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Advances and Future Developments in Liver Transplantation for Cancers

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Transplant Oncology".

Deadline for manuscript submissions: closed (17 March 2024) | Viewed by 5510

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Special Issue Editors

Dr. Nicolas Golse

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Guest Editor

Department of Surgery, Paul-Brousse Hospital, Assistance Publique Hôpitaux de Paris, Centre Hepato-Biliaire, 94800 Villejuif, France
Interests: hepatocellular carcinoma; cholangiocarcinoma; liver transplantation; portal hypertension; augmented reality; fluorescence; digital twin

Dr. Giammauro Berardi

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Guest Editor

Department of General, Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo Forlanini Hospital of Rome, 00152 Rome, Italy
Interests: liver transplantation; liver resection; minimally invasive HPB surgery

Dr. François Cauchy

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Guest Editor

Department of Hepatobiliary Surgery and Liver Transplantation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
Interests: open and mini-invasive (laparoscopic and robotic) hepatobiliary and pancreatic surgery; complex liver surgery; open and laparoscopic living donor hepatectomy for adult-child living donor liver transplantation; liver transplantation

Dr. Takashi Kokudo

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Guest Editor

Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 1138421, Japan
Interests: hepatocellular carcinoma; liver resection; liver transplantation

Special Issue Information

Dear Colleagues,

Liver transplantation is undoubtedly the best treatment for HCC and end-stage liver disease. It is a procedure that has clearly reached maturity despite very large regional differences (including preferential access to deceased versus living donors). However, the global shortage of organs limits access to transplantation and the foreseeable increase in indications, as well as rising epidemiology of primary liver cancers, make it possible to anticipate a worrying worsening of this shortage in the near future. It is therefore urgent to propose solutions to improve access to grafts, using marginal, partial, ex vivo perfused or artificial organs. Innovations have already been implemented, and many others are under development.

This issue invites hepatobiliary and transplant surgeons, hepatologists, and oncologists to discuss recent advances in the field of liver transplantation with a key interest in recent oncologic advances and their interaction with liver transplantation.

We aim to focus on:

Currently debated indications and potential evolution of recipients’ demographics;
New onco-surgical strategies for HCC (immunotherapy, radioembolization, etc.) and impact on transplantation: timing, specific surgical risks, downstaging, post-transplant oncological results, etc.;
Ex vivo liver perfusion;
Orthotopic and heterotopic auxiliary liver transplantation—the RAPID procedure;
Living donor liver transplantation in Eastern and Western countries;
Artificial livers, organoids, bioengineering: dream or reality in the short term?
Mathematical models and numerical simulations in the field of transplantation: why should they be of interest for the surgeon for the selection of patients?
New surgical strategies/technical tips in LT: portal thrombosis, complex vascular reconstructions, redo-LT, management of large-for-size syndrome, portal flow modulation, etc.;
Challenges and pitfalls of combined transplants (heart, lungs).

Dr. Nicolas Golse
Dr. Giammauro Berardi
Dr. François Cauchy
Dr. Takashi Kokudo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

machine perfusion
marginal graft
split liver
immunotherapy
auxiliary liver transplantation
digital twin
modeling
organoïd

Published Papers (5 papers)

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Research

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14 pages, 1084 KiB

Open AccessArticle

Liver Transplantation from Elderly Donors (≥85 Years Old)

by Pierluigi Romano, Luis Cano, Daniel Pietrasz, Nassiba Beghdadi, Marc-Antoine Allard, Chady Salloum, Frédérique Blandin, Oriana Ciacio, Gabriella Pittau, René Adam, Daniel Azoulay, Antonio Sa Cunha, Eric Vibert, Luciano De Carlis, Alessandro Vitale, Umberto Cillo, Daniel Cherqui and Nicolas Golse

