Geographical Disparities of Outcomes of Hepatocellular Carcinoma in France: The Heavier Burden of Alcohol Compared to Hepatitis C.

BACKGROUND: Data on alcohol-related HCC are limited. AIMS: Our aim was to describe the incidence, management, and prognosis of alcohol compared to Hepatitis C (HCV)-related HCC at a national level. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Idarubicin-loaded Beads for Chemoembolization of Hepatocellular Carcinoma: The IDASPHERE II Single-Arm Phase II Trial.

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.

Geographical variations in incidence, management and survival of hepatocellular carcinoma in a Western country.

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.

Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib.

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.

Optimal cut points for quality of life questionnaire-core 30 (QLQ-C30) scales: utility for clinical trials and updates of prognostic systems in advanced hepatocellular carcinoma.

BACKGROUND: Health-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). METHODS: We 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). RESULTS: We 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. CONCLUSION: These 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.

Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib.

The multikinase inhibitor sorafenib is currently the treatment of reference for advanced hepatocellular carcinoma (HCC). In our report, we examined the cytotoxic effects of sorafenib on HCC cells. We report that the depletion of the intracellular iron stores achieved by using the iron chelator deferoxamine (DFX) strikingly protects HCC cells from the cytotoxic effects of sorafenib. The protective effect of the depletion of intracellular iron stores could not be explained by an interference with conventional forms of programmed cell death, such as apoptosis or autophagic cell death. We also found that DFX did not prevent sorafenib from reaching its intracellular target kinases. Instead, the depletion of intracellular iron stores prevented sorafenib from inducing oxidative stress in HCC cells. We examined the possibility that sorafenib might exert a cytotoxic effect that resembles ferroptosis, a form of cell death in which iron-dependent oxidative mechanisms play a pivotal role. In agreement with this possibility, we found that pharmacological inhibitors (ferrostatin-1) and genetic procedures (RNA interference against IREB-2) previously reported to modulate ferroptosis, readily block the cytotoxic effects of sorafenib in HCC cells. Collectively, our findings identify ferroptosis as an effective mechanism for the induction of cell death in HCC. Ferroptosis could potentially become a goal for the medical treatment of HCC, thus opening new avenues for the optimization of the use of sorafenib in these tumors.

The added value of quality of life (QoL) for prognosis of overall survival in patients with palliative hepatocellular carcinoma.

BACKGROUND & AIMS: Several prognostic classifications (PCs) have been developed for use in palliative care in patients with hepatocellular carcinoma (HCC). We have recently suggested that CLIP combined with WHO PS has the greatest discriminative power. We evaluated the prognostic value of quality of life (QoL) data and whether the latter could improve classification of palliative HCC patients. METHODS: This was a reanalysis from the CHOC trial with an evaluation of the discriminative power for overall survival (OS) of the established CLIP/GRETCH/BCLC/BoBar prognostic systems alone and then in association with each of the following groups of parameters: selected clinical factors, QoL as continuous variables, dichotomized QoL, selected clinical factors and continuous QoL, selected clinical factors and dichotomized QoL. Baseline QoL was assessed using the EORTC QLQ-C30. Discriminative power was evaluated with the Harrell's C-index and net reclassification improvement. RESULTS: Quality of life was available in 79% of the patients (n=271). Univariate analysis revealed that better role functioning (HR=0.991 [0.987-0.995]) and better physical functioning (0.991 [0.984-0.997]) scores were associated with longer survival. In contrast, poorer score for fatigue (1.011 [1.006-1.015]) and diarrhoea (1.008 [1.002-1.013]) were associated with shorter survival. After adjustment for clinical and sociodemographic variables, only better role functioning score (0.993 [0.988-0.998]) was associated with longer survival. Adding oedema, hepatomegaly, fatigue and diarrhoea QoL scales to CLIP resulted in the best performance. CONCLUSIONS: Our results confirm that QoL scales are independent prognostic factors of OS in palliative HCC patients. Incorporation of QoL data improved all the studied PCs.

EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib.

Sorafenib is currently the medical treatment of reference for hepatocellular carcinoma (HCC), but it is not known whether sorafenib is equally active in all HCC. Here, our aim was to explore intrinsic differences in the response of HCC cells to sorafenib, to identify potential mechanisms leading to primary resistance to this treatment. We analyzed a panel of six human HCC cell lines and compared the activity of the main oncogenic kinase cascades, their clonogenic potential, proliferation and apoptosis upon exposure to sorafenib. We report that HCC cells present important differences in their response to sorafenib, and that some cell lines are more resistant to the actions of sorafenib than others. We identify the activated epidermal growth factor receptor (EGFR) as a parameter that promotes the resistance of HCC cells to sorafenib. In resistant cells, the efficacy of sorafenib was increased when EGFR was inhibited, as was demonstrated using two chemical inhibitors (erlotinib or gefitinib), a monoclonal antibody directed against EGFR (cetuximab), and RNA interference directed against EGFR. A combination of EGFR inhibitors and sorafenib affords a better control over HCC proliferation, most likely through an improved blockade of the RAF kinases. Our findings therefore confirm the importance of RAF kinases as therapeutic targets in HCC, and identify EGFR as a determinant of the sensitivity of HCC cells to sorafenib. Our findings bear possible implications for the improvement of the efficacy of sorafenib in HCC, and might be useful for the identification of predictive biomarkers in this context.

