Purpose To assess the safety and efficacy of irreversible electroporation (IRE) in the treatment of patients with inoperable hepatocellular carcinoma (HCC) who are ineligible for thermal ablative ...techniques. Materials and Methods This retrospective study was approved by an ethics review board, and the requirement to obtain informed written consent was waived. From March 2012 to June 2015, 58 patients (median age, 65.4 years; range 41.6-90 years) with cirrhosis received IRE for the treatment of 75 HCC tumors. The median tumor diameter was 24 mm (range, 6-90 mm). IRE was selected because of tumor location (48 patients) or the patient's poor general condition (10 patients). Treatment response was assessed with magnetic resonance (MR) imaging 1 month after treatment and every 3 months thereafter. Overall local tumor progression-free survival (PFS) per nodule (including initial treatment failures) was assessed by using the Kaplan-Meier method. The marginal Cox proportional hazards model was used to assess the factors associated with overall local tumor PFS. Complications were recorded and graded according to the Clavien-Dindo classification. Results Of 75 tumors, 58 (77.3%), 67 (89.3%), and 69 (92%) were completely ablated after one, two, and three IRE procedures, respectively. After a median follow-up of 9 months (range, 3 days to 31 months), the 6- and 12-month overall local tumor PFS rates for the 75 treated nodules were 87% (95% confidence interval CI: 77%, 93%) and 70% (95% CI: 56%, 81%), respectively. A preablative serum α-fetoprotein level higher than 200 ng/mL (hazard ratio: 9.94 95% CI: 2.82, 35.06, P = .0004) was the only factor linked with overall local tumor PFS. Complications occurred in 11 of the 58 patients (19%) and were classified as grade I in three patients, grade II in five patients, grade IV in two patients, and grade V in one patient. The three (5.2%) complications classified as grade III or higher were liver failures occurring in patients with Child-Pugh class B disease; one led to death. Conclusion IRE offers safe, complete ablation of HCC tumors in patients with contraindications to other commonly used ablative techniques.
RSNA, 2017 Online supplemental material is available for this article.
Background: Percutaneous radiofrequency ablation (RFA) is one of the main treatments of small hepatocellular carcinoma (HCC). However, it remains unclear whether this local treatment can induce ...systemic immune variations.
Methods: We conducted a prospective study in a tertiary center including consecutive cirrhotic patients with unifocal HCC<5 cm treated by a first RFA between 2010 and 2014. Peripheral blood mononuclear cells were isolated on the day before (D0), day after (D1) and month after RFA (M1). Frequencies and phenotypes of myeloid cells, T cells, and NK cells were compared between timepoints. Overall recurrence and associated variables were estimated using Kaplan-Meier, log-rank and Cox proportional-hazards models.
Results: 80 patients were included (69% male, median age: 67 years old). Main aetiologies of HCC were alcohol (51%), hepatitis C virus (45%), non-alcoholic steatohepatitis (36%) and hepatitis B virus (9%). Median overall survival was 55 months (M); median progression-free survival was 29.5M. Among innate immune populations, we observed variations between D0, D1 and M1 in NKp30+ NK cells (p < .0001) and in plasmacytoid dendritic cells (pDC, p < .01). Concerning adaptive immunity, we observed variations in CD8 Central Memory (p < .05) and CD28+ CD8 Central Memory (p < .01). An early dynamic (D0/D1) of activated NKp30
+
NK cells was associated with a decreased overall recurrence (log-rank, p = .016, median delay 25.1 vs 40.6 months). In contrast, a late dynamic (D1/M1) of immature NK cells (CD56
bright
) and altered myeloid DC (PDL1
+
) was associated with an increased overall recurrence (log-rank, p = .011 and p = .0044, respectively). In multivariate analysis, variation of immature NK cells predicts tumor recurrence independently of classical clinical prognostic features (HR = 2.41, 95% CI: 1.15-5.057), p = .019).
