Risk factors of de novo malignancies after liver transplantation: a French national study on 11004 adult patients.

BACKGROUND: After liver transplantation (LT),de novo malignancies are one of the leading causes of late mortality. The aim of the present retrospective study was to identify the risk factors of de novo malignancies in a large cohort of LT recipients in France, using Fine and Gray competing risks regression analysis. METHODS: The study population consisted in 11004 adults transplanted between 2000 and 2013, who had no history of pre-transplant malignancy, except primary liver tumor. A Cox model adapted to the identification of prognostic factors (competitive risks) was used. RESULTS: From the entire cohort, one (or more)de novo malignancy was reported in 1480 L T recipients (13.45%). The probability to develop a de novo malignancy after LT was 2.07% at 1 year, 13.30% at 5 years, and 28.01% at 10 years. Of the known reported malignancies, the most common malignancies were hematological malignancy (22.36%), non-melanoma skin cancer (19.53%) and lung cancer (12.36%). According to Fine and Gray competing risks regression multivariate analysis, were significant risk factors for post-LT de novo malignancy: recipient age (Subdistribution Hazard Ratio (SHR) = 1.03 95%CI 1.03-1.04), male gender (SHR = 1.45 95%CI 1.27-1.67), non-living donor (SHR = 1.67 95%CI 1.14-2.38), a first LT (SHR = 1.35 95%CI 1.09-1.69) and the type of initial liver disease (alcohol-related liver disease (SHR = 1.63 95%CI 1.22-2.17), primary sclerosing cholangitis (SHR = 1.98 95%CI 1.34-2.91), and primary liver tumor (SHR = 1.88 95%CI 1.41-2.54)). Initial immunosuppressive regimen had no significant impact. CONCLUSION: The present study confirms that LT recipient characteristics are associated with the risk ofde novo malignancy and this underlines the need for personalized screening in order to improve survival.

Liver transarterial chemoembolization and sunitinib for unresectable hepatocellular carcinoma: Results of the PRODIGE 16 study.

BACKGROUND: Trans-arterial chemoembolization (TACE) is one first-line option therapy for patients with hepatocellular carcinoma (HCC) not suitable for surgical resection. AIMS: We evaluated the effects of sunitinib plus doxorubicin-TACE on bleeding or liver failure. METHODS: Seventy-eight patients with HCC were included in this randomized, double-blind study. They received one to three TACE plus either sunitinib or placebo four weeks out of six for one year. The occurrence of severe bleeding or liver failure was assessed during the week after the TACE. The safety and survival outcomes were evaluated. RESULTS: No bleeding complication was reported. One and two liver failures were respectively observed in sunitinib and placebo patients. Compliance to sunitinib treatment was acceptable. Sunitinib dose reduction occurred in 37% of patients due to acute toxicity. Main grade 3-4 toxicities were: thrombocytopenia, neutropenia, increased bilirubin, increased ALT and asthenia. In the sunitinib group, the median PFS and OS were 9.05 [5.81;11.63] and 25.0 [13.5;36.8] months, respectively. In the placebo group, the median PFS and OS were 5.51 [4.14;7.79] and 20.5 [15.1;30.6] months, respectively. CONCLUSIONS: TACE plus sunitinib in the first-line therapy for patients with HCC not suitable for surgical resection was feasible. CLINICALTRIALS. GOV NUMBER: NCT01164202.

Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). Combining sorafenib with another treatment, to improve overall survival (OS) within an acceptable safety profile, might be the next step forward in the management of patients with advanced HCC. We aimed to assess whether a combination of sorafenib and a statin improved survival in patients with HCC. METHODS: The objective of the PRODIGE-11 trial was to compare the respective clinical outcomes of the sorafenib-pravastatin combination (arm A) versus sorafenib alone (arm B) in patients with advanced HCC. Child-Pugh A patients with advanced HCC who were naive to systemic treatment (n = 323) were randomly assigned to sorafenib-pravastatin combination (n = 162) or sorafenib alone (n = 161). The primary endpoint was OS; secondary endpoints were progression-free survival, time to tumor progression, time to treatment failure, safety, and quality of life. RESULTS: After randomization, 312 patients received at least 1 dose of study treatment. After a median follow-up of 35 months, 269 patients died (arm A: 135; arm B: 134) with no difference in median OS between treatments arms (10.7 months vs. 10.5 months; hazard ratio = 1.00; p = 0.975); no difference was observed in secondary survival endpoints either. In the univariate analysis, the significant prognostic factors for OS were CLIP score, performance status, and quality of life scores. The multivariate analysis showed that the only prognostic factor for OS was the CLIP score. The main toxicity was diarrhea (which was severe in 11% of patients in arm A, and 8.9% in arm B), while severe nausea-vomiting was rare, and no toxicity-related deaths were reported. CONCLUSION: Adding pravastatin to sorafenib did not improve survival in patients with advanced HCC. LAY SUMMARY: Sorafenib has proven efficacy for the treatment of patients with advanced hepatocellular carcinoma. However, overall survival remains poor in these patients, so we were interested to see if the addition of a statin, pravastatin, improved outcomes in patients with advanced HCC. This randomized-controlled trial demonstrated that the sorafenib-pravastatin combination did not improve overall survival in this study population compared to sorafenib alone. Clinical trial number: NCT01075555.

Longterm Risk of Solid Organ De Novo Malignancies After Liver Transplantation: A French National Study on 11,226 Patients.

De novo malignancies are one of the major late complications and causes of death after liver transplantation (LT). Using extensive data from the French national Agence de la Biomédecine database, the present study aimed to quantify the risk of solid organ de novo malignancies (excluding nonmelanoma skin cancers) after LT. The incidence of de novo malignancies among all LT patients between 1993 and 2012 was compared with that of the French population, standardized on age, sex, and calendar period (standardized incidence ratio; SIR). Among the 11,226 LT patients included in the study, 1200 de novo malignancies were diagnosed (10.7%). The risk of death was approximately 2 times higher in patients with de novo malignancy (48.8% versus 24.3%). The SIR for all de novo solid organ malignancies was 2.20 (95% confidence interval [CI], 2.08-2.33). The risk was higher in men (SIR = 2.23; 95% CI, 2.09-2.38) and in patients transplanted for alcoholic liver disease (ALD; SIR = 2.89; 95% CI, 2.68-3.11). The cancers with the highest excess risk were laryngeal (SIR = 7.57; 95% CI, 5.97-9.48), esophageal (SIR = 4.76; 95% CI, 3.56-6.24), lung (SIR = 2.56; 95% CI, 2.21-2.95), and lip-mouth-pharynx (SIR = 2.20; 95% CI, 1.72-2.77). In conclusion, LT recipients have an increased risk of de novo solid organ malignancies, and this is strongly related to ALD as a primary indication for LT.

A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.

BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).

12 Weeks of a Ribavirin-Free Sofosbuvir and Nonstructural Protein 5A Inhibitor Regimen Is Enough to Treat Recurrence of Hepatitis C After Liver Transplantation.

