James O’Beirne

Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma

BACKGROUND & AIMS Recurrence of hepatocellular carcinoma (HCC) is a major complication after liver transplantation (LT). The initial immunosuppression protocol may influence HCC recurrence, but the optimal regimen is still unknown. METHODS 219 HCC consecutive patients under Milan criteria, who received an LT at 2 European centres between 2000 and 2010, were included. Median follow-up was 51 months (IQR 26-93). Demographic characteristics, HCC features, and immunosuppression protocol within the first month after LT were evaluated against HCC recurrence by using Cox regression. RESULTS In the explanted liver, 110 patients (50%) had multinodular HCC, and largest nodule diameter was 3±2.1cm. Macrovascular invasion was incidentally detected in 11 patients (5%), and microvascular invasion was present in 41 patients (18.7%). HCC recurrence rates were 13.3% at 3 years and 17.6% at 5 years. HCC recurrence was not influenced by the use/non-use of steroids and antimetabolites (p=0.69 and p=0.70 respectively), and was similar with tacrolimus or cyclosporine (p=0.25). Higher exposure to calcineurin inhibitors within the first month after LT (mean tacrolimus trough concentrations >10ng/ml or cyclosporine trough concentrations >300ng/ml), but not thereafter, was associated with increased risk of HCC recurrence (27.7% vs. 14.7% at 5 years; p=0.007). The independent predictors of HCC recurrence by multivariate analysis were: high exposure to calcineurin inhibitors defined as above (RR=2.82; p=0.005), diameter of the largest nodule (RR=1.31; p<0.001), microvascular invasion (RR=2.98; p=0.003) and macrovascular invasion (RR=4.57; p=0.003). CONCLUSIONS Immunosuppression protocols with early CNI minimization should be preferred in LT patients with HCC in order to minimize tumour recurrence.

Early tacrolimus exposure after liver transplantation: Relationship with moderate/severe acute rejection and long-term outcome

BACKGROUND & AIMS Liver transplant (LT) patients might be overimmunosuppressed as recommendations for tacrolimus trough concentrations (TC) within 4-6 weeks after liver transplantation are set too high (10-15 ng/ml). Early tacrolimus exposure was evaluated in relation to acute rejection and long-term outcomes. METHODS Four hundred and ninety-three consecutive LT patients receiving tacrolimus as primary immunosuppression (1995-2008) were analyzed. Acute rejection was diagnosed using protocol biopsies at day 6.1 ± 2.5. Median follow-up was 7.3 years (IQR 3.9-10.5). Early tacrolimus exposure (<15 days) was evaluated against moderate/severe acute rejection, chronic rejection, graft loss, chronic renal impairment and mortality using multiple logistic and Cox regression. RESULTS Maintenance immunosuppression was tacrolimus monotherapy (48.1%), double therapy combination with antimetabolites or steroids (18%), or triple therapy combination with antimetabolites and steroids (33.9%). Histological grade of acute rejection was moderate in 157 cases (31.8%) and severe in 19 cases (3.9%). Tacrolimus TC>7 ng/ml on the day of protocol biopsy was associated with less moderate/severe rejection (23.8%) compared with<7 ng/ml (41.2%) (p = 0.004). Mean tacrolimus TC 7-10 ng/ml within 15 days after LT were associated with reduced risk of graft loss (RR = 0.46; p = 0.014) compared to TC 10-15 ng/ml. A peak TC>20 ng/ml within this period was independently related to higher mortality (RR = 1.67; p = 0.005), particularly due to cardiovascular events, infections and malignancy (RR = 2.15; p = 0.001). Early tacrolimus exposure did not influence chronic rejection (p = 0.58), or chronic renal impairment (p = 0.25). CONCLUSIONS During the first 2 weeks after LT, tacrolimus TC between 7 and 10 ng/ml are safe in terms of acute rejection and are associated with longer graft survival.

Validation of the Baveno VI criteria to identify low risk cirrhotic patients not requiring endoscopic surveillance for varices

