Even though the combined use of ultrasound (US) and alpha-fetoprotein (AFP) is recommended for the surveillance of hepatocellular carcinoma (HCC), the utilization of AFP has its challenges, including accuracy dependent on its cut-off levels, degree of liver necroinflammation, and etiology of liver disease. Though various studies have demonstrated the utility of protein induced by vitamin K absence II (PIVKA-II) in surveillance, treatment monitoring, and predicting recurrence, it is still not recommended as a routine biomarker test. A panel of 17 experts from Asia-Pacific, gathered to discuss and reach a consensus on the clinical usefulness and value of PIVKA-II for the surveillance and treatment monitoring of HCC, based on six predetermined statements. The experts agreed that PIVKA-II was valuable in the detection of HCC in AFP-negative patients, and could potentially benefit detection of early HCC in combination with AFP. PIVKA-II is clinically useful for monitoring curative and intra-arterial locoregional treatments, outcomes, and recurrence, and could potentially predict microvascular invasion risk and facilitate patient selection for liver transplant. However, combining PIVKA-II with US and AFP for HCC surveillance, including small HCC, still requires more evidence, whilst its role in detecting AFP-negative HCC will potentially increase as more patients are treated for hepatitis-related HCC. PIVKA-II in combination with AFP and US has a clinical role in the Asia-Pacific region for surveillance. However, implementation of PIVKA-II in the region will have some challenges, such as requiring standardization of cut-off values, its cost-effectiveness and improving awareness among healthcare providers.

BACKGROUND The study objective was to evaluate the effect of everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared with a standard TAC (sTAC) regimen on hepatocellular carcinoma (HCC) recurrence in de novo living-donor liver transplantation recipients (LDLTRs) with primary HCC at liver transplantation through 5 years after transplantation. MATERIAL AND METHODS In this multicenter, non-interventional study, LDLTRs with primary HCC, who were previously randomized to either everolimus plus reduced tacrolimus (EVR+rTAC) or standard tacrolimus (sTAC), and who completed the 2-year core H2307 study, were followed up. Data were collected retrospectively (end of core to the start of follow-up study), and prospectively (during the 3-year follow-up study). RESULTS Of 117 LDLTRs with HCC at LT in the core H2307 study (EVR+rTAC, N=56; sTAC, N=61), 86 patients (EVR+rTAC, N=41; sTAC, N=45) entered the follow-up study. Overall HCC recurrence was lower but statistically non-significant in the EVR+rTAC group (3.6% vs 11.5% in sTAC; P=0.136) at 5 years after LT. There was no graft loss or chronic rejection. Acute rejection and death were comparable between treatment groups. Higher mean estimated glomerular filtration rate in the EVR+rTAC group (76.8 vs 65.8 mL/min/1.73 m² in sTAC) was maintained up to 5 years. Reported adverse events were numerically lower in the EVR+rTAC group (41.0% vs 53.5% sTAC) but not statistically significant. CONCLUSIONS Although statistically not significant, early EVR initiation reduced HCC recurrence, with comparable efficacy and safety, and better long-term renal function, than that of sTAC treatment.

In a multicenter, open-label, study, 284 living-donor liver transplant patients were randomized at 30 ± 5 days posttransplant to start everolimus+reduced tacrolimus (EVR+rTAC) or continue standard tacrolimus (TAC Control). EVR+rTAC was non-inferior to TAC Control for the primary efficacy endpoint of treated BPAR, graft loss or death at 12 months posttransplant: difference -0.7% (90% CI -5.2%, 3.7%); P < .001 for non-inferiority. Treated BPAR occurred in 2.2% and 3.6% of patients, respectively. The key secondary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, achieved non-inferiority (P < .001 for non-inferiority), but not superiority and was similar between groups overall (mean -8.0 vs. -12.1 mL/min/1.73 m2 , P = .108), and in patients continuing randomized treatment (-8.0 vs. -13.3 mL/min/1.73 m2 , P = .046). In the EVR+rTAC and TAC control groups, study drug was discontinued in 15.5% and 17.6% of patients, adverse events with suspected relation to study drug occurred in 57.0% and 40.4%, and proteinuria ≥1 g/24 h in 9.3% and 0%, respectively. Everolimus did not negatively affect liver regeneration. At 12 months, hepatocellular recurrence was only seen in the standard TAC-treated patients (5/62; 8.1%). In conclusion, early introduction of EVR+rTAC was non-inferior to standard tacrolimus in terms of efficacy and renal function at 12 months, with hepatocellular carcinoma recurrence only in TAC Control patients. ClinicalTrials.gov Identifier: NCT01888432.