Conclusions: Percutaneous RFA of small HCC leads to systemic modifications of innate and adaptive immunity closely linked with overall tumor recurrence.
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•HCC annual incidence is 2.9%, emphazising the need for its screening in alcoholic cirrhosis.•Independent risk factors for HCC are age, male gender, baseline AFP and surrogate markers ...of minimal liver failure.•Only 56% of the patients diagnosed with HCC underwent a curative treatment.•The main reasons not to treat were liver failure and/or impaired general status at diagnosis.•Increased use of radiological ablative therapies for patients with alcoholic cirrhosis is needed.
More than 90% of cases of hepatocellular carcinoma (HCC) occur in patients with cirrhosis, of which alcohol is a major cause. The CIRRAL cohort aimed to assess the burden of complications in patients with alcoholic cirrhosis, particularly the occurrence of HCC.
Patients with biopsy-proven compensated alcoholic cirrhosis were included then prospectively followed. The main endpoint was the incidence of HCC. Secondary outcomes were incidence of hepatic focal lesions, overall survival (OS), liver-related mortality and event-free survival (EFS).
From October 2010 to April 2016, 652 patients were included in 22 French and Belgian centers. During follow-up (median 29 months), HCC was diagnosed in 43 patients. With the limitation derived from the uncertainty of consecutive patients’ inclusion and from a sizable proportion of dropouts (153/652), the incidence of HCC was 2.9 per 100 patient-years, and one- and two-year cumulative incidences of 1.8% and 5.2%, respectively. Although HCC fulfilled the Milan criteria in 33 cases (77%), only 24 patients (56%) underwent curative treatment. An explorative prognostic analysis showed that age, male gender, baseline alpha-fetoprotein, bilirubin and prothrombin were significantly associated with the risk of HCC occurrence. Among 73 deaths, 61 had a recorded cause and 27 were directly attributable to liver disease. At two years, OS, EFS and cumulative incidences of liver-related deaths were 93% (95% CI 90.5–95.4), 80.3% (95% CI 76.9–83.9), and 3.2% (95% CI 1.6–4.8) respectively.
This large prospective cohort incompletely representative of the whole population with alcoholic cirrhosis showed: a) an annual incidence of HCC of up to 2.9 per 100 patient-years, suggesting that surveillance might be cost effective in these patients; b) a high proportion of HCC detected within the Milan criteria, but only one-half of detected HCC cases were referred for curative treatments; c) a two-year mortality rate of up to 7%.
Cirrhosis is a risk factor for primary liver cancer, leading to recommendations for periodic screening. However, for alcohol-related liver disease the rational of periodic screening for hepatocellular carcinoma (HCC) is controversial, as registry and databased studies have suggested a low incidence of HCC in these patients and highly competitive mortality rates. In this study, a large cohort of patients with biopsy-proven alcoholic cirrhosis prospectively screened for HCC demonstrated a high annual incidence of HCC (2.9%) and a high percentage of small cancers theoretically eligible for curative treatment. This suggests that patients with liver disease related to alcohol should not be ruled out of screening.
Context:
Insulin resistance plays a role in hepatocarcinogenesis and is decreased by metformin treatment.
Objective:
The aim of the study was to assess the influence of metformin treatment on the ...prognosis of compensated hepatitis C virus (HCV) cirrhosis in patients with type 2 diabetes.
Design and Setting:
We studied an observational prospective cohort (1988–2007) at a university hospital referral center.
Patients:
A total of 100 consecutive diabetic patients (53 men, age 61 ± 11 yr) with ongoing HCV cirrhosis and no contraindication for metformin were included in a screening program for hepatocellular carcinoma (HCC).
Main Outcomes:
The patients were prospectively followed up for HCC incidence, liver-related death, or hepatic transplantation.