Sofosbuvir (SOF) combined with nonstructural protein 5A (NS5A) inhibitors has demonstrated its efficacy in treating a recurrence of hepatitis C virus (HCV) after liver transplantation (LT). However, the duration of treatment and need for ribavirin (RBV) remain unclear in this population. Our aim was to determine whether LT recipients could be treated with an SOF + NS5A inhibitor-based regimen without RBV for 12 weeks post-LT. Between October 2013 and December 2015, 699 LT recipients experiencing an HCV recurrence were enrolled in the multicenter ANRS CO23 CUPILT cohort. We selected patients receiving SOF and NS5A inhibitor ± RBV and followed for at least 12 weeks after treatment discontinuation. The primary efficacy endpoint was a sustained virological response 12 weeks after the end of treatment (SVR12). Among these 699 patients, 512 fulfilled the inclusion criteria. Their main characteristics were: 70.1% genotype 1, 18.2% genotype 3, 21.1% cirrhosis, and 34.4% previously treated patients. We identified four groups of patients according to their treatment and duration: SOF + NS5A without RBV for 12 (156 patients) or 24 (239 patients) weeks; SOF + NS5A + RBV for 12 (47 patients) or 24 (70 patients) weeks. SVR12 values reached 94.9%, 97.9%, 95.7%, and 92.9%, respectively (P = 0.14). Only 20 patients experienced a treatment failure. Under multivariate analysis, factors such as fibrosis stage, previous treatment, HCV genotype, and baseline HCV viral load did not influence SVR12 rates in the four groups (P = 0.21). Hematological adverse events (AEs) were more common in the RBV group: anemia (P < 0.0001) and blood transfusion (P = 0.0001). CONCLUSION: SOF + NS5A inhibitors without RBV for 12 weeks constituted reliable therapy for recurrent HCV post-LT with an excellent SVR12 whatever the fibrosis stage, HCV genotype, and previous HCV treatment. (Hepatology 2018; 00:000-000).

Recipient Selection for Optimal Utilization of Discarded Grafts in Liver Transplantation.

BACKGROUND: In France, liver grafts that have been refused by at least 5 teams are considered for rescue allocation (RA), with the choice of the recipient being at the team's discretion. Although this system permits the use of otherwise discarded grafts in a context of organ shortage, outcomes and potential benefits need to be assessed. METHODS: Between 2011 and 2015, outcomes of RA grafts (n = 33) were compared with SA grafts (n = 321) at a single French center. RESULTS: Liver grafts in the RA group were older (63 ± 17 years vs 54 ± 18 years, P = 0.007) and had a higher DRI (1.86 ± 0.45 vs 1.61 ± 0.47, P = 0.010). Recipients in this group had a lower Model for End-Stage Liver Disease score (14 ± 5 vs 22 ± 10, P < 0.001) and had mostly hepatocellular carcinoma (67.0% vs 40.4%, P = 0.010). The balance of risk score was significantly lower in the RA group (5.5 ± 2.9 vs 9.2 ± 5.5, P < 0.001). There were higher rates of early and delayed hepatic artery thrombosis (15.2% vs 3.1%, P = 0.001) and retransplantation (18.2% vs 4.7%, P = 0.002) in the RA group. Patient survival was not different between groups, but graft survival was impaired (95% vs 82% at 1 year and 94% vs 74% at 3 years, P = 0.001). CONCLUSION: Our results show that discarded liver grafts can be used provided that there is a strict recipient selection process, although hepatic artery thrombosis and retransplantation are more frequent. This strategy enables utilization of otherwise discarded grafts in the context of organ shortage.

Direct-acting antiviral agent-based regimen for HCV recurrence after combined liver-kidney transplantation: Results from the ANRS CO23 CUPILT study.

Hepatitis C virus (HCV) infection is associated with reduced patient survival following combined liver-kidney transplantation (LKT). The aim of this study was to assess the efficacy and safety of second-generation direct-acting antivirals (DAAs) in this difficult-to-treat population. The ANRS CO23 "Compassionate use of Protease Inhibitors in Viral C Liver Transplantation" (CUPILT) study is a prospective cohort including transplant recipients with recurrent HCV infection treated with DAAs. The present work focused on recipients with recurrent infection following LKT. The study population included 23 patients. All patients received at least one NS5B inhibitor (sofosbuvir) in their antiviral regimen an average of 90 months after LKT. Ninety-six percent of recipients achieved a sustained virological response (SVR) at week 12 (SVR12). In terms of tolerance, 39% of recipients presented with at least one serious adverse event. None of the patients experienced acute rejection during therapy and there were no deaths during follow-up. The glomerular filtration rate (GFR) decreased significantly from baseline to the end of therapy. However, this study did not show that the decline in GFR persisted over time or that it was directly related to DAAs. The DAA-based regimen is well tolerated with excellent results in terms of efficacy. It will become the gold standard for the treatment of recurrent HCV following LKT.

Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence - The ANRS CUPILT study.

BACKGROUND & AIMS: HCV recurrence remains a major issue in the liver transplant field, as it has a negative impact on both graft and patient survival. The purpose of this study was to investigate the efficacy and safety of treating HCV recurrence with sofosbuvir (SOF) and daclatasvir (DCV) combination therapy. METHODS: From October 2013 to March 2015, 559 liver recipients were enrolled in the prospective multicentre France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) Compassionate use of Protease Inhibitors in viral C Liver Transplantation cohort. We selected 137 patients with an HCV recurrence receiving SOF and DCV, whatever the genotype or fibrosis stage. The use of ribavirin and the duration of therapy were at the investigator's discretion. The primary efficacy end point was a sustained virological response (SVR) 12weeks after the end of treatment. RESULTS: The SVR rate 12weeks after completing treatment was 96% under the intention-to treat analysis and 99% when excluding non-virological failures. Only two patients experienced a virological failure. The serious adverse event (SAE) rate reached 17.5%. Four patients (3%) stopped their treatment prematurely because of SAEs. Anaemia was the most common AE, with significantly more cases in the ribavirin group (56% vs. 18%; p<0.0001). A slight but significant reduction in creatinine clearance was reported. No clinically relevant drug-drug interactions were noted, but 52% of patients required a change to the dosage of immunosuppressive drugs. CONCLUSIONS: Treatment with SOF plus DCV was associated with a high SVR12 and low rates of serious adverse events among liver recipients with HCV recurrence. LAY SUMMARY: The recurrence of hepatitis C used to be the first cause of graft failure in infected liver transplanted recipients. Our study demonstrates the great efficacy of one combination of new all-oral direct-acting antiviral, sofosbuvir and daclatasvir, to treat the recurrence of hepatitis C on the graft. Ninety-six per cent of recipients were cured. The safety profile of this combination seemed to be good, especially no relevant drug-drug interaction with immunosuppressive drugs.

HybridKnife high-pressure glycerol jet injection for endoscopic submucosal dissection increases procedural ease and speed: a randomised study in pigs and a human case series.

BACKGROUND AND AIMS: Good use of the submucosal space is key during endoscopic submucosal dissection (ESD). High-pressure injection of a long-lasting viscous solution using the HybridKnife water-jet system has been demonstrated to be feasible. We compared jet injection of glycerol and normal saline during pig gastric ESD and assessed its feasibility and efficiency during human ESD. MATERIALS AND METHODS: A blinded randomised controlled study of ESD with the HybridKnife injecting either a glycerol mixture or normal saline and a prospective human case series were performed. Twenty gastric pig dissections (10/group) and 38 human ESDs along the gastrointestinal tract were performed. Dissection speed, specimen size, procedure duration, rates of en bloc and R0 resection, and rates of bleeding and perforation were prospectively recorded. An evaluation of operator comfort and perceived safety (dissection score) was performed using a visual analogue scale with zero being the worst score and ten the best. RESULTS: Dissection was significantly more rapid (1.38-fold) with glycerol injection than with normal saline injection (28.94 vs. 20.91 mm(2)/min; p = 0.037). The dissection score was significantly higher in the glycerol group than in the normal saline group (7.3 vs. 4.7; p = 0.0064). No differences were observed in the rates of en bloc resection, bleeding, or perforation. The 38 human cases along the gastrointestinal tract revealed good results (en bloc resection rate = 100 %, R0 resection rate = 90 %) without any complications. CONCLUSION: High-pressure jet injection of glycerol with the HybridKnife for ESD increased the speed and operator comfort of the procedure compared with the use of normal saline, and the procedure was safe and efficient for human ESD. The advantages of using a combination of the HybridKnife system and a viscous glycerol solution will help to spread the use of the ESD technique, particularly in non-Asian countries.