TTS 2018. 27th International Congress of The Transplantation Society. June 30-July 5 Madrid, Spain. CRAD0001H2307 Introduction Early initiation of everolimus (EVR) with reduced-exposure tacrolimus (rTAC) has been shown to maintain an efficacy and safety profile comparable to that of a standard-exposure TAC (sTAC) regimen and preserves renal function in living-donor liver transplant recipients (LDLTRs) up to 12 months post-LT. Here, we present 24-month (M) renal function outcomes from the H2307 study involving LDLTRs receiving EVR+rTAC or sTAC regimens. Methods H2307 (NCT01888432) was a 24M, multicentre, open-label trial in which 284 adult de novo LDLTRs were randomized (1:1) on Day 30±5 post-LT to receive EVR+rTAC (EVR trough level [C0]: 3-8 ng/mL; TAC C0: 3-5 ng/mL) or sTAC (TAC C0: randomization (RND)-M4: 8-12 ng/mL; after M4: 6-10 ng/mL) regimen. Efficacy assessment at M24 was incidence of composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death in EVR+rTAC and sTAC arms. Renal assessments at M24 included estimated glomerular filtration (eGFR [MDRD4]) in overall study population and in patients with hepatocellular carcinoma (HCC). Other assessments included evaluation of proteinuria and renal adverse events (AEs) up to M24. Results Overall results are presented in Table 1. Of 284 randomized patients, 88% in both arms completed the 24M study. At M24, 78% of patients in EVR+rTAC arm were within EVR C0 range although mean TAC C0 was below target range in sTAC arm. EVR+rTAC was non-inferior to sTAC for the primary endpoint of composite efficacy failure at M24 (9.0% vs 8.0%; P<0.001 by one-sided test for non-inferiority). In the overall population, eGFR was comparable between EVR+rTAC and sTAC (78.4 and 75.3 mL/min/1.73 m2) arms, with between-arm least square mean change from RND to M24 not significantly different in the full analysis and on-treatment populations. Among patients with HCC at LT, eGFR was significantly higher in the EVR+rTAC arm (P = 0.009). In overall population, proportion of patients with M24 eGFR ≥60 mL/min/1.73 m2 was higher in the EVR+rTAC (76.4%) vs sTAC (66.9%) arm. Although mean proteinuria and urinary protein creatinine ratio (UPCR) were significantly higher in EVR+rTAC vs sTAC arm (P<0.001), most patients in both arms remained in the low-to-mild categories for proteinuria (>80% with <0.5 g/24 h/SA) and UPCR (>70% with ≥30-<300 mg/g) at M24. Incidence of AEs and AEs leading to study drug discontinuation was comparable between arms; however, discontinuations due to renal AEs such as renal failure and renal impairment were numerically lower in EVR+rTAC vs sTAC arm (Table 2). Conclusions At M24, early EVR initiation with rTAC in LDLTRs resulted in comparable renal function outcomes as sTAC regimen. Significantly better renal function was observed in patients with HCC on EVR+rTAC, which warrants additional analysis. JOURNAL/trans/04.02/00007890-201807001-00035/table1-35/v/2018-08-28T120805Z/r/image-tiff JOURNAL/trans/04.02/00007890-201807001-00035/table2-35/v/2018-08-28T120805Z/r/image-tiff Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Chronic renal failure is a frequent complication in liver transplantation. Telbivudine, anti-hepatitis B virus (HBV) nucleoside, can improve renal function. It is interesting if using telbivudine for prophylaxis of HBV recurrence has additional value on renal function improvement. 120 liver transplant recipients with lamivudine prophylaxis for HBV recurrence were 1 : 1 randomized into lamivudine-continuous (n = 60) and telbivudine-replacement (n = 60) groups. Fifty-eight patients in lamivudine-continuous group and 54 in telbivudine-replacement group completed the study. In telbivudine-replacement group, the estimated glomerular filtration rate (eGRF) was improved from 63.0 ± 16.3 ml/min to 72.8 ± 21.1 ml/min at 12 months after telbivudine administration (p = 0.003). Stratifying the patients according to renal function staging, the eGRF was improved from 74.7 ± 6.9 ml/min to 84.2 ± 16.6 ml/min (p = 0.002) in 32 stage II patients and from 48.2 ± 7.3 ml/min to 59.7 ± 11.8 ml/min in 20 stage III patients after 12 months of telbivudine administration (p < 0.001). Eleven (18.3%) patients with telbivudine developed polyneuritis during the trial and post hoc following-up. In conclusion, renal function was improved by telbivudine in liver transplant recipients with long-term chronic kidney disease. However, the high incidence of polyneuritis induced by telbivudine has to be closely monitored. This trial is registered with ClinicalTrials NCT02447705.