Results:
The level of platelet count was significantly lower in patients treated with metformin (n = 26) compared with those not treated with metformin (n = 74) 117 (interquartile range, 83–166) vs. 149 (105–192) Giga/liter, P = 0.045. During a median follow-up of 5.7 (3.8–9.5) yr, one patient was lost to follow-up, 39 developed a HCC, and 33 died from liver causes or were transplanted. The 5-yr incidence of HCC was 9.5 and 31.2% (P = 0.001) and of liver-related death/transplantation, 5.9 and 17.4% (P = 0.013), in patients who received metformin treatment and in those who did not, respectively. In multivariate analysis, metformin treatment was independently associated with a decrease in HCC occurrence hazard ratio, 0.19 (95% confidence interval, 0.04–0.79); P = 0.023 and liver-related death or transplantation hazard ratio, 0.22 (95% confidence interval, 0.05–0.99); P = 0.049.
Conclusions:
In patients with type 2 diabetes and HCV cirrhosis, use of metformin is independently associated with reduced incidence of HCC and liver-related death/transplantation.
The harmful impact of heavy alcohol consumption and recurrence in patients with alcohol-related cirrhosis is long-established, although this is based on old studies. However, the drivers of long-term ...outcome still need to be clearly investigated.
All patients with biopsy-proven compensated alcohol-related cirrhosis included in the CIRRAL cohort (22 centers) were prospectively studied. Prognostic variables of survival and liver event-free survival were assessed using multivariable Cox models with stepwise selection. The prognostic impact of alcohol recurrence during follow-up (computed in glass-years in the same way as pack-years for tobacco) was assessed using a time-dependent covariable.
From 2010 to 2016, 650 patients were included. The median age at baseline was 58.4 years, 67.4% were men and the median BMI was 27.8 kg/m2, 63.8% had a history of liver decompensation, and 70.2% had discontinued alcohol. At 5 years, recurrence occurred in 30.9% of abstinent patients and this risk was higher in patients with a history of drug abuse and in those with shorter alcohol discontinuation times. Median survival was 97 months. Age, alcohol consumption at baseline, platelet count and Child-Pugh score >5 were associated with overall and liver event-free survival on multivariate analysis. Alcohol consumption of more than 25 glass-years during follow-up was independently associated with lower survival and with a trend toward lower liver event-free survival, with the risk increasing from 1 glass-year, though not significantly. Simon & Makuch plots confirm the benefit of no alcohol consumption (<1 glass/week) on both outcomes and the dose-dependent impact of alcohol over time.
This prospective study in patients with compensated alcohol-related cirrhosis identifies factors predictive of alcohol recurrence during follow-up and shows that moderate alcohol consumption during follow-up negatively impacts outcomes. Patients with alcohol-related cirrhosis should be advised to completely stop drinking alcohol.
CIRRAL (NCT01213927) cohort was registered at ClinicalTrials.gov and the full protocol is available at the following link: https://clinicaltrials.gov/ct2/show/NCT01213927.
In patients with alcohol-related cirrhosis, data are lacking about the impact of the amount of alcohol consumed on both survival and liver-related events. The present study based on the CIRRAL cohort demonstrates that alcohol recurrence occurs in more than 30% of patients with compensated cirrhosis and that even a moderate recurrence strongly influences outcomes. Patients with compensated alcohol-related cirrhosis should be advised to completely discontinue alcohol consumption, even in small amounts, as the present study shows that no alcohol consumption can be regarded as safe when cirrhosis has developed.
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•Alcohol recurrence occurs in more than 30% of cases after a diagnosis of cirrhosis.•A history of drug abuse and a recent alcohol withdrawal are drivers of recurrence.•Even a moderate recurrence influences outcomes in patients with cirrhosis.•Patients with cirrhosis should be advised to stop drinking alcohol, even at low levels.
Abstract
Background
Alcohol-related cirrhosis is a frequent and difficult-to-treat disease. Despite the low hepatic metabolism of baclofen, data on its use in this subgroup are scarce. The French ...multicenter Observatory of patients treated with Baclofen for Alcohol DEpendence real-life cohort assessed: (a) prescription modalities of baclofen in liver units; (b) safety profile of baclofen; and (c) declared alcohol intake, biological markers of excessive alcohol intake and hepatic function at 12 months.