Development and validation of a new prognostic score of death for patients with hepatocellular carcinoma in palliative setting.

BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) in a palliative setting have a poor prognosis despite recent therapeutic progress. Several prognostic scores, such as the BCLC and the CLIP, have been shown to be useful in helping select treatment options ranging from transplantation to palliative care. However, the discriminatory ability of these scores is inadequate in palliative settings, which concern about 70% of HCC patients. In this paper, we propose and validate a new prognostic score for patients in the palliative setting. METHODS: The prognostic score was developed on a set of 416 patients from a negative randomized clinical trial conducted by the Fédération Francophone de Cancers Digestifs. It was then subsequently validated on a second set of 271 patients from another negative trial. Backward selection was used to identify independent baseline characteristics. Measures of discrimination and predictive values were computed to assess the quality of the developed score. Comparisons with the BCLC and the CLIP - with and without the WHO performance status (PS) score - were performed. RESULTS: Tumour morphology, portal vein obstruction, metastasis, ascites, jaundice, alpha-foetoprotein, and serum alkaline phosphatase were included in the final score. From the training dataset, three groups of increasing risk were defined, and these were associated with hazard ratios (HR) of 2.13 and HR = 5.72. Similar results were obtained on the validation dataset. This score provides a better discriminatory ability than BCLC and CLIP in this setting. Unfortunately, absolute performances for these scores remain poor. CONCLUSIONS: The new prognostic score and CLIP + PS are recommended in palliative settings. However, new prognostic variables are necessary.

Hepatocellular carcinoma: French Intergroup Clinical Practice Guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, AFEF, SIAD, SFR/FRI).

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.

Early decrease in serum amphiregulin or vascular endothelial growth factor levels predicts sorafenib efficacy in hepatocellular carcinoma.

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 post­transcriptional 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 progression­free 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, 0.173­0.673; 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.

Prevalence of hepatitis C infection and risk factors in hospitalized diabetic patients: results of a cross-sectional study.

OBJECTIVES: Although there may exist a nosocomial risk of hepatitis C virus (HCV) infection in patients with type 1 or type 2 diabetes, this risk has not been fully investigated thus far and its magnitude is unknown. The aim of this multicenter cross-sectional study was to evaluate the prevalence of, and risk factors for, hepatitis C infection in consecutive hospitalized patients with diabetes and to assess the nosocomial risk and magnitude of HCV infection in these patients. PATIENTS AND METHODS: Consecutive hospitalized patients with diabetes seen in 11 French hepatogastroenterology and diabetology departments were studied. The prevalence of anti-HCV antibodies was compared with that observed in healthy blood donors and individuals seen during routine medical checkup. Diabetic patients with anti-HCV antibodies were compared with patients without anti-HCV antibodies for assessment of risk factors. RESULTS: In total 1561 patients were studied. Independent risk factors for HCV infection were assessed through multivariate analysis. Thirty-three patients (2.11%) had anti-HCV antibodies and 21 (63.70%) had HCV identified risk factors. The prevalence of HCV infection was higher in patients with diabetes than in blood donors (0.08%) or healthy controls (0.20%) (P<0.001). Multivariate analysis identified four independent risk factors for HCV infection: blood transfusion before 1991 [odds ratio (OR)=2.88, P=0.033], intravenous drug use (OR=21.37, P=0.012), treatment in a hepatogastroenterology center (OR=4.17, P=0.002) and a high number (>2) of previous admissions since the onset of diabetes (OR=2.52, P=0.039). CONCLUSION: A nosocomial source of HCV infection in hospitalized diabetic patients is suggested by the increased risk of HCV infection associated with the number of hospitalizations. This may account for at least 36% of cases of HCV infection.

Hepatocellular carcinoma (HCC): an update.

In the absence of large randomized trials, the current treatment strategy for hepatocellular carcinoma (HCC) remains a matter of choice depending mostly on retrospective studies, experience of centers, and the technical therapeutic possibilities. In fact, treatment decisions must be based on HCC extension and liver function, which is dependent on underlying liver disease. Cirrhosis limits therapeutic choices, life expectancy, and tolerance to therapy. Surgical resection and/or local destruction are the most common curative treatments. Orthotopic liver transplantation is probably the best treatment for small HCC developed in cirrhosis because it treats tumor, cirrhosis, and preneoplastic lesions at the same time. However, this treatment method is feasible in fewer than 5% of cases. Adjuvant treatments include transarterial chemoembolization, chemotherapy, polyprenoic acid, interferon, adoptive immunotherapy, and intra-arterial radioactive lipiodol. Results from trials warrant confirmation in larger randomized trials to show a clear survival benefit on recurrence rate, secondary prevention, and overall survival. Chemoembolization is the only palliative treatment that has been proven to be active, unlike systemic chemotherapy, immunotherapy, and hormone therapy, whose activity is largely questionable and must all be restricted to clinical trials. Possible future therapeutic strategies include epidermal growth factor receptor inhibitors, antivascular endothelial growth factor therapies, cyclin D inhibitors, and HMG-CoA reductase inhibitors.