International Liver Transplantation Society. Chicago, Illinois. July 8 -11. 2015

11th World Congress of the International Hepato-Pancreato-Biliary Association Seoul South Korea.

BACKGROUND:

It is sometimes difficult and harmful to insert a nasogastric tube (NGT) into a patient with a tendency to bleed and anesthetized recipient of liver transplantation. As a "Rusch" intubation stylet tied by a slipknot, Highwayman's hitch, to the NGT, it is easy to introduce the NGT through nasal cavity and oropharyngeal space. We designed this study to evaluate the usage of this novel method in the guidance of NGT insertion in liver transplant recipients.

METHODS:

Eighty recipients were randomly allocated to both groups. In the control group (group C), the NGT was inserted with the patient's head in neutral position. In the stylet group (group S), the NGT was inserted with the assistance of a Rusch intubation stylet tied together at the tips. The success rates, duration of insertions, and occurrences of complications were recorded. All of the failed cases in group C and the rescue success rate with the new technique were also evaluated.

RESULTS:

Successful insertions were recorded in 38/40 patients (95%) in group S and in 27/40 patients (67.5%) in group C, and the difference was statistically significant. The incidences of kinked NGT were 17.5% in group C and 2.5% in group S, respectively, and the difference was statistically significant. The rates of nasal mucosal bleeding were 22.5% in group C and 25% in group S. The rescue success rate of 13 failure cases in the group C was 84.6%.

CONCLUSION:

The intubation stylet-guided method is reliable, with high success rate of NGT insertion in patients with a tendency to bleed anesthetized recipients of liver transplantation.

OBJECTIVE:

Ischemic reperfusion (IR) injury is known to have an important influence on the success of transplant surgery and the occurrence of complications. Malondialdehyde (MDA) is an intermediate metabolite of lipid peroxidation resulting from IR-induced reactive oxygen species. This study was designed to investigate the protective effects of propofol on IR injury in liver transplant recipients.

METHODS:

We analyzed 19 recipients prospectively by measuring the blood levels of MDA at nine predefined intervals; before induction of anesthesia (baseline, T0), 1 hour after surgical incision (T1), 1 minute before reperfusion (T2), 30 seconds after reperfusion (T3), as well as 1, 3, 5, 30, and 60 minutes thereafter (T4-8). These patients were randomly allocated to two groups. The propofol group received an infusion (2 mg/kg per hr) after an induction bolus (2 mg/kg). The control group was prescribed midazolam (0.2 mg/kg) for induction without intravenous anesthetic infusion for maintenance.

RESULTS:

The highest MDA level occured at T6 in the controls and T7 in the propofol group. Compared with the blood levels at baseline, the MDA levels increased significantly at T2-T8 among controls versus T2, T3, T4, and T7 in the propofol group. Compared to the control group, propofol significantly lowered MDA values at T5-T8.

CONCLUSION:

There were significantly higher MDA levels among the control versus the propofol group at 3, 5, 30, and 60 minutes after reperfusion in liver transplant recipients.