Methods
All consecutive patients with cirrhosis who received baclofen to reduce alcohol consumption or maintain abstinence were prospectively included. Psychosocial management was always associated. Clinical and biological data were collected every 3 months for 1 year.
Results
Between November 2013 and December 2016, 71 in- or outpatients were included from 10 liver units. Of the patients, 25% had ascites. After 12 months, 52 patients (73%) were still being followed, and 41 (57.7%) were still receiving baclofen at a mean dosage of 75 mg/day (r30-210). The overall declared consumption decreased from 100.2 to 14.7 g/day (P < 0.0001), and 29 patients (40.8%) reached abstinence. Significant improvement in the usual biomarkers of excessive alcohol intake (AST, GGT and MCV) and liver function (Prothrombin ratio (PTr), albumin levels) were observed. The usual side effects such as drowsiness were frequent (22%) but no serious adverse events (AEs) or overt encephalopathy related to baclofen was reported.
Conclusion
In this 1-year follow-up series, baclofen was combined with psychosocial treatment in patients with cirrhosis and was well tolerated. This treatment was associated with a significant decrease in declared alcohol consumption as well as improvement in hepatic function.
Short Summary: In this series of 71 patients with alcohol-related cirrhosis, 12 months’ baclofen use at a dose of 75 mg/day associated with psycho-social care was well tolerated and associated with the improvement of liver function.
Propranolol bears antioxidant, anti-inflammatory, and antiangiogenic properties and antitumoral effects and therefore is potentially active in the prevention of hepatocellular carcinoma (HCC). We ...retrospectively assessed the impact of propranolol treatment on HCC occurrence in a cohort of 291 patients with compensated viral C (HCV) cirrhosis, prospectively followed and screened for HCC detection. Of the 291 patients included in the cohort, 93 patients 50 males: mean age, 59.5 ± 12 years; body mass index (BMI), 25.7 ± 4.4 kg/m(2); and platelet count, 111 ± 53 Giga/L developed esophageal varices (OV) or had OV at inclusion and 198 patients (111 males: mean age, 55.8 ± 13 years; BMI, 25.7 ± 5 kg/m(2); platelet count, 137 ± 59 Giga/L) did not. Among patients with OV, 50 received treatment by propranolol. During a median follow-up of 54 months interquartile range (32-82), 61 patients developed an HCC. The 3- and 5-year HCC incidence was 4% and 4%, and 10% and 20% for patients treated and not treated by propranolol, respectively (Gray test, P = 0.03). In multivariate analysis, propranolol treatment was associated with a decrease risk of HCC occurrence HR, 0.25; 95% confidence interval (CI), 0.09-0.65; P = 0.004, and was the only independent predictive factor of HCC occurrence in patients with OV (HR, 0.16; CI, 0.06-0.45; P = 0.0005). The benefit of propranolol was further supported by propensity scores analyses.
This retrospective long-term observational study suggests that propranolol treatment may decrease HCC occurrence in patients with HCV cirrhosis. These findings need to be verified by prospective clinical trial.
