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Objectives Thermal ablation (TA) is an established treatment for early HCC. There is a lack of data on the efficacy of repeated TA for recurrent HCC, resulting in uncertainty whether good oncologic outcomes can be obtained without performing orthotopic liver transplantation (OLTx). This study analyses outcomes after TA, with a special focus on repeat TA for recurrent HCC, either as a stand-alone therapy, or in relationship with OLTx. Methods Data from a prospectively registered database on interventions for HCC in a tertiary hepatobiliary centre was completed with follow-up until December 2020. Outcomes studied were rate of recurrence after primary TA and after its repeat interventions, the occurrence of untreatable recurrence, OS and DSS after primary and repeat TA, and complications after TA. In cohorts matched for confounders, OSS and DSS were compared after TA with and without the intention to perform OLTx. Results After TA, 100 patients (56·8%) developed recurrent HCC, of whom 76 (76·0%) underwent up to four repeat interventions. During follow-up, 76·7% of patients never developed a recurrence unamenable to repeat TA or OLTx. OS was comparable after primary TA and repeat TA. In matched cohorts, OS and DSS were comparable after TA with and without the intention to perform OLTx. Conclusions We found TA to be an effective and repeatable therapy for primary and recurrent HCC. Most recurrences can be treated with curative intent. There are patients who do well with TA alone without ever undergoing OLTx. Key Points • Recurrent HCC after primary TA can often be treated effectively with repeat TA. Survival after repeat TA is comparable to primary TA . • In matched cohorts, outcomes after TA with and without subsequent waitlisting for OLTx are comparable . • There are patients who do well for many years with primary and repeat TA alone; some despite multiple recurrences.

Background The major concern in liver transplantation of grafts from donation after circulatory death (DCD) donors remains the high incidence of non-anastomotic biliary strictures (NAS). Machine perfusion has been proposed as an alternative strategy for organ preservation which reduces ischemia-reperfusion injury (IRI). Experimental studies have shown that dual hypothermic oxygenated machine perfusion (DHOPE) is associated with less IRI, improved hepatocellular function, and better preserved mitochondrial and endothelial function compared to conventional static cold storage (SCS). Moreover, DHOPE was safely applied with promising results in a recently performed phase-1 study. The aim of the current study is to determine the efficacy of DHOPE in reducing the incidence of NAS after DCD liver transplantation. Methods This is an international multicenter randomized controlled trial. Adult patients (≥18 yrs. old) undergoing transplantation of a DCD donor liver (Maastricht category III) will be randomized between the intervention and control group. In the intervention group, livers will be subjected to two hours of end-ischemic DHOPE after SCS and before implantation. In the control group, livers will be subjected to care as usual with conventional SCS only. Primary outcome is the incidence of symptomatic NAS diagnosed by a blinded adjudication committee. In all patients, magnetic resonance cholangiography will be obtained at six months after transplantation. Discussion DHOPE is associated with reduced IRI of the bile ducts. Whether reduced IRI of the bile ducts leads to lower incidence of NAS after DCD liver transplantation can only be examined in a randomized controlled trial. Trial registration The trial was registered in Clinicaltrials.gov in September 2015 with the identifier NCT02584283 .

In a multicenter, controlled trial, patients undergoing transplantation of a liver from a donor after circulatory death were randomly assigned to receive the liver after hypothermic oxygenated machine perfusion or conventional static cold storage. Hypothermic perfusion led to a lower risk of post-transplantation nonanastomotic biliary strictures.

IntroductionExtended criteria donor (ECD) livers are increasingly accepted for transplantation in an attempt to reduce the gap between the number of patients on the waiting list and the available number of donor livers. ECD livers; however, carry an increased risk of developing primary non-function (PNF), early allograft dysfunction (EAD) or post-transplant cholangiopathy. Ischaemia-reperfusion injury (IRI) plays an important role in the development of these complications. Machine perfusion reduces IRI and allows for reconditioning and subsequent evaluation of liver grafts. Single or dual hypothermic oxygenated machine perfusion (DHOPE) (4°C–12°C) decreases IRI by resuscitation of mitochondria. Controlled oxygenated rewarming (COR) may further reduce IRI by preventing sudden temperature shifts. Subsequent normothermic machine perfusion (NMP) (37°C) allows for ex situ viability assessment to facilitate the selection of ECD livers with a low risk of PNF, EAD or post-transplant cholangiopathy.Methods and analysisThis prospective, single-arm study is designed to resuscitate and evaluate initially nationwide declined ECD livers. End-ischaemic DHOPE will be performed for the initial mitochondrial and graft resuscitation, followed by COR of the donor liver to a normothermic temperature. Subsequently, NMP will be continued to assess viability of the liver. Transplantation into eligible recipients will proceed if all predetermined viability criteria are met within the first 150 min of NMP. To facilitate machine perfusion at different temperatures, a perfusion solution containing a haemoglobin-based oxygen carrier will be used. With this protocol, we aim to transplant extra livers. The primary endpoint is graft survival at 3 months after transplantation.Ethics and disseminationThis protocol was approved by the medical ethical committee of Groningen, METc2016.281 in August 2016 and registered in the Dutch Trial registration numberTrial registration numberNTR5972, NCT02584283.