BACKGROUND & AIMS The Baveno VI guidelines propose that cirrhotic patients with a liver stiffness measurement (LSM) <20kPa and a platelet count >150,000/μl can avoid screening endoscopy as their combination is highly specific for excluding clinically significant varices. The aim of the study was to validate these criteria. METHODS Transient elastography data was collected from two institutions from 2006-2015. Inclusion criteria were a LSM ⩾10kPa and an upper gastrointestinal endoscopy within 12months, with a diagnosis of compensated chronic liver disease. Exclusion criteria were porto-mesenteric-splenic vein thrombosis and non-cirrhotic portal hypertension. Varices were graded as low risk (grade <2) or high risk (grade ⩾2). RESULTS The study included 310 patients (169 (55%) hepatitis C, and 275 (89%) Child-Pugh A). Varices were present in 23% cases, with 5% prevalence of high risk varices. Overall 102/310 (33%) met the Baveno VI criteria. Within this group 11% had varices and 2% had high risk varices, representing 2/15 (13%) of all high risk varices. The Baveno VI criteria gave a sensitivity 0.87, specificity 0.34, positive predictive value 0.06, negative predictive value 0.98, positive likelihood ratio 1.31 and negative likelihood ratio 0.39. The AUROC for LSM and platelet count combined was 0.746. CONCLUSIONS The Baveno VI criteria performed well correctly identifying 98% of patients who could safely avoid endoscopy. LAY SUMMARY This study examines the effectives of a recent set of guidelines published by the Baveno VI conference, which states that patients with chronic liver disease and a low liver stiffness (<20kPa) and high platelet count (>150) are at low risk of having varices and do not need a screening endoscopy. Varices are a complication of cirrhosis, confer a risk of serious bleeding, and can be diagnosed and treated by endoscopy. Our study reviewed the clinical records of patients who have had liver stiffness scans and endoscopy over a 9-year period at two hospitals. The results show that only about 2% of patients who meet the Baveno VI criteria will be miss-classified as not having varices.

Predicting severity and clinical course of acute rejection after liver transplantation using blood eosinophil count

Acute cellular rejection remains an important source of morbidity after liver transplantation, particularly if rejection is moderate or severe, as this usually is treated. Currently liver biopsies are seldom performed, so diagnostic noninvasive markers would be useful. We evaluated 690 consecutive first liver transplant patients to assess whether peripheral eosinophilia could predict moderate‐severe rejection and its course. A protocol biopsy was performed 6 ± 2.5 days after transplant. A second biopsy was taken 6.1 ± 2 days after the first in 487 patients to assess histological improvement. Liver function tests, peripheral eosinophil count and changes between first and second biopsy, were evaluated using logistic regression. Histological rejection was present in 532 patients (77.1%), with moderate (30.6%) and severe rejection (3.9%). Peripheral eosinophil count was strongly associated with moderate‐severe rejection (OR = 2.15; P = 0.007), although the area under ROC curve (AUROC) was 0.58. On second biopsy, rejection improved in 119 (24.4%) patients. The delta in eosinophil count between the first and second biopsies was the only independent predictor of histological improvement (OR = 3.12; P = 0.001), irrespective of whether bolus steroids were used (OR = 2.77; P = 0.004); AUROC was 0.72. Peripheral eosinophilia is not sufficiently predictive of moderate‐severe histological rejection. However the changes in eosinophil count over time can accurately predict the histological resolution of rejection.

Transarterial chemoembolisation is not superior to embolisation alone: The recent European Association for the Study of the Liver (EASL)–European Organisation for Research and Treatment of Cancer (EORTC) guidelines

The recent European Association for the Study of the Liver (EASL)–European Organisation for Research and Treatment of Cancer (EORTC) guidelines on hepatocellular carcinoma (HCC) state that transarterial chemoembolisation (TACE) is superior to transarterial embolisation (TAE) and should be considered as the therapy of choice. Interestingly and unlike other recommendations, this was not given any grade of evidence. However evidence exists which suggests that TACE and TAE have similar therapeutic efficacy, whilst the latter has lower costs and avoids the side-effects of chemotherapy as we have highlighted previously. The lack of standardisation of embolisation therapies, which includes the use of different embolising and chemotherapeutic agents and the timing and interval between treatment sessions have led to varying results. This may be one reason why the recent Cochrane meta-analysis showed no therapeutic benefit of TACE/TAE compared to the controls, as no consideration was given to the heterogeneity of techniques. Here we summarise the exist-

Randomized Controlled Trials to Define Viral Load Thresholds for Cytomegalovirus Pre-Emptive Therapy