Progenitor‐derived regeneration gives rise to the aberrant expression of biliary markers such as cytokeratin 7 (K7) and epithelial cell adhesion molecule (EpCAM) in hepatocytes. We aimed to describe ...the expression of these molecules in patients with compensated hepatitis C virus (HCV)–related cirrhosis and to investigate its potential influence on cirrhosis complications. Among patients with Child‐Pugh A uncomplicated HCV‐related cirrhosis enrolled in the prospective ANRS CO12 CirVir cohort, we selected individuals with a liver biopsy collected within 2 years before inclusion in the study. K7 and EpCAM immunostaining identified intermediate hepatobiliary cells. The influence of biliary marker expres‐sion in hepatocytes on decompensation events and the occurrence of hepatocellular carcinoma (HCC) was studied using a multivariate Cox proportional hazards regression model. Among the 337 patients eligible for the study (men, 67%; median age, 52 years), 198 (58.8%) had biopsies with K7‐positive hepatocytes including extensive staining in 40 (11.9%) and 203 had EpCAM‐positive hepatocytes (60.6%). During follow‐up (median, 54.2 months), 47 patients (14%) experienced a decompensation event, and HCC was diagnosed in 37 patients (11%). Extensive K7 staining was independently associated with the occurrence of a decompensation event (hazard ratio HR, 3.00; 95% confidence interval CI, 1.30‐6.89; P = 0.010). EpCAM expression was independently associated with HCC occurrence (HR, 2.37; 95% CI, 1.07‐5.23; P =0.033) along with age and a low prothrombin ratio. Conclusion: Progenitor‐derived regeneration depicted by K7 and EpCAM immunostaining of hepatocytes in liver biopsies of patients with compensated HCV‐related cirrhosis marks a cirrhosis stage more prone to develop complications. (HEPATOLOGY 2018; 68:1534‐1548).
There is growing evidence suggesting that maintaining an adequate nutritional status for patients with liver cirrhosis (LC) is relevant to prevent complications. The present study aimed to describe ...dietary behaviours of patients with compensated and non-complicated LC and comparing them with those of subjects from the general population.
In this case-control study, patients were volunteers enrolled in the ALICIR (ALImentation et CIRrhose) study, an observational survey nested in two French prospective cohorts of patients with biopsy-proven compensated cirrhosis related either to excessive alcohol consumption (CIRRAL) or to hepatitis B or C virus infection (CirVir). Controls were selected from the NutriNet-Santé cohort. Dietary data were collected through a semi quantitative food frequency questionnaire. Dietary and nutritional data were compared using multi-adjusted paired Student's tests.
Between June 2014 and February 2016, 174 patients of CirVir (
= 97) or CIRRAL (
= 77) were matched with 348 controls from the NutriNet-Santé cohort, according to gender, age, BMI and educational level. Compared to controls, patients (mean ± SD) consumed more sodas (236.0 ± 29.8 mL vs. 83.0 ± 33.0 mL) and water (1787.6 ± 80.6 mL vs. 933.6 ± 85.3 mL), and lower amounts of salty snacks (4.2 ± 1.42 g vs. 9.0 ± 1.6 g) and alcoholic beverages (71.8 ± 23.4 g vs. 151.2 ± 25.9 g), with all
values < 0.0001. Dietary behaviours differed according to LC aetiology.
Dietary behaviour of patients significantly differed from subjects from the general population.
We aimed to identify the main determinants of long-term overall survival (OS), including virologic control, and recurrence after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) on ...cirrhosis.
Cirrhotic patients treated by RFA for HCC within Milan criteria were included. Associations between patient features and events were estimated by the Kaplan–Meier method with the log rank test and using uni/multivariate Cox models.
389 cirrhotic patients (Child–Pugh A 86.6%, 473 tumors) were included. OS was 79.8%, 42.4% and 16%, and overall tumor recurrence 45%, 78% and 88% at 2, 5 and 10 years, respectively. In multivariate analysis, age, Child–Pugh, GGT, HCC near major vessels, esophageal varices, alkaline phosphatase and HBV predicted OS. Gender, ALT, AFP and alcohol intake were associated with tumor recurrence. Multinodular HCC (19.5%) was associated with risk of tumor recurrence outside Milan criteria. HBV patients had longer OS than other patients (P = 0.0059); negative HBV PCR at RFA was associated with decreased tumor recurrence (P = 0.0157). Using time-dependent analysis in HCV patients, a sustained virologic response was associated with increased OS (124.5 months) compared to other patients (49.2 months, P < 0.001).
Virologic response and severity of underlying liver disease were the main determinants of long-term OS after RFA for HCC developing on cirrhosis.
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