It has been demonstrated that hepatic apparent diffusion coefficients (ADC) are decreasing in patients with a Fontan circulation. It remains however unclear whether this is a true decrease of molecular diffusion, or rather reflects decreased microperfusion due to decreased portal blood flow. The purpose of this study was therefore to differentiate diffusion and microperfusion using intravoxel incoherent motion (IVIM) modeled diffusion-weighted imaging (DWI) for different liver segments in patients with a Fontan circulation, compare to a control group, and relate with liver function, chronic hepatic congestion and hepatic disease. For that purpose, livers of 59 consecutively included patients with Fontan circulation (29 men; mean-age, 19.1 years) were examined (Oct 2012─Dec 2013) with 1.5T MRI and DWI (b = 0,50,100,250,500,750,1500,1750 s/mm2). IVIM (Dslow, Dfast, ffast) and ADC were calculated for eight liver segments, compared to a control group (19 volunteers; 10 men; mean-age, 32.9 years), and correlated to follow-up duration, clinical variables, and laboratory measurements associated with liver function. The results demonstrated that microperfusion was reduced (p<0.001) in Fontan livers compared to controls with ─38.1% for Dfast and ─32.6% for ffast. Molecular diffusion (Dslow) was similar between patients and controls, while ADC was significantly lower (─14.3%) in patients (p<0.001). ADC decreased significantly with follow-up duration after Fontan operation (r = ─0.657). Dslow showed significant inverse correlations (r = ─0.591) with follow-up duration whereas Dfast and ffast did not. From these results it was concluded that the decreasing ADC values in Fontan livers compared with controls reflect decreases in hepatic microperfusion rather than any change in molecular diffusion. However, with the time elapsed since the Fontan operation molecular diffusion and ADC decreased while microperfusion remained stable. This indicates that after Fontan operation initial blood flow effects on the liver are followed by intracellular changes preceding the formation of fibrosis and cirrhosis.

Background No prognostic score is currently available for long‐term survival in autoimmune hepatitis (AIH) patients. Objective The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis. Methods The prognostic score was developed using uni‐ & multivariate Cox regression in a 4‐center Dutch cohort and validated in an independent 6‐center Belgian cohort. Results In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow‐up 118 months; interquartile range 60–202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non‐caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C‐statistic 0.827; 95% CI 0.790–0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow‐up of 74 months (interquartile range: 25–142 months). Predicted 5‐year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%–24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%–9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%–11.4%); C‐statistic 0.744 [95% CI 0.644–0.844]). Conclusions A Dutch‐Belgian prognostic score for long‐term transplant‐free survival in AIH patients at diagnosis was developed and validated.

BackgroundFew studies with diverging results and a small sample size have compared autoimmune hepatitis (AIH) in the elderly to younger patients.AimTo unbiasedly investigate the role of age in behaviour and treatment outcome of AIH.MethodsAll patients with probable or definite AIH type 1 in four tertiary academic centres were included in this retrospective—and since 2006 prospective—cohort study. Influence of age on presentation, remission and outcome of AIH were investigated.Results359 patients were included. Presence of cirrhosis at AIH diagnosis around 30% was independent of age. ALAT was higher at age 30–60 years on AIH diagnosis, and above age 60 there were less acute onset, less jaundice and more concurrent autoimmune disease. Remission was reached in 80.2%, incomplete remission in 18.7%, only 1.1% (all aged 50–65) was treatment-refractory. Age was not an independent predictor of remission, while cirrhosis was. Above age 45 there was more diabetes, above age 60 more loss of remission. Rate of progression to cirrhosis was 10% in the 10 years after diagnosis and unrelated to age at AIH diagnosis. With onset below age 30, there was more development of decompensated cirrhosis over time. With higher age at AIH diagnosis there was a lower survival free of liver-related death or liver transplantation.ConclusionsAIH presents at all ages. Age influences features at diagnosis, but not response to treatment, while survival without liver-related death or liver transplantation decreases with higher age at diagnosis.

Background Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. Methods CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. Discussion The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. Trial registration EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016. Graphical Abstract

Background Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. Methods The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. Discussion This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. Trial registration ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021–003420-33. Prospectively registered on 16 June 2021.

PurposeMany laboratory values are abnormal after surgery for a ruptured abdominal aortic aneurysm (RAAA). However, these changes have not been comprehensively evaluated. We analyzed the changes in routine laboratory values and how these changes related to outcome in a consecutive series of RAAA patients.MethodsAll patients who underwent surgery for an RAAA between January 1990 and June 2003 at our hospital were included in this study. We analyzed laboratory data acquired during the first week for all patients and at discharge for survivors. We categorized 29 different measurements into six categories based on the related pathological process, including hematology and coagulation, metabolism, systemic inflammation, renal function, liver function, and electrolytes.ResultsA total of 290 patients underwent RAAA surgery, with a hospital mortality of 34%. Hemorrhage was the most common cause of early death, whereas multiple-organ failure (MOF) was the most common cause of death several days after surgery. Most laboratory values deviated from normal at multiple time points and they differed significantly between survivors and nonsurvivors.ConclusionsBoth survivors and nonsurvivors of RAAA surgery displayed characteristic time-dependent laboratory abnormalities. Awareness of these responses may help us predict patients prone to complications.