Background To help decide when to start and when to stop pre-emptive therapy for cytomegalovirus infection, we conducted two open-label randomized controlled trials in renal, liver and bone marrow transplant recipients in a single centre where pre-emptive therapy is indicated if viraemia exceeds 3000 genomes/ml (2520 IU/ml) of whole blood. Methods Patients with two consecutive viraemia episodes each below 3000 genomes/ml were randomized to continue monitoring or to immediate treatment (Part A). A separate group of patients with viral load greater than 3000 genomes/ml was randomized to stop pre-emptive therapy when two consecutive levels less than 200 genomes/ml (168 IU/ml) or less than 3000 genomes/ml were obtained (Part B). For both parts, the primary endpoint was the occurrence of a separate episode of viraemia requiring treatment because it was greater than 3000 genomes/ml. Results In Part A, the primary endpoint was not significantly different between the two arms; 18/32 (56%) in the monitor arm had viraemia greater than 3000 genomes/ml compared to 10/27 (37%) in the immediate treatment arm (p = 0.193). However, the time to developing an episode of viraemia greater than 3000 genomes/ml was significantly delayed among those randomized to immediate treatment (p = 0.022). In Part B, the primary endpoint was not significantly different between the two arms; 19/55 (35%) in the less than 200 genomes/ml arm subsequently had viraemia greater than 3000 genomes/ml compared to 23/51 (45%) among those randomized to stop treatment in the less than 3000 genomes/ml arm (p = 0.322). However, the duration of antiviral treatment was significantly shorter (p = 0.0012) in those randomized to stop treatment when viraemia was less than 3000 genomes/ml. Discussion The results illustrate that patients have continuing risks for CMV infection with limited time available for intervention. We see no need to alter current rules for stopping or starting pre-emptive therapy.

Using an ‘action set’ for the management of acute upper gastrointestinal bleeding

Background: We studied the management of patients with acute upper gastrointestinal (GI) bleeding (AUGIB) at the Royal Free Hospital. The aim was to compare our performance with the national standard and determine ways of improving the delivery of care in accordance with the recently published ‘Scope for improvement’ report. Methods: We randomly selected patients who presented with haematemesis, melaena, or both, and had an oesophageogastroduodenoscopy (OGD) between April and October 2009. We developed local guidelines and presented our findings in various forums. We collaborated with the British Medical Journal’s Evidence Centre and Cerner Millennium electronic patient record system to create an electronic ‘Action Set’ for the management of patients presenting with AUGIB. We re-audited using the same standard and target. Results: With the action set, documentation of pre-OGD Rockall scores increased significantly (p ≤ 0.0001). The differences in the calculation and documentation of post-OGD full Rockall scores were also significant between the two audit loops (p = 0.007). Patients who inappropriately received proton-pump inhibitors (PPIs) before endoscopy were reduced from 73.8% to 33% (p = 0.02). Patients receiving PPIs after OGD were also reduced from 66% to 50% (p = 0.01). Discharges of patients whose full Rockall score was less than or equal to two increased from 40% to 100% (p = 0.43). Conclusion: The use of the Action Set improved calculation and documentation of risk scores and facilitated earlier hospital discharge for low-risk patients. Significant improvements were also seen in inappropriate use of PPIs. Actions sets can improve guideline adherence and can potentially promote cost-cutting and improve health economics.

Consensus Statements: Management of the Acute Bleeding Episode

Six-week mortality should be the primary end point for studies for treatment of acute variceal bleeding (5;D).

A la Carte Treatment of Acute Variceal Bleeding

Failure to control bleeding remains challenging to define, despite many attempts of the community of experts. Even if it is associated with survival, regulatory agencies do not consider this endpoint as a reliable one for clinical trials. Moreover, identifying patients before early rebleeding or at risk of refractory bleeding is probably the most important issue. Mortality at 6 weeks seems to be a reasonable endpoint for RCTs. Refractory bleeding and its attendant mortality remain a challenging condition. Some therapeutic options, besides salvage TIPS, are currently developed but need to be tested in RCTs. As of today, most prognostic variables and scores lack external validation, and a majority include subjective or time-dependent variables and are, therefore, inconsistently evaluated. Identification of solid and unbiased predicting factors of treatment failure and rebleeding have become an urgent need, especially after the demonstration that placement of a TIPS improves survival in patients with acute variceal bleeding and high risk of failure. Identifying the best prognostic factors defining high risk should be our priority. The greatest improvement in the last years in the management of acute variceal bleeding is early TIPS in selected high-risk patients. Selection of patients needs to be refined.

P0387 : Identification of optimal cut-offs in alpha-fetoprotein and the “AFP Score” to maximise the accuracy of selection of liver transplant candidates with hepatocellular carcinoma

P0386 PREDICTING LIVER DECOMPENSATION AFTER RESECTION FOR HEPATOCELLULAR CARCINOMA: A RECURSIVE PARTITIONING ANALYSIS OF PROGNOSTIC FACTORS D. Citterio, C. Sposito, A. Facciorusso, M. Flores Reyes, M. Mazzola, V. Mazzaferro. Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, National Cancer Institute (Istituto Nazionale Tumori), Milan, Gastroenterology Unit, University of Foggia, Foggia, Italy E-mail: davide.citterio@istitutotumori.mi.it