Cancers 2024, 16(10), 1803; https://doi.org/10.3390/cancers16101803 - 8 May 2024

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Abstract

Background: Despite the ongoing trend of increasing donor ages in liver transplantation (LT) setting, a notable gap persists in the availability of comprehensive guidelines for the utilization of organs from elderly donors. This study aimed to evaluate the viability of livers grafts from donors aged ≥85 years and report the post-LT outcomes compared with those from “ideal” donors under 40 years old. Methods: Conducted retrospectively at a single center from 2005 to 2023, this study compared outcomes of LTs from donors aged ≥85 y/o and ≤40 y/o, with the propensity score matching to the recipient’s gender, age, BMI, MELD score, redo-LT, LT indication, and cause of donor death. Results: A total of 76 patients received grafts from donors ≥85 y/o and were compared to 349 liver grafts from donors ≤40 y/o. Prior to PSM, the 5-year overall survival was 63% for the elderly group and 77% for the young group (p = 0.002). After PSM, the 5-year overall survival was 63% and 73% (p = 0.1). A nomogram, developed at the time of graft acceptance and including HCC features, predicted 10-year survival after LT using a graft from a donor aged ≥85. Conclusions: In the context of organ scarcity, elderly donors emerge as a partial solution. Nonetheless, without proper selection, LT using very elderly donors yields inferior long-term outcomes compared to transplantation from very young donors ≤40 y/o. The resulting nomogram based on pre-transplant criteria allows for the optimization of elderly donor/recipient matching to achieve satisfactory long-term results, in addition to traditional matching methods. Full article

(This article belongs to the Special Issue Advances and Future Developments in Liver Transplantation for Cancers)

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18 pages, 1581 KiB

Open AccessArticle

Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation

by Paolo De Simone, Arianna Precisi, Quirino Lai, Juri Ducci, Daniela Campani, Piero Marchetti and Stefano Gitto

Cancers 2024, 16(7), 1243; https://doi.org/10.3390/cancers16071243 - 22 Mar 2024

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Abstract

To obtain long-term data on the use of everolimus in patients who underwent liver transplantation for hepatocellular carcinoma, we conducted a retrospective, single-center analysis of adult recipients transplanted between 2013 and 2021. Patients on everolimus-incorporating immunosuppression were matched with those on tacrolimus using an inverse probability of treatment weighting methodology. Two propensity-matched groups of patients were thus compared: 233 (45.6%) receiving everolimus versus 278 (54.4%) on tacrolimus. At a median (interquartile range) follow-up of 4.4 (3.8) years after transplantation, everolimus patients showed a reduced risk of recurrence versus tacrolimus (7.7% versus 16.9%; RR = 0.45; p = 0.002). At multivariable analysis, microvascular infiltration (HR = 1.22; p < 0.04) and a higher tumor grading (HR = 1.27; p < 0.04) were associated with higher recurrence rate while being within Milan criteria at transplant (HR = 0.56; p < 0.001), a successful pre-transplant downstaging (HR = 0.63; p = 0.01) and use of everolimus (HR = 0.46; p < 0.001) had a positive impact on the risk of post-transplant recurrence. EVR patients with earlier drug introduction (≤30 days; p < 0.001), longer treatment duration (p < 0.001), and higher drug exposure (≥5.9 ng/mL; p < 0.001) showed lower recurrence rates versus TAC. Based on our experience, everolimus provides a reduction in the relative risk of hepatocellular carcinoma recurrence, especially for advanced-stage patients and those with earlier drug administration, higher drug exposure, and longer time on treatment. These data advocate for early everolimus introduction after liver transplantation to reduce the attrition rate consequent to chronic immunosuppression. Full article

(This article belongs to the Special Issue Advances and Future Developments in Liver Transplantation for Cancers)

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14 pages, 1659 KiB

Open AccessArticle

Liver Transplantation for Hepatocellular Carcinoma beyond the Milan Criteria: A Specific Role for Living Donor Liver Transplantation after Neoadjuvant Therapy

by Oliver Rohland, Lea Freye, Laura Schwenk, Aladdin Ali-Deeb, Michael Ardelt, Astrid Bauschke, Utz Settmacher, Falk Rauchfuß and Felix Dondorf

Cancers 2024, 16(5), 920; https://doi.org/10.3390/cancers16050920 - 25 Feb 2024

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Abstract

Purpose: This study was designed to elucidate the various new classifications and the use of LDLT and bridging therapy for HCC in this context beyond the Milan criteria (MC). Methods: The clinical data of patients with HCC outside the MC who underwent LT at Jena University between January 2007 and August 2023 were retrospectively analysed. Eligible patients were classified according to various classification systems. Clinicopathological features, overall and disease-free survival rates were compared between LT and LDLT within the context of bridging therapy. The Results: Among the 245 patients analysed, 120 patients did not meet the MC, and 125 patients met the MC. Moreover, there were comparable overall survival rates between patients outside the MC for LT versus LDLT (OS 44.3 months vs. 28.3 months; 5-year survival, 56.4% vs. 40%; p = 0.84). G3 tumour differentiation, the presence of angioinvasion and lack of bridging were statistically significant risk factors for tumour recurrence according to univariate and multivariate analyses (HR 6.34; p = 0.0002; HR 8.21; p < 0.0001; HR 7.50; p = 0.0001). Bridging therapy before transplantation provided a significant survival advantage regardless of the transplant procedure (OS: p = 0.008; DFS: p < 0.001). Conclusions: Patients with HCC outside the MC who underwent LT or LDLT had worse outcomes compared to those of patients who met the MC but still had a survival advantage compared to patients without transplantation. Nevertheless, such patients remain disadvantaged on the waiting list, which is why LDLT represents a safe alternative to LT and should be considered in bridged HCC patients because of differences in tumour differentiation, size and tumour marker dynamics. Full article