Management practices for gastrointestinal hemorrhage related to portal hypertension in cirrhotic patients: evaluation of the impact of the Paris consensus workshop.

OBJECTIVES: The purpose of this before-after observational survey was to evaluate compliance with good clinical practice guidelines for gastrointestinal hemorrhage related to portal hypertension and the impact of the French Consensus Workshop held in Paris in 2003. METHODS: Data were recorded concerning episodes of gastrointestinal hemorrhage occurring in cirrhotic patients using a survey questionnaire in 2003 before the workshop and again in 2004. RESULTS: Seventy-six index episodes were included in 2003 and 84 in 2004 in patients attending French hospitals. Before hospital admission, primary prophylaxis was similar in 2003 and 2004, but beta blockers were used alone more often in 2004 for secondary prophylaxis (42% vs 19%, P=0.018). The time from onset of bleeding to hospital admission was greater than 12 hours for 43 and 42% of patients and was not shorter in the event of recurrent hemorrhage. At admission, vasoactive drugs were given earlier in 2004 (<2h: 68% vs 35%, P<0.001). Use of antibiotic prophylaxis was similar in 2003 and 2004 (70% vs 61%, P=0.098), and was more common for Child-Pugh B or C patients (P=0.044). CONCLUSION: The Paris Consensus Workshop enabled improved clinical practices. Weak points were insufficient screening for cirrhosis, long delay before admission, insufficient use of antibiotic prophylaxis which should be systematic.

[Care pathway of patients with hepatocellular carcinoma in France: State of play in 2017]. / Parcours de soins du patient atteint de carcinome hépatocellulaire en France : état des lieux en 2017.

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.

Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma.

PURPOSE: Randomized studies on tamoxifen treatment of hepatocellular carcinoma (HCC) produced conflicting results. The aim of this study was to assess the efficacy of tamoxifen administration in improving overall survival of patients with advanced HCC. PATIENTS AND METHODS: A total of 420 patients with HCC who were not suitable for surgery or local treatment were randomly assigned between April 1995 and May 2000: 210 in the control group and 210 in the tamoxifen group (20 mg/d orally). Patients with WHO performance status greater than 2, belonging to Child-Pugh class C, or with serum creatinine greater than 130 mumol/L were not eligible. RESULTS: Tolerance was good and the main reported adverse effects were thrombophlebitis (three patients), nausea (two patients), and hot flushes (three patients). Outcome did not differ between the two treatment arms: estimated median survival was 4.8 and 4.0 months in the tamoxifen and in the control groups, respectively (P = .25). Univariate analysis showed significant association of survival with age, Okuda stage, WHO performance status, Child-Pugh class, intrahepatic tumor stage, alpha-fetoprotein serum concentration, and presence of extrahepatic spread, portal vein thrombosis, hepatomegaly, or hepatalgia. In a Cox proportional hazards model we found a significant beneficial effect of tamoxifen on survival in patients belonging to Okuda I or II stages. CONCLUSION: In this large study, tamoxifen did not improve the survival of patients with advanced HCC, but there is a suggestion that patients without major hepatic insufficiency seem to have some survival benefit. New trials involving this specific population are warranted.

Management of digestive bleeding related to portal hypertension in cirrhotic patients: A French multicenter cross-sectional practice survey.

AIM: To investigate the conformity of management practices of gastrointestinal hemorrhage in cirrhotic patients with relevant guidelines. METHODS: A questionnaire on the management of digestive bleeding was completed for all consecutive cirrhotic patients admitted to 31 French hospitals. RESULTS: One hundred and twenty-six bleeding events were recorded. It was the first bleeding episode in 79 patients (63%), of whom 40 (51%) had a prior diagnosis of cirrhosis and 25 (32%) had previously undergone an endoscopy. The bleeding episode was a recurrence in 46 patients (37%). The median time between onset and admission was 4 h, but exceeded 12 h in 42% of cases. There was an agreement between centers for early vasoactive drug administration (87% of cases), association with ligation (42%) more often than sclerosis (21%) at initial endoscopy, and antibiotic prophylaxis (64%). By contrast, prescription of beta-blockade alone or in combination (0 to 100%, P = 0.003) for secondary prophylaxis and lactulose (26% to 86%, P = 0.04), differed among centers. CONCLUSION: In French hospitals, management of bleeding related to portal hypertension in cirrhotic patients is generally in keeping with the consensus. Broad variability still remains concerning beta-blockade use for secondary prophylaxis. Screening for esophageal varices, the use of antibiotic prophylaxis and patients information need to be improved.

Alpha-foetoprotein (AFP): A multi-purpose marker in hepatocellular carcinoma.

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.

Alpha-fetoprotein is a biomarker of unfolded protein response and altered proteostasis in hepatocellular carcinoma cells exposed to sorafenib.

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.