear whether the Rb status modulates the response of HCC cells to sorafenib. Here, we examined this question in HCC cells with reduced levels of Rb achieved through stable RNA interference. We show that HCC cells with reduced levels of Rb exhibit a two- to threefold increase in cell death induction upon exposure to sorafenib compared with controls. Sorafenib treatment of Balb/c nude mice that received tumour xenografts derived from HCC cells with reduced Rb levels resulted in complete tumour regression in 50% of the animals treated, compared with tumour stabilization in mice that received control cells. We show that, upon exposure to sorafenib, the Rb-negative status of HCC cells promotes the occurrence of ferroptosis, a form of oxidative necrosis. The findings highlight the role of Rb in the response of HCC cells to sorafenib and the regulation of ferroptosis.

The recent and historical publications of IARC/OMS/GLOBOCAN allowed us to compose a picture of incidence and of mortality of primitive liver cancer in Romania and to compare them with the data from the other countries. In 2012, the incidence rates were 9.2/100 000 in males and of 3/100 000 in females and the mortality rates were 11/100 000 in males and of 4.2/100 000 in females. The primitive liver cancer represented 2.8% of cancers and 5.9% of the mortality by cancer. It was situated in the 4 th rank of the digestive cancers in terms of frequency and in the 3 rd rank of the digestive cancers in terms of mortality. The incidence was one of higher registered in Europe. The mortality rate, upper to that of the incidence and in constant increase since 1980, is compatible with a late diagnosis of this cancer in Romania. This important problem of public health requires, as in the other countries, the implementation of specialized indicators and especially the launch of actions aiming at the improvement of the precocity of the diagnosis.

BACKGROUNDHealth-related quality of life (QoL) has been validated as a prognostic factor for cancer patients; however, to be used in routine practice, QoL scores must be dichotomized. Cutoff points are usually based on arbitrary percentile values. We aimed to identify optimal cutoff points for six QoL scales and to quantify their added utility in the performance of four prognostic classifications in patients with hepatocellular carcinoma (HCC).METHODSWe reanalyzed data of 271 patients with advanced HCC recruited between July 2002 and October 2003 from 79 institutions in France in the CHOC trial, designed to assess the efficacy of long-acting octreotide. QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30). The scores ranged from 0 to 100. Identification of optimal cutoff points was based on the method of Faraggi and Simon [Stat Med 1996;15:2203-2213]. Improvement in the performance of prognostic classifications was studied with Harrell's C-index, the net reclassification improvement (NRI), and integrated discrimination improvement (IDI).RESULTSWe found that optimal cutoff points were 50 for global health, 58.33 for physical functioning, 66.67 for role functioning, 66.67 for fatigue, 0 for dyspnea, and 33.33 for diarrhea. The addition of QoL and clinical factors improved the performance of all four prognostic classifications, with improvement in the range of 0.02-0.09 for the C-index, 0.24-0.78 for 3-month NRI, and 0.02-0.10 for IDI.CONCLUSIONThese cutoff values for QoL scales can be useful to identify HCC patients with very poor prognosis and thus improve design of clinical trials and treatment adjustment for these patients.

The treatment of hepatocellular carcinoma (HCC) is difficult due to the underlying cirrhosis which has its own influence on therapeutic issues. An inquiry was performed in centres with specialized multidisciplinary team meetings dedicated to HCC (HCC-MTM) or in centres with non-specialized (digestive oncology or general oncology) multidisciplinary team meetings (NS-MTM). The number of cases of HCCs taken in charge yearly was significantly higher in HCC-MTM than in NS-MTM (p=0,0014). Interventional radiologists and transplant surgeons were more frequently implied in HCC-MTM than in NS-MTM (respectively p=0,009 and p=0,02). On site availability of every treatment of HCC was higher in RCP-MTM than in NS-MTM (p=0,015). There were no inclusion in clinical trials in 40.5 % of NS-MTM versus only 17.6 % of HCC-MTM (p=0,0086). In three clinical cases out of seven there were discrepancies between the therapeutic options of HCC-MTM and NS-MTM. In all three cases, the treatment offered to the patient by HCC-MTM was more consistent with clinical standards. These results prompt to perform more studies on the quality of management of patients with HCCs by MTMs.