Multicenter Experience with Boceprevir or Telaprevir to Treat Hepatitis C Recurrence after Liver Transplantation: When Present Becomes Past, What Lessons for Future?

BACKGROUND AND AIMS: First generation protease inhibitors (PI) with peg-interferon (PEG-IFN) and ribavirin (RBV) have been the only therapy available for hepatitis C virus (HCV) genotype 1 infection in most countries for 3 years. We have investigated the efficacy and tolerance of this triple therapy in transplanted patients experiencing a recurrence of HCV infection on the liver graft. PATIENTS: This cohort study enrolled 81 liver transplant patients (Male: 76%, mean age: 55.8±9.7 years) with severe HCV recurrence (F3 or F4: n = 34 (42%), treatment experienced: n = 44 (54%)), treated with boceprevir (n = 36; 44%) or telaprevir (n = 45; 56%). We assessed the percentages of patients with sustained virological responses 24 weeks after therapy (SVR24), and safety. RESULTS: The SVR24 rate was 47% (telaprevir: 42%; boceprevir: 53%, P = ns). At baseline, a normal bilirubin level (p = 0.0145) and albumin level >35g/L (p = 0.0372) and an initial RBV dosage of ≥800 mg/day (p = 0.0033) predicted SVR24. During treatment, achieving an early virological response after 12 weeks was the strongest independent factor to predict SVR24 (p<0.0001). A premature discontinuation of anti-HCV therapy due to a serious adverse event (SAE) was observed in 22 patients (27%). Hematological toxicity, infections and deaths were observed in 95%, 28% and 7% of patients, respectively. A history of post-LT antiviral therapy and thrombocytopenia (<50G/L) during treatment were both independent predictors of the occurrence of infections or SAE (p = 0.0169 and p = 0.011). CONCLUSIONS: The use of first generation PI after liver transplantation enabled an SVR24 rate of 47% in genotype 1 patients, but induced a high rate of SAE. The identification of predictive factors for a response to treatment, and the occurrence of SAE, have enabled us to establish limits for the use of this anti-HCV therapy in the transplant setting.

High-pressure injection of glycerol with HybridKnife for ESD is feasible and increases the ease and speed of the procedure: an in vivo study in pigs and first use in human.

BACKGROUND AND AIMS: The HybridKnife water-jet system (ERBE, Tubingen, Germany) has been shown to increase dissection speed and decreased the risk of perforation during endoscopic submucosal dissection (ESD). Glycerol mixture is a viscous, long-lasting solution preferentially used by Japanese ESD experts. The combination of the HybridKnife system with a glycerol solution has not been evaluated to date. MATERIALS AND METHODS: A prospective non-randomised comparative study of ESD with HybridKnife injecting of either a glycerol mixture or normal saline was performed. Twenty dissections (ten per group) were performed on four anaesthetised domestic mini-pigs. Dissection speed (mm(2)/min), size of the specimen (mm(2)), duration (min), en bloc resection rate, and bleeding and perforation rates were prospectively recorded. An evaluation of operator comfort and perception of safety (dissection score) was performed using a visual analogue scale with 0 being the worst score and 10 the best. RESULTS: High-pressure injection of the glycerol mixture and dissection with the HybridKnife was feasible without complications. Dissection was significantly more rapid (1.67-fold) with glycerol injection than normal saline injection (27.44 vs. 16.44 mm(2)/min; p < 0.001). The dissection score was significantly higher in the glycerol group than in the normal saline group (5.9 vs. 2.9; p < 0.001). No differences were observed in the rates of en bloc resection, bleeding and perforation. Seven first human cases were also easy without need of preliminary incision and technical complication. CONCLUSION: High-pressure jet injection of glycerol with HybridKnife for ESD is feasible and increases the speed and safety of the procedure compared with use of normal saline.