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Introduction

Transplantation techniques and immunosuppression treatments have been increasing notably in the past years, particularly when considering liver transplant (LT). LT is the preferred treatment for early-stage hepatocellular carcinoma (HCC). Despite the use of the Milan criteria, recurrence remains a major concern, with an estimated incidence ranging from 5% to 20%. Therefore, our objective is to assess potential risk factors, including clinical, laboratory and pathological parameters, as well as prognosis of HCC recurrence in LT recipients.

Aims & Methods

Retrospective evaluation of medical records from a Brazilian tertiary hospital, including adults who were submitted to LT due to HCC, during the period of 01/01/2002 up to 31/12/2021. Patients who had a LT for other causes, who presented a follow-up less than 1 year or with incidental detection of HCC in the liver explants were excluded. Data collection included demographic information, immunosuppressive treatments, clinical, radiological and histhopathological findings related to the HCC, as well as characteristics associated with the post-transplant follow-up and tumoral recurrence, including death. Primary outcome was recurrence of HCC, whereas secondary outcomes were survival and adopted treatments after cancer recurrence, as well as time elapsed until HCC recrudescence.

Results

150 patients were included (males 95 [63.3%], median age 60 years-old [IQR 56-66]), 130 (86.6%) were classified as Milan-in. The main cirrhosis etiologies were viral (88%) and metALD (10%). Half of patients presented an A CHILD score (50%) and a median MELDNa score of 12 (IQR 9-14). Main locoregional therapies included transarterial chemoembolization (TACE) and percutaneous ethanol injection (PEI), accounting for 48 (32%) and 45 (30%) respectively. 47 (31.33%) patients underwent two or more locoregional therapy modalities, and downstaging was achieved in 20 patients (13.3%). Explant analysis with microvascular invasion and Milan-out were detected in 18 (12%) and 30 (20.1%) individuals, respectively. HCC recurrence occurred in 21/150 patients (14%), while non-HCC neoplasias in 27/150 (18.1%) after LT. The median time to recurrence was 30 months (IQR 20-43), and systemic therapy to HCC with sorafenib was used in 12/21 patients (57.14%). Among those who presented recurrence, 19/21 died (90.4%), and prognosis after recurrence was dismal (median survival of 14.5 months, IQR 3.25-33.5). Evaluation of possible associations between HCC recurrence and clinical, laboratorial, imaging and histopathological parameters was performed, but none showed impact on HCC recurrence after LT. However, there was a trend to an association between recurrence and CHILD score (p = 0.06) and smoking (p = 0.08). Also, when evaluating patients who presented early recurrence (less than 24 months after LT), a trend of an association with the number of involved liver segments was found (p = 0.07).

Conclusion

Identifying patients at risk of HCC recurrence after LT remains as a great challenge. There are some parameters previously suggested as possible predictors, but, in accordance to literature findings, our study didn't identify significant associations. Nonetheless, the possible association between early recurrence and the number of affected liver segments hasn't been studied yet, and this is the first study that suggests an association. Thus, evaluating the number of liver segments affected by HCC might help physicians to identify patients with higher risk of recurrence, as well as giving another possible parameter to investigate in further studies.

EVALUATION OF RISK FACTORS AND PROGNOSIS OF HEPATOCELLULAR CARCINOMA RECURRENCE AFTER LIVER TRANSPLANTATION

Sophia Andreola Borba 1, Bruna Teston Cini 2, Leonardo de Lima Cezimbra 3, Vitória Dall Agnol Bouvier 3, Jonas Michel Wolf 4, Carlos Thadeu Schmidt Cerski 5, Alexandre Araujo 6

1 Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil|||Hospital Moinhos de Vento, Porto Alegre, Brazil

2 Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

3 Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

4 Hospital Moinhos de Vento, Porto Alegre, Brazil

5 Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil|||Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

6 Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil|||Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil|||Hospital Moinhos de Vento, Porto Alegre, Brazil

Conference

UEG Week Vienna 2024

Topics

Hepatobiliary

Submission format

Abstract

Session

LIVER (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Introduction

Steatotic liver disease (SLD) is a common problem after liver transplantation (LT). Previous studies have confirmed the role of donor PNPLA3 rs738409 G allele as a risk factor for post-LT SLD, but the role of other recipient and donor genetic risk variants is largely unknown.

Aims & Methods

Aims: To study the prevalence of genetic risk variants for SLD in LT recipients and donors and their impact on development of post-LT SLD.
Methods: Of 807 adult patients undergoing LT in Finland between 2000–2019, 56 SLD-associated genetic risk variants were extracted from genotype data for 666 donor-recipient-pairs. Recipient genotypes were compared with ~10 000 Finnish population controls from gnomAD database. Incident post-LT SLD was assessed from protocol liver biopsies. The impact of donor and recipient genetic variants was studied in multivariate Cox regression analysis adjusted for phenotype factors.