(This article belongs to the Special Issue Advances and Future Developments in Liver Transplantation for Cancers)

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12 pages, 2358 KiB

Open AccessArticle

The Role of PIVKA-II as a Predictor of Early Hepatocellular Carcinoma Recurrence-Free Survival after Liver Transplantation in a Low Alpha-Fetoprotein Population

by Monique J. C. Devillers, Johanna K. F. Pluimers, Maria C. van Hooff, Michail Doukas, Wojciech G. Polak, Robert A. de Man, Milan J. Sonneveld, Andre Boonstra and Caroline M. den Hoed

Cancers 2024, 16(1), 4; https://doi.org/10.3390/cancers16010004 - 19 Dec 2023

Cited by 1 | Viewed by 750

Abstract

Introduction: AFP and the RETREAT score are currently used to predict HCC recurrence after LT. However, superior discriminating models are needed for low AFP populations. The aim of this study is to investigate the predictive value of PIVKA-II on recurrence-free survival after LT in a low AFP population and microvascular invasion on explant. Methods: A retrospective cohort study including all consecutive patients transplanted for HCC between 1989 and 2019 in the Erasmus MC University Medical Center in Rotterdam, the Netherlands, was used. AFP and PIVKA-II levels were determined in serum samples collected at the time of transplantation. Data on tumor load and microvascular invasion were retrieved from patients’ records. Results: The study cohort consisted of 121 patients, with HCC recurrence in 15 patients (12.4%). The median AFP was 7.7 ng/mL (4.4–20.2), and the median PIVKA-II was 72.0 mAU/mL (41.0–213.5). Patients with low AFP (≤8 ng/mL) and PIVKA-II (≤90 mAU/mL) had a 5-year recurrence-free survival of 100% compared to 85.7% in patients with low AFP and high PIVKA-II (p = 0.026). Regardless of the AFP level, patients within the Milan criteria (based on explant pathology) with a low PIVKA-II level had a 5-year recurrence-free survival of 100% compared to patients with a high PIVKA-II level of 81.1% (p = 0.002). In patients with microvascular invasion, the AUC for PIVKA-II was slightly better than the AUC for AFP (0.775 vs. 0.687). Conclusions: The dual model of PIVKA-II ≤ 90 mAU/mL with either AFP ≤ 8 ng/mL or with patients within the Milan criteria identifies patient groups which can be exempted from HCC surveillance after LT in a low AFP population. PIVKA-II may be a better predictor for explant microvascular invasion than AFP and could play a role in future models identifying LT candidates with the highest risk for HCC recurrence. Full article

(This article belongs to the Special Issue Advances and Future Developments in Liver Transplantation for Cancers)

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Review

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16 pages, 791 KiB

Open AccessReview

Liver Transplant Oncology: Towards Dynamic Tumor-Biology-Oriented Patient Selection

by Matthias Ilmer and Markus Otto Guba

Cancers 2022, 14(11), 2662; https://doi.org/10.3390/cancers14112662 - 27 May 2022

Cited by 6 | Viewed by 1976

Abstract

While liver transplantation was initially considered as a curative treatment modality only for hepatocellular carcinoma, the indication has been increasingly extended to other tumor entities over recent years, most recently to the treatment of non-resectable colorectal liver metastases. Although oncologic outcomes after liver transplantation (LT) are consistently good, organ shortage forces stringent selection of suitable candidates. Dynamic criteria based on tumor biology fulfill the prerequisite of an individual oncological prediction better than traditional morphometric criteria based on tumor burden. The availability of specific (neo-)adjuvant therapies and customized modern immunosuppression may further contribute to favorable post-transplantation outcomes on the one hand and simultaneously open the path to LT as a curative option for advanced stages of tumor patients. Herein, we provide an overview of the oncological LT indications, the selection process, and expected oncological outcome after LT. Full article

(This article belongs to the Special Issue Advances and Future Developments in Liver Transplantation for Cancers)

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