Results

Of 56 risk variants, the minor allele frequencies (MAFs) of 17 variants were significantly different between LT recipients and population controls. The greatest MAF differences were observed for PNPLA3 rs738409-G (0.33 vs 0.22, p = 2.56 x 10^-20), TNF rs1800629-A (0.19 vs 0.12, p = 1.48 x 10^-12), IFNL4 rs12979860-T (0.29 vs 0.24, p = 7 x 10^-6 ), CD14 rs2569190-A (0.41 vs 0.37, p = 0.005) and MERTK rs4374383-A (0.36 vs 0.33, p = 0.014).
Patients transplanted for metabolic dysfunction-associated steatohepatitis (MASH) (n = 42) exhibited high prevalence of PNPLA3 rs738409-G (0.63 vs 0.22, p = 1.47 x 10^-19) and low prevalence of the protective HSD17B13 rs6834314-G (0.07 vs 0.21, p = 0.001) and MARC1 rs2642438-A (0.14 vs 0.29, p = 0.002)
Incidence of post-LT SLD was 29.1% in median follow-up time of 7.6 years. The lowest incidence (14.8%) was observed among patients transplanted for acute liver failure, and the highest (52.9%) in patients transplanted for MASH.
Final multivariate regression model to predict post-LT SLD included high SLD-risk indication (HR 2.03, p < 0.001), BMI (HR 1.10, p < 0.001), diabetes (HR 1.37, p = 0.016) and alcohol consumption (HR 2.01, p < 0.001). Table 1 shows the hazard ratios of the donor and recipient genetic variants most strongly predicting post-LT SLD after adjusting for recipient phenotype factors (high-SLD risk indication, BMI, diabetes, and alcohol consumption).

Table 1. Genetic variants significantly associated with post-LT SLD
Risk allelle	Adjusted hazard ratio / number of risk alleles			p-values
	0	1	2	p
Recipient PSD3 rs71519934-G	indicator	0.80	0.66	0.11	0.15	0.04
Recipient FADS1 rs174556-T	indicator	1.01	1.63	0.03	0.94	0.02
Recipient UCP2 rs695366-G	indicator	0.63	0.50	0.003	0.002	0.04
Donor MERTK rs4374383-A	indicator	1.51	1.46	0.02	0.007	0.10
Donor HSD17B13 rs6834314-G	indicator	0.68	0.46	0.02	0.02	0.07
Donor TM6SF2 rs58542926-T	indicator	1.61	1.71	0.08	0.03	0.46
Donor PNPLA3 rs738409-G	indicator	1.39	2.51	0.002	0.03	0.001

Conclusion

SLD-associated risk alleles were common in LT recipients, especially in MASH. Post-LT SLD incidence was high (29.1%), but with large variation across transplantation indications. Donor, but not recipient, PNPLA3 allele was most strongly associated with post-LT SLD. Several other donor and recipient genetic variants also contributed to post-LT SLD. Both LT recipient and donor genotypes provide novel insights into the genetic determinants of SLD after LT, providing help in future individual risk assessment.

GENETIC RISK FACTORS FOR STEATOTIC LIVER DISEASE AFTER LIVER TRANSPLANTATION

Ville Liukkonen 1, Maria Semenova 2, Kati Hyvärinen 2, Jouni Lauronen 2, Jukka Partanen 2, Arno Nordin 3, Johanna Arola 4, Martti A. Färkkilä 3, Fredrik Åberg 3

1 University of Helsinki, Helsinki, Finland|||North Carelia Central Hospital, Joensuu, Finland

2 Finnish Red Cross Blood Service, Helsinki, Finland

3 Helsinki University Hospital, Helsinki, Finland

4 University of Helsinki, Helsinki, Finland|||Helsinki University Hospital, Helsinki, Finland

Conference

UEG Week Vienna 2024

Topics

Hepatobiliary

Submission format

Abstract

Session

Basic science in HPB: Genetic, metabolic and immune (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Introduction

Liver transplantation has become one of the key curative treatment options for hepatocellular carcinoma (HCC). However, a subset of patients experiences HCC recurrence after transplantation. Furthermore, due to the shortage of donor organs, there is a great need to identify patients with the best possible outcome who may be eligible for transplantation. While several clinical models aimed to predict recurrence and are integrated into clinical practice such as Milan-Criteria, there is a great need for molecular biomarkers that would allow objective assessment taken to account tumor-biology to better predict diseases recurrence. MicroRNAs (miRNAs) play a crucial role in the regulation of gene expression, contributing to the development and progression of HCC and are considered as potential HCC biomarkers.

Aims & Methods

This study aimed to explore miRNAs form the HCC prior transplantation as predictive biomarker for post-transplant HCC recurrence and to assess their value in combination with other tools as a personalized predictive score. The proof-of-concept study included 20 HCC patients who underwent liver transplantation between 2007 and 2021 (n = 10 with recurrence, n = 10 without). MiRNA profiling was performed on formalin-fixed, paraffin-embedded (FFPE) HCC tissue obtained at the time of transplantation. MiRNAs were extracted using the Qiagen miRNeasy Kit and analyzed via Agilent miRNA microarray. The recurrence-free survival (RFS) of the subject population was assessed using a Kaplan–Meier analysis. The predictive value of different miRNAs was evaluated using a receiver operating characteristic (ROC) analysis.

Results

Out of approximately 4,000 analyzed miRNAs, three candidates (miR-3692-5p, miR-424, miR-718) demonstrated the strongest discriminatory power between recurrence and non-recurrence. miR-3692-5p alone exhibited excellent predictive accuracy (AUC = 0.995, p < 0.0001), clearly outperforming traditional models such as the Milan criteria (AUC = 0.550, p = 0.706). The other two miRNAs also showed significant but comparatively lower predictive value. However, combined as a 3-miRNA signature, they achieved excellent overall predictive performance (AUC = 0.9, p < 0.05). Furthermore, the study revealed that the expression levels of miR-3692-5p can effectively classify patients into high- and low-risk categories for HCC recurrence. The high-risk group, characterized by low expression levels, exhibited a significantly shorter median recurrence-free survival (RFS) of 17 months compared to 38.5 months (p <0.005).

Conclusion

This study identified three miRNAs capable of distinguishing between recurrent and non-recurrent HCC post-transplantation, both individually and as a combined miRNA-signature. Integrating molecular biomarkers into existing clinical risk models improved predictive and prognostic accuracy, highlighting the potential of personalized molecular biomarkers in transplant oncology.

INVESTIGATION OF TUMOR-DERIVED MICRORNAS FOR PREDICTION OF HCC RECURRENCE FOLLOWING ORTHOTOPIC LIVER TRANSPLANTATION

Theresa Lederer 1, Konrad Lehr 1, Stefanie Bobe 2, Philipp Schindler 3, Cosima Thon 1, Emily Hoffmann 3, Wolfgang Roll 3, Florian Rennebaum 3, Haluk Morgül 3, Max Masthoff 3, Osman Öcal 4, Jonel Trebicka 3, Moritz Wildgruber 5, Alexander Link 1

1 Otto-von-Guericke University Magdeburg, Magdeburg, Germany

2 University of Münster, Münster, Germany|||University of Münster, Münster, Germany

3 University of Münster, Münster, Germany

4 University of Heidelberg, Heidelberg, Germany

5 LMU München, Munich, Germany

Conference

UEG Week Berlin 2025

Topics

Hepatobiliary

Submission format

Abstract

Session

Liver transplantation: Complication management and surveillance (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Transplantation for borderline hepatocellular carcinoma: Radiologist and surgeon

Thomas Helmberger 1, Fabrizio Panaro 2

1 Klinikum München, None, Germany

2 CHU de Montpellier, Monpellier, France

Event

UEG Week Vienna 2024

Topics

Digestive Oncology Hepatobiliary Pancreas Radiology & Imaging Surgery

Session

Never waste a good disaster: HPB

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Introduction

Hepatocellular carcinoma (HCC) is one of the main indication for liver transplantation (LT) worldwide, however, despite various proposed selection criteria, HCC recurrence rate after LT remains up to 20%. An earlier diagnosis allows for more effective treatments and survival benefit. Recently, the RETREAT score has been proposed showing high accuracy.

Aims & Methods

Our aim was to validate the RETREAT score in a single center cohort.
This is a retrospective study including patients who underwent LT for HCC at Padua University-Hospital between January 2016 and December 2018. Clinical and radiological data before and after LT (aFP, liver function according to MELD and CHILD score, tumor morphology, downstaging and/or bridging treatments) and explant pathology features were collected. RETREAT and TTV/aFP scores, based on explant pathology, were calculated. Cox regression and LogRank models have been used for the association between HCC scores and tumor recurrence.

Results

During the study period, 123 patients underwent LT for HCC (HCV 35%, median MELD 11). After HCC diagnosis, 115 patients (93%) underwent downstaging (47% ≥2 treatments), and 64 of them (56%) received bridging therapies. The median aFP at LT was 4.8 ng/mL. On explant pathology, microvascular invasion was found in 27%, G3 nodules in 30%. On explant pathology, 65 patients (53%) were Milan-out, 44 patients (36%) were TTV/aFP-out, 77 patients (62%) had a RETREAT score ≥2. During the follow-up of 50 months (IQR 39-60), 16 patients (13%) showed post-transplant HCC recurrence, at median time of 14 months (IQR 8-36); 75% of them had extrahepatic recurrence. RETREAT score was associated with the risk of HCC recurrence (p<0.001, HR 1.703, 95%CI 1.30-2.22). Patients with RETREAT score 0-1, 2-4 and 5-8 had a 1 year-HCC recurrence of 2%, 4% and 21%, respectively (log-rank<0.001). TTV/AFP has not been associated with HCC recurrence (p=0.680).

Conclusion

RETREAT score is a reliable tool to improve the selection of patients at higher risk of HCC recurrence and to guide the post-LT management, defining shorten tumor surveillance post-LT. Thus, an earlier diagnosis of tumor recurrence might allow more efficacious treatments and patient